Publications abstracts

    To date, the Vapourtec R-Series system has featured in 860 or more peer reviewed publications.
    Use the filter tools to see the sort of things that are possible, but note that most published papers will require a journal subscription.

    Continuous Processing of Concentrated Organolithiums in Flow Using Static and Dynamic Spinning Disc Reactor Technologies

    • Ulrich Wietelmanna
    • Johannes Klösenera
    • Peter Rittmeyera
    • Stefan Schnipperinga
    • Henk Batsb
    • Wouter Stamb
    • aAlbemarle Germany GmbH, Industrial Park Hoechst, D-65926 Frankfurt am Main, Germany
    • bFlowid, Achtseweg Zuid 157C, NL-5651 GW Eindhoven, The Netherlands

    Organometallic reactions involving highly reactive organolithium reagents are widely used in organic synthesis. However, the use of such organometallics in batch mode on a pilot and industrial scale is challenging for safety reasons and frequently requires expensive cryogenic process conditions. A change to continuous processing in flow mode can provide major advantages for process safety and economics. In this study, we compare static and dynamic flow reactor technologies for two important organolithium (butyllithium and hexyllithium)-enabled transformations: deprotonations and bromine/lithium exchange reactions. Using higher concentrated (≥3 M) butyllithium (BuLi) solutions, that is, reaction mixtures with reduced hydrocarbon content, decreases the risk of reactor fouling and allows for increased space/time yields. In the flow mode, the observed reactions could be carried out under more convenient conditions, that is, at higher temperatures compared to the batch mode, and the deprotonation reaction even at ambient temperature instead of −78 °C. The formation of precipitates with the risk of clogging can be further reduced by changing from static flow to dynamic spinning disc reactor technology. The SpinPro reactor system from Flowid has been identified to ensure robust performance, as it tolerates salt precipitations and can provide excellent mass transfer conditions. Flow process technology using concentrated organolithium products can provide unique benefits for the manufacturing of pharmaceutical intermediates, agrochemical products, and specialty chemicals.

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    Process Intensive Synthesis of Propofol Enabled by Continuous Flow Chemistry

    • Laurent Vineta
    • Lorenzo Di Marcoa
    • Vanessa Kairouza
    • André B. Charettea
    • aCentre in Green Chemistry and Catalysis, Center for Continuous Flow Synthesis, Department of Chemistry, Université de Montréal, 1375, av. Thérèse Lavoie-Roux, Montréal, Québec H2V 0B3, Canada

    A multi-step process using continuous flow chemistry to produce propofol is described. A scale-up of a 5-stage process (two continuous flow chemical steps, two extractions using a semi-batch approach, and one purification) provided propofol in high purity. This process minimizes the number of impurities formed during the double Friedel–Crafts reaction allowing to run two continuous flow chemical steps sequentially. The use of simple, inexpensive, and readily available reagents affords a viable process for this widely employed active pharmaceutical ingredient.

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    Immobilized Eosin Y for the photocatalytic oxidation of tetrahydroisoquinolines in flow

    • Fabian Herbrika,b
    • Sergio Rossia
    • Miguel Sanzb
    • Alessandra Puglisia
    • Maurizio Benagliaa
    • aDipartimento di Chimica, Università degli Studi di Milano, Via Camillo Golgi 19, 20133 Milano, Italy
    • bTaros Chemicals GmbH & Co. KG, Emil-Figge-Strasse 76A, 44227 Dortmund, Germany

    A new easy-to-synthesize solid supported Eosin Y and its application in the building of a catalytic continuous flow reactor is reported. The fluidic device was employed to perform tertiary amines in-flow photooxidations followed by a nucleophile addition, with overall productivity increased by one order magnitude. When using the iminium-ions in situ generated or in a telescoped fashion, the resulting Mannich-products were isolated with high diastereoselectivity and up to 90% enantioselectivity, simply using air as terminal oxidant.

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    Sn-Catalyzed Criegee-Type Rearrangement of Peroxyoxindoles Enabled by Catalytic Dual Activation of Esters and Peroxides

    • Moreshwar B. Chaudharia
    • Krishna Jayana
    • Boopathy Gnanaprakasama
    • aDepartment of Chemistry, Indian Institute of Science Education and Research, Pune 411008, India

    We report here the Sn-catalyzed mild protocol for ring expansion of peroxyoxindoles to afford the series of substituted-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives. In this protocol, we showed the in situ conversion of tert-butyl peroxy compounds into peresters with the aid of external esters, which then underwent the ring-expansion process, and the incipient carbocation was trapped with the alcohol residue generated from the esters. The reaction is also demonstrated in a continuous flow process to afford the rearranged product in 22 min of residence time.

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    The Ugly Duckling Metamorphosis: The Ammonia/Formaldehyde Couple Made Possible in Ugi Reactions.

    • Thaissa Pasquali F. Rosalbaa
    • Samia Sayegh A. Kasa
    • Ana Beatriz S. Sampaioa
    • Dr. Carlos Eduardo M. Salvadora
    • Dr. Carlos Kleber Z. Andradea
    • aInstituto de Química, Laboratório de Química Metodológica e Orgânica Sintética (LaQMOS), Universidade de Brasília, Campus Universitário, Asa Norte, 70904-970 Brasília, Brasil

    Ugi reactions are still a challenge when the concomitant use of ammonia and formaldehyde is required. Herein, we propose a strategy to overcome this challenge using hexamethylenetetramine (HMTA) as a singular key for the employment of these two simple starting materials in the Ugi reaction. Acylaminoacetamide derivatives were prepared in good to excellent yields by this new methodology. The scope and optimization of the reaction conditions were investigated. This novel methodology was successfully applied in the synthesis of two different diketopiperazines (DKPs) using the Ugi/Deprotection+Activation/Cyclization (UDAC) method. A continuous flow approach was also used in this methodology.

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    Continuous-Flow Hofmann Rearrangement Using Trichloroisocyanuric Acid for the Preparation of 2-Benzoxazolinone

    • Guido Gambacortaa
    • Ian R. Baxendalea
    • a Department of Chemistry, University of Durham, South Road, Durham DH1 3LE, U.K.

    A continuous-flow preparation of 2-benzoxazolinone via the Hofmann rearrangement of salicylamide has been implemented employing trichloroisocyanuric acid as the stable and atom-economic chlorinating agent. The system was optimized to avoid solid accumulation and allow the preparation of hundreds of grams of the pure desired material over a working day. Furthermore, a trichloroisocyanuric acid (TCCA)-based chlorination of 2-benzoxazolone to the corresponding 5-chloro derivative was also carried out under batch conditions.

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    Boosting the Productivity of H2-Driven Biocatalysis in a Commercial Hydrogenation Flow Reactor Using H2 From Water Electrolysis

    Barnabas Poznanskya, Sarah E. Clearya, Lisa A. Thompsona, Holly A. Reevea, Kylie A. Vincent*a

    • aInorganic Chemistry Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom

    Translation of redox biocatalysis into a commercial hydrogenation flow reactor, with in-built electrolytic H2 generation, was achieved using immobilized enzyme systems. Carbon-supported biocatalysts were first tested in batch mode, and were then transferred into continuous flow columns for H2-driven, NADH-dependent asymmetric ketone reductions. The biocatalysts were thus handled comparably to heterogeneous metal catalysts, but operated at room temperature and 1–50 bar H2, highlighting that biocatalytic strategies enable implementation of hydrogenation reactions under mild–moderate conditions. Continuous flow reactions were demonstrated as a strategy for process intensification; high conversions were achieved in short residence times, with a high biocatalyst turnover frequency and productivity. These results show the prospect of using enzymes in reactor infrastructure designed for conventional heterogeneous hydrogenations.

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    Continuous flow heterogeneous catalytic reductive aminations under aqueous micellar conditions enabled by an oscillatory plug flow reactor

    • Michaela Wernika,b
    • Gellért Siposc,d
    • Balázs Buchholcze
    • Ferenc Darvasc,d
    • Zoltán Novákf
    • Sándor B. Ötvösa,b
    • C. Oliver Kappea,b
    • aInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, A-8010 Graz, Austria
    • bCenter for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, A-8010 Graz, Austria
    • cThalesNano Inc., Záhony u. 7, 1031 Budapest, Hungary
    • dComInnex Inc., Záhony u. 7, 1031 Budapest, Hungary
    • eInnostudio Inc., Záhony u. 7, 1031 Budapest, Hungary
    • fELTE “Lendület” Catalysis and Organic Synthesis Research Group, Faculty of Science, Institute of Chemistry, Eötvös Loránd University, Pázmány Péter stny. 1/a, 1117 Budapest, Hungary

    Despite the fact that continuous flow processing exhibits well-established technical advances, aqueous micellar chemistry, a field that has proven extremely useful in shifting organic synthesis to sustainable water-based media, has mostly been explored under conventional batch-based conditions. This is particularly because of the fact that the reliable handling of slurries and suspensions in flow has been considered as a significant technical challenge. Herein, we demonstrate that the strategic application of an oscillatory plug flow reactor enables heterogeneous catalytic reductive aminations in aqueous micellar media enhancing mass transport and facilitating process simplicity, stability and scalability. The micellar flow process enabled a broad range of substrates, including amino acid derivatives, to be successfully transformed under reasonably mild conditions utilizing only very low amounts of Pd/C as a readily available heterogeneous catalyst. The preparative capabilities of the process along with the recyclability of the heterogenous catalyst and the aqueous reaction media were also demonstrated.

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    Continuous flow processing of bismuth-photocatalyzed atom transfer radical addition reactions using an oscillatory flow reactor

    • Pauline Bianchia
    • Jason D. Williamsa,b
    • C. Oliver Kappea,b
    • aInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria
    • bCenter for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering (RCPE), Inffeldgasse 13, 8010 Graz, Austria

    Metal oxides represent an abundant and non-toxic class of photocatalysts for organic transformations. However, their use in larger scale processes is complicated by incompatibilities with continuous flow processing – a proven scale-up route for photochemistry. We detail the development of an efficient atom transfer radical addition protocol using a sustainable solvent system (acetone : PEG 400) and a low loading (2 mol%) of Bi2O3, which can be handled in an oscillatory flow reactor. Optimization of the reaction and oscillatory parameters led to high throughput (36 g in 4 h, 89% yield, 599 g L−1 h−1), with a process mass intensity (PMI) of just 8.5. The process also facilitates high recyclability (3 cycles with no loss of yield), and was demonstrated to be applicable to a range of other substrates on multigram scale, in moderate to excellent yields.

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    Automated Chemical Solid-Phase Synthesis of Glycans

    • Xiaona Lia
    • You Yanga
    • aShanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, Engineering Research Center of Pharmaceutical Process Chemistry, Ministry of Education, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237 China

    Automated chemical solid-phase synthesis is an automation platform for rapid and reliable synthesis of glycans. Since the seminal work of Automated Glycan Assembly (AGA) disclosed by Seeberger in 2001, AGA has evolved from a proof-of-concept to a robust and reliable technology for streamlined production of various types of glycans. Through more than 20 years of unceasing efforts, the major breakthroughs in AGA including linkers, approved building blocks, and synthesizers have been acquired, and numerous influential achievements have been made in complex glycan synthesis. In addition, the HPLC-assisted automated synthesis emerges as a promising automation platform to access glycans. In this review, we highlight the key advances in the field of automated chemical solid-phase synthesis, especially in AGA. The synthesis of representative glycans based on AGA is also described.

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    Cutting edge of diphenyl phosphorazidate (DPPA) as a synthetic reagent–A fifty-year odyssey

    • Takayuki Shioiria
    • Kotaro Ishiharaa
    • Masato Matsugia
    • aFaculty of Agriculture, Meijo University, Shiogamaguchi, Tempaku, Nagoya 468-8502, Japan

    Recent advances of diphenyl phosphorazidate (DPPA) as a versatile synthetic reagent was described. It works as an azide anion equivalent, 1,3-dipole, electrophile, and nitrene. Thus it can be conveniently used for amide synthesis, ester synthesis, modified Curtius reaction, phosphorylation, C-acylation, azide synthesis, Pummerer rearrangement, cycloadditions, diazotization, triazoline formation, Staudinger reaction, amidine and guanidine synthesis, C–H phosphorazidation, nitrene insertion, decarbonylation, etc.

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    Cobalt-electrocatalytic HAT for functionalization of unsaturated C–C bonds

    • Samer Gnaima, Adriano Bauera, Hai-Jun Zhanga, Longrui Chena, Cara Gannettb, Christian A. Malapitc, David E. Hilld, David Vogtc, Tianhua Tangc, Ryan A. Daleya, Wei Haoa, Rui Zengb, Mathilde Quertenmonte, Wesley D. Beckc, Elya Kandaharid, Julien C. Vantourouta, Pierre-Georges Echeverriae, Hector D. Abrunab, Donna G. Blackmonda, Shelley D. Minteerc, Sarah E. Reismand, Matthew S. Sigmanc & Phil S. Barana
    • aDepartment of Chemistry, The Scripps Research Institute (TSRI), La Jolla, CA, USA
    • bDepartment of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA
    • cDepartment of Chemistry, University of Utah, Salt Lake City, UT, USA
    • dThe Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA
    • eMinakem Recherche, Beuvry-la-Forêt, France

    The study and application of transition metal hydrides (TMHs) has been an active area of chemical research since the early 1960s1, for energy storage, through the reduction of protons to generate hydrogen2,3, and for organic synthesis, for the functionalization of unsaturated C–C, C–O and C–N bonds4,5. In the former instance, electrochemical means for driving such reactivity has been common place since the 1950s6 but the use of stoichiometric exogenous organic- and metal-based reductants to harness the power of TMHs in synthetic chemistry remains the norm. In particular, cobalt-based TMHs have found widespread use for the derivatization of olefins and alkynes in complex molecule construction, often by a net hydrogen atom transfer (HAT)7. Here we show how an electrocatalytic approach inspired by decades of energy storage research can be made use of in the context of modern organic synthesis. This strategy not only offers benefits in terms of sustainability and efficiency but also enables enhanced chemoselectivity and distinct, tunable reactivity. Ten different reaction manifolds across dozens of substrates are exemplified, along with detailed mechanistic insights into this scalable electrochemical entry into Co–H generation that takes place through a low-valent intermediate.

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    Total Synthesis of Phytotoxic Radulanin A Facilitated by the Photochemical Ring Expansion of a 2,2-Dimethylchromene in Flow

    • Bruce Lockett-Waltersa
    • Simon Thuilliera,b
    • Emmanuel Baudouinb
    • Bastien Nay*a
    • aLaboratoire de Synthèse Organique, Ecole Polytechnique, CNRS, Institut Polytechnique de Paris, 91128 Palaiseau, France
    • bInstitut de Biologie Paris-Seine (IBPS), Laboratoire de Biologie du Développement, Sorbonne Université, CNRS, UMR7622, F-75005 Paris, France

    The radulanins are biologically active bibenzyl natural products featuring a synthetically challenging 2,5-dihydro-1-benzoxepine core. In contrast with previous reports exhibiting lengthy strategies, we demonstrate the shortest synthesis of radulanin A to date, featuring a largely unexplored photochemical ring expansion reaction of a 2,2-dimethylchromene precursor. This work was adapted to a continuous-flow setup for larger-scale preparation, in view of biological investigations into the herbicidal properties of this natural product.

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    Practical Ferrioxalate Actinometry for the Determination of Photon Fluxes in Production-Oriented Photoflow Reactors

    • Bavo Vandekerckhovea
    • Nicola Piensb
    • Bert Mettenb
    • Christian V. Stevensa
    • Thomas S. A. Heugebaert*a
    • aSynBioC Research Group, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
    • bAjinomoto Bio-Pharma Services, Cooppallaan 91, 9230 Wetteren, Belgium

    Accurate determination of the photon flux is of major importance to evaluate and characterize photochemical reactor setups. Knowing the photon flux ensures reproducible reactor operation and facilitates predictable scale-up. Over the past years, flow reactors have proven to be the key enabling technology for photochemistry to become relevant on production scales. This is mainly due to the mitigation of the limited penetration depth of photons in typical batch reactors. However, due to the practical drawbacks of the widely accepted standard for photon flux determination (ferrioxalate actinometry) concerning precipitation and gas formation at higher conversion, reliable actinometry in flow reactors is still challenging. In this paper, three practical approaches for the ferrioxalate-based determination of the photon flux are presented, which address these problems. These “dimmed emitter,” “segment-based,” and “time-resolved” methods thus allow photon flux determination in flow reactors with higher irradiated volumes and more powerful light sources, which is of utmost importance in the context of future scale-up.

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    Continuous Flow Technology as an Enabler for Innovative Transformations Exploiting Carbenes, Nitrenes, and Benzynes

    • Kian Donnellya
    • Marcus Baumanna
    • aSchool of Chemistry, Science Centre South, University College Dublin, D04 N2E2 Dublin, Ireland

    Miniaturization offered by microreactors provides for superb reaction control as well as excellent heat and mass transfer. By performing chemical reactions in microreactors or tubular systems under continuous flow conditions, increased safety can be harnessed which allows exploitation of these technologies for the generation and immediate consumption of high-energy intermediates. This Synopsis demonstrates the use of flow technology to effectively exploit benzynes, carbenes, and nitrenes in synthetic chemistry programs.

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    Online reaction monitoring with fast and flow-compatible diffusion NMR spectroscopy

    • Achille Marchanda
    • Rituraj Mishraa
    • Aurélie Bernarda
    • Jean-Nicolas Dumeza
    • aUniversité,CNRS, CEISAM UMR6230,F-44000 Nantes, France

    Online monitoring by flow NMR spectroscopy is a powerful approach to study chemical reactions and processes, which can provide mechanistic understanding, and drive optimisations. However, some of the most useful methods for mixture analysis and reaction monitoring are not directly applicable in flow conditions. This is the case of classic diffusion-ordered NMR spectroscopy (DOSY) methods, which can be used to separate the spectral information for mixture’s components. We describe a fast and flow compatible diffusion NMR experiment, that makes it possible to collect accurate diffusion data for samples flowing at up to 3 mL/min. We use it to monitor the synthesis of a Schiff base with a flow-tube with a time resolution of approximately 2 minutes. The one-shot flow-compatible diffusion NMR described here open many avenues for reaction monitoring applications.

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    Analytical Tools Integrated in Continuous-Flow Reactors: Which One for What?

    • Mireia Rodriguez-Zubiria
    • François-Xavier Felpina
    • aNantes Université, CNRS, CEISAM, UMR 6230, F-44000 Nantes, France

    The concept and practices of chemical synthesis are being profoundly transformed toward the development of fully autonomous continuous processes. Critical to the development of autonomous continuous processes is the efficient monitoring of the reaction composition and product quality by in-line and online analyses. The in-line/online acquisition of analytical data allows one to monitor at regular intervals the reaction composition, including hazardous or air-sensitive intermediates with the possibility of adapting reaction parameters or interrupting the flow process when a chemical or technical failure is detected. This review presents the main in-line/online analytical tools that can be integrated into flow reactors for the monitoring of chemical reactions. This contribution is more a guide at the service of synthetic chemists illustrated by selected published examples from leading research laboratories than an exhaustive list of published articles. Ultimately, we would like this review to be an answer to the following recurrent, yet complex, question: “Which is/are the most suitable analytical solution(s) to monitor my chemical reaction?”.

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    Development of a palladium-catalyzed decarboxylative arene cross-coupling of pyrrole derivatives in a flow reactor

    • Cindy Buonomanoa,b
    • Michael Holtz-Mulhollanda,b
    • Sydney Sullivana,b
    • Pat Forgionea,b
    • aDepartment of Chemistry and Biochemistry, Concordia University, 7141 Sherbrooke O, Montréal, QC, H4B 1R6, Canada
    • bCentre in Green Chemistry and Catalysis, Montréal, QC, H3C 3J7, Canada

    Palladium-catalyzed decarboxylative cross-coupling was employed to synthesize 2-arylpyrroles via a flow process. This reaction features palladium as the only metal catalyst and uses easily accessible starting materials. The reaction temperature, the residence time, and the quantity of different reactants were investigated to achieve optimal reaction conditions. A variety of N-alkylated and N-arylated 2-arylpyrroles were produced in good to excellent yields. A N-methyl-2-arylpyrrole derivative was produced in 220 min on a 3 g scale in 84% yield. The flow set-up presented in this work is featuring a fixed bed reactor to load the insoluble Cs2CO3 necessary for the decarboxylative cross-coupling to occur, it also comprises a sample loop, and a stainless-steel reactor. This study demonstrated the excellent potential of utilizing a flow process for the synthesis of 2-arylpyrroles derivatives.

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    Continuous synthesis of benzaldehyde by ozonolysis of styrene in a micro-packed bed reactor

    • Fengyan Loua,b,c
    • Qiang Caoa
    • Chenghao Zhanga
    • Ning Aic
    • Qining Wangb
    • Jisong Zhanga
    • aThe State Key Lab of Chemical Engineering, Department of Chemical Engineering, Tsinghua University, 100084, Beijing, China
    • bCollege of Chemical Engineering, Zhejiang University of Technology, 310014, Hangzhou, Zhejiang, China
    • cCollege of Biological, Chemical Science and Engineering, Jiaxing University, 314001, Jiaxing, Zhejiang, China

    Due to the inherent safety and high mass/heat transfer efficiency of microreactor, the continuous micro-reaction technology has been widely applied in hazardous chemistry recently. In this work, a continuous ozonolysis system based on micro-packed bed reactors (µPBRs) was developed with the synthesis of benzaldehyde as a model reaction. The effects of operating variables (e.g., stirring time, molar ozone/olefin ratio, reaction pressure, reaction temperature and liquid residence time) on the olefins conversion and product distribution were investigated. Based on the experimental results, the optimum reaction conditions are as follows: stirring time 1 h, molar ratio of ozone to olefin 1.2, reaction pressure 0.1 MPa, and the reaction temperature ranging from − 15 to 10℃, as opposed to the low temperature (<-50℃) routinely employed for batch operation. In addition, the full conversion of styrene and a benzaldehyde yield of ~ 93% was observed with the liquid residence time of 3.8–30.8 s. Consequently, the flow ozonolysis technique upon µPBRs allows for a sustainable, safe and efficient approach to oxidize olefins to aldehydes/ketones compared to traditional methods.

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    α-Amino Radical Halogen Atom Transfer Agents for Metallaphotoredox Catalyzed Cross-Electrophile Couplings of Distinct Organic Halides

    • Xianhai Tiana
    • Jaspreet Kaura
    • Shahboz Yakubova
    • Joshua P. Barhama
    • aInstitute of Organic Chemistry, University of Regensburg Universitätsstr. 31, 93053 Regensburg (Germany)

    α-Amino radicals, from simple tertiary amines, were employed as halogen atom transfer agents in metallaphotoredox catalysis for cross-electrophile couplings of organic bromides with organic iodides. This XAT strategy proved to be efficient for the generations of carbon radicals from a range of partners; alkyl, aryl, alkenyl and alkynyl iodides. The reactivities of these radical intermediates were captured by nickel catalysis with organobromides including aryl, heteroaryl, alkenyl and alkyl bromides, enabling six diverse C−C bond formations. Classic named reactions including Negishi, Suzuki, Heck and Sonogashira reactions were readily achieved in a net-reductive fashion under mild conditions. More importantly, the cross coupling is viable with either organic bromide or iodide as limiting reactant based on the availability of substrates, which is beneficial to the late-stage functionalization of complex molecules. The scalability of this method in batch and flow was investigated, further demonstrating its applicability.

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    Enzymatic continuous-flow preparation of nature-inspired phenolic esters as antiradical and antimicrobial agents

    • Francesca Annunziataa
    • Martina L.Contenteb
    • Valentina Anzia
    • Silvia Donzellab
    • Paola Contia
    • Francesco Molinarib
    • Piera Anna Martinoc
    • Gabriele Meronic
    • Valerio Massimo Sorac
    • Lucia Tamborinia
    • Andrea Pintob
    • aDepartment of Pharmaceutical Sciences (DISFARM), University of Milan, via Mangiagalli 25, 20133 Milan, Italy
    • bDepartment of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, via Celoria 2, 20133 Milan, Italy
    • cDepartment of Biomedical, Surgical and Dental Sciences (DSBCO), One Health Unit, University of Milan, via Pascal 36, 20133 Milan, Italy

    A collection of nature-inspired lipophilic phenolic esters have been prepared by an enzymatic synthesis under flow conditions, using the immobilized lipase B from Candida antarctica (Novozyme 435®) as a catalyst in cyclopentyl methyl ether (CPME), a non-conventional and green solvent. Their antimicrobial activity against four selected bacterial strains together with their efficiency as radical scavengers were evaluated. The obtained compounds were characterized by enhanced lipophilicity in comparison with the parent non-esterified compounds, which increased the possibility of their use as additives in the food industry.

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    Integration of Liquid–Liquid Biphasic Flow Alkylation and Continuous Crystallization Using Taylor Vortex Flow Reactors

    • Masahiro Hosoyaa
    • Masashi Tanakaa
    • Atsushi Manakaa
    • Shogo Nishijimaa
    • Naoki Tsunoa
    • a API R&D Laboratory, CMC R&D Division, Shionogi and Company Ltd., 1-3, Kuise Terajima 2-chome, Amagasaki, Hyogo 660-0813, Japan

    This work established the integration of a continuous flow reaction and continuous crystallization using Taylor vortex flow reactors. We previously developed liquid–liquid biphasic flow alkylation using a Taylor vortex flow reactor, which is a scalable flow reactor with high mixing efficiency. To maximize the efficiency of this methodology, we evaluated process parameters and instrumental parameters, such as the rotating speed and tilt of the reactor, and optimized the reaction conditions. As a result, the throughput increased more than 20-fold compared to our previous work, and a long-run experiment verified its robustness. Liquid–liquid biphasic flow alkylation, quenching, phase separation, continuous crystallization, and filtration were integrated by using Taylor vortex flow reactors for both the flow reaction and continuous crystallization. The integrated system using two Taylor vortex flow reactors provided the alkylated product continuously from the solution of the starting material.

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    Cutting edge of diphenyl phosphorazidate (DPPA) as a synthetic reagent – A fifty-year odyssey

    • Takayuki Shioiria
    • Kotaro Ishiharaa
    • and Masato Matsugia
    • aFaculty of Agriculture, Meijo University, Shiogamaguchi, Tempaku, Nagoya 468- 8502, Japan

    Recent advances of diphenyl phosphorazidate (DPPA) as a versatile synthetic reagent was described. It works as an azide anion equivalent, 1,3-dipole, an electrophile, and nitrene. Thus it can be conveniently used for amide synthesis, ester synthesis, modified Curtius reaction, phosphorylation, C-acylation, azide synthesis, Pummerer rearrangement, cycloadditions, diazotization, triazoline formation, Staudinger reaction, amidine and guanidine synthesis, C-H phosphorazidation, nitrene insertion, decarbonylation, etc. 1. Introduction 2. Preparation of DPPA 3. Amides and Lactams Synthesis 4. Esterification 5. The Modified Curtius Reaction 6. O- and N-Phosphorylations 7. Oxazoles Synthesis based on C-Acylation 8. Direct Conversion of Hydroxyl Groups to Azides 8.1 The Bose-Mitsunobu Azidation 8.2 The Merck Azidation 9. Pummerer Rearrangement of Sulfoxides 10. Cycloadditions 10.1 Reaction with Enamines 10.2 Synthesis of 1,2,3-Triazoles 10.3 Synthesis of Tetrazoles 11. Reaction with Organometallics 12. Staudinger Reaction 13. Synthesis of Amidines and Guanidines 14. C-H Phosphorazidation 15. As a Nitrene Source 16. Reaction with Silylene, Germylene, and Stanylene 17. Decarbonylation 18. Dimerization of Ynamides 19. Conclusion and Outlook.

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    A concise total synthesis of phytotoxic radulanin A facilitated by the photochemical ring expansion of a 2,2-dimethylchromene in flow

    • Bruce Lockett-Walters1
    • Simon Thuillier1,2
    • Emmanuel Baudouin2
    • Bastien Nay*1
    • 1Laboratoire de Synthèse Organique, Ecole Polytechnique, CNRS, Institut Polytechnique de Paris, 91128 Palaiseau, France
    • 2Sorbonne Université, CNRS, Institut de Biologie Paris-Seine (IBPS), Laboratoire de Biologie du Développement, UMR7622, F-75005, Paris, France

    The radulanins are biologically active bibenzyl natural products featuring a synthetically challenging 2,5-dihydro-1-benzoxepine core. In contrast with previous reports exhibiting lengthy strategies, we demonstrate the shortest synthesis of radulanin A to date, featuring a largely unexplored photochemical ring expansion reaction of a 2,2-dimethylchromene precursor. This work was adapted to a continuous flow setup for larger scale preparation, in view of biological investigations into the herbicidal properties of this natural product.

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    An environmentally benign and high-rate Appel type reaction

    • Nicolas Mattias Del Rio Fuenzalidaa
    • Eirin Almea
    • Frida Johanne Lundevalla
    • Hans-René Bjørsvika
    • aDepartment of Chemistry, University of Bergen, Allégaten 41, 5007 Bergen, Norway

    A high rate, selective, and productive Appel type reaction was developed. The method allows for ipso-substitution of the alcoholic hydroxy group with halogens ∈ [Cl, Br, I]. The method demands mild reaction conditions that include a very short reaction time, <15 min only, versus reaction times of several hours or days using the classical Appel reaction conditions (PPh3 + CCl4 + R–OH). The method was demonstrated to operate with the cheap and easily available 1,3-dihalo-5,5-dimethylhydantoins and N-halo succinimides (halo ∈ [Cl, Br, I]) as the reagent that performs the halogenation of PPh3. The reaction protocol operated with several acceptable solvents rather than DCM that was used in the classical Appel reaction. Furthermore, the batch protocol was also translated and successfully implemented on a flow reactor platform (t < 5 min, y = 95%).

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    Selective Photochemical Continuous Flow Benzylic Monochlorination

    • Robbie Radjagobaloua
    • Miguel Imbrattab
    • Julie Bergraserb
    • Marion Gaudeaub
    • Gildas Lyvinecb
    • Dominique Delbrayelleb
    • Olivier Jentzerb
    • Jérémy Roudina
    • Benjamin Larochea
    • Stéphanie Ogniera
    • Michael Tatouliana
    • Janine Cossya
    • Pierre-Georges Echeverriab
    • aParis FLOW Tech − PSL, ENSCP, 11 rue Pierre et Marie Curie, Paris 75005, France
    • bMinakem Recherche, 145 Chemin des Lilas, Beuvry-La-Forêt 59310, France

    A selective photochemical monochlorination of 2-fluorotoluene has been developed by a continuous flow process using two different flow reactors, one for the tuning of the conditions and the second one for the scale-up. The key reaction parameters were optimized using one-factor-at-a-time and design of experiment methods, with the goal of minimizing the formation of the dichlorinated by-product. This transformation has been performed on a multi decagram scale.

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    Continuous flow process for preparing budesonide

    • Manjinder Singh Phulla,b
    • Surender Singh Jadavc,d
    • Chander Singh Boharab
    • Rambabu Gundlaa
    • Prathama S Mainkarc,d
    • aDepartment of Chemistry, School of Science, GITAM (Deemed to Be University), Hyderabad, Telangana, 502329, India
    • bCipla Limited Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg, Lower Parel, Mumbai, 400013, India
    • cDepartment of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India
    • dAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

    Budesonide, a glucocorticosteroid, is used as anti-asthmatic drug that became generic in 2019. Existing preparation methods of budesonide require utilization of corrosive acids and involve expensive purification process. Thus, a new cost-effective continuous flow process for the synthesis of budesonide which belongs to the class of 16,17 acetals of pregnane core, is discussed in the present research findings. Flow reactor parameters such as flow rate, temperature, residence time, solution volumes, anti-solvents and reactor frequency are subjected to investigation on the preparation of molar ratio of budesonide epimers. Further, the suitable parameters entail for obtaining the desired molar ratio of epimers. In another aspect, particle size optimization studies are also performed to get the desired budesonide solid product. A continuous flow process for preparation of budesonide is identified from the present research investigation which can be readily transferred to industrial scale up.

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    Chemical Recycling of Polystyrene to Valuable Chemicals via Selective Acid-Catalyzed Aerobic Oxidation under Visible Light

    • Zhiliang Huanga
    • Muralidharan Shanmugamb
    • Zhao Liuc
    • Adam Brookfieldb
    • Elliot L. Bennetta
    • Renpeng Guana
    • David E. Vega Herreraa
    • Jose A. Lopez-Sancheza
    • Anna G. Slatera
    • Eric J. L. McInnesb
    • Xiaotian Qi*c
    • Jianliang Xiaoa
    • aDepartment of Chemistry, University of Liverpool, Liverpool L69 7ZD, U.K.
    • bDepartment of Chemistry and Photon Science Institute, The University of Manchester, Manchester M13 9PL, U.K.
    • cEngineering Research Center of Organosilicon Compounds & Materials, Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, P. R. China

    Chemical recycling is one of the most promising technologies that could contribute to circular economy targets by providing solutions to plastic waste; however, it is still at an early stage of development. In this work, we describe the first light-driven, acid-catalyzed protocol for chemical recycling of polystyrene waste to valuable chemicals under 1 bar of O2. Requiring no photosensitizers and only mild reaction conditions, the protocol is operationally simple and has also been demonstrated in a flow system. Electron paramagnetic resonance (EPR) investigations and density functional theory (DFT) calculations indicate that singlet oxygen is involved as the reactive oxygen species in this degradation process, which abstracts a hydrogen atom from a tertiary C–H bond, leading to hydroperoxidation and subsequent C–C bond cracking events via a radical process. Notably, our study indicates that an adduct of polystyrene and an acid catalyst might be formed in situ, which could act as a photosensitizer to initiate the formation of singlet oxygen. In addition, the oxidized polystyrene polymer may play a role in the production of singlet oxygen under light.

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    Sustainable and Scalable Synthesis of Noroxymorphone via a Key Electrochemical N-Demethylation Step

    Florian Sommera,b, Roman Gerber Aeschbacherc, Urs Thurnheerc, C. Oliver Kappea,b, David Cantilloa,b

    • aInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010, Graz, Austria
    • bCenter for Continuous Flow Synthesis and Processing (CCFLOW), Research Center, Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria.
    • bAZAD Pharma AG, Durachweg 15, CH-8200 Schaffhausen, Switzerland

    Noroxymorphone is a pivotal intermediate in the synthesis of important opioid antagonists such as naloxone and naltrexone. The preparation of noroxymorphone from thebaine, a naturally occurring opioate isolated from poppy extract, is a multistep sequence in which oxycodone is first generated and then N- and O-demethylated. Both demethylations are problematic from the safety and sustainability viewpoint, as they involve harmful reagents such as alkyl chloroformates or boron tribromide. Herein, we present a green, safe an efficient telescoped process for the N- and O-demethylation of oxycodone. The method is based on the anodic oxidative intramolecular cyclization of the N-methyl tertiary amine with the 14-hydroxyl group of the morphinan, followed by hydrolysis with hydrobromic acid, which releases the carbon from both heteroatoms. The electrolysis process has been transferred to a scalable flow electrolysis cell, significantly improving the reaction throughput and increasing the space-time yield over 300-fold with respect to batch. The sustainability of the new methodology has been assessed by means of green metrics and qualitative indicators. The sustainability assessment has demonstrated that the new methodology is far superior to the conventional chloroformate process.

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    Spheroplasts preparation boosts the catalytic potential of a terpene cyclase

    Ana I. Benítez-Mateos1, Andreas Schneider2, Eimear Hegarty1, Bernhard Hauer2, Francesca Paradisi1

    • 1 Department of Chemistry, Biochemistry and Pharmaceutical Sciences. University of Bern Freiestrasse 3, 3012 Bern (Switzerland)
    • 2Institute of Biochemistry and Technical Biochemistry, University of Stuttgart Allmandring 31, 70569 Stuttgart-Vaihingen (Germany)

    Squalene-hopene cyclases (SHCs) are a highly valuable and attractive class of membrane-bound enzymes as sustainable biotechnological tools to produce aromas and bioactive compounds at industrial scale. However, their application as whole-cell biocatalysts suffer from the outer cell membrane acting as a diffusion barrier for the highly hydrophobic substrate/product, while the use of purified enzymes leads to dramatic loss of stability. Here we present an unexplored strategy for biocatalysis: the application of SHC spheroplasts. By removing the outer cell membrane, we produced stable and substrate-accessible biocatalysts. SHC spheroplasts exhibited up to 100-fold higher activity than their whole-cell counterparts for the biotransformations of squalene, geranyl acetone, farnesol, and farnesyl acetone. Their catalytic ability was also higher than the purified enzyme for all high molecular weight terpenes. In addition, we introduce a new concept for the carrier-free immobilization of spheroplasts via crosslinking, CLS (crosslinked spheroplasts). The CLS maintained the same catalytic activity of the spheroplasts, offering additional advantages such as recycling and reuse. These timely solutions contribute not only to harness the catalytic potential of the SHCs, but also to make biocatalytic processes even greener and more cost-efficient.

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    Scale-Up of Diazonium Salts and Azides in a Three-Step Continuous Flow Sequence

    • Hansjoerg Lehmanna
    • Thomas Ruppena
    • Thomas Knoepfela
    • aGlobal Discovery Chemistry, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland

    Rapid synthesis and scale-up of active molecules to support the development process of new drug candidates is key in the pharmaceutical industry. Herein, we describe the development of a scalable continuous flow procedure for three key steps in the synthesis of 2H-indazoles, which were identified as highly potent and selective TLR7 and TLR8 antagonists. Transformation of hazardous diazonium salt and azide chemistries from the batch mode to continuous flow mode helped mitigate and limit the risks associated with the handling of large amounts of hazardous reagents and intermediates in the batch mode. In a two-step approach, we first screened and optimized the reaction parameter for a diazotization─azidation─cyclization three-step sequence using a commercial research-scale plug flow reactor. In the second step, we demonstrated the robustness and scalability of this reaction sequence, which finally enabled us to rapidly prepare and deliver the required amount of material in high quality.

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    Quantitative and convenient real-time reaction monitoring using stopped-flow benchtop NMR

    • Tristan Maschmeyera
    • Lars P. E. Yunkera
    • Jason E. Heina
    • aDepartment of Chemistry, The University of British Columbia, Vancouver, BC V6T 1Z1, Canada

    Nuclear magnetic resonance (NMR) spectroscopy has the potential to serve as a widely applied reaction monitoring tool, particularly given the growth in commercially available benchtop NMR systems and accompanying flow cells. We herein present a stopped-flow benchtop NMR system devised of commercially available hardware components, all centrally controlled by an internally developed Python script. This system circumvents complications arising with continuous-flow NMR analyses and results in the ability to conveniently acquire quantitative reaction monitoring data. In our work, we first determine a set of 19F NMR acquisition parameters using benchtop NMR, allowing for quantitation using the absolute intensity method thereafter. This system and set of acquisition parameters are then applied to quantitatively monitor model reaction systems (via 19F NMR, 57 MHz) that are difficult to otherwise monitor due to gas evolution, use/formation of toxic reagents, and formation of species otherwise difficult to detect. These reactions include the activation of a carboxylic acid using sulfuryl fluoride (SO2F2) and the formation of a carbamate via modified Curtius rearrangement with diphenylphosphoryl azide (DPPA).

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    Amino Alcohols as Potential Antibiotic and Antifungal Leads

    • Jennifer R. Baker1
    • Peter J. Cossar1
    • Mark A. T. Blaskovich2
    • Alysha G. Elliott2
    • Johannes Zuegg2
    • Matthew A. Cooper2
    • Peter J. Lewis3,4
    • Adam McCluskey1
    • 1Chemistry, School of Environmental & Life Sciences, The University of Newcastle, University Drive Callaghan, Newcastle, NSW 2308, Australia
    • 2Community for Open Antimicrobial Drug Discovery, Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
    • 3Biology, School of Environmental & Life Sciences, The University of Newcastle, University Drive Callaghan, Newcastle, NSW 2308, Australia
    • 4Molecular Horizons, School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia

    Five focused compound libraries (forty-nine compounds), based on prior studies in our laboratory were synthesized and screened for antibiotic and anti-fungal activity against S. aureus, E. coli, K. pneumoniae, P. aeruginosa, A. baumannii, C. albicans and C. neoformans. Low levels of activity, at the initial screening concentration of 32 μg/mL, were noted with analogues of (Z)-2-(3,4-dichlorophenyl)-3-phenylacrylonitriles which made up the first two focused libraries produced. The most promising analogues possessing additional substituents on the terminal aromatic ring of the synthesised acrylonitriles. Modifications of the terminal aromatic moiety were explored through epoxide installation flowed by flow chemistry mediated ring opening aminolysis with discreet sets of amines to the corresponding amino alcohols. Three new focused libraries were developed from substituted anilines, cyclic amines, and phenyl linked heterocyclic amines. The aniline-based compounds were inactive against the bacterial and fungal lines screened. The introduction of a cyclic, such as piperidine, piperazine, or morpholine, showed >50% inhibition when evaluated at 32 μg/mL compound concentration against methicillin-resistant Staphylococcus aureus. Examination of the terminal aromatic substituent via oxirane aminolysis allowed for the synthesis of three new focused libraries of afforded amino alcohols. Aromatic substituted piperidine or piperazine switched library activity from antibacterial to anti-fungal activity with ((Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)phenyl)acrylonitrile), ((Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(4-(4-hydroxyphenyl)piperazin-1-yl)propoxy)-phenyl)acrylonitrile) and ((Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile) showing >95% inhibition of Cryptococcus neoformans var. grubii H99 growth at 32 μg/mL. While (Z)-3-(4-(3-(cyclohexylamino)-2-hydroxypropoxy)phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile, (S,Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, (R,Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, (Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(D-11-piperidin-1-yl)propoxy)phenyl)-acrylonitrile, and (Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile 32 μg/mL against Staphylococcus aureus.

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    Continuous-Flow Synthesis of Alkyl Zinc Sulfinates for the Direct Photofunctionalization of Heterocycles

    • José Luis Nova-Fernándeza,b
    • Montaña J. Garcíaa
    • Leonardo Mollaria
    • Gustavo Pascual-Cocab
    • Silvia Cabrerac,d,e
    • José Alemánad,e
    • aOrganic Chemistry Department, M1, Universidad Autónoma de Madrid, 28049, Madrid, Spain.
    • bSynthelia Organics Labs, C/ Faraday, 7, Labs 2.05 and 0.03, Parque Científico de Madrid, 28049, Madrid, Spain.
    • cInorganic Chemistry Department, M7, Universidad Autónoma de Madrid, 28049, Madrid, Spain.
    • dInstitute for Advanced Research in Chemical Sciences (IAdChem), Universidad Autónoma de Madrid, 28049, Madrid, Spain.
    • eCenter for Innovation in Advanced Chemistry (ORFEO-CINQA), Universidad Autónoma de Madrid.

    A sustainable strategy for the alkylation of heterocycles is presented. The protocol relies on the in-situ generation and further in-line use of alkyl zinc sulfinates through a continuous-flow system. The environmentally friendly character of the protocol is assured by the use of a green solvent mixture, the presence of a metal free oxidant and low waste generation.

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    Continuous flow Meerwein–Ponndorf–Verley reduction of HMF and furfural using basic zirconium carbonate

    • Henrique Magri Marçona
    • Julio Cezar Pastrea
    • aInstitute of Chemistry, University of Campinas – UNICAMP, PO Box 6154, Zip Code 13083-970, Campinas, SP, Brazil

    Continuous Flow Microreactors and Green Chemistry are areas with promising applications, especially when allied. In this scenario, the main goal of this study was to develop new strategies for the synthesis of bio-based compounds under a flow regime. We worked towards the flow synthesis of furfuryl alcohol and DHMF (dihydroxymethylfuran), from their respective aldehydes, through a Meerwein–Ponndorf–Verley reaction with iso-propanol catalysed by basic zirconium carbonate. Furfuryl alcohol was prepared in essentially quantitative yield with productivities as high as 67 mg min−1. Efforts towards DHMF synthesis were performed and the process was also optimized using design of experiments. The optimal conditions were defined for DHMF at 0.25 M and were determined to be 120 °C and 50 s of residence time, giving yields of up to 99% and productivity of 50 mg min−1. The use of a FT-IR device for the in-line continuous monitoring was pivotal for the fast optimization of the processes, securing steady-state operations, and design of experiments ensured a greater understanding of the effect of temperature, residence time and concentration, alongside their interactions in yield, selectivity and productivity.

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    “Green Is the Color”: An Update on Ecofriendly Aspects of Organoselenium Chemistry

    • Juliano B. Azeredo1
    • Filipe Penteado2
    • Vanessa Nascimento3
    • Luca Sancineto4
    • Antonio L. Braga5
    • Eder João Lenardao2
    • Claudio Santi4
    • 1Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Pampa, Uruguaiana, Uruguaiana 97501-970, RS, Brazil
    • 2Laboratório de Síntese Orgânica Limpa-LaSOL-CCQFA, Universidade Federal de Pelotas-UFPel, P.O. Box 354, Pelotas 96010-900, RS, Brazil
    • 3Laboratório SupraSelen, Departamento de Química Orgânica, Instituto de Química, Campus do Valonguinho, Universidade Federal Fluminense, Niteroi 24020-150, RJ, Brazil
    • 4Group of Catalysis Synthesis and Organic Green Chemistry, Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06100 Perugia, Italy
    • 5Departamento de Química, Universidade Federal de Santa Catarina—UFSC, Florianopolis 88040-900, SC, Brazil

    Organoselenium compounds have been successfully applied in biological, medicinal and material sciences, as well as a powerful tool for modern organic synthesis, attracting the attention of the scientific community. This great success is mainly due to the breaking of paradigm demonstrated by innumerous works, that the selenium compounds were toxic and would have a potential impact on the environment. In this update review, we highlight the relevance of these compounds in several fields of research as well as the possibility to synthesize them through more environmentally sustainable methodologies, involving catalytic processes, flow chemistry, electrosynthesis, as well as by the use of alternative energy sources, including mechanochemical, photochemistry, sonochemical and microwave irradiation.

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    Chip-Scale Solar-Thermal-Electrical Power Generation

    • Zhihang Wang1
    • Zhenhua Wu2
    • Zhiyu Hu2
    • Jessica Orrego-Hernandez1
    • Erzhen Mu3
    • Zhao-Yang Zhang4
    • Martyn Jevric1
    • Yang Liu2
    • Xuecheng Fu5
    • Fengdan Wang5
    • Tao Li4
    • Kasper Moth-Poulsen1
    • 1Chalmers University of Technology - Department of Chemistry and Chemical Engineering
    • 2Shanghai Jiao Tong University (SJTU) - National Key Laboratory of Science and Technology on Micro/Nano Fabrication
    • 3Henan Polytechnic University - School of Materials Science and Engineering
    • 4Shanghai Jiao Tong University (SJTU) - Shanghai Key Laboratory of Electrical Insulation and Thermal Aging
    • 5Shanghai Jiao Tong University (SJTU) - Center for Advanced Electronic, Materials and Devices (AEMD)

    Electricity derived from photovoltaics is limited by solar intermittency. Storing solar energy for on-demand power production could address this challenge. Here, we combined both solution- and neat film-based molecular solar thermal (MOST) systems, where solar energy can be stored as chemical energy and released as heat, with microfabricated thermoelectric generators (MEMS-TEG) to produce electricity when solar radiation is not available. The novel small-scale hybrid integrated devices demonstrated continuous power densities of up to 1.3 W·m-3 by storing solar energy in Sweden then releasing heat and generating electricity in China. Our results show that, the proof-of-principle on a small scale and independent of time and geographical restrictions, opportunities exist for local solar energy storage and power production beyond traditional photovoltaic-electrochemical cell technologies.

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    A continuous-flow protocol for photoredox-catalyzed multicomponent Petasis reaction

    • Monica Oliva1
    • Frederick Martens1
    • Erik V.Van der Eycken1,2
    • Upendra Kumar Sharma1
    • 1Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, KU Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium
    • 2Peoples’ Friendship University of Russia (RUDN University), Miklukho-Maklaya street 6, Moscow 117198, Russia

    Here, we present a robust protocol for the facile and rapid synthesis of functionalized secondary amines in continuous flow. More specifically, we describe a detailed guide to perform a photocatalyzed Petasis reaction within 50 min using alkyl boronic acid as radical precursor and a Vapourtec E-series as key equipment. The desired functionalized amine has been synthesized in mmol scale and with a productivity rate of 0.2 mmol/h. The protocol is limited to alkyl boronic acids.

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    Continuous-Flow Preparation of Benzotropolones: Combined Batch and Flow Synthesis of Epigenetic Modulators of the (JmjC)-Containing Domain

    • Dr. José A. Souto
    • Departamento de Química Orgánica, Facultade de Química, Centro de Investigacións Biomédicas (CINBIO) and IIS Galicia Sur., Universidade de Vigo, 36310 Vigo, Spain

    A continuous flow synthetic protocol for the preparation of benzotropolones, and further derivatization to yield a recently described inhibitor of (JmjC)-containing domain enzymes is described. Our procedure renders the desired compound in an efficient and reproducible manner and paves the way towards the preparation of higher amounts of the product, needed for more extensive biological studies.

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    Continuous flow synthesis of Celecoxib from 2-bromo-3,3,3-trifluoropropene

    • Maria Ivanova1
    • Julien Legros1
    • Thomas Poisson1,2
    • Philippe Jubault1
    • 1INSA Rouen, CNRS, UNIROUEN, COBRA, Normandie Univ, 76000 Rouen, France
    • 2Institut Universitaire de France, 1 Rue Descartes, 75231 Paris, France

    We describe the total flow synthesis of the widely prescribed anti-inflammatory COX-2 inhibitor Celecoxib from 2-bromo-3,3,3-trifluoropropene, as a convenient and available trifluoromethyl building block, to generate trifluoropropynyl lithium and to trap it immediately with an aldehyde. Oxidation of the obtained alcohol into ketone followed by condensation with 4-sulfamidophenylhydrazine afforded the targeted drug with full regioselectivity. It is noteworthy that the quality of these flow reactions (50% overall yield within 1 h cumulated residence time over 3 steps) directly furnished the target API and intermediates with excellent purity.

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    Scalable Synthesis of Norbornadienes via in situ Cracking of Dicyclopentadiene Using Continuous Flow Chemistry

    • Jessica Orrego-Hernández[a]
    • Helen Hölzel[a]
    • Maria Quant[a]
    • Zhihang Wang[a]
    • KasperMoth-Poulsen[a]
    • [a]Departmentof Chemistry and Chemical Engineering, Chalmers University of Technology, Kemigården4, 412 96 Gothenburg, Sweden

    The norbornadiene (NBD)-quadricyclane (QC) photoswitch has recently attracted attention due to its use in molecular solar thermal energy systems (MOST). Normally for device testing, several grams are needed. One way of synthesizing NBDs efficiently is through the Diels-Alder reaction between alkynes and cyclopentadiene. However, scaling up the reaction can be troublesome in a research lab environment. Also, dicyclopentadiene needs cracking before utilization which is a time-consuming step. Here, we developed a method where we both scale up the synthesis in a single reaction step that involves both in situ cracking of dicyclopentadiene and the direct reaction of cyclopentadiene with acetylene derivatives using a tubular coiled stainless steel flow reactor. As a proof-of-concept, we synthesized six different NBD compounds and scaled the synthesis to produce 87 g of a novel NBD in 9 h. The NBD is further characterized, showing promising properties for MOST applications. Our new method shows that flow chemistry is an attractive technique for the fast and efficient synthesis of large quantities of NBDs, needed to develop future real-life devices and applications.

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    Photoredox Iridium–Nickel Dual Catalyzed Cross-Electrophile Coupling: From a Batch to a Continuous Stirred-Tank Reactor via an Automated Segmented Flow Reactor

    • Rohit Duvadiea
    • Alexander Pombergerb
    • Yiming Mob
    • Erhan I. Altinogluc
    • Hsiao-Wu Hsieha
    • Kakasaheb Y. Nandiwalea
    • Victor L. Schultzb
    • Klavs F. Jensenb
    • Richard I. Robinsona
    •   aGlobal Discovery Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
    • bDepartment of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
    • cChemical and Pharmaceutical Profiling, Novartis Global Drug Development, 700 Main Street South, Cambridge, Massachusetts 02139, United States

    Organic reaction optimization for batch to flow transfer represents a main challenge for process chemists in drug synthesis. Several factors such as reactant concentration, residence/reaction time, or homo-/heterogeneity need to be taken into consideration during the fine-tuning of reaction conditions toward typical scale-up goals, such as high space–time yield. Herein, we present reaction optimization for photoredox iridium–nickel dual catalyzed cross-electrophile coupling with a focus on developing homogeneous starting conditions. During the screening, special attention was put on the replacement of inorganic bases with homogeneous organic bases, and the effect of pKa on the reaction yield was investigated. Screening was conducted via an automated segmented flow reactor at 15 μL scale, and subsequentially, the conditions were transferred to a 5 mL photo-continuous stirred-tank reactor (CSTR) cascade to demonstrate multigram continuous flow synthesis during a 24 h steady operation.

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    Continuous flow technology-a tool for safer oxidation chemistry

    • Li Wana
    • Meifen Jianga
    • Dang Chenga
    • Minjie Liua
    • Fener Chen*ab
    • aEngineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China
    • bShanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China

    The oxidation reaction is one of the most important transformations in synthetic chemistry, allowing for the introduction and modification of various functional groups. Continuous flow chemistry involving the use of channels or tubing to conduct a reaction has received a remarkable amount of attention in academia and industry. The technology provides reduced reaction times, higher selectivities, straightforward scalability, and the possibility to safely use hazardous intermediates and gaseous reactants. This review presents an up-to-date overview of oxidation chemistry using various oxidants in continuous flow microreactors. In addition, the advantages of using molecular oxygen as the most environmentally benign oxidant in photochemistry and biochemistry are discussed.

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    Continuous Flow Synthesis of a Blocked Polyisocyanate: Process Intensification, Reaction Monitoring Via In-Line FTIR Analysis, and Comparative Life Cycle Assessment

    • Gabriel Glotza,b
    • Katharina Wanieka,c
    • Josef-Peter Schögglc
    • David Cantilloa,b
    • Clemens Stuecklerd
    • Anton Arztd
    • Andreas Gollnerd
    • Rudolf Schipferd
    • Rupert J. Baumgartnerc
    • C. Oliver Kappea,b
    • aInstitute of Chemistry, NAWI Graz, University of Graz, Heinrichstrasse 28, A-8010 Graz, Austria
    • bCenter for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
    • cChristian Doppler Laboratory for Sustainable Product Management, Institute of Systems Sciences, Innovation and Sustainability Research, University of Graz, Merangasse 18/I, 8010 Graz, Austria
    • dAllnex Austria GmbH, Bundesstrasse 175, 8402 Werndorf, Austria

    The traditional batch production of blocked polyisocyanates, key components in the preparation of self-cross-linking resins, has significant drawbacks associated with the exothermic character of the reaction and the high viscosity of some of the materials involved. We have developed a continuous flow strategy for the generation of a methyl ethyl ketoxime-blocked polyisocyanate. The neat oxime and the viscous polyisocyanate were pumped and mixed in continuous flow using a Kenics static mixer. The homogeneous mixture obtained was fully converted to the target blocked polyisocyanate in a residence time unit downstream of the mixer. Real-time reaction monitoring, via in-line Fourier-transform infrared analysis at the reactor outlet, has been implemented, enabling fast optimization of the reaction conditions and providing a sensitive and reliable method to control product quality. The process has been intensified in flow by stepwise increase of the temperature of the residence time unit. Full conversion after only 15 s of overall residence time has been achieved at 155 °C, providing a productivity of ca. 1 kg per hour for a reactor of only 4.5 mL volume. The ecological impacts of a conceptualized upscaled flow process compared to the industrial batch procedure have been evaluated by a comparative life cycle assessment (LCA) according to the ISO 14040/44 LCA framework. The LCA results illustrate the capabilities of continuous processing to enable more sustainable production of blocked polyisocyanates.

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    Towards 4th industrial revolution efficient and sustainable continuous flow manufacturing of active pharmaceutical ingredients

    • Cloudius R. Sagandiraa
    • Sinazo Nqeketoa
    • Kanyisile Mhlanaa
    • Thembela Sontia
    • Sibongiseni Gaqaa
    • Paul Watts*a
    • aNelson Mandela University, University Way, Port Elizabeth, South Africa

    Continuous flow chemistry has opened a new paradigm in both the laboratory and pharmaceutical industry. This review details the recently reported literature on continuous multistep telescoped synthesis of active pharmaceutical ingredients (APIs), inline flow downstream processing, in-process monitoring by process analytical technology (PAT) in flow, flow automation and artificial intelligence (AI) and robotics. We envisage that the integration of all these techniques can ensure an ‘ideal’ smart and efficient 21st century API chemical process that dramatically improves efficiency, agility, quality and flexibility in the manufacturing of pharmaceuticals.

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    Flow-Assisted Synthesis of Alkyl Citrate Natural Products

    • Nikolai Piers Rossouwa
    • Mark A. Rizzacasa*a
    • Anastasios Polyzos*a,b
    • aSchool of Chemistry, The University of Melbourne, Parkville 3010, Victoria, Australia
    • bCSIRO Manufacturing, Research Way, Clayton 3168, Victoria, Australia

    The development of a flow-assisted synthesis of alkyl citrate natural products is described. The flow route harnesses a number of steps including the generation of ketene silyl acetal, a formal [2 + 2] cycloaddition, and a methanolysis cascade to efficiently generate a highly substituted, and stereodefined tetrahydrofuran intermediate. A heterogeneous pseudo-Finkelstein reaction and zinc-mediated elimination furnish a key alkene alkyl citrate fragment in high yield over a multistep sequence that provides direct entry to compounds such as (−)-CJ-13982 (1), (−)-CJ-13,981 (2), L-731,120 (3), and related natural products. The flow methodology developed in this study enables a new machine-assisted approach toward the efficient and scalable synthesis of the alkyl citrate family of natural products.

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    Continuous Flow Acylation of (Hetero)aryllithiums with Polyfunctional N,N-Dimethylamides and Tetramethylurea in Toluene

    • Dimitrije Djukanovica
    • Benjamin Heinza
    • Dr. Francesca Mandrellib
    • Dr. Serena Mostardab
    • Dr. Paolo Filipponib
    • Dr. Benjamin Martinb
    • Prof. Dr. Paul Knochela
    • aDepartment Chemie, Ludwig-Maximilians-Universität München, Butenandtstraße 5–13, Haus F, 81377 Munich, Germany
    • bNovartis Pharma AG, Chemical Development Fabrikstraße, 4002 Basel, Switzerland

    N,N-Dimethylamides for continuous flow acylations: A new acylation of (hetero)aryllithiums with polyfunctional and enolizable N,N-dimethylamides in toluene in continuous flow was reported. The required lithium species was prepared at 25 °C from (hetero)aryl bromides and sec-BuLi in toluene. Additionally, a new telescoped procedure, using tetramethylurea as C1-building block, was described providing highly functionalized unsymmetrical ketones.

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    In Situ Investigation of Multicomponent MOF Crystallization during Rapid Continuous Flow Synthesis

    • Brandon Hea,b
    • Lauren K. Macreadiec,d
    • James Gardinerb
    • Shane G. Telferd
    • Matthew R. Hill*a,b
    • aDepartment of Chemical Engineering, Monash University, Clayton, VIC 3800, Australia
    • bCSIRO Private Bag 10, Clayton South, VIC 3169, Australia
    • c,School of Chemistry, University of Sydney, Sydney, NSW 2006, Australia
    • dMacDiarmid Institute for Advanced Materials and Nanotechnology Institute of Fundamental Sciences, Massey University, Palmerston North 4442, New Zealand

    Access to the potential applications of metal–organic frameworks (MOFs) depends on rapid fabrication. While there have been advances in the large-scale production of single-component MOFs, rapid synthesis of multicomponent MOFs presents greater challenges. Multicomponent systems subjected to rapid synthesis conditions have the opportunity to form separate kinetic phases that are each built up using just one linker. We sought to investigate whether continuous flow chemistry could be adapted to the rapid formation of multicomponent MOFs, exploring the UMCM-1 and MUF-77 series. Surprisingly, phase pure, highly crystalline multicomponent materials emerge under these conditions. To explore this, in situ WAXS was undertaken to gain an understanding of the formation mechanisms at play during flow synthesis. Key differences were found between the ternary UMCM-1 and the quaternary MUF-7, and key details about how the MOFs form were then uncovered. Counterintuitively, despite consisting of just two ligands UMCM-1 proceeds via MOF-5, whereas MUF-7 consists of three ligands but is generated directly from the reaction mixture. By taking advantage of the scalable high-quality materials produced, C6 separations were achieved in breakthrough settings.

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    Biocatalyzed Synthesis of Vanillamides and Evaluation of Their Antimicrobial Activity

    • Cecilia Pinna1
    • Piera Anna Martino2
    • Gabriele Meroni2
    • Valerio Massimo Sora2
    • Lucia Tamborini3
    • Sabrina Dallavalle1
    • Martina L. Contente*1
    • Andrea Pinto1
    • 1Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, via Celoria 2, 20133 Milan, Italy
    • 2Department of Biomedical, Surgical and Dental Sciences (DSBCO), One Health Unit, University of Milan, via Pascal 36, 20133 Milan, Italy
    • 3Department of Pharmaceutical Sciences (DISFARM), University of Milan, via Mangiagalli 25, 20133 Milan, Italy

    A series of vanillamides were easily synthesized, exploiting an acyltransferase from Mycobacterium smegmatis (MsAcT). After their evaluation as antimicrobial agents against a panel of Gram-positive and Gram-negative bacteria, three compounds were demonstrated to be 9-fold more effective toward Pseudomonas aeruginosa than the vanillic acid precursor. Taking into consideration the scarce permeability of the Gram-negative bacteria cell envelope when compared to Gram-positive strains or yeasts, these molecules can be considered the basis for the generation of new nature-inspired antimicrobials. To increase the process productivity and avoid any problem related to the poor water solubility of the starting material, a tailored flow biocatalyzed strategy in pure toluene was set up. While a robust immobilization protocol exploiting glyoxyl-agarose was employed to increase the stability of MsAcT, in-line work-up procedures were added downstream the process to enhance the system automation and reduce the overall costs.

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    Multi-gram preparation of cinnamoyl tryptamines as skin whitening agents through a chemo-enzymatic flow process

    • David Roura Padrosaa
    • Martina L. Contenteb
    • aDepartment of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland
    • bDepartment of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, via Celoria 2, 20133, Milan, Italy

    A 2-step flow-based chemo-enzymatic synthesis of selected cinnamoyl tryptamines as potential cosmetic ingredients has been developed. A first reaction catalyzed by immobilized Pd(OAc)2 gave the acyl donors employed as starting material in the second step, with very good yields (67–70%) and rapid reaction times (30 min). A second bioreactor made of imm-MsAcT, a glyoxyl-agarose immobilized acyl transferase from Mycobacterium smegmatis, was employed for the fast and efficient preparation of the desired amides (58–70% m.c., 15 min). In-line work-up allowing for the recovery and reuse of the unreacted substrates was added downstream the process, enhancing its automation. The combination of flow facilities, high substrate-to-catalyst ratio and closed-loop strategies make this methodology a sustainable and cost-effective procedure. Computational studies were carried out to provide insights into the enzymatic active site and substrate recognition.

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    Flow Chemistry as an Enabling Technology for Synthetic Organic Chemistry

    • Nicholas E. Leadbeater
    • Department of Chemistry, University of Connecticut, Storrs, USA

    Continuous-flow processing is proving to be an enabling technology for synthetic organic chemists. After an introduction to the advantages and disadvantages of flow processing and an overview of the equipment currently available, the use of flow chemistry in a range of avenues of organic chemistry is showcased. Attention is focused on areas such as hazardous transformations, multistep synthesis, photochemistry, electrochemistry, and organocatalysis. The scope of the chapter is also broadened to techniques used for monitoring flow processes and the incorporation of flow chemistry into the undergraduate teaching laboratory.

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    Synthesis and chemical reactions of thieno[3,2-c]quinolines from arylamine derivatives, part (V): a review

    • Ameen A. Abu-Hashema, b
    • A. B. A. El-Gazzara
    • Ahmed A. M. Abdelgawadb, c
    • Moustafa A. Goudad, e
    • aPhotochemistry Department (Heterocyclic Unit), National Research Centre, Dokki, Giza, Egypt
    • bChemistry Department, Faculty of Science, Jazan University, Jazan, Saudi Arabia
    • cMedicinal and Aromatic Plants Department, Desert Research Center, Cairo, Egypt
    • dDepartment of Chemistry, Faculty of Science and Arts, Taibah University, Ulla, Medina, Saudi Arabia
    • eDepartment of Chemistry, Faculty of Science, Mansoura University, Mansoura, Egypt

    This review describes the procedures for the synthesis of thieno[3,2-c]quinoline derivatives by use of the following reagents and aryl-amine derivatives as starting material, and the chemical reactions of the resulting thieno[3,2-c]quinolines: 1-naphthyl amine, 2,4-dichloroquinoline-3-carbonitrile, methyl 2-bromothiophene-3-carboxylate, methyl 2-amino-3-bromobenzoate, 4-chloro-3-(2-chloroallyl)-2-methylquinoline, methyl 2-[(1-phenylethylidene)amino]benzoate, 2-methylquinolin-4-ol, 4-chloro-2-oxo-1,2-dihydroquinoline-3-carbaldehyde, 1,2-dichloro-3,3,4,4,5,5-hexafluorocyclopent-1-ene, benzo[b]thiophen-2(3H)-one, 2-(thiophen-2-yl)aniline, 2-chlorothiophene-3-carboxylic acid, 2-chlorothiophene-3-carboxylic acids, N-[2-(thiophen-2-yl)phenyl]formamide, 2-(2-isocyano-5-methylphenyl)thiophene, boric acid, [1,1′-biphenyl]-2-amine, benzo[b]thiophene, methyl 4-amino-3-(benzo[b]thiophen-2-yl)benzoate, 1-(2-substituted-phenyl)-4-substituted-4,5-dihydro-1H-1,2,3-triazol-5-yl)morpholine, 6,8-dibromo-4-chloro-quinoline-3-carbaldehyde.

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    From Platform to Knowledge Graph: Evolution of Laboratory Automation

    • Jiaru Bai1
    • Liwei Cao1
    • Sebastian Mosbach1, 2
    • Jethro Akroyd1, 2
    • Alexei A. Lapkin1, 2
    • Markus Kraft1, 2, 3, 4
    • 1Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge, CB3 0AS, United Kingdom
    • 2CARES, Cambridge Centre for Advanced, Research and Education in Singapore, 1 Create Way, CREATE Tower, #05-05, Singapore, 138602
    • 3School of Chemical and Biomedical Engineering, Nanyang Technological University, 62 Nanyang Drive, Singapore, 637459
    • 4The Alan Turing Institute, London, NW1 2DB, United Kingdom

    High-fidelity computer-aided experimentation is becoming more accessible with the development of computing power and artificial intelligence tools. The advancement of experimental hardware also empowers researchers to reach a level of accuracy that was not possible in the past. Marching towards the next generation of self-driving laboratories, the orchestration of both resources lies at the focal point of autonomous discovery in chemical science. To achieve such a goal, algorithmically-accessible data representations and standardised communication protocols are indispensable. In this perspective, we recategorise the recently introduced approach based on Materials Acceleration Platforms into five functional components and discuss recent case studies that focus on the data representation and exchange scheme between different components. Emerging technologies for interoperable data representation and multi-agent systems are also discussed with their recent applications in chemical automation. We hypothesise that knowledge graph technology, orchestrating semantic web technologies and multi-agent systems will be the driving force to bring data to knowledge, evolving our way of automating laboratory.

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    Dimeric cyclobutane formation under continuous flow conditions using organophotoredox catalysed [2+2]-cycloaddition

    • Helena F. Granthama
    • Marc C. Kimbera
    • aSchool of Science, Department of Chemistry, Loughborough University, LE11 3TU, UK

    Radical cation-initiated dimerization of electron rich alkenes is an expedient method for the synthesis of cyclobutanes. By merging organophotoredox catalysis and continuous flow technology a batch versus continuous flow study has been performed providing a convenient synthetic route to an important carbazole cyclobutane material dimer t-DCzCB using less only 0.1 mol% of an organophotoredox catalyst. The scope of this methodology was explored giving a new class of functional materials, as well as an improved synthetic route to styrene based lignan dimeric natural products. The cyclobutane dimers could be isolated in higher chemical yields under continuous flow conditions and reaction times were reduced significantly compared to traditional batch reaction conditions.

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    Synthesis of 2H-Indazoles via the Cadogan Reaction in Batch and Flow Mode

    • Matilda Duffy
    • Mara Di Filippo
    • Marcus Baumann
    • University College Dublin, School of Chemistry, Science Centre South, Dublin D04 N2E5, Ireland

    A continuous flow protocol is reported for the synthesis of 2H-indazoles via the thermal Cadogan reaction. Triethyl phosphite serves as a readily available deoxygenation reagent providing a facile entry to a series of drug-like 2H-indazoles in high chemical yields. Compared to an analogous batch approach, the flow process was advantageous as it provides for a contained environment where boiling of the reagent is suppressed by using a back-pressure regulator (BPR) which in turn leads to faster kinetics. Straightforward scale-up provided multi-gram quantities of 2H-indazoles whose further functionalisation via light-driven and regiospecific acetylation was demonstrated in flow mode.

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    DNDI-6148: A Novel Benzoxaborole Preclinical Candidate for the Treatment of Visceral Leishmaniasis

    • Charles E. Mowbray*1, Stéphanie Braillard1, Paul A. Glossop2, Gavin A. Whitlock2, Robert T. Jacobs3, Jason Speake3, Bharathi Pandi3, Bakela Nare3, Louis Maes4, Vanessa Yardley5, Yvonne Freund6, Richard J. Wall7, Sandra Carvalho7, Davide Bello7, Magali Van den Kerkhof4, Guy Caljon4, Ian H. Gilbert7, Victoriano Corpas-Lopez7, Iva Lukac7, Stephen Patterson7, Fabio Zuccotto7, Susan Wyllie*7
    • 1Drugs for Neglected Diseases initiative (DNDi), 15 Chemin Louis-Dunant, 1202 Geneva, Switzerland
    • 2Sandexis Medicinal Chemistry Ltd, Innovation House, Discovery Park, Ramsgate Road, Sandwich, Kent CT13 9ND, U.K.
    • 3Scynexis, 3501 C Tricenter Boulevard, Durham, North Carolina 27713, United States
    • 4Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium
    • 5Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, U.K.
    • 6Anacor Pharmaceuticals, 1020 East Meadow Circle, Palo Alto, California 94303, United States
    • 7Division of Biological Chemistry and Drug Discovery, Wellcome Centre for Anti-infectives Research, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.

    Visceral leishmaniasis (VL) is a parasitic disease endemic across multiple regions of the world and is fatal if untreated. Current therapies are unsuitable, and there is an urgent need for safe, short-course, and low-cost oral treatments to combat this neglected disease. The benzoxaborole chemotype has previously delivered clinical candidates for the treatment of other parasitic diseases. Here, we describe the development and optimization of this series, leading to the identification of compounds with potent in vitro and in vivo antileishmanial activity. The lead compound (DNDI-6148) combines impressive in vivo efficacy (>98% reduction in parasite burden) with pharmaceutical properties suitable for onward development and an acceptable safety profile. Detailed mode of action studies confirm that DNDI-6148 acts principally through the inhibition of Leishmania cleavage and polyadenylation specificity factor (CPSF3) endonuclease. As a result of these studies and its promising profile, DNDI-6148 has been declared a preclinical candidate for the treatment of VL.

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    SBA15-Supported Nano-ruthenium Catalyst for the Oxidative Cleavage of Alkenes to Aldehydes under Flow Conditions

    • Alessandro Di Michelea
    • Stefano Giovagnolib
    • Paolo Filipponib
    • Francesco Venturonib
    • Antimo Gioiellob
    • aDepartment of Physics and Geology, University of Perugia, Via A. Pascoli 1, 06123 Perugia, Italy
    • bDepartment of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06122 Perugia, Italy

    SBA15-supported ruthenium nanoparticles were prepared and employed as catalytic system for the oxidative cleavage of olefins under flow conditions. Design of experiments was adopted to optimize the reaction parameters and was instrumental to develop a fast and robust method for producing aldehydes from alkenes. Utilizing a simple flow set-up, the process provided high conversions in only few minutes with 0.5% mol of ruthenium under mild reaction conditions and high flow rates.

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    Iron-catalyzed synthesis of pyridines from α,β-unsaturated ketoxime acetates and N-acetyl enamides

    • Gaochen Xu1
    • Huan Yan1
    • Sai Zhang1
    • Qinghuan Wu1
    • Jindian Duan1
    • Kai Guo1
    • 1College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, China

    A new method of FeCl2-catalyzed [4 + 2] annulation of α,β-unsaturated ketoxime acetates with N-acetyl enamides in batch and flow is reported. The current strategy features low-cost catalytic system, use of electron-rich olefins, operational simplicity and broad substrate scope, thus providing a facile and efficient access to substituted pyridines in moderate to good yields.

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    Photoredox Iridium–Nickel Dual Catalyzed Cross-Electrophile Coupling: From a Batch to a Continuous Stirred-Tank Reactor via an Automated Segmented Flow Reactor

    • Rohit Duvadie1
    • Alexander Pomberger1
    • Yiming Mo1
    • Erhan I. Altinoglu2
    • Hsiao-Wu Hsieh3
    • Kakasaheb Y. Nandiwale1
    • Victor L. Schultz1
    • Klavs F. Jensen*1
    • Richard I. Robinson3
    • 1Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
    • 2Chemical and Pharmaceutical Profiling, Novartis Global Drug Development, 700 Main Street South, Cambridge, Massachusetts 02139, United States
    • 3Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States

    Organic reaction optimization for batch to flow transfer represents a main challenge for process chemists in drug synthesis. Several factors such as reactant concentration, residence/reaction time, or homo-/heterogeneity need to be taken into consideration during the fine-tuning of reaction conditions toward typical scale-up goals, such as high space–time yield. Herein, we present reaction optimization for photoredox iridium–nickel dual catalyzed cross-electrophile coupling with a focus on developing homogeneous starting conditions. During the screening, special attention was put on the replacement of inorganic bases with homogeneous organic bases, and the effect of pKa on the reaction yield was investigated. Screening was conducted via an automated segmented flow reactor at 15 μL scale, and subsequentially, the conditions were transferred to a 5 mL photo-continuous stirred-tank reactor (CSTR) cascade to demonstrate multigram continuous flow synthesis during a 24 h steady operation.

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    Method for preparing epoxidized trans-1, 4-polyisoprene by using micro-reaction device

    Inventor: 乔凯, 张锴, 李玉光, 何伟, 郭凯

    • Assignee: Nanjing Advanced Biomaterials And Process Equipment Research Institute Co ltd

    The invention discloses a method for preparing epoxidized trans-1, 4-polyisoprene by using a micro-reaction device, which comprises the following steps: (1) dissolving trans-1, 4-polyisoprene TPI by using an organic solvent to obtain a homogeneous solution A; (2) mixing hydrogen peroxide and a formic acid solution in proportion to obtain a peroxyformic acid solution B; (3) and (3) simultaneously pumping the solution A and the solution B obtained in the steps (1) and (2) into a microreactor of a micro-reaction device, wherein a catalyst is immobilized in the microreactor, reacting, and collecting effluent liquid to obtain the catalyst. Compared with the prior art, the invention has the following advantages: (1) the method has the advantages of quick reaction, low yield, low cost, high safety, good operability, small reaction volume, short time and less corrosion to equipment; (2) the production method has simple process, can realize continuous production, and has higher operation safety and controllability.

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    Synthesis of 7-Chloroquinoline Derivatives Using Mixed Lithium-Magnesium Reagents

    • Valter E. Muriea
    • Paula V. Nicolinoa
    • Thiago dos Santosa
    • Guido Gambacortab
    • Rodolfo H. V. Nishimuraa
    • Icaro S. Perovanic
    • Luciana C. Furtadod
    • Leticia V. Costa-Lotufod
    • Anderson Moraes de Oliveirac
    • Ricardo Vessecchic
    • Ian R. Baxendaleb
    • Giuliano C. Clososkib, c
    • aDepartamento de Ciências BioMoleculares, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café S/N, Ribeirão Preto 14040-903, Brazil
    • bDepartment of Chemistry, Durham University, South Road, Durham DH1 3LE, United Kingdom
    • cDepartamento de Química, Faculdade de Filosofia Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes 3900, Ribeirão Preto 14040-901, Brazil
    • dDepartamento de Farmacologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Av. Prof. Lineu Prestes 1524, São Paulo 05508-900, Brazil

    We have prepared a library of functionalized quinolines through the magnesiation of 7-chloroquinolines under mild conditions, employing both batch and continuous flow conditions. The preparation involved the generation of mixed lithium-magnesium intermediates, which were reacted with different electrophiles. Mixed lithium-zinc reagents allowed the synthesis of halogenated and arylated derivatives. Some of the synthesized 4-carbinol quinolines have shown interesting antiproliferative properties, their hydroxyl group being a suitable amino group bioisostere. We also report a two-step approach for optically active derivatives.

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    Photocatalytic Hydroaminoalkylation of Styrenes with Unprotected Primary Alkylamines

    • Hannah E. Askeya
    • James D. Graysona
    • Joshua D. Tibbettsa
    • Jacob C. Turner-Dorea
    • Jake M. Holmesa
    • Gabriele Kociok-Kohnb
    • Gail L. Wrigleyc
    • Alexander J. Cresswella
    • aDepartment of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.
    • bMaterials and Chemical Characterisation Facility (MC), University of Bath, Claverton Down, Bath BA2 7AY, U.K.
    • cOncology R&D, Research & Early Development, AstraZeneca, Darwin Building, 310, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.

    Catalytic, intermolecular hydroaminoalkylation (HAA) of styrenes provides a powerful disconnection for pharmacologically relevant γ-arylamines, but current methods cannot utilize unprotected primary alkylamines as feedstocks. Metal-catalyzed HAA protocols are also highly sensitive to α-substitution on the amine partner, and no catalytic solutions exist for α-tertiary γ-arylamine synthesis via this approach. We report a solution to these problems using organophotoredox catalysis, enabling a direct, modular, and sustainable preparation of α-(di)substituted γ-arylamines, including challenging electron-neutral and moderately electron-rich aryl groups. A broad range of functionalities are tolerated, and the reactions can be run on multigram scale in continuous flow. The method is applied to a concise, protecting-group-free synthesis of the blockbuster drug Fingolimod, as well as a phosphonate mimic of its in vivo active form (by iterative α-C–H functionalization of ethanolamine). The reaction can also be sequenced with an intramolecular N-arylation to provide a general and modular access to valuable (spirocyclic) 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydronaphthyridines. Mechanistic and kinetic studies support an irreversible hydrogen atom transfer activation of the alkylamine by the azidyl radical and some contribution from a radical chain. The reaction is photon-limited and exhibits a zero-order dependence on amine, azide, and photocatalyst, with a first-order dependence on styrene.

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    Photocatalysis in the Life Science Industry

    • Lisa Candisha
    • Karl D. Collinsb
    • Gemma C. Cookc
    • James J. Douglasd
    • Adrián Gómez-Suáreze
    • Anais Jolitf
    • Sebastian Keessf
    • aDrug Discovery Sciences, Pharmaceuticals, Bayer AG, 42113 Wuppertal, Germany
    • bBayer Foundation, Public Affairs, Science and Sustainability, Bayer AG, 51368 Leverkusen, Germany
    • cDiscovery High-Throughput Chemistry, Medicinal Science and Technology, GlaxoSmithKline, Stevenage SG1 2NY, U.K.
    • dEarly Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, Macclesfield SK10 2NA, U.K.
    • eOrganic Chemistry, Bergische Universität Wuppertal, 42119 Wuppertal, Germany
    • fMedicinal Chemistry Department, Neuroscience Discovery Research, AbbVie Deutschland GmbH & Co. KG, 67061 Ludwigshafen, Germany

    In the pursuit of new pharmaceuticals and agrochemicals, chemists in the life science industry require access to mild and robust synthetic methodologies to systematically modify chemical structures, explore novel chemical space, and enable efficient synthesis. In this context, photocatalysis has emerged as a powerful technology for the synthesis of complex and often highly functionalized molecules. This Review aims to summarize the published contributions to the field from the life science industry, including research from industrial-academic partnerships. An overview of the synthetic methodologies developed and strategic applications in chemical synthesis, including peptide functionalization, isotope labeling, and both DNA-encoded and traditional library synthesis, is provided, along with a summary of the state-of-the-art in photoreactor technology and the effective upscaling of photocatalytic reactions.

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    Continuous slurry plug flow Fe/ppm Pd nanoparticle-catalyzed Suzuki–Miyaura couplings in water utilizing novel solid handling equipment

    • Alex B. Wooda
    • Scott Plummerb
    • Richard I. Robinsonb
    • Marie Smithc
    • Jim Changc
    • Fabrice Galloud
    • Bruce H. Lipshutza
    • aDepartment of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106, USA
    • bGlobal Discovery Chemistry – Chemistry Technology Group, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA
    • cGenomics Institute of the Novartis Research Foundation, 10675 John J Hopkins Dr., San Diego, CA 92121, USA
    • dNovartis Pharma AH, CH-4057 Basel, Switzerland

    Herein are reported initial efforts to develop a generally accessible flow process, applying a heterogenous nanocatalyst to aqueous micelle-enabled Suzuki–Miyaura coupling reactions. Also disclosed is a new engineering solution (i.e., a self-draining back pressure regulator), which, when applied, enabled 1.5 hours of continuous operation leading to the production of 20 grams of a pharmaceutical intermediate.

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    Photoredox-Catalyzed Multicomponent Petasis Reaction in Batch and Continuous Flow with Alkyl Boronic Acids

    • Monica Oliva1
    • Prabhat Ranjan1
    • Serena Pillitteri1
    • Guglielmo Attilio Coppola1
    • Monica Messina1
    • Erik V. Van der Eycken1,2
    • Upendra Kumar Sharma1
    • 1Laboratory for Organic and Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, KU Leuven, Celestijnenlaan 200F, Leuven B-3001, Belgium
    • 2Peoples’ Friendship University of Russia (RUDN University), Miklukho-Maklaya street 6, Moscow RU-117198, Russia

    Multicomponent reactions (MCRs) are ideal platforms for the generation of a wide variety of organic scaffolds in a convergent and atom-economical manner. Many strategies for the generation of highly substituted and diverse structures have been developed and among these, the Petasis reaction represents a viable reaction manifold for the synthesis of substituted amines via coupling of an amine, an aldehyde and a boronic acid (BA). Despite its synthetic utility, the inherent drawbacks associated with the traditional two-electron Petasis reaction have stimulated continuous research towards more facile and tolerant methodologies. In this regard, we present the use of free alkyl boronic acids as effective radical precursors in this MCR through a single-electron transfer mechanism under mild reaction conditions. We have further demonstrated its applicability to photo-flow reactors, facilitating the reaction scale-up for the rapid assembly of complex molecular structures.

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    Photoredox-Catalyzed Dehydrogenative Csp3–Csp2 Cross-Coupling of Alkylarenes to Aldehydes in Flow

    • Oliver M. Griffithsa
    • Henrique A. Estevesa
    • Yiding Chena
    • Karin Sowaa,b
    • Oliver S. Maya
    • Peter Morsec
    • David C. Blakemorec
    • Steven V. Ley*a
    • aYusuf Hamied Department of Chemistry, University of Cambridge, CB2 1EW Cambridge, U.K.
    • bDepartment of Chemistry, University of Münster, 48149 Münster, Germany
    • cMedicine Design, Pfizer, Inc., Groton, Connecticut 06340, United States

    Executing photoredox reactions in flow offers solutions to frequently encountered issues regarding reproducibility, reaction time, and scale-up. Here, we report the transfer of a photoredox-catalyzed benzylic coupling of alkylarenes to aldehydes to a flow chemistry setting leading to improvements in terms of higher concentration, shorter residence times, better yields, ease of catalyst preparation, and enhanced substrate scope. Its applicability has been demonstrated by a multi-gram-scale reaction using high-power light-emitting diodes (LEDs), late-stage functionalization of selected active pharmaceutical ingredients (APIs), and also a photocatalyst recycling method.

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    Drug Discovery Automation and Library Synthesis in Flow

    • Paul Richardson1
    • Irini Abdiaj2
    • 1Pfizer Medicine Design, Pfizer, La Jolla, USA
    • 2Janssen Research and Development, Toledo, Spain

    The spiraling costs, competitive nature, and stringent timelines associated with Drug Discovery fuel investigations into new technologies that can potentially alleviate the pressures associated with these factors. Whereas advantages of the implementation of Flow Chemistry in the Development phase of a campaign appear obvious specifically toward the large-scale synthesis of the molecule of interest, in early Discovery it is often harder to justify the time to investigate/develop and validate enabling technologies particularly given the fact that there may be no near-term tangible return on this investment. The current chapter takes a detailed look at several case studies on innovative flow-based technologies developed to expedite the Drug Discovery process and evaluates the overall advantages/disadvantages of each approach as well as their overall sustainability in terms of potential uptake within the industry.

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    Homogeneous Catalytic C(sp3 )–H Functionalization of Gaseous Alkanes

    • Antonio Pulcinellaa
    • Daniele Mazzarellaa
    • Timothy Noëla
    • aFlow Chemistry Group, Van ’t Hoff Institute for Molecular Sciences (HIMS), University of Amsterdam

    The conversion of light alkanes into bulk chemicals is becoming an important challenge as it avoids effectively the use of prefunctionalized alkylating reagents. The implementation of such processes is, however, hampered by their gaseous nature and low solubility, as well as the low reactivity of the C–H bonds. Efforts have been made to enable both polar and radical processes to activate these inert compounds. In addition, these methodologies also benefit significantly from the development of a suitable reactor technology that intensifies gas-liquid mass transfer. In this review, we critically highlight these developments, both from a conceptual and a practical point of view. The recent expansion of these mechanisticallydifferent methods have enabled the use of various gaseous alkanes for the development of different bond-forming reactions, including C–C, C–B, C–N, C–Si and C–S bonds.

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    Telescoped Lithiation, C-Arylation and Methoxylation in Flow-Batch Hybrid toward the Synthesis of Canagliflozin

    • Dominik Polterauera,b
    • Jason D. Williamsa,b
    • Christopher A.Honea,b
    • C. Oliver Kappea,b
    • aCenter for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering (RCPE), Inffeldgasse 13, A-8010 Graz, Austria
    • bInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, A-8010 Graz, Austria

    We report a highly efficient three-step flow-batch hybrid procedure for the synthesis of a key canagliflozin intermediate. The telescoped process provides exquisite control over an exothermic and mixing sensitive lithiation and subsequent C-arylation within a microstructured flow reactor. Methoxylation reagents are then added in flow, before undergoing completion in a batch vessel. The flow process afforded the target intermediate in 76% yield, with a throughput of 26.8 g/h.

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    A small footprint oxycodone generator based on continuous flow technology and real-time analytics

    • Florian Sommera,b
    • David Cantilloa,b
    • C. Oliver Kappea,b
    • aInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010, Graz, Austria
    • bCenter for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010, Graz, Austria

    A scalable continuous flow setup for the preparation of the opioid medication oxycodone is presented. The process is based on a two-step synthetic sequence consisting of C14 hydroxylation of thebaine with performic acid, followed by catalytic hydrogenation of the ensuing 14-hydroxycodeinone intermediate. Safe and efficient oxidation with performic acid has been achieved by generating the reagent in situ in the presence of the starting material using a micromixer. Catalytic hydrogenation has been carried out in a scalable shell-and-tube reactor equipped with palladium-electroplated catalytic static mixers. Acquisition of real-time process data has been enabled by integrating online UHPLC analysis at the reactor output. The continuous process features safe operation, high atom economy, simple workup and production of 7 g/h of high purity oxycodone in a small footprint setup.

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    Unlocking the Accessibility of Alkyl Radicals from Boronic Acids through Solvent-Assisted Organophotoredox Activation

    • Prabhat Ranjana
    • Serena Pillitteria
    • Guglielmo Coppolaa
    • Monica Olivaa
    • Erik V. Van der Eyckena,b
    • Upendra K. Sharmaa
    • aLaboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven (KU Leuven), Celestijnenlaan 200F, B-3001 Leuven, Belgium
    • bPeoples’ Friendship University of Russia (RUDN University), Miklukho-Maklaya Street 6, 117198 Moscow, Russia

    Despite their prevalence in organic synthesis, the application of boronic acids (BAs) as alkyl radical precursors in visible-light-assisted photocatalyzed reactions has been limited by their high oxidation potential. This study demonstrates the prominent ability of amide solvents, namely, N,N-dimethylacetamide, to participate in hydrogen-bonding interactions with BAs, thus enabling the modulation of their oxidation potential toward the generation of alkyl radicals. The developed protocol is simple and robust and demonstrates broad applicability for alkylation, allylation, and elimination reactions in batch and continuous flow. The application toward dehydroalanine allows the synthesis of unnatural amino acids. Furthermore, the chemoselective generation of radical species from BAs in the presence of boronic ester-containing molecules is now feasible, endorsing plausible boron-selective (bio-) orthogonal modifications.

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    Organic–inorganic hybrid electro-optic material with Disperse Red 1 chromophore fabricated by flow chemistry

    • Yoonseok Koa
    • Minsang Kima
    • Changho Noha
    • Mi-Jeong Kima
    • Keechang Leea
    • Jongback Kimb
    • Sung Dug Kima
    • Sang Soo Jeea
    • aPolymer Research Lab, Samsung Advanced Institutes of Technology (SAIT), Samsung Electronics, Suwon-si, Gyeonggi-do, Korea
    • bAnalytical Engineering Group, Samsung Advanced Institutes of Technology (SAIT), Samsung Electronics, Suwon-si, Gyeonggi-do, Korea

    Flow chemistry (FC) has been studied extensively because of its advantages, such as precise controllability of process variables and superior mass and heat transfer, as well as process automation for obtaining autonomous chemical synthesis platforms. In this study, FC was utilized to fabricate bulky tirethoxysilane-modified Disperse Red 1 chromophore (TES-DR1) that showed electro-optic (EO) activity. The product yield of TES-DR1 was only 35% using the traditional batch method. By contrast, a significant product yield of 95% was obtained using the proposed FC system in which the reaction could be performed at temperatures above the boiling point of the solvent, providing sufficient energy for accelerating the reaction. Study of reaction kinetics revealed that the reaction mechanism was altered in the high-temperature region. During hybridization, the TES-DR1 was well-dispersed and chemically fixed in the organic–inorganic hybrid matrix composed of SiO2 and polymethylmethacrylate modified with tetramethyl orthosilicate. With the subsequent electric-field poling process, the chromophores were aligned uniaxially in response to the applied electric field, leading to EO behavior. The r33 value of the polymeric EO material is normally decreased at the glass transition temperature because the polymer matrix in the rubbery state allows the chromophores to move randomly. However, the average r33 value representing EO activity remained stable at 14.67 pm/V after the thermal stability test performed at 225 °C. Therefore, TES-DR1 was bound and confined to the stable hybrid framework, restricting chromophore movement at high temperatures.

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    Technological Innovations in Photochemistry for Organic Synthesis: Flow Chemistry, High-Throughput Experimentation, Scale-up, and Photoelectrochemistry

    • Laura Buglionia,b
    • Fabian Raymenantsa
    • Aidan Slatterya
    • Stefan D. A. Zondaga
    • Timothy Noëla
    • aFlow Chemistry Group, van ’t Hoff Institute for Molecular Sciences (HIMS), Universiteit van Amsterdam (UvA), Science Park 904, 1098 XH, Amsterdam, The Netherlands
    • bMicro Flow Chemistry and Synthetic Methodology, Department of Chemical Engineering and Chemistry, Eindhoven University of Technology, Het Kranenveld, Bldg 14—Helix, 5600 MB, Eindhoven, The Netherlands

    Photoinduced chemical transformations have received in recent years a tremendous amount of attention, providing a plethora of opportunities to synthetic organic chemists. However, performing a photochemical transformation can be quite a challenge because of various issues related to the delivery of photons. These challenges have barred the widespread adoption of photochemical steps in the chemical industry. However, in the past decade, several technological innovations have led to more reproducible, selective, and scalable photoinduced reactions. Herein, we provide a comprehensive overview of these exciting technological advances, including flow chemistry, high-throughput experimentation, reactor design and scale-up, and the combination of photo- and electro-chemistry.

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    Pyrrolidine and bicycloheteroaryl containing oga inhibitor compounds

    Inventor: José Manuel Bartolomé-Nebreda, Andrés Avelino TRABANCO-SUÁREZ, Ana Isabel De Lucas Olivares, Sergio-Alvar Alonso-De Diego

    • Assignee: Janssen Pharmaceutica Nv

    The present invention relates to O-GIcNAc hydrolase (OGA) inhibitors. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which inhibition of OGA is beneficial, such as tauopathies, in particular Alzheimer’s disease or progressive supranuclear palsy; and neurodegenerative diseases accompanied by a tau pathology, in particular amyotrophic lateral sclerosis or frontotemporal lobe dementia caused by C90RF72 mutations; or alpha synucleinopathies, in particular Parkinson’s disease, dementia due to Parkinson’s (or neurocognitive disorder due to Parkinson’s disease), dementia with Lewy bodies, multiple system atrophy, or alpha synucleinopathy caused by Gaucher’s disease.

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    Flow chemistry synthesis of isocyanates

    Inventors: Michael D. BurkartThien An PHUNG HAI

    • Assignee: The Regents Of The University Of California

    The disclosure provides, inter alia, safe and environmentally-friendly methods, such as flow chemistry, to synthesize isocyanates, such as methylene diphenyl diisocyanate, toluene diisocyanate, hexamethylene diisocyanate, isophorone diisocyanate, and tetramethylxylene diisocyanate.

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    Cyclodextrin

    Inventors: Tammy Savage, Stephen Wicks, John Mitchell

    • Assignee: CURADEV PHARMA PRIVATE Ltd

    The invention provides a method for preparing sulphoalkyl ether-β-cyclodextrin. The method comprises first contacting cyclodextrin with a base to form activated cyclodextrin. The method then comprises separately contacting the activated cyclodextrin with an alkyl sultone to form sulphoalkyl ether-β-cyclodextrin. The activation reaction is carried in batch and the sulphoalkylation reaction is carried out under continuous flow conditions.

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    Compounds and compositions as inhibitors of endosomal toll-like receptors

    Inventors: Phillip Alper, Jonathan DEANE, Songchun Jiang, Tao Jiang, Thomas Knoepfel, Pierre-Yves Michellys, Daniel Mutnick, Wei Pei, Peter SYKA, Guobao Zhang, Yi Zhang

    • Assignee: Novartis AG, Novartis Institutes for BioMedical Research Inc

    The invention disclosed herein relates to 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinyl compounds and 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinyl compounds of Formula (A), pharmaceutical compositions comprising such compounds and the use of such compounds in the treatment of autoimmune diseases.

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    High-Yielding Flow Synthesis of a Macrocyclic Molecular Hinge

    • Christopher D. Jonesa
    • Laurence J. Kershaw Cooka
    • David Marquez-Gameza
    • Konstantin V. Luzyanina
    • Jonathan W. Steedb
    • Anna G. Slatera
    • aDepartment of Chemistry and Materials Innovation Factory, University of Liverpool, Crown Street, Liverpool L69 7ZD, U.K.
    • bDepartment of Chemistry, Durham University, South Road, Durham DH1 3LE, U.K.

    Many molecular machines are built from modular components with well-defined motile capabilities, such as axles and wheels. Hinges are particularly useful, as they provide the minimum flexibility needed for a simple and pronounced conformational change. Compounds with multiple stable conformers are common, but molecular hinges almost exclusively operate via dihedral rotations rather than truly hinge-like clamping mechanisms. An ideal molecular hinge would better reproduce the behavior of hinged devices, such as gates and tweezers, while remaining soluble, scalable, and synthetically versatile. Herein, we describe two isomeric macrocycles with clamp-like open and closed geometries, which crystallize as separate polymorphs but interconvert freely in solution. An unusual one-pot addition cyclization reaction was used to produce the macrocycles on a multigram scale from inexpensive reagents, without supramolecular templating or high-dilution conditions. Using mechanistic information from NMR kinetic studies and at-line mass spectrometry, we developed a semicontinuous flow synthesis with maximum conversions of 85–93% and over 80% selectivity for a single isomer. The macrocycles feature voids that are sterically protected from guests, including reactive species such as fluoride ions, and could therefore serve as chemically inert hinges for adaptive supramolecular receptors and flexible porous materials.

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    Application of Flow and Biocatalytic Transaminase Technology for the Synthesis of a 1-Oxa-8-azaspiro [4.5] decan-3-amine

    • Jeffrey T. Kohrta
    • Peter H. Dorffa
    • Michael Burnsb
    • Chewah Leeb
    • Steven V. O’Neilb
    • Robert J. Maguireb
    • Rajesh Kumarb
    • Melissa Wagenaarb
    • Loren Pricea
    • Manjinder S. Lalla
    • aMedicine Design, Pfizer Inc., 445 Eastern Point Road, Groton, Connecticut 06340, United States
    • bChemical Research and Development, Pfizer Inc., 445 Eastern Point Road, Groton, Connecticut 06340, United States

    Spirocyclic ring systems are useful intermediates in the design and synthesis of medicinally active agents and commonly found as cores in natural products. Recently, syntheses of a key intermediate Boc-protected-1-oxa-8-azaspiro[4.5]decan-3-amine 1 were examined. While multigram quantities of the racemic material could be made from the reduction of an energic azide intermediate, larger scale reactions and a chiral synthesis required further investigations. Herein, we describe the use of a continuous three-step flow process to scale the formation and reduction of an azide intermediate, and the use of a transaminase to prepare the desired enantiomer in high yield and enantiomeric excess.

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    Scalable Synthesis of Norbornadienes via in situ Cracking of Dicyclopentadiene using Continuous Flow Chemistry

    • Jessica Orrego-Hernándeza
    • Helen Hölzela
    • Maria Quanta
    • Zhihang Wanga
    • Kasper Moth-Poulsena
    • aChalmers University of Technology: Chalmers tekniska hogskola, Chemistry, Sweden

    The norbornadiene (NBD)-quadricyclane (QC) photoswitch has recently attracted attention due to its use in molecular solar thermal energy systems (MOST). Normally for device testing, several grams are needed. One way of synthesizing NBDs efficiently is through the Diels-Alder reaction between alkynes and cyclopentadiene. However, scaling up the reaction can be troublesome in a research lab environment. Also, dicyclopentadiene needs cracking before utilization as a time-consuming step. Here, we developed a method where we both scale up the synthesis in a single reaction step that involves both in situ cracking of dicyclopentadiene and direct reaction of cyclopentadiene with acetylene derivatives using a tubular coiled stainless steel flow reactor. As a proof-of-concept, we synthesized 6 different NBD compounds, and scaled the synthesis to produce 87 g of a novel NBD in 9 h. The NBD is further characterized, showing promising properties for MOST applications. Our new method shows that flow chemistry is an attractive technique for the fast and efficient synthesis of large quantities of NBDs, needed to develop future real-life devices and applications.

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    Delineating a green, catalyst free synthesis of a popular nutraceutical methylsulfonylmethane (MSM) in continuous flow

    • Chinmay A. Shuklaa
    • Bantu Udaykumara
    • Y. Saisivanarayanaa
    • Arsh Ismailia
    • T Haripriyaa
    • Manish M. Shindeb
    • Srinivasan Netic
    • Maheshkumar Uppadaa
    • Vishnuvardhana Edac
    • Saikat Senc
    • Srinivas Orugantia,b,c
    • a10X Chemical Process Automation Laboratory, Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad, 500 046, India
    • bFlow Chemistry Technology Hub, Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad, 500 046, India
    • cCentre for Process Research and Innovation, Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad, 500 046, India

    A green and potentially scalable continuous flow synthesis of a popular sulfone containing nutraceutical, methylsulfonylmethane (MSM), has been demonstrated in a Vapourtec tubular reactor platform via metal catalyst-free hydrogen peroxide mediated oxidation of dimethyl sulfoxide. Under optimized conditions, MSM could be obtained in >85% isolated yield and purity >99% with a productivity of 23.6 g/h simply by cooling the reaction mixture collected at the output.

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    Evaluation of a Continuous-Flow Photo-Bromination Using N-Bromosuccinimide for Use in Chemical Manufacture

    • Matthew Waterforda
    • Simon Sauberna
    • Christian H. Hornunga
    • aCSIRO Manufacturing, Bag 10, Clayton South, Vic. 3169, Australia.

    A continuous-flow photo-bromination reaction on benzyl and phenyl groups was conducted using N-bromosuccinimide as the bromine source inside a preparatory-scale glass plate reactor. This flow reactor system was capable of independently controlling light intensity, wavelength, and reaction temperature, hence exerting an exceptional level of control over the reaction. A short optimisation study for the synthesis of 2-bromomethyl-4-trifluoromethoxyphenylboronic acid pinacol ester resulted in best conditions of 20°C and 10 min residence time using an LED (light-emitting diode) array at 405 nm and acetonitrile as the solvent. The present study evaluates the potential for this easy-to-handle bromination system to be scaled up for chemical manufacture inside a continuous-flow glass plate reactor. The combination with an in-line continuous flow liquid–liquid extraction and separation system, using a membrane separator, demonstrates the potential for continuous flow reaction with purification in an integrated multi-stage operation with minimal manual handling in between.

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    Scalability of photochemical reactions in continuous flow mode

    • Kian Donnellya
    • Marcus Baumanna
    • aSchool of Chemistry, Science Centre South, University College Dublin, D04 N2E2, Dublin, Ireland

    Continuous flow photochemistry as a field has witnessed an increasing popularity over the last decade in both academia and industry. Key drivers for this development are safety, practicality as well as the ability to rapidly access complex chemical structures. Continuous flow reactors, whether home-built or from commercial suppliers, additionally allow for creating valuable target compounds in a reproducible and automatable manner. Recent years have furthermore seen the advent of new energy efficient LED lamps that in combination with innovative reactor designs provide a powerful means to increasing both the practicality and productivity of modern photochemical flow reactors. In this review article we wish to highlight key achievements pertaining to the scalability of such continuous photochemical processes.

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    Synthesis of Enantiopure Unnatural Amino Acids by Metallaphotoredox Catalysis

    • Tomer M. Faraggia
    • Caroline Rouget-Virbela
    • Juan A. Rincónb
    • Mario Barberisb
    • Carlos Mateosb
    • Susana García-Cerradab
    • Javier Agejasb
    • Oscar de Frutosb
    • David W. C. MacMillana
    • aMerck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States
    • bCentro de Investigación Eli Lilly, S. A. Avda de la Industria 30, Alcobendas-Madrid 28108, Spain

    We describe herein a two-step process for the conversion of serine to a wide array of optically pure unnatural amino acids. This method utilizes a photocatalytic cross-electrophile coupling between a bromoalkyl intermediate and a diverse set of aryl halides to produce artificial analogues of phenylalanine, tryptophan, and histidine. The reaction is tolerant of a broad range of functionalities and can be leveraged toward the scalable synthesis of valuable pharmaceutical scaffolds via flow technology.

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    Biocatalyzed Flow Oxidation of Tyrosol to Hydroxytyrosol and Efficient Production of Their Acetate Esters

    • Francesca Annunziata1
    • Martina L. Contente2
    • Cecilia Pinna2
    • Lucia Tamborini1
    • Andrea Pinto2
    • 1Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133 Milan, Italy
    • 2Department of Food, Environmental and Nutritional Sciences, University of Milan, Via Celoria 2, 20133 Milan, Italy

    Tyrosol (Ty) and hydroxytyrosol (HTy) are valuable dietary phenolic compounds present in olive oil and wine, widely used for food, nutraceutical and cosmetic applications. Ty and HTy are endowed with a number of health-related biological activities, including antioxidant, antimicrobial and anti-inflammatory properties. In this work, we developed a sustainable, biocatalyzed flow protocol for the chemo- and regio-selective oxidation of Ty into HTy catalyzed by free tyrosinase from Agaricus bisporus in a gas/liquid biphasic system. The aqueous flow stream was then in-line extracted to recirculate the water medium containing the biocatalyst and the excess ascorbic acid, thus improving the cost-efficiency of the process and creating a self-sufficient closed-loop system. The organic layer was purified in-line through a catch-and-release procedure using supported boronic acid that was able to trap HTy and leave the unreacted Ty in solution. Moreover, the acetate derivatives (TyAc and HTyAc) were produced by exploiting a bioreactor packed with an immobilized acyltransferase from Mycobacterium smegmatis (MsAcT), able to selectively act on the primary alcohol. Under optimized conditions, high-value HTy was obtained in 75% yield, whereas TyAc and HTyAc were isolated in yields of up to 80% in only 10 min of residence time.

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    Supporting-Electrolyte-Free Anodic Oxidation of Oxamic Acids into Isocyanates: An Expedient Way to Access Ureas, Carbamates, and Thiocarbamates

    • Alessia Pettia
    • Corentin Fagnana
    • Carlo G. W. van Melisa
    • Nour Tanbouzab
    • Anthony D. Garciaa
    • Andrea Mastrodonatoa
    • Matthew C. Leecha
    • Iain C. A. Goodalla
    • Adrian P. Dobbsa
    • Thierry Ollevierb
    • Kevin Lam*a
    • aSchool of Science, University of Greenwich, Chatham Maritime, Chatham, Kent ME4 4TB, U.K.
    • bDépartement de Chimie, Université Laval, 1045 avenue de la Médecine, Québec, QC G1V 0A6, Canada

    We report a new electrochemical supporting-electrolyte-free method for synthesizing ureas, carbamates, and thiocarbamates via the oxidation of oxamic acids. This simple, practical, and phosgene-free route includes the generation of an isocyanate intermediate in situ via anodic decarboxylation of an oxamic acid in the presence of an organic base, followed by the one-pot addition of suitable nucleophiles to afford the corresponding ureas, carbamates, and thiocarbamates. This procedure is applicable to different amines, alcohols, and thiols. Furthermore, when single-pass continuous electrochemical flow conditions were used and this reaction was run in a carbon graphite Cgr/Cgr flow cell, urea compounds could be obtained in high yields within a residence time of 6 min, unlocking access to substrates that were inaccessible under batch conditions while being easily scalable.

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    Application of reactor engineering concepts in continuous flow chemistry: a review

    • Nicole C. Neyta
    • Darren L. Riley*a
    • aFaculty of Natural and Agricultural Sciences, Department of Chemistry, University of Pretoria, South Africa

    The adoption of flow technology for the manufacture of chemical entities, and in particular pharmaceuticals, has seen rapid growth over the past two decades with the technology now blurring the lines between chemistry and chemical engineering. Current indications point to a future in which flow chemistry and related technologies will be a major player in modern chemical manufacturing and the 4th industrial revolution. In this review we highlight the application of new reactor configurations and designs in the context of either bespoke or commercial flow apparatus specifically related to microwave chemistry, photochemical transformations, electrochemical promoted reactions and multi-phasic reactions. In addition, we look at how 3D printing in reactor design and computer-aided automation is growing within the field and finally describe how innovative solutions are being developed to tackle challenging down-stream processing operations.

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    In situ sensors for flow reactors – a review

    • Jun Lia
    • Helena Šimekb
    • David Ilioaec
    • Nicole Jungb
    • Stefan Bräseb
    • Hans Zappec
    • Roland Dittmeyera
    • Bradley P. Ladewig*a
    • aInstitute for Micro Process Engineering (IMVT), Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, Eggenstein-Leopoldshafen, Germany
    • bInstitute of Biological and Chemical Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, Eggenstein-Leopoldshafen, Germany
    • cGisela and Erwin Sick Laboratory for Micro-optics, Department of Microsystems Engineering, University of Freiburg, Germany

    The integration of specific sensors into microfluidic reactors and devices is crucial for the optimization of controllable variables such as flow, temperature, energy input (light, microwaves etc.). In this review, we highlight the state of the art for the integration of in situ sensors.

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    Mechanism and kinetics of the aerobic oxidation of benzyl alcohol to benzaldehyde catalyzed by cobalt porphyrin in a membrane microchannel reactor

    • Qi Hana
    • Xian-Tai Zhoua
    • Xiao-Qi Hed
    • Hong-Bing Jib, c
    • aFine Chemical Industry Research Institute, School of Chemical Engineering and Technology, Sun Yat-sen University, Zhuhai 519082, China
    • bFine Chemical Industry Research Institute, School of Chemistry, Sun Yat -sen University, Guangzhou 510275, China
    • cSchool of Chemical Engineering, Guangdong University of Petrochemical Technology, Maoming 525000, China
    • dHuizhou Research Institute, Sun Yat-sen University, Huizhou 516081, China

    The highly efficient selective aerobic oxidation of benzyl alcohol to benzaldehyde catalyzed by cobalt porphyrin was achieved in a membrane microchannel reactor. The efficiency of benzyl alcohol oxidation was remarkably improved in the micro-structured chemical system, achieving a conversion and benzaldehyde selectivity of 82% and 98%, respectively, in 6.5 min. The classification and transfer of free radicals, as well as the oxygen-transfer mechanism, were determined by in situ EPR (electron paramagnetic resonance) and in situ UV–visible spectroscopy. Further kinetic studies revealed that the oxidation of benzyl alcohol follows the Michaelis–Menten kinetics, with Km = 0.133 mol/L.A mathematic kinetic model was proposed, and the kinetic model fitted the experimental data well. The mathematical model can predict the reaction process at a wide range of benzyl alcohol concentrations, which is beneficial for the process optimization and reactor design.

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    Expanding the Tool Kit of Automated Flow Synthesis: Development of In-line Flash Chromatography Purification

    • Christopher G. Thomsona
    • Colin Banksb
    • Mark Allenc
    • Graeme Barkera, d
    • Christopher R. Coxona
    • Ai-Lan Lee*a
    • Filipe Vilela*a, d
    • aInstitute of Chemical Sciences, School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, Scotland EH14 4AS, United Kingdom
    • bCheshire Sciences (UK) Limited, Kao Hockham Building, Edinburgh Way, Harlow, Essex, England CM20 2NQ, United Kingdom
    • cAdvion (UK) Limited, Kao Hockham Building, Edinburgh Way, Harlow, Essex, England CM20 2NQ, United Kingdom
    • dContinuum Flow Lab, Heriot-Watt University, Edinburgh, Scotland EH14 4AS, United Kingdom

    Recent advancements in in-line extraction and purification technology have enabled complex multistep synthesis in continuous flow reactor systems. However, for the large scope of chemical reactions that yield mixtures of products or residual starting materials, off-line purification is still required to isolate the desired compound. We present the in-line integration of a commercial automated flash chromatography system with a flow reactor for the continuous synthesis and isolation of product(s). A proof-of-principle study was performed to validate the system and test the durability of the column cartridges, performing an automated sequence of 100 runs over 2 days. Three diverse reaction systems that highlight the advantages of flow synthesis were successfully applied with in-line normal- or reversed-phase flash chromatography, continuously isolating products with 97–99% purity. Productivity of up to 9.9 mmol/h was achieved, isolating gram quantities of pure product from a feed of crude reaction mixture. Herein, we describe the development and optimization of the systems and suggest guidelines for selecting reactions well suited to in-line flash chromatography.

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    The integration of catalyst design and process intensification in the efficient synthesis of 5-hydroxymethyl-2-furancarboxylic acid from fructose

    • Wei Hea1
    • Congcong Zhangb1
    • Wenyan Zhanga
    • YuchenZhuc
    • Zheng Fanga
    • Lili Zhaob
    • Kai Guoa, d
    • aCollege of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, PR China
    • bInstitute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing 211816, China
    • cSchool of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China
    • dState Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing 210009, PR China

    The integration of catalyst design and process intensification in the synthesis of 5‑hydroxymethyl-2-furancarboxylic acid was realized directly from fructose. A novel bifunctional catalyst derived from lignin was developed for the dehydration of fructose. Supported catalysts derived from silver was developed for the oxidation of 5-hydroxymethylfurfural for 5‑hydroxymethyl-2-furancarboxylic acid. The product distribution both in dehydration and oxidation process would be controlled through the adjustment of solvent effect. The structure in bifunctional catalysts was adjusted to reveal the effect of molecular skeletons on the catalytic performance. The constitution of supported catalysts was investigated to illustrate the support effect. Accordingly, the mechanism and synergetic effect in the catalyst were proposed through computational studies based on density functional theory and control experiments. Microwave irradiation was applied in the dehydration reaction, requiring adequate and efficient energy supply. Flow chemistry was employed in the oxidation of HMF, improving reaction efficiency.

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    (Trifluoromethylselenyl)methylchalcogenyl as Emerging Fluorinated Groups: Synthesis under Photoredox Catalysis and Determination of the Lipophilicity

    • Kevin Grollier[a]
    • Arnaud De Zordo-Banliat[b]
    • Flavien Bourdreux[b]
    • Bruce Pegot[b]
    • Guillaume Dagousset[b]
    • Emmanuel Magnier*[b]
    • Thierry Billard*[a, c]
    • [a]Institute of Chemistry and Biochemistry (ICBMS, UMR CNRS 5246) Univ Lyon, Universite Lyon 1, CNRS,CPE, INSA43 Bd du 11 novembre 1918, 69622 Villeurbanne (France)
    • [b]InstitutLavoisierdeVersailles (UMR CNRS 8180)Universit Paris-Saclay,UVSQ,CNRS78035 Versailles (France)
    • [c]CERMEP-In vivo imaging59 Bd Pinel, 69677 Lyon (France)

    The synthesis of molecules bearing (trifluoromethylselenyl)methylchalcogenyl groups is described via an efficient two-step strategy based on a metal-free photoredox catalyzed decarboxylative trifluoromethylselenolation with good yields up to 88 %, which raised to 98 % in flow chemistry conditions. The flow methods allowed also to scale up the reaction. The mechanism of this key reaction was studied. The physicochemical characterization of these emerging groups was performed by determining their Hansch–Leo lipophilicity parameters with high values up to 2.24. This reaction was also extended to perfluoroalkylselenolation with yields up to 95 %. Finally, this method was successfully applied to the functionalization of relevant bioactive molecules such as tocopherol or estrone derivatives.

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    «Quick, convenient, and clean»: Advancing education in green chemistry and nanocatalysis using sol-gel catalysts under flow

    • Antonino Scurriaa
    • Mario Pagliaroa
    • Rosaria Ciriminnaa
    • aIstituto per lo Studio dei Materiali Nanostrutturati, CNR, via U. La Malfa 153, 90146 Palermo, Italy

    Removing one key barrier to the industrial uptake of green chemistry and nanocatalysis in the fine and specialty
    chemical industry requires to fill an ongoing “talent shortage” via expanded chemistry education. In this study we
    show how the use of hybrid sol-gel catalysts to synthesize fine chemicals and active pharmaceutical ingredients in
    flow chemistry reactors illustrates new ideas to reshape chemistry education based on recent research outcomes,
    visualization and digital tools. Aiming to expand the knowledge base, skills and competencies that comprise the
    aforementioned new professional talent in catalysis and green chemistry currently in high demand, we identify
    several lessons learned from the industrial and academic utilization of these materials.

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    Scale-Up and Optimization of a Continuous Flow Carboxylation of N-Boc-4,4-difluoropiperidine Using s-BuLi in THF

    • Jean-Paul Kestemonta
    • James R. Frostb
    • Jérôme Jacqa
    • Patrick Pasaua
    • Frédéric Perla
    • Julien Brownb
    • Matthieu Tissot*a
    • aUCB Biopharma SPRL, Avenue de l’industrie, 1420 Braine l’Alleud, Belgium
    • bUCB, 216 Bath Road, Slough SL1 3WE, United Kingdom

    We report a large-scale carboxylation of N-Boc-4,4-difluoropiperidine (1) enabled by a continuous flow process. The flow process involved N-Boc-directed α-deprotonation using s-BuLi in THF and subsequent trapping with CO2 gas. Flow chemistry enabled the safe and scalable preparation of 400 g of carboxylic acid 2 over the course of a day to support our medicinal chemistry research program.

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    Exploration of continuous-flow benchtop NMR acquisition parameters and considerations for reaction monitoring

    • Tristan Maschmeyera
    • Paloma L. Prietoa
    • Shad Grunerta
    • Jason E. Heina
    • aDepartment of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada

    This study focused on fundamental data acquisition parameter selection for a benchtop nuclear magnetic resonance (NMR) system with continuous flow, applicable for reaction monitoring. The effect of flow rate on the mixing behaviors within a flow cell was observed, along with an exponential decay relationship between flow rate and the apparent spin–lattice relaxation time (T1*) of benzaldehyde. We also monitored sensitivity (as determined by signal-to-noise ratios; SNRs) under various flow rates, analyte concentrations, and temperatures of the analyte flask. Results suggest that a maximum SNR can be achieved with low to medium flow rates and higher analyte concentrations. This was consistent with data collected with parameters that promote either slow or fast data acquisition. We further consider the effect of these conditions on the analyte’s residence time, T1*, and magnetic field inhomogeneity that is a product of continuous flow. Altogether, our results demonstrate how fundamental acquisition parameters can be manipulated to achieve optimal data acquisition in continuous-flow NMR systems.

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    Amino alcohol acrylonitriles as broad spectrum and tumour selective cytotoxic agents

    • Jennifer R. Bakera
    • Cecilia C. Russella
    • Jayne Gilbertb
    • Adam McCluskeya
    • Jennette A. Sakoffb
    • aChemistry, School of Environmental & Life Sciences, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia
    • bExperimental Therapeutics Group, Department of Medical Oncology, Calvary Mater Newcastle Hospital, Edith Street, Waratah, NSW 2298, Australia

    We have identified specific dichlorophenylacrylonitriles as lead compounds in the development of novel anticancer compounds, notably, (Z)-N-(4-(2-cyano-2-(3,4-dichlorophenyl)vinyl)phenyl)acetamide (1) and ANI-7 (2). Herein we specifically probe the SAR associated with the terminal aromatic ring and associated cytoxicity in a broad range of human cancer cell lines. Synthesis of three focused libraries revealed a poor tolerance for electron withdrawing and donating moieties (Library A). A clear preference for hydrophobic substituents on a terminal piperazine moiety (Library B) with good levels of broad spectrum cytotoxicity, e.g.13a (GI50 2.5–6.0 μM), as did the introduction of a methylene spacer with 13i (4-CH3PhCH2; GI50 1.5–4.5 μM). Removal of the aromatic moiety and installation of simple hydrophobic groups (Library C), in particular an adamantyl moiety, afforded highly active broad spectrum cytotoxic agents with GI50 values ranging from 1.7 μM (14k; 1-adamantyl) to 5.6 μM (14i; pyrrolidine). Within these libraries we note lung cancer selectivity, relative to normal cells, of 13h (fluoro substituted acrylonitrile, GI50 1.6 μM, 9.3-fold selective); the colorectal selectivity of 14h (methylpiperidine analogue, GI50 0.36 μM, 6.9-fold selective) and the breast cancer selectivity of 13f (nitrile substituted acrylonitrile, GI50 2.3–6.0 μM, up to 20-fold selective). The latter was confirmed as a novel AhR ligand and a CYP1A1 activating compound, that likely induces cell death following bioactivation; a phenomenon previously described in breast cancer cell populations.

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    Ozone-Mediated Amine Oxidation and Beyond: A Solvent Free, Flow-Chemistry Approach

    Eric A. Skrotzkia, Jaya Kishore Vandavasia, Stephen G. Newmana

    • aCentre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie-Curie, Ottawa, Ontario K1N 6N5, Canada.

    Ozone is a powerful oxidant, most commonly used for oxidation of alkenes to carbonyls. The synthetic utility of other ozone-mediated reactions is hindered by its high reactivity and propensity to over-oxidize organic molecules, including most solvents. This challenge can largely be mitigated by adsorbing both substrate and ozone onto silica gel, providing a solvent-free oxidation method. In this manuscript, a flow-based packed bed reactor approach is described that provides exceptional control of reaction temperature and time of this reaction to achieve improved control and chemoselectivity over this challenging reaction. A powerful method to oxidize primary amines into nitroalkanes is achieved. Examples of pyridine, C–H bond, and arene oxidations are also demonstrated, confirming the system is generalizable to diverse ozone-mediated processes.

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    A sustainable and scalable multicomponent continuous flow process to access fused imidazoheterocycle pharmacophores

    • Blake J. M. Bakera, b
    • William J. Kerr*b
    • David M. Lindsayb
    • Vipul kumar K. Patela
    • Darren L. Poolea
    • aGlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, UK
    • bDepartment of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, UK

    Described herein is a green, continuous flow process for the synthesis of various aminoimidazoheterocycles, through the Gröebke–Blackburn–Bienaymé reaction (GBBR). This multicomponent procedure combines aminoazines, aldehydes and isocyanides to generate a wide variety of medicinally privileged, aminated imidazoheterocycle architectures. This method is performed in ethanol, using only mineral acid rather than the standard metal-based catalysts typical to the field. These sustainability benefits have been demonstrated even on multigram scale, exemplifying the facile scalability of the procedure. The process also boasts shorter reaction times, wider scope robustness, and improved yields compared to the currently available methods, with no requirement for an aqueous work-up procedure, affording resulting scaffolds of notable relevance, to a range of medicinal targets of academic and industrial interest.

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    Reproducible and rapid synthesis of a conjugated polymer by Stille polycondensation in flow: Effects of reaction parameters on molecular weight

    • Woojin Shina, 1
    • Wonyoung Koa, 1
    • Seung-Hwan Jina
    • Taeshik Earmmeb
    • Ye-Jin Hwanga
    • aDepartment of Chemistry and Chemical Engineering, Education and Research Center for Smart Energy and Materials, Inha University, 100 Inha-ro, Michuhol-gu, Incheon, Republic of Korea
    • bDepartment of Chemical Engineering, Hongik University, 94 Wausan-ro, Mapo-gu, Seoul 04066, Republic of Korea

    The batch-to-batch variations in molecular weight and molecular weight dispersity (Đ) values are large for conjugated polymers synthesized by step-growth polymerization, which can lead to irreproducible device performance. We developed a rapid flow synthesis system that can perform step-growth polymerizations of conjugated polymers in a reproducible manner by utilizing nitrogen gas as a carrier. The use of gas carrier, instead of organic solvents or fluorinated oils, eliminates the common diffusion problems at the beginning and the end of the reaction stream to the carrier fluid. Without the diffusion problem, our system provides high reproducibility and uniform reaction conditions in all regions of reaction stream. To highlight the performance of our flow system, we conducted Stille polycondensations to synthesize a representative conjugated polymer, PTB7. We found that PTB7 with a number average molecular weight (Mn) over 30 kDa was synthesized in only 3 min, with very low deviations of 2.6% and 3.1% for Mn and Đ values, respectively, compared to deviations of 66% for Mn and 43% for Đ in control reactions using pure solvent as a carrier. The effect of catalyst loading and reaction temperature was also studied, which enabled tuning the Mn of PTB7 within the range of 30.6–57.9 kDa. The quality of PTB7 synthesized in our system was also confirmed by fabricating photovoltaic devices which gave maximum power conversion efficiency of 7.02% with PC71BM as an acceptor.

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    Innovation in delivering synthetically challenging bicyclic arginase inhibitors to enhance immunotherapy

    • Derun Lia, Hongjun Zhanga, Thomas W. Lyonsa, Theodore A. Martinota, Abdelghani Achaba, Min lua, Lisa M. Noglea, Spencer McMinna, Matthew J. Mitcheltreea, Matthew Childersa, Qinglin Pua, Symon Gathiakaa, Anand Palania, Kalyan Chakravarthya, Amy D. DeCastroa, Jennifer O'Neila, Roshi Afshara, Nicole C. Walsha, Peter W. Fana, Mangeng Chenga, Richard Millera, Amy Dotya, Rachel Paltea, Hai-Young Kima, Josep Sauría, Adam Bearda, Christopher Brynczkaa and Christian Fischera
    • aMerck Research Laboratory, Boston, MA.

    Arginase overexpression has been associated with poor survival rates in advanced cancer patients treated with Keytruda. High levels of Arginase may lead to a depletion of arginine within the tumor microenvironment, inhibiting the immune response. Thus, arginase inhibition has the potential to greatly enhance immunotherapy treatment. Discovering novel arginase inhibitors was met with several challenges including analyzing/purifying extremely polar chemical matter without chromophores, synthetically challenging space, and poor bioavailability of compounds with ClogP less than minus two.

    Cross-functional collaborations and innovations rapidly overcame these challenges. Structural chemistry and modeling guided the design of novel arginase inhibitors. Analytical and purification groups developed innovative analytical/purification methods. Novel technologies including ReatIR and Vapourtec flow system, provided key intermediates to enable chartering into synthetically challenging space. Through creative cyclization strategies and active transport strategy to improve bioavailability, the team ultimately delivered a diverse set of potent and extremely synthetically challenging arginase inhibitors to study the potential of arginase inhibition. Preliminary in vivo evaluation showed single agent efficacy in an EMT6 model. These arginase inhibitors have the potential to enhance immunotherapy.

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    A revised 1D equivalent model for the determination of incident photon flux density in a continuous-flow LED-driven spiral-shaped microreactor using the actinometry method with Reinecke’s salt

    • Robbie Radjagobaloua
    • Victoria Dias Da Silva Freitasa
    • Jean-François Blancoa
    • Fabrice Grosb
    • Jérémy Dauchetb
    • Jean-François Cornetb
    • Karine Loubierea
    • aLaboratoire de Génie Chimique (LGC), Université de Toulouse, CNRS, INPT, UPS, 4 allée Emile Monso, CS 84234, 31 432, Toulouse, France
    • bUniversité Clermont Auvergne, Clermont Auvergne INP, CNRS, Institut Pascal, F-63000, Clermont-Ferrand, France

    Continuous-flow microstructured technologies are now recognized as promising alternatives to batch processing for organic photochemistry, especially when light emitting diodes (LEDs) are employed as light sources. To evaluate and optimize productivity and energetic efficiency, the knowledge of the incident photon flux density is crucial. In this context, the objectives of the present work are dual: first, to transfer the classical actinometry method with Reinecke’s salt to a continuous-flow LED-driven spiral-shaped reactor and second, to propose a revised one-dimensional equivalent model for the accurate determination of the incident photon flux density in this microreactor. Experimental measurements were carried out under controlled conditions. The effects of the spectral domain and radiant power emitted, the tubing length, the presence of gas-liquid Taylor flow, and the material of the support plate were especially investigated. An expression was established for the revised one-dimensional Cartesian model, taking into account the diffuse emission of the LED array and the reflection induced by the material of the plate in which the tubing was inserted (i.e. the reflection by the backside of the microreactor wall). In this way, the incident photon flux density could be estimated with an acceptable level of accuracy, which was not the case if the usual 1D model was applied (collimated emission and no reflection).

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    Interrupted Curtius Rearrangements of Quaternary Proline Derivatives: A Flow Route to Acyclic Ketones and Unsaturated Pyrrolidines

    • Marcus Baumanna
    • Thomas S. Moodyb, c
    • Megan Smythb
    • Scott Wharryb
    • aSchool of Chemistry, University College Dublin, Science Centre South, Belfield D04 N2E2, Ireland
    • bDepartment of Technology, Almac Sciences, 20 Seagoe Industrial Estate, Craigavon BT63 5QD, United Kingdom
    • cArran Chemical Company, Roscommon N37 DN24, Ireland

    Conversion of N-Boc-protected quaternary proline derivatives under thermal Curtius rearrangement conditions was found to afford a series of ring-opened ketone and unsaturated pyrrolidine products instead of the expected carbamate species. The nature of the substituent on the quaternary carbon thereby governs the product outcome due to the stability of a postulated N-acyliminium species. A continuous flow process with in-line scavenging was furthermore developed to streamline this transformation and safely create products on a gram scale.

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    Flow electrochemistry: a safe tool for fluorine chemistry

    • Bethan Wintersona
    • Tim Rennigholtza
    • Thomas Wirtha
    • aSchool of Chemistry, Cardiff University, Park Place, Main Building, Cardiff, Cymru/Wales, UK

    The heightened activity of compounds containing fluorine, especially in the field of pharmaceuticals, provides major impetus for the development of new fluorination procedures. A scalable, versatile, and safe electrochemical fluorination protocol is conferred. The strategy proceeds through a transient (difluoroiodo)arene, generated by anodic oxidation of an iodoarene mediator. Even the isolation of iodine(III) difluorides was facile since electrolysis was performed in the absence of other reagents. A broad range of hypervalent iodine mediated reactions were achieved in high yields by coupling the electrolysis step with downstream reactions in flow, surpassing limitations of batch chemistry. (Difluoroiodo)arenes are toxic and suffer from chemical instability, so the uninterrupted generation and immediate use in flow is highly advantageous. High flow rates facilitated productivities of up to 834 mg h−1 with vastly reduced reaction times. Integration into a fully automated machine and in-line quenching was key in reducing the hazards surrounding the use of hydrofluoric acid.

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    Flow Electrosynthesis of Sulfoxides, Sulfones, and Sulfoximines without Supporting Electrolytes

    • Nasser Amri1 and Thomas Wirth1
    • 1School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, United Kingdom

    An efficient electrochemical flow process for the selective oxidation of sulfides to sulfoxides and sulfones and of sulfoxides to N-cyanosulfoximines has been developed. In total, 69 examples of sulfoxides, sulfones, and N-cyanosulfoximines have been synthesized in good to excellent yields and with high current efficiencies. The synthesis was assisted and facilitated through a supporting electrolyte-free, fully automated electrochemical protocol that highlights the advantages of flow electrolysis.

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    Discrete Ti−O−Ti Complexes: Visible-Light-Activated, Homogeneous Alternative to TiO2 Photosensitisers

    • Kira Behma
    • Dr. Eszter Fazekasa
    • Prof. Martin J. Patersona
    • Dr. Filipe Vilelaa
    • Dr. Ruaraidh D. McIntosha
    • aInstitute of Chemical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS UK

    A series of novel bimetallic TiIV amine bis(phenolate) complexes was synthesised and fully characterised. X-ray crystallography studies revealed distorted octahedral geometries around the Ti centres with single or double oxo-bridges connecting the two metals. These robust, air- and moisture-stable complexes were employed as photosensitisers generating singlet oxygen following irradiation with visible light (420 nm) LED module in a commercial flow reactor. All five complexes showed high activity in the photo-oxygenation of α-terpinene and achieved complete conversion to ascaridole in four hours at ambient temperature. The excellent selectivity of these photosensitisers towards ascaridole (vs. transformation to p-cymene) was demonstrated with control experiments using a traditional TiO2 catalyst. Further comparative studies employing the free pro-ligands as well as a monometallic analogue highlighted the importance of the ‘TiO2-like’ moiety in the polymetallic catalysts. Computational studies were used to determine the nature of the ligand to metal charge transfer (LMCT) states and singlet–triplet gaps for each complex, the calculated trends in the UV-vis absorption spectra across the series agreed well with the experimental results.

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    Stereospecific amination of mesylated cyclobutanol in continuous flow

    • Matthieu Tissota
    • Jérôme Jacqa
    • Patrick Pasaua
    • UCB Biopharma SPRL, Avenue de l’industrie, 1420 Braine l’Alleud, Belgiuma

    We report an amination of mesylated cyclobutanol enabled by a multistep continuous flow process. The flow sequence involved an azidation followed by a Staudinger reduction which avoids the handling and isolation of a hazardous alkyl azide compound. The process is stereospecific with the azidation step proceeding to complete stereochemical inversion.

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    Chemo-enzymatic oxidative cleavage of isosafrole for the synthesis of piperonal

    • Francesca Tentori*a
    • Elisabetta Brenna*a
    • Chiara Ferraria
    • Francesco G. Gattia
    • Maria Chiara Ghezzia
    • Fabio Parmeggiania
    • aDipartimento di Chimica, Materiali ed Ingegneria Chimica “Giulio Natta”, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133, Milano, Italy.

    Piperonal is a key ingredient of flavour and fragrance industry and a useful intermediate for the synthesis of fine chemicals. It is currently prepared by either ozonolysis or chromic acid oxidation of isosafrole, obtained upon isomerization of naturally abundant safrole. A chemo-enzymatic three-step procedure for the conversion of isosafrole into piperonal is herein described. Lipase-mediated perhydrolysis of EtOAc in the presence of H2O2 is employed to generate peracetic acid in situ and promote the epoxidation of isosafrole. The reaction mixture is submitted to methanolic KOH treatment to recover the corresponding mixture of vicinal diols. The latter is efficiently oxidized to piperonal using MnO2, periodically regenerated at the expense of tert-butylhydroperoxide (TBHP), which represents the terminal oxidant of this transformation. The use of continuous-flow conditions using a continuously-stirred tank reactor for the epoxidation, and a packed bed reactor for the final oxidation improves the productivity and stability of the whole method, with space-time yields of 75 mmol·g–1·h–1 and 120 mmol·g–1·h–1 , calculated as amount of generated product per catalyst amount per time.

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    Radical alpha-Trifluoromethoxylation of Ketones by Means of Organic Photoredox Catalysis

    Thibaut Duhail[a]†, Tommaso Bortolato[b]†, Javier Mateos[b], Elsa Anselmi[a,c], Benson Jelier[d], Antonio Togni[d], Emmanuel Magnier[a], Guillaume Dagousset[a], Luca Dell’Amico[b]

    • [a] Université Paris-Saclay, UVSQ, CNRS, UMR 8180, Institut Lavoisier de Versailles, 78035 Versailles Cedex (France)
    • [b]Department of Chemical Sciences, University of Padova, Via Marzolo 1, 35131, Padova (Italy)
    • [c] Université de Tours, Faculté des Sciences et Techniques, 37200 Tours (France)
    • [d]Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, ETH Zurich, Vladimir-Prelog-Weg 2, 8093 Zurich (Switzerland)

    The first light-driven method for the alpha-trifluoromethoxylation of ketones is reported. Enol carbonates, in particular Boc derivatives, react with N-trifluoromethoxy-4-cyano-pyridinium triflimide (2a) using the photoredox-catalyst 4-CzIPN (5 mol-%) under irradiation at 456 nm affording the corresponding α-trifluoromethoxy ketones in up to 50% isolated yield and virtually complete chemoselectivity. As shown by 35 examples, representing a great variety of substrates, the reaction is general and proceeds rapidly under batch (1h) and flow conditions (2 min). Mechanistic investigations reveal that a radical-chain propagation is operative, as efficiently orchestrated by the activity of the organic photoredox catalyst. Diverse products manipulations, including ketone reduction and reductive amination, demonstrate the synthetic potential of the disclosed method to accessing elusive trifluoromethoxylated potentially bioactive ingredients.

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    Rapid Optimization of Photoredox Reactions for Continuous-Flow Systems Using Microscale Batch Technology

    • María González-Esguevillasa
    • David F. Fernándeza
    • Juan A. Rincónb
    • Mario Barberisb
    • Oscar de Frutosb
    • Carlos Mateosb
    • Susana García-Cerradab
    • Javier Agejasb
    • David W. C. MacMillan*a
    • aMerck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States
    • bCentro de Investigación Eli Lilly, S. A., Avda. de la Industria 30, 28108 Alcobendas, Madrid, Spain

    Photoredox catalysis has emerged as a powerful and versatile platform for the synthesis of complex molecules. While photocatalysis is already broadly used in small-scale batch chemistry across the pharmaceutical sector, recent efforts have focused on performing these transformations in process chemistry due to the inherent challenges of batch photocatalysis on scale. However, translating optimized batch conditions to flow setups is challenging, and a general approach that is rapid, convenient, and inexpensive remains largely elusive. Herein, we report the development of a new approach that uses a microscale high-throughput experimentation (HTE) platform to identify optimal reaction conditions that can be directly translated to flow systems. A key design point is to simulate the flow-vessel pathway within a microscale reaction plate, which enables the rapid identification of optimal flow reaction conditions using only a small number of simultaneous experiments. This approach has been validated against a range of widely used photoredox reactions and, importantly, was found to translate accurately to several commercial flow reactors. We expect that the generality and operational efficiency of this new HTE approach to photocatalysis will allow rapid identification of numerous flow protocols for scale.

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    Microfluidic synthesis of CsPbBr3/Cs4PbBr6 nanocrystals for inkjet printing of mini-LEDs

    • Zhen Baoa,1
    • Jian-Wen Luob,1
    • Yu-Sin Wangc
    • Ting-Chou Huc
    • Sung-Yu Tsaic
    • Yi-Ting Tsaid
    • Huang-Chia Wangd
    • Fu-Hsin Chend
    • Yu-Chun Leed
    • Tzong-Liang Tsaid
    • Ren-Jei Chungb
    • Ru-Shi Liua,e
    • aDepartment of Chemistry, National Taiwan University, Taipei 106, Taiwan
    • bDepartment of Chemical Engineering and Biotechnology, National Taipei University of Technology, Taipei 106, Taiwan
    • cChina Glaze Co., Ltd., Hsinchu 310, Taiwan
    • dLextar Electronics Corporation, Hsinchu 300, Taiwan
    • eAdvanced Research Center of Green Materials Science and Technology, National Taiwan University, Taipei 106, Taiwan

    Zero-dimensional Cs4PbX6 (X = Cl, Br, I) perovskite material is recognized as a potential luminescent material and host owing to its excellent optical properties. However, the synthesis of large-scale CsPbBr3/Cs4PbBr6 complex nanocrystals (NCs) is difficult, and their application in mini- or micro-LEDs remains limited. Herein, we applied a microfluidic system for a simple, continuous, and stable synthesis of CsPbBr3/Cs4PbBr6 NCs. The CsPbBr3/Cs4PbBr6 complex NCs were obtained after the optimization of the Cs/Pb precursor ratio and alkaline environment, and their photoluminescent quantum yield is up to 86.9%. These as-synthesized CsPbBr3/Cs4PbBr6 NCs were used to produce a luminescent ink with the optimization of different solvents. This ink was successfully used to print large and high-resolution patterns, and fabricated mini-sized color-converted LED. The narrow green emission of the LED well obeyed the requirements of the Rec. 2020 standard, demonstrating the potential of this material in the inkjet printing applications of color-converted mini- or micro-LED arrays.

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    Decatungstate-mediated C(sp3 )‒H Heteroarylation via Radical Polar Crossover in Batch and Flow

    • Ting Wana
    • Luca Capaldoa
    • Gabriele Laudadioa
    • Alexander V. Nyuchevb
    • Juan A. Rincónc
    • Pablo García-Losadac
    • Carlos Mateosc
    • Michael O. Frederickd
    • Manuel Nuñoe
    • Timothy Noël*a
    • aFlow Chemistry Group, Van ’t Hoff Institute for Molecular Sciences(HIMS), University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands
    • bDepartment of Organic Chemistry, Lobachevsky State University of Nizhny Novgorod Gagarina Avenue 23, 603950, Nizhny Novgorod, Russia
    • cCentro de Investigación Lilly S.A. Avda. de la Industria 30, Alcobendas-Madrid 28108, Spain.
    • dSmall Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
    • eVapourtec Ltd., Park Farm Business Centre, Fornham St Genevieve, Bury St Edmunds, Suffolk IP28 6TS, United Kingdom.

    Photocatalytic hydrogen atom transfer is a very powerful strategy for the regioselective C(sp3)‒H functionalization of organic molecules. Herein, we report on the unprecedented combination of decatungstate hydrogen atom transfer photocatalysis with the oxidative Radical-Polar Crossover concept to access the direct netoxidative C(sp3)‒H heteroarylation. The present methodology demonstrates a high functional group tolerance (40 examples) and is scalable when using continuous-flow reactor technology. The developed protocol is also amenable to the late-stage functionalization of biologically relevant molecules such as stanozolol, (‒)-ambroxide, podophyllotoxin and dideoxyribose.

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    Highly Permeable Fluorinated Polymer Nanocomposites for Plasmonic Hydrogen Sensing

    • Ida Östergren1, Amir Masoud Pourrahimi1, Iwan Darmadi2, Robson da Silva1, Alicja Stolaś1, Sarah Lerch1, Barbara Berke2, Manuel Guizar-Sicairos3, Marianne Liebi2, Giacomo Foli4, Vincenzo Palermo4,5, Matteo Minelli6, Kasper Moth-Poulsen1, Christoph Langhammer2, and Christian Müller1
    • 1Department of Chemistry and Chemical Engineering, Chalmers University of Technology, Göteborg 412 96, Sweden
    • 2Department of Physics, Chalmers University of Technology, Göteborg 412 96, Sweden
    • 3Paul Scherrer Institut, Villigen PSI 5232, Switzerland
    • 4Institute of Organic Synthesis and Photoreactivity, National Research Council, Bologna 40129, Italy
    • 5Department of Industrial and Materials Science, Chalmers University of Technology, Göteborg 412 96, Sweden
    • 6Department of Civil, Chemical, Environmental and Materials Engineering, Alma Mater Studiorum—University of Bologna, Bologna 40131, Italy

    Hydrogen (H2) sensors that can be produced en masse with cost-effective manufacturing tools are critical for enabling safety in the emerging hydrogen economy. The use of melt-processed nanocomposites in this context would allow the combination of the advantages of plasmonic hydrogen detection with polymer technology; an approach which is held back by the slow diffusion of H2 through the polymer matrix. Here, we show that the use of an amorphous fluorinated polymer, compounded with colloidal Pd nanoparticles prepared by highly scalable continuous flow synthesis, results in nanocomposites that display a high H2 diffusion coefficient in the order of 10–5 cm2 s–1. As a result, plasmonic optical hydrogen detection with melt-pressed fluorinated polymer nanocomposites is no longer limited by the diffusion of the H2 analyte to the Pd nanoparticle transducer elements, despite a thickness of up to 100 μm, thereby enabling response times as short as 2.5 s at 100 mbar (≡10 vol. %) H2. Evidently, plasmonic sensors with a fast response time can be fabricated with thick, melt-processed nanocomposites, which paves the way for a new generation of robust H2 sensors.

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    Efficient Amino Donor Recycling in Amination Reactions: Development of a New Alanine Dehydrogenase in Continuous Flow and Dialysis Membrane Reactors

    • David Roura Padrosa1
    • Zoya Nisar2
    • Francesca Paradisi1,2
    • 1Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland
    • 2School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK

    Transaminases have arisen as one of the main biocatalysts for amine production but despite their many advantages, their stability is still a concern for widespread application. One of the reasons for their instability is the need to use an excess of the amino donor when trying to synthesise amines with unfavourable equilibria. To circumvent this, recycling systems for the amino donor, such as amino acid dehydrogenases or aldolases, have proved useful to push the equilibria while avoiding high amino donor concentrations. In this work, we report the use of a new alanine dehydrogenase from the halotolerant bacteria Halomonas elongata which exhibits excellent stability to different cosolvents, combined with the well characterised CbFDH as a recycling system of L-alanine for the amination of three model substrates with unfavourable equilibria. In a step forward, the amino donor recycling system has been co-immobilised and used in flow with success as well as re-used as a dialysis enclosed system for the amination of an aromatic aldehyde.

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    Iron-catalyzed [4 + 2] annulation of α,β-unsaturated ketoxime acetates with enaminones toward functionalized pyridines

    • Jindian Duan
    • Gaochen Xu
    • Binsen Rong
    • Huan Yan
    • Sai Zhang
    • Qinghuan Wu
    • Ning Zhu
    • Kai Guo
    • College of Biotechnology and Pharmaceutical Engineering, State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, 211816, China

    The iron-catalyzed [4 ​+ ​2] annulation of α,β-unsaturated ketoxime acetates with enaminones has been developed, providing efficient access to highly substituted pyridines in moderate to good yields. Notable features of the present strategy include low-cost catalytic system, simple and mild reaction condition and wide substrate scope. Mechanistic studies reveal that FeCl2 may directly serve as a Lewis acid to activate the α,β-unsaturated ketoxime acetates for the nucleophilic addition.

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    Enzyme-electrochemical continuous flow cascades synthesis of substituted benzimidazoles

    • Ting-Ting Shia,b
    • Shu-Zhan Wanga
    • Zhao Yangc
    • Yilin Wanga
    • Chengkou Liua
    • Wei He*a
    • Zheng Fang*a,d
    • Kai Guoad
    • aCollege of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, P. R. China.
    • bDepartment of Chemistry, Bengbu Medical College, 233030, P. R. China.
    • cSchool of Engineering, China Pharmaceutical University, No.639 Longmian Avenue, Nanjing 211198, China
    • dState Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing 211816, P. R. China.

    A green and efficient method for the synthesis of substituted benzimidazoles has been developed in a two-step continuous flow system. Enzyme-electrochemical cascade reactions between aromatic alcohols with o-phenylenediamines is reported. The reaction was performed under mild reaction conditions with air as “green” oxidant and oxidase as biocatalyst. Alcohols oxidation and substituted benzimidazoles formation were integrated into a single operation which is usually accomplished separately. The scale up experiment was completed successfully in continuous flow system which offers an industrially relevant, practical and efficient method.

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    A Practical Transferring Method from Batch to Flow Synthesis of Dipeptides via Acid Chloride Assisted by Simulation of the Reaction Rate

    • Masahiro Hosoya
    • *Go Shiino
    • Naoki Tsuno
    • API R&D Laboratory, CMC R&D Division, Shionogi and Co., Ltd., 1-3, Kuise Terajima 2-chome, Amagasaki, Hyogo 660-0813, Japan

    This paper proposes a technical approach for seamlessly setting the conditions of continuous flow synthesis from batch data. We directly detected the acid chloride formation from Fmoc-l-Phe-OH in batch using the in-line monitoring technology ReactIR and logically calculated the residence time under continuous flow conditions based on kinetic study. Assisted by this simulation method, the sequential flow operations, which consist of acid chloride formation from Fmoc-l-Phe-OH, cooling and coupling with Fmoc-l-Phe-Cl and H2N-l-Phe-OMe, were completed in approximately 1 min.

    Direct detection and quantification of acid chloride was performed by using ReactIR as an in-line monitoring tool. Based on kinetics calculated from the in-line monitoring results, the residence time for acid chloride formation under continuous flow conditions was set. A rapid flow synthesis of a dipeptide via acid chloride was guided by optimized batch conditions.

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    Synthesis of the Lipophilic Amine Tail of Abediterol Enabled by Multiphase Flow Transformations

    • Jorge García-Lacuna1
    • Tobias Fleiß1,2
    • Rachel Munday3
    • Kevin Leslie3
    • Anne O’Kearney-McMullan3
    • Christopher A. Hone*1,2
    • C. Oliver Kappe*1,2
    • 1Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, A-8010 Graz, Austria
    • 2Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
    • 3Chemical Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, United Kingdom

    The development of a continuous-flow sequence for the synthesis of an important drug candidate precursor is reported. Abediterol is a β2-adrenoceptor agonist that has undergone phase IIa clinical trials for the treatment of respiratory disease. A flow sequence is developed for the preparation of the lipophilic amine tail portion of abediterol. The sequence comprises of a phase-transfer-catalyzed liquid/liquid O-alkylation, a rhodium-catalyzed hydroformylation, and a ruthenium-catalyzed reductive amination. The reactions were optimized separately within continuous-flow environments to identify important parameter effects. The strongly basic O-alkylation operates with greater than 90% conversion within a 23 min residence time. The hydroformylation uses 1 mol % Rh(acac)(CO)2 (acac = acetylacetone) as a catalyst and 6 mol % Xantphos as a ligand with 1.1 equiv of hydrogen and carbon monoxide. The optimized O-alkylation and hydroformylation telescoped flow process was successfully operated over 6 h. The protocol is shown to be high yielding for the desired linear aldehyde (75% gas chromatography yield, ∼2.5 g/h). The sequence requires a solvent switch prior to the reductive amination. The final step is a high-pressure (40 bar) and high-temperature (150 °C) Ru-catalyzed reductive amination using ammonia and hydrogen to afford the amine tail. The solution yield for the formation of the amine tail was 78%. The yield of the reductive amination with an unoptimized isolation was 50%, resulting in an overall isolated yield for the three-step sequence of 38%. This compares favorably against the batch yield of 26% using a different synthetic route.

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    The CO2 photoconversion over reduced graphene oxide based on Ag/TiO2 photocatalyst in an advanced meso-scale continuous-flow photochemical reactor

    • Samar Nabil1
    • Ahmed S. Hammad2
    • Haitham M. El-Bery3
    • Elsayed A. Shalaby1
    • Ahmed H. El-Shazly4,5
    • 1Department of Environmental Studies, Institute of Graduate Studies and Research, Alexandria University, Alexandria, 21526, Egypt
    • 2Chemical Engineering Department, Faculty of Engineering, Port Said University, Port Said, Egypt
    • 3Advanced Functional Materials Laboratory, Chemistry Department, Faculty of Science, Assiut University, Assiut, 71515, Egypt
    • 4Chemical and Petrochemicals Engineering Department, Egypt-Japan University of Science and Technology, Alexandria, 21934, Egypt
    • 5Chemical Engineering Department, Faculty of Engineering, Alexandria University, Alexandria, 21544, Egypt

    This study aims at examining the use of an advanced meso-scale continuous-flow photochemical reactor for the photocatalytic conversion of CO2 with water into fuel over TiO2 (P25), Ag/TiO2, and Ag/TiO2/RGO catalysts. The silver loaded photocatalysts were prepared by one-step process via hydrothermal method. The prepared photocatalysts were characterized by various characterization techniques in order to identify the morphological, chemical, physical, and optical properties. The photocatalytic activity of the as-prepared catalysts was firstly examined by the photoelectrochemical (PEC) measurements and secondly by the photocatalytic reduction of CO2 in the proposed setup. Liquid products were analyzed using gas chromatography-mass spectrometry (GC-MS) and total organic carbon (TOC) techniques. It was found that the ternary composite revealed an outstanding performance towards CO2 photocatalytic reduction, where its selectivity was directed towards methanol production. The incorporation of graphene nanosheets enhanced the photocatalytic reduction of CO2 by 3.3 and 9.4 times compared with Ag/TiO2 and bare TiO2, respectively, using the proposed photochemical reactor in a continuous mode. This study sheds the light on a novel type of a photocatalytic reactor where CO2 conversion over Ag/TiO2/RGO ternary composite was evaluated.

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    Entropy-driven binding of gut bacterial β-glucuronidase inhibitors ameliorates irinotecan-induced toxicity

    • Hsien-Ya Lin1,2,7
    • Chia-Yu Chen1,2,7
    • Ting-Chien Lin1,2,7
    • Lun-Fu Yeh1
    • Wei-Che Hsieh1
    • Shijay Gao1
    • Pierre-Alain Burnouf3
    • Bing-Mae Chen3
    • Tung-Ju Hsieh1
    • Punsaldulam Dashnyam1
    • Yen-Hsi Kuo1
    • Zhijay Tu1
    • Steve R. Roffler3,4
    • Chun-Hung Lin1,2,5,6
    • 1Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
    • 2Department of Chemistry, National Taiwan University, Taipei, Taiwan
    • 3Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
    • 4Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
    • 5Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan
    • 6The Genomics Research Center, Academia Sinica, Taipei, Taiwan
    • 7These authors contributed equally

    Irinotecan inhibits cell proliferation and thus is used for the primary treatment of colorectal cancer. Metabolism of irinotecan involves incorporation of β-glucuronic acid to facilitate excretion. During transit of the glucuronidated product through the gastrointestinal tract, an induced upregulation of gut microbial β-glucuronidase (GUS) activity may cause severe diarrhea and thus force many patients to stop treatment. We herein report the development of uronic isofagomine (UIFG) derivatives that act as general, potent inhibitors of bacterial GUSs, especially those of Escherichia coli and Clostridium perfringens. The best inhibitor, C6-nonyl UIFG, is 23,300-fold more selective for E. coli GUS than for human GUS (Ki = 0.0045 and 105 μM, respectively). Structural evidence indicated that the loss of coordinated water molecules, with the consequent increase in entropy, contributes to the high affinity and selectivity for bacterial GUSs. The inhibitors also effectively reduced irinotecan-induced diarrhea in mice without damaging intestinal epithelial cells.

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    Enantio-Complementary Continuous-Flow Synthesis of 2-Aminobutane Using Covalently Immobilized Transaminases

    • Christian M. Heckmanna
    • Beatriz Dominguezb
    • Francesca Paradisia,c
    • aSchool of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, United Kingdom
    • bJohnson Matthey, 28 Cambridge Science Park, Milton Road, Cambridge, CB4 0FP, United Kingdom
    • cDept. of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH-3012, Bern, Switzerland

    Chiral amines are a common feature of many active pharmaceutical ingredients. The synthesis of very small chiral amines is particularly challenging, even via biocatalytic routes, as the level of discrimination between similarly sized R-groups must be exceptional, yet their synthesis creates attractive building blocks that may then be used to prepare diverse compounds in further steps. Herein, the synthesis of one of the smallest chiral amines, 2-aminobutane, using transaminases, is being investigated. After screening a panel of mainly wild-type transaminases, two candidates were identified: an (S)-selective transaminase from Halomonas elongata (HEwT) and a precommercial (R)-selective transaminase from Johnson Matthey (*RTA-X43). Notably, a single strategic point mutation enhanced the enantioselectivity of HEwT from 45 to >99.5% ee. By covalently immobilizing these candidates, both enantiomers of 2-aminobutane were synthesized on a multigram scale, and the feasibility of isolation by distillation without the need for any solvents other than water was demonstrated. The atom economy of the process was calculated to be 56% and the E-factors (including waste generated during enzyme expression and immobilization) were 55 and 48 for the synthesis of (R)-2-aminobutane and (S)-2-aminobutane, respectively.

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    A Machine Learning‐Enabled Autonomous Flow Chemistry Platform for Process Optimization of Multiple Reaction Metrics

    • Dr. Mohammed I. Jeraala
    • Dr. Simon Sunga
    • Prof. Alexei A. Lapkina,b
    • aCambridge Centre for Advanced Research and Education in Singapore Ltd., 1 Create Way, CREATE Tower #05-05, 138602 Singapore
    • bDepartment of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, CB3 0AS UK

    Self‐optimization of chemical reactions using machine learning multi‐objective algorithms has the potential to significantly shorten overall process development time, providing users with valuable information about economic and environmental factors. Using the Thompson Sampling Efficient Multi‐Objective (TS‐EMO) algorithm, the self‐optimization flow chemistry system in this report demonstrates the ability to identify optimum reaction conditions and trade‐offs (Pareto fronts) between conflicting optimization objectives, such as yield, cost, space‐time yield, and E‐factor, in a data efficient manner. Advantageously, the robust system consists of exclusively commercially available equipment and a user‐friendly MATLAB graphical user interface, and was shown to autonomously run 131 experiments over 69 hours uninterrupted.

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    Enzymatic esterification of lauric acid to give monolaurin in a microreactor

    • Shanshan Miao
    • Xin Li
    • College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, P.R. China

    Monolaurin is a naturally occurring compound widely utilized in food and cosmetics. In this paper, we present a new method for the synthesis of monolaurin by esterification between lauric acid and glycerol catalyzed by Novozym® 435 using a microreactor. The conversion of lauric acid is 87.04% in 20min, compared with 70.54% via the batch approach in 5 h. Using an optimized solvent system consisting of t-BuOH/tert-amyl alcohol (1:1, v/v), the selectivity using the microreactor method is enhanced to 90.63% and the space–time yield of the process is 380.91 g/h/L. This newly devised method has the potential for application to other multiphase and enzymatic reactions.

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    A continuous flow synthesis of [1.1.1]propellane and bicyclo[1.1.1]pentane derivatives

    • Kian Donnelly
    • Marcus Baumann
    • School of Chemistry, University College Dublin, Science Centre South, Belfield, Ireland

    A continuous flow process to generate [1.1.1]propellane on demand is presented rendering solutions of [1.1.1]propellane that can directly be derivatised into various bicyclo[1.1.1]pentane (BCP) species. This was realised in throughputs up to 8.5 mmol h−1 providing an attractive and straightforward access to gram quantities of selected BCP building blocks. Lastly, a continuous photochemical transformation of [1.1.1]propellane into valuable BCPs bearing mixed ester/acyl chloride moieties was developed.

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    A Process for Making Brominating Agents in Flow

    Inventors:, Dermaut, Wim (Mortsel, BE), Cappuyns, Bart (Mortsel, BE), Moens, Matthias (Mortsel, BE), Stevens, Christian (Mortsel, BE)

    • Assignee:
    • AGFA NV
    • UNIVERSITEIT GENT

    A process for making a brominating agent includes the step of continuously feeding a bromide source and an oxidizing agent into a continuous flow reactor.

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    Dimethyl Fumarate: Heterogeneous Catalysis for the Development of an Innovative Flow Synthesis

    • Fabiana Dedè1
    • Oreste Piccolo2
    • Daniele Vigo1
    • 1Cambrex Profarmaco Milano S.r.l., via Curiel 34, 20067 Milan, Paullo, Italy
    • 2Studio di Consulenza scientifica, via Bornò 5, 23896 Lecco, Sirtori, Italy

    The present work describes the development of an improved synthesis of the active pharmaceutical ingredient (API) dimethyl fumarate. The use of continuous flow technology and the newly developed methylation conditions solve some of the issues of previous commercial production strategies, e.g., reaching complete conversion and avoiding the formation of toxic impurities. The optimization was carried out using the design of experiment approach and afforded a very efficient, sustainable process, suitable for the industrial application.

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    Flow Biocatalysis 101: design, development and applications

    • Ana I. Benítez-Mateos
    • Martina Letizia Contente
    • David Roura Padrosa
    • Francesca Paradisi
    • Department of Chemistry and Biochemistry University of Bern, Freiestrasse 3, Bern (Switzerland)

    The integration of enzyme-catalyzed reactions in flow systems has been boosted during the last few years. Flow chemistry has been proposed in modern synthetic chemistry as a technology for process intensification. On the other hand, biocatalysis is officially recognized as a tool to increase reaction specificity and sustainability, however applications are sometimes characterized by low productivity. A logical step to improve the performance of biocatalytic reactions is represented by the combination of enzymes and flow facilities. This tutorial review aims at introducing the key concepts of flow biocatalysis, guiding the reader through its advantages and highlighting the current trends in the field to encourage innovative applications of enzymes in flow reactors.

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    Coupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and β-amino acid derivatives

    • Alexander Leslie1
    • Thomas S. Moody2,3
    • Megan Smyth2
    • Scott Wharry2
    • Marcus Baumann1
    • 1School of Chemistry, University College Dublin, D04 N2E2, Ireland
    • 2Almac Group Ltd., Craigavon BT63 5QD, United Kingdom
    • 3Arran Chemical Company, Athlone, Co. Roscommon N37 DN24, Ireland

    A continuous flow process is presented that couples a Curtius rearrangement step with a biocatalytic impurity tagging strategy to produce a series of valuable Cbz-carbamate products. Immobilized CALB was exploited as a robust hydrolase to transform residual benzyl alcohol into easily separable benzyl butyrate. The resulting telescoped flow process was effectively applied across a series of acid substrates rendering the desired carbamate structures in high yield and purity. The derivatization of these products via complementary flow-based Michael addition reactions furthermore demonstrated the creation of β-amino acid species. This strategy thus highlights the applicability of this work towards the creation of important chemical building blocks for the pharmaceutical and speciality chemical industries.

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    Development of a Continuous Photochemical Benzyne-Forming Process

    • Cormac Brackena
    • Andrei S. Batsanovb
    • Marcus Baumanna
    • aSchool of Chemistry, University College Dublin, Science Centre South, D04 N2E2, Dublin, Ireland
    • bDepartment of Chemistry, University of Durham, South Road, DH1 3LE, Durham, UK

    A continuous-flow process is presented that enables the safe generation and derivatization of benzyne under photochemical conditions. This is facilitated by a new high-power LED lamp emitting light at 365 nm. The resulting flow process effectively controls the release of gaseous by-products based on an adjustable backpressure regulator and delivers a series of heterocyclic products in a short residence time of 3 minutes. The robustness of this methodology is demonstrated for the rapid generation of benzotriazoles, 2H-indazoles and various furan-derived adducts, facilitating the preparation of these important heterocyclic scaffolds via a simple and readily scalable flow protocol.

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    Photocatalytic (Het)arylation of C(sp3)–H Bonds with Carbon Nitride

    • Saikat Dasa
    • Kathiravan Murugesana
    • Gonzalo J. Villegas Rodrígueza
    • Jaspreet Kaura
    • Joshua. P. Barhama
    • Aleksandr Savateevb
    • Markus Antoniettib
    • Burkhard Königa
    • aFakultät für Chemie und Pharmazie, Universität Regensburg, 93040 Regensburg, Germany
    • bDepartment of Colloid Chemistry, Max-Planck Institute of Colloids and Interfaces, Research Campus Golm, 14424 Potsdam, Germany

    Graphitic carbon nitride materials have attracted significant interest in recent years and found applications in diverse light-to-energy conversions such as artificial photosynthesis, CO2 reduction, or degradation of organic pollutants. However, their utilization in synthetic photocatalysis, especially in the direct functionalization of C(sp3)–H bonds, remains underexplored. Herein, we report mesoporous graphitic carbon nitride (mpg-CN) as a heterogeneous organic semiconductor photocatalyst for direct arylation of C(sp3)–H bonds in combination with nickel catalysis. Our protocol has a broad synthetic scope (>70 examples including late-stage functionalization of drugs and agrochemicals), is operationally simple, and shows high chemo- and regioselectivities. Facile separation and recycling of the mpg-CN catalyst in combination with its low preparation cost, innate photochemical stability, and low toxicity are beneficial features overcoming typical shortcomings of homogeneous photocatalysis. Detailed mechanistic investigations and kinetic studies indicate that an unprecedented energy-transfer process (EnT) from the organic semiconductor to the nickel complex is operating.

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    The rise of continuous flow biocatalysis – fundamentals, very recent developments and future perspectives

    • Piera De Santisa
    • Lars-Erik Meyera
    • Selin Karaa
    • aAarhus University, Department of Engineering, Biological and Chemical Engineering Section, Biocatalysis and Bioprocessing Group, Gustav Wieds Vej 10, DK 8000 Aarhus, Denmark

    Biocatalysis community has witnessed a drastic increase in the number of studies for the use of enzymes in continuously operated flow reactors. This significant interest arose from the possibility of combining the strengths of the two worlds: enhanced mass transfer and resource efficient synthesis achieved in flow chemistry at micro-scales and excellent selectivities obtained in biocatalysis. Within this review, we present very recent (from 2018 to September 2020) developments in the field of biocatalysis in continuously operated systems. Briefly, we describe the fundamentals of continuously operated reactors with a special focus on enzyme-catalyzed reactions. We devoted special attention on future perspectives in this key emerging technological area ranging from process analytical technologies to digitalization.

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    Corymbia citriodora: A Valuable Resource from Australian Flora for the Production of Fragrances, Repellents, and Bioactive Compounds

    • Tyler Goodinea
    • Michael Oelgemöllera,b
    • aJames Cook University, College of Science and Engineering, 1 James Cook Drive, 4811 Townsville, Queensland, Australia
    • bGhent University, Department of Organic and Macromolecular Chemistry, Krijgslaan 281 S4, 9000 Gent, Belgium

    As global chemical manufacturing has historically relied on inexpensive feedstocks from the petrochemical industry, the identification of new naturally derived feedstocks represents an important and sustainable alternative. This review introduces Corymbia citriodora (Hook.) K.D.Hill & L.A.S.Johnson as an attractive renewable resource of natural compounds for organic chemical transformations. Although native to Australia, this plant species is now grown and harvested worldwide. The chemical composition of citriodora oils varies with location, harvesting season and age of leaves. Beyond their historic uses as fragrances or repellents, the more abundant terpenes found in citriodora oils such as citronellal, citronellol, and isopulegol have notable roles in the manufacture of fine chemicals. This review highlights several industrial processes intimately related to the citriodora terpenes, some advances in fragrances and repellents, as well as the use of these terpenes in the most recently reported synthesis of bioactive compounds. Where relevant, processes highlighting the adoption of green chemistry principles are presented and briefly discussed.

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    Combining Radial and Continuous Flow Synthesis to Optimize and Scale-up the Production of Medicines

    • Mara Guidia,b
    • Sooyeon Moona,b
    • Lucia Anghileria,b
    • Dario Cambiéa
    • Peter H. Seeberger*a,b
    • Kerry Gilmore*a,c
    • aDepartment of Biomolecular Systems Max Planck Institute of Colloids and Interfaces Am Mühlenberg 1, 14476 Potsdam (Germany)
    • bDepartment of Chemistry and Biochemistry Freie Universität Berlin Arnimallee 22, 14195 Berlin (Germany)
    • cUniversity of Connecticut, Storrs, CT 06269 (United States)

    Current drug production in batch cannot adapt rapidly to market demands, evidenced by recent shortages in many markets globally of essential medicines. Flow chemistry is a valuable tool for on-demand production of active pharmaceutical ingredients (APIs). Here, we reveal a new concept to develop and produce APIs, where an automated synthesizer that works with discrete volumes of solutions is employed at the discovery stage to identify the optimal synthetic route and conditions before a commercially available continuous flow system is used for scale-up. This concept is illustrated by the synthesis of nifedipine and paracetamol, in short supply in Germany during the COVID-19 pandemic, and the local anesthetic lidocaine.

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    Additive manufacturing of intricate and inherently photocatalytic flow reactor components

    • Adilet Zhakeyeva,b
    • Mary C.Jonesb
    • Christopher G.Thomsonb
    • John M.Tobinc
    • Huizhi Wangd
    • Filipe Vilelab
    • Jin Xuana
    • aDepartment of Chemical Engineering, Loughborough University, Loughborough, LE11 3TU, UK
    • bSchool of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS, UK
    • cSchool of Chemistry, The University of Edinburgh, Edinburgh, EH9 3FJ, UK
    • dDepartment of Mechanical Engineering, Imperial College London, Exhibition Road, South Kensington Campus, London, SW7 2AZ, UK

    A 2,1,3-benzothiadiazole-based photosensitiser has been successfully incorporated into a commercially available 3D printing resin and utilised to fabricate inherently photocatalytic flow reactor components. The freedom of design provided by additive manufacturing enabled the production of photoactive monolith structures with intricate architectures, imparting functionality for heterogeneous photocatalysis and interesting manipulation of fluid dynamics within a fixed bed reactor column. The resultant monoliths were applied and validated in the photosensitisation of singlet oxygen in aqueous media, under continuous flow conditions and visible light irradiation (420 nm). The photo-generated singlet oxygen cleanly converted furoic acid to the γ-lactone, 5-hydroxy-5H-furan-2-one, with a peak space-time yield of 2.34 mmol m-2 h-1 achieved using the Voronoi monolith.

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    Continuous Flow Synthesis and Antimicrobial Evaluation of NHC* Silver Carboxylate Derivatives of SBC3 in vitro and in vivo

    • Cillian O’Beirne†a
    • Magdalena E. Piatekb
    • Jen Fossenc
    • Helge Müller-Bunza
    • David R. Andesc
    • Kevin Kavanaghb
    • Siddappa A. Patild
    • Marcus Baumanna
    • Matthias Tacke†a
    • aSchool of Chemistry, University College Dublin, Belfield, Stillorgan, Dublin 4, Republic of Ireland
    • bSSPC Pharma Research Centre, Department of Biology, Maynooth University, Maynooth, W23F2H6, Co. Kildare, Republic of Ireland
    • cJ. Fossen, Prof. D. R. Andes, Department of Medicine, 600 Highland Avenue, University of Wisconsin, Madison, USA
    • dCentre for Nano and Material Sciences, Jain University, Bangalore, Karnataka, India

    N-Heterocyclic silver carbene compounds have been extensively studied and shown to be active agents against a host of pathogenic bacteria and fungi. By incorporating hypothesised virulence targeting substituents into NHC-silver systems via salt metathesis, an atom efficient complexation process can used to develop new complexes to target the passive and active systems of a microbial cell. The incorporation of fatty acids and an FtsZ inhibitor have been achieved, and creation of both the intermediate salt and subsequent silver complex has been streamlined into a continuous flow process. Biological evaluation was conducted with in vitro toxicology assays showing these novel complexes had excellent inhibition against Gram-negative strains E. coli, P. aeruginosa and K. pneumonia; further studies also confirmed the ability to inhibit biofilm formation in Methicillin-resistant S. aureus and C. Parapsilosis. In vivo testing using a murine thigh infection model showed promising inhibition of MRSA for the lead compound SBC3, which is derived from 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene(NHC*).

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    γ-Amino phosphonates via the photocatalytic α-C–H alkylation of primary amines

    • James D. Grayson
    • Alexander J. Cresswell
    • Department of Chemistry, University of Bath, 1 South, Claverton Down, Bath, BA2 7AY, UK

    We report a simple photocatalytic protocol for the direct synthesis of γ-amino phosphonates via the α-C–H alkylation of unprotected, aliphatic primary amines with diethyl vinylphosphonate. These motifs are valuable bioisosteres of γ-amino acids and O-phosphorylated amino alcohols. Visible-light photoredox catalysis in combination with hydrogen atom transfer (HAT) catalysis is used to access the necessary α-amino radical intermediates for C–C bond formation. The procedure is also demonstrated on gram-scale in continuous flow for the synthesis of a racemic, protected derivative of the mGlu agonist 2-amino-4-phosphonobutyric acid (AP4).

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    Development and Proof of Concept for a Large-Scale Photoredox Additive-Free Minisci Reaction

    • Mark A. Graham*a
    • Gary Noonan*a
    • Janette H. Cherrymana
    • Miguel Gonzalezb
    • Lucinda V. Jacksona
    • Kevin Lesliea
    • Zhi-qing Liub
    • David McKinneya
    • Rachel H. Mundaya
    • Chris D. Parsonsc
    • David T. E. Whittakerc
    • En-xuan Zhangb
    • Jun-wang Zhangb
    • aChemical Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield SK10 2NA, U.K.
    • bAsymchem Laboratories (Tianjin) Co. Ltd., TEDA, Tianjin 300457, P. R. China
    • cEarly Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, Macclesfield SK10 2NA, U.K.

    New route development activities toward ceralasertib (AZD6738) have resulted in the discovery of an efficient, acid additive-free, photoredox Minisci reaction. Mechanistic understanding resulting from LED-NMR reaction profiling, quantum yield measurements, and Stern–Volmer quenching studies have enabled optimization of the catalyst system, resulting in a significant enhancement in the rate of reaction. A large-scale continuous photoflow process has been developed, providing encouraging proof-of-concept data for the future application of this technology in the clinical manufacture of ceralasertib.

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    Achieving selectivity in porphyrin bromination through a DoE-driven optimization under continuous flow conditions

    • Paolo Zardi
    • Michele Maggini
    • Tommaso Carofiglio
    • Dipartimento di Scienze Chimiche, Università degli Studi di Padova, Via Marzolo 1, 35131, Padova, Italy

    The post-functionalization of porphyrins through the bromination in β position of the pyrrolic rings is a relevant transformation because the resulting bromoderivatives are useful synthons to covalently link a variety of chemical architectures to a porphyrin ring. However, single bromination of porphyrins is a challenging reaction for the abundancy of reactive β-pyrrolic positions in the aromatic macrocycle. We herein report a synthetic procedure for the efficient preparation of 2-bromo-5,10,15,20-tetraphenylporphyrin (1) under continuous flow conditions. The use of flow technology allows to reach an accurate control over critical reaction parameters such as temperature and reaction time. Furthermore, by performing the optimization process through a statistical DoE (Design of Experiment) approach, these parameters could be properly adjusted with a limited number of experiments. This process led us to a better understanding of the relevant factors that govern porphyrins monobromination and to obtain compound 1 with an unprecedent 80% yield.

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    A scalable continuous photochemical process for the generation of aminopropylsulfones

    • Stefano Bonciolinia
    • Mara Di Filippoa
    • Marcus Baumanna
    • aSchool of Chemistry, University College Dublin, Science Centre South, Belfield, Ireland

    An efficient continuous photochemical process is presented that delivers a series of novel γ-aminopropylsulfones via a tetrabutylammonium decatungstate (TBADT) catalysed HAT-process. Crucial to this success is the exploitation of a new high-power LED emitting at 365 nm that was found to be superior to an alternative medium-pressure Hg lamp. The resulting flow process enabled the scale-up of this transformation reaching throughputs of 20 mmol h−1 at substrate concentrations up to 500 mM. Additionally, the substrate scope of this transformation was evaluated demonstrating the straightforward incorporation of different amine substituents as well as alkyl appendages next to the sulfone moiety. It is anticipated that this methodology will allow for further exploitations of these underrepresented γ-aminopropylsulfone scaffolds in the future.

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    Recent Advances in Continuous-Flow Reactions Using Metal-Free Homogeneous Catalysts

    • Naoto Sugisawa1,2
    • Hiroyuki Nakamura>1
    • Shinichiro Fuse3
    • 1Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama 226-8503, Japan
    • 2School of Life Science and Technology, Tokyo Institute of Technology, Yokohama 226-8501, Japan
    • 3Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya 464-8601, Japan

    Developments that result in high-yielding, low-cost, safe, scalable, and less-wasteful processes are the most important goals in synthetic organic chemistry. Continuous-flow reactions have garnered much attention due to many advantages over conventional batch reactions that include precise control of short reaction times and temperatures, low risk in handling dangerous compounds, and ease in scaling up synthesis. Combinations of continuous-flow reactions with homogeneous, metal-free catalysts further enhances advantages that include low-cost and ready availability, low toxicity, higher stability in air and water, and increased synthetic efficiency due to the avoidance of the time-consuming removal of toxic metal traces. This review summarizes recently reported continuous-flow reactions using metal-free homogeneous catalysts and classifies them either as acidic catalysts, basic catalysts, or miscellaneous catalysts. In addition, we compare the results between continuous-flow conditions and conventional batch conditions to reveal the advantages of using flow reactions with metal-free homogeneous catalysts.

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    Continuous Flow Photo-RAFT and Light-PISA

    • Jian Wanga,c
    • Xin Hub,c
    • Ning Zhua,c
    • Kai Guoc
    • aCollege of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, Jiangsu 211800, China
    • bCollege of Materials Science and Engineering, Nanjing Tech University, Nanjing, Jiangsu 211800, China
    • cState Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, Jiangsu 211800, China

    The combinations of microflow technology and photo-induced reversible-addition fragmentation chain transfer polymerization (photo-RAFT) and light-mediated polymerization-induced self-assembly (light-PISA) have enabled distinguished advantages that cannot be done in the traditional batch reactor. Recently, well-defined polymers with precise chemical and topological structures, and advanced nano-objects with high-order morphologies have been reported by using microreactor-based photo-RAFT and light-PISA strategies. In this mini-review, continuous flow photoiniferter polymerization, RAFT with photoinitiator, and PET-RAFT are summarized in order. Moreover, the emerging light-PISA in microflow is introduced, and finally, the remained challenges are proposed for the discussion of opportunities. We hope it would provide insights into flow chemistry, polymer precision synthesis, and nanoscience.

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    Tandem Continuous Flow Curtius Rearrangement and Subsequent Enzyme-Mediated Impurity Tagging

    • Marcus Baumann1
    • Alexander Leslie1
    • Thomas S. Moody2, 3
    • Megan Smyth*2
    • Scott Wharry2
    • 1School of Chemistry, Science Centre, University College Dublin, South Belfield, Dublin 4, Ireland
    • 2Almac Group Ltd., 20 Seagoe Industrial Estate, Craigavon BT63 5QD, United Kingdom
    • 3Arran Chemical Company, Unit 1 Monksland Industrial Estate, Athlone, Co. Roscommon N37 DN24, Ireland

    The use of continuous flow as an enabling technology within the fine chemical and pharmaceutical industries continues to gain momentum. The associated safety benefits with flow for handling of hazardous or highly reactive intermediates are often exploited to offer industrially relevant and scalable Curtius rearrangements. However, in many cases the Curtius rearrangement requires excess nucleophile for the reaction to proceed to high conversions. This can complicate work procedures to deliver high-purity products. However, tandem processing and coupling of the Curtius rearrangement with an immobilized enzyme can elegantly facilitate chemoselective tagging of the residual reagent, resulting in a facile purification process under continuous flow.

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    An open source toolkit for 3D printed fluidics

    Adam J. N. Price1, Andrew J. Capel2, Robert J. Lee1, Patrick Pradel3, Steven D. R. Christie1

    • 1School of Science, Loughborough University, Loughborough LE11 3TU, UK
    • 2School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough LE11 3TU, UK
    • 3Design School, Loughborough University, Loughborough LE11 3TU, UK

    As 3D printing technologies become more accessible, chemists are beginning to design and develop their own bespoke printable devices particularly applied to the field of flow chemistry. Designing functional flow components can often be a lengthy and laborious process requiring complex 3D modelling and multiple design iterations. In this work, we present an easy to follow design workflow for minimising the complexity of this design optimization process. The workflow follows the development of a 3D printable ‘toolkit’ of common fittings and connectors required for constructing basic flow chemistry configurations. The toolkit components consist of male threaded nuts, junction connectors and a Luer adapter. The files have themselves been made freely available and open source. The low cost associated with the toolkit may encourage educators to incorporate flow chemistry practical work into their syllabus such that students may be introduced to the principles of flow chemistry earlier on in their education and furthermore, may develop an early appreciation of the benefits of 3D printing in scientific research. In addition to the printable toolkit, the use of the 3D modelling platform – Rhino3D has been demonstrated for its application in fluidic reactor chip design modification. The simple user interface of the programme reduces the complexity and workload involved in printable fluidic reactor design.

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    Bicyclic Quinazolinone Derivatives

    Inventors:, Hert, Jerome (Basel, CH), Hunziker, Daniel (Basel, CH), Kuratli, Christoph (Basel, CH), Martin, Rainer E. (Basel, CH), Mattei, Patrizio (Basel, CH), Satz, Alexander Lee (Basel, CH)

    • Assignee: Hoffmann-La Roche Inc. (Little Falls, NJ, US)

    The invention provides novel compounds having the general formula (I) – Figure shown in link to paper

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    Characterization of reaction enthalpy and kinetics in a microscale flow platform.

    • Agnieszka Ladosz
    • Christina Kuhnle
    • Klavs F Jensen
    • Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA

    We report an isothermal flow calorimeter for characterization of reaction enthalpy and kinetics. The platform consists of a thermoelectric element and a glass-silicon microreactor to measure heat flux and an inline IR spectrometer to monitor reaction conversion. The thermally insulated assembly is calibrated with a thin film heater placed between the microreactor and the thermoelectric element. Without any reconfiguration of hardware, the setup can also be used to efficiently characterize reaction kinetics in transient flow experiments. We tested the calorimeter with hydrolysis of acetic anhydride as a model reaction. We determined the exothermic reaction enthalpy and the endothermic heat of mixing of the reagent to be -63 +/- 3.0 kJ/mol and +8.8 +/-2.1 kJ/mol respectively, in good agreement with literature values and theoretical predictions. Following calorimetry studies, we investigated reaction kinetics by applying carefully controlled residence time ramps at four different temperatures, and we obtained kinetic rate constants of 0.129 min-1 up to 0.522 min-1 for temperatures between 20°C to 56.3°C, also fitting well with data reported in literature.

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    Photochemical Flow Oximation of Alkanes

    • Oliver M. Griffithsa, b
    • Michele Ruggeria
    • Ian R. Baxendale∗a
    • aDepartment of Chemistry, University of Durham, South Road, Durham, Durham, DH1 3LE, UK
    • bDepartment of Chemistry, Cambridge University, South Road, Cambridge, Cambridgeshire, CB2 1EW, UK

    The nitrosation of several alkanes using tert-butyl nitrite has been performed in flow showing a remarkable reduction in the reaction time compared with batch processing. Due to the necessity for large excesses of the alkane component a continuous recycling process was devised for the preparation of larger quantities of material.

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    Development of a packed-bed flow process for the production scale hydrogenation of 7-oxo-lithocholic acid to ursodeoxycholic acid

    • Seung Jae Lee1, 2
    • Yashwardhan R. Malpani2
    • Il Won Kim1
    • 1Department of Chemical Engineering, Soongsil University, 369 Sangdo-ro, Dongjak-gu 06978 Seoul, Republic of Korea
    • 2API Synthesis Team, Daewoong-Bio, 29-Jeyakdanji-ro, Hyangnam-eup, Hwaseung-si, Gyeonggi-do 18608, Republic of Korea

    A continuous flow process for the synthesis of ursodeoxycholic acid (UDCA) from 7-oxo-lithocholic acid (7-oxo-LCA) through catalytic hydrogenation was developed from the lab scale to the final production scale. Various parameters, such as catalyst, solvent, base equivalence, feed flow rate, temperature, and pressure, were optimized under the flow conditions suitable for the final production in the pilot and production scale. Heterogeneous Raney-Ni catalyst was optimal in terms of conversion ratio and stereoselectivity when solvent and base equivalence were 2-propanol and > 1.5, respectively. It was employed under the packed-bed flow conditions with hydrogen gas. The scale-up was carried out up to 155 kg lot production scale. The developed process has an advantage over the widely used alkali metal reduction of 7-oxo-LCA to UDCA being more convenient and safer. Also, it produces UDCA with high stereoselectivity (> 23) and a fast production rate (> 4 kg/h). The synthesized product is suitable for the recrystallization to generate a high purity UDCA (> 99.5%) in a sufficient isolation yield (ca. 70%). Overall a production scale continuous process for UDCA was realized in a highly efficient manner.

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    A Vilsmeier Chloroformylation by Continuous Flow Chemistry

    • Manuel Carrera1
    • Laurens De Coen1
    • Michelle Coppens2
    • Wim Dermaut2
    • Christian V. Stevens2
    • 1Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Campus Coupure, Coupure Links 653, Gent B-9000, Belgium
    • 2Agfa-Gevaert NV, Septestraat 27, Mortsel B-2640, Belgium

    Chloroformylation reactions are versatile reactions that allow the introduction of a chlorine atom and an aldehyde group in enolizable ketones, employing the well-known Vilsmeier reagent. However, the use of this unstable reagent is usually associated with hazards, especially when it is used on an industrial scale. The present article describes the preparation and use of the Vilsmeier reagent under continuous flow conditions for the preparation of an important intermediate in the synthesis of cyanine dyes. In addition, the traditionally used dimethylformamide has been substituted with more desirable formamides, together with the removal of the halogenated solvent usually employed in the reaction. Consequently, the optimized conditions allow the continuous production of the target compound in a 79–81% isolated yield in a more environmentally friendly, fast, and secure manner.

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    Exploration of continuous flow benchtop NMR acquisition parameters and considerations for reaction monitoring

    • Tristan Maschmeyer
    • Paloma L. Prieto
    • Shad Grunert Jason E. Hein
    • Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada

    This study focused on fundamental data acquisition parameter selection for a benchtop nuclear magnetic resonance (NMR) system with continuous flow, applicable for reaction monitoring. The effect of flow rate on the mixing behaviors within a flow cell was observed, along with an exponential decay relationship between flow rate and the apparent spin–lattice relaxation time (T1*) of benzaldehyde. We also monitored sensitivity (as determined by signal‐to‐noise ratios; SNRs) under various flow rates, analyte concentrations, and temperatures of the analyte flask. Results suggest that a maximum SNR can be achieved with low to medium flow rates and higher analyte concentrations. This was consistent with data collected with parameters that promote either slow or fast data acquisition. We further consider the effect of these conditions on the analyte’s residence time, T1*, and magnetic field inhomogeneity that is a product of continuous flow. Altogether, our results demonstrate how fundamental acquisition parameters can be manipulated to achieve optimal data acquisition in continuous‐flow NMR systems.

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    Predicting performance of photochemical transformations for scaling up in different platforms by combining high-throughput experimentation with computational modeling

    • Melda Sezen-Edmonds1,‡,*
    • Jose E. Tabora1
    • Benjamin M. Cohen1
    • Serge Zaretsky1
    • Eric M. Simmons1
    • Trevor C. Sherwood2
    • Antonio Ramirez1
    • 1Chemical Process Development, Bristol Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States
    • 2Discovery Chemistry, Bristol Myers Squibb, Lawrenceville, New Jersey 08543, United States
    • These authors contributed equally to this work.

    Using light to drive a chemical transformation introduces challenges for ensuring the robust transferability of photochemical reactions across different platforms and scales. We demonstrate a modeling tool to predict the performance of a photochemical reaction as a function of reactor geometry, concentration of the photoactive species, irradiance of the light source, and the residence time. High throughput experimentation is utilized to optimize reaction conditions, and to determine kinetic parameters and quantum yield. Optical characterization of the photoactive reaction species and the reactor is performed to determine photon absorption rate. The experimental data is combined with computational modeling to predict photochemical conversion for different vial or flow reactors across multiple scales for a [2+2] photocycloaddition reaction and a photoredox-mediated decarboxylative intramolecular arene alkylation reaction. The method developed in this work facilitates the transferability of the photochemical processes between different photoreactors without the need for an intensive experimental optimization for each, and enables a robust and efficient scale-up.

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    Application of a Dual Catalytic Nickel/Iridium-Based Photoredox Reaction to Synthesize 2-Alkyl-N-Arylindoles in a Continuous Flow

    • Jasmin C. Wilson
    • Michael J. Boyd
    • Simon Giroux
    • Upul K. Bandarage*
    • Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, Massachusetts 02210, United States

    A versatile one-pot procedure for the preparation of 2-alkyl-substituted N-arylindoles is described. The method combines a visible light-mediated Ni/Ir-photoredox dual catalytic N-arylation of alkynyl anilines under continuous flow conditions with a subsequent base-mediated cyclization to afford the desired substituted indoles. The initial Ni/Ir photoredox-promoted N-arylation of alkynylanilines proceeds efficiently in a continuous flow to afford the desired products in moderate to excellent yields with a short residence time (20 min) and mild conditions at ambient temperature and without the exclusion of air. The methodology was amenable for a multi-gram scale-up to deliver 2-alkyl-N-arylindoles in high yields followed with only a single purification step.

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    Convenient Continuous Flow Synthesis of N-Methyl Secondary Amines from Alkyl Mesylates and Epoxides

    • Gary Mathieu
    • Heena Patel
    • Hélène Lebel
    • Department of Chemistry and Center in Green Chemistry and Catalysis (CGCC), Université de Montréal, P.O. Box 6128, Station, Downtown, Montréal, QC H3C 3J7, Canada

    The first continuous flow process was developed to synthesize N-methyl secondary amines from alkyl mesylates and epoxides via a nucleophilic substitution using aqueous methylamine. A variety of N-methyl secondary amines were produced in good to excellent yields, including a number of bioactive compounds, or their precursors. Up to 10.6 g (88% yield) of a N-methyl secondary amine was produced in 140 min process time. The amination procedure included an in-line workup, and the starting mesylate material was also produced in continuous flow from the corresponding alcohol. Finally, an in-line process combining the mesylate synthesis and nucleophilic substitution was developed.

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    Synthesis of metal-organic frameworks (MOFs) and its application in food packaging: A critical review

    • P.S.Sharanyakanth
    • R.Mahendran
    • Centre of Excellence in Nonthermal Processing, Indian Institute of Food Processing Technology (IIFPT), Pudukkottai Road, Thanjavur, India

    Background
    Food product safety, especially at the consumer level, is a major concern around the world. Maintaining product safety from processing to acceptable consumption level is very necessary to avoid the negative effect on human health. The addition of functional material such as Metal-organic frameworks (MOFs) into food packaging material creates a path to ensure product safety.

    Scope and approach
    The role of food packaging can be improvised with the help of other unique technology incorporation such as MOFs, with a group of functional materials possessing unique chemical and physical properties, significantly promising towards food safety due to its high surface area and porous structure. The current review deals with the application of MOF in food packaging, its different synthesis methods, toxicity, future perspectives, and potential purpose in food packaging.

    Key findings and conclusion
    MOFs act as active agents, especially in active food packaging, by improving shelf-life, quality, and maintaining the safety of packed foods. Incorporation of MOFs into packaging material in different forms supervised the progress in the field of food packaging to ensure product safety with the perspective of implementing novel solutions in the food supply chain. Antimicrobial properties, active molecule removal, and dishonestly labeled food products are some of the challenges faced in traditional food packaging; thus, the emergence of new materials such as MOFs can be a remedy to overcome these challenges. Properties such as good biocompatibility and non-reacting behavior with the host have made MOFs be an integral part of food packaging.

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    Flow chemistry as a tool to access novel chemical space for drug discovery

    • Enol Lópeza
    • María Lourdes Linaresb
    • Jesús Alcázarb
    • aFacultad de Ciencias y Tecnologías Químicas, Universidad de Castilla-La Mancha, Av. Camilo José Cela, 14, Ciudad Real, 13005, Spain
    • bJanssen Research & Development, Janssen-Cilag, S.A., Jarama, 75A, Toledo, 45007, Spain

    This perspective scrutinizes flow chemistry as a useful tool for medicinal chemists to expand the current chemical capabilities in drug discovery. This technology has demonstrated his value not only for the traditional reactions used in Pharma for the last 20 years, but also for bringing back to the lab underused chemistries to access novel chemical space. The combination with other technologies, such as photochemistry and electrochemistry, is opening new avenues for reactivity that will smoothen the access to complex molecules. The introduction of all these technologies in automated platforms will improve the productivity of medicinal chemistry labs reducing the cycle times to get novel and differentiated bioactive molecules, accelerating discovery cycle times.

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    Continuous flow synthesis of lipophilic cations derived from benzoic acid as new cytotoxic chemical entities in human head and neck carcinoma cell lines

    • Mabel Catalán,‡a
    • Vicente Castro-Castillo,‡§b
    • Javier Gajardo-de la Fuenteb
    • Jocelyn Aguilerac
    • Jorge Ferreiraa
    • Ricardo Ramires-Fernandezd
    • Ivonne Olmedoe
    • Alfredo Molina-Berríosc
    • Charlotte Palominosa
    • Marcelo Valenciaa
    • Marta Domínguezf
    • José A. Souto*f
    • José A. Jara*c
    • *Corresponding authors
    • aClinical and Molecular Pharmacology Program, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago, Chile
    • bDepartment of Organic and Physical Chemistry, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Santos Dumont 964, Santiago 8380494, Chile
    • cInstitute for Research in Dental Sciences (ICOD), Faculty of Dentistry, Universidad de Chile, Santiago, Chile
    • dDentistry School, Universidad Mayor, Santiago 8340585, Chile
    • ePhysiopathology Program, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
    • fDepartamento de Química Orgánica, Facultad de Química, CINBIO and IIS Galicia Sur, Universidade de Vigo, Vigo, Spain

    Continuous flow chemistry was used for the synthesis of a series of delocalized lipophilic triphenylphosphonium cations (DLCs) linked by means of an ester functional group to several hydroxylated benzoic acid derivatives and evaluated in terms of both reaction time and selectivity. The synthesized compounds showed cytotoxic activity and selectivity in head and neck tumor cell lines. The mechanism of action of the molecules involved a mitochondrial uncoupling effect and a decrease in both intracellular ATP production and apoptosis induction.

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    Antibody Conjugation Method

    Inventor: Spedaliere, Christopher J. (Allentown, PA, US)

    • Assignee: FUJIREBIO DIAGNOSTICS, INC. (MALVERN, PA, US)

    Provided herein are methods and materials for making antibody-polypeptide conjugates.

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    Novel Applications of α-Diazocarbonyl Compounds and Enabling Technologies in Stereoselective Synthesis

    Micol Santi

    • PhD Thesis, May 2020, Cardiff University

    α-Diazocarbonyl compounds are widely used in organic chemistry as versatile carbene precursors which enable concise synthesis towards complex asymmetric molecules. Due to their intrinsic highly energetic nature, flow technology can be applied to ensure safer, scalable and efficient protocols. Other modern enabling tools such as Design of Experiment (DoE) and online analysis, provide great advantages to achieve faster analysis and optimisations of chemical transformations.

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    Efficient Chemo-Enzymatic Flow Synthesis of High Value Amides and Esters

    • Francesca Annunziata1
    • Martina Letizia Contente2
    • Daniele Betti1
    • Cecilia Pinna1
    • Francesco Molinari3
    • Lucia Tamborini1*
    • Andrea Pinto3
    • 1Department of Pharmaceutical Sciences (DISFARM), University of Milan, via Mangiagalli 25, 20133 Milan, Italy
    • 2School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
    • 3 Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, via Celoria 2, 20133 Milan, Italy

    A flow-based chemo-enzymatic synthesis of selected APIs (i.e., butacaine, procaine and procainamide) has been developed. A bioreactor made of MsAcT, a versatile acyltransferase from Mycobacterium smegmatis, immobilised on glyoxyl–garose, was exploited to efficiently prepare amide and ester intermediates in gram scale. Immobilised MsAcT was employed in pure organic solvent, demonstrating high stability and reusability. In-line purification of the key intermediates using polymer-bound sulphonyl chloride was added after the bioreactor, enhancing the automation of the process. A final hydrogenation step using the H-Cube reactor was further carried out to obtain the selected APIs in excellent yields (>99%), making the process fast, safe and easily handled.

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    Continuous Flow Synthesis of Quinolines via a Scalable Tandem Photoisomerization-Cyclization Process

    • Mara Di Filippo
    • Marcus Baumann
    • School of Chemistry, University College Dublin, Science Centre South, Belfield, Dublin D04 N2E2, Ireland

    A continuous photochemical process is presented that renders a series of quinoline products via an alkene isomerization and cyclocondensation cascade. It is demonstrated that a high-power LED lamp generates the desired targets with higher productivity and efficiency than a medium-pressure Hg-lamp. The scope of this tandem process is established and allows for the generation of various substituted quinolines in high yields and with throughputs of greater than one gram per hour. Finally, this effective flow process is coupled with a telescoped hydrogenation reaction to render a series of tetrahydroquinolines including the antimalarial natural product galipinine.

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    Toward Secure Supply of Remdesivir via a 2-Pot Triazine Synthesis: Supply Centered Synthesis

    Dinesh J. Paymodea, Flavio S. P. Cardosoa, Joshua D. Siebera, John W. Tomlina, Daniel W. Cookb, Justina Burnsb, Rodger W. Stringhamb, B. Frank Guptona, David Sneada, Toolika Agrawala

    • aChemical Development, Medicines for All Institute, 737 N. 5th St., Box 980100, Richmond VA, 23298-0100
    • bAnalytical Development, Medicines for All Institute, 737 N. 5th St., Box 980100, Richmond VA, 23298-0100

    Pyrrolotriazine 1 is an important precursor to Remdesivir, and an efficient synthesis is disclosed. This route features atom economy and reduced derivatization of starting materials, by making use of highly abundant, commoditized raw material inputs. The yield of triazine was doubled from 31% to 59%, and the synthetic step count was reduced from 4 to 2. A one-pot cascade sequence was developed for direct cyanation of pyrrole. Amination and cyclization with formamidine acetate complete the synthesis. The problematic nature of typically dilute electrophilic aminations was solved with semi-continuous processing. Moreover, development of a continuous platform afforded access to the ideal yet non-commercial aminating reagent, monochloramine. These efforts help to secure the Remdesivir supply chain.

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    Process of Manufacturing Polyols

    Inventors: Raghuraman, Arjun (Pearland, TX, US) Heath, William H. (Lake Jackson, TX, US), Mukhopadhyay, Sukrit (Midland, MI, US), Spinney, Heather A. (Midland, MI, US), Wilson, David R. (Midland, MI, US), Gies, Anthony P. (Lake Jackson, TX, US), Paradkar, Manjiri R. (Lake Jackson, TX, US), Notestein, Justin M. (Evanston, IL, US), Nguyen, Sonbinh T. (Evanston, IL, US)

    • Assignees:
    • Dow Global Technologies LLC (Midland, MI, US)
    • Northwestern University (Evanston, IL, US)

    A method of producing a polyether polyol that includes reacting a low molecular weight initiator with one or more monomers in the presence of a polymerization catalyst, the low molecular weight initiator having a number average molecular weight of less than 1,000 g/mol and a nominal hydroxyl functionality at least 2, the one or more monomers including at least one selected from propylene oxide and butylene oxide, and the polymerization catalyst being a Lewis acid catalyst having the general formula M(R1)1(R2)1(R3)1(R4)0 or 1. Whereas, M is boron, aluminum, indium, bismuth or erbium, R1, R2, and R3 each includes a same fluoroalkyl-substituted phenyl group, and optional R4 includes a functional group or functional polymer group. The method further includes forming a polyether polyol having a number average molecular weight of greater than the number average molecular weight of the low molecular weight initiator in the presence of the Lewis acid catalyst.

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    Accelerating gas–liquid chemical reactions in flow

    • Suyong Hana
    • Marjan Alsadat Kashfipoura
    • Mahdi Ramezania
    • Milad Abolhasani*a
    • aDepartment of Chemical and Biomolecular Engineering, North Carolina State University, 911 Partners Way, Raleigh, NC, USA

    Over the past decade, continuous flow reactors have emerged as a powerful tool for accelerated fundamental and applied studies of gas–liquid reactions, offering facile gas delivery and process intensification. In particular, unique features of highly gas-permeable tubular membranes in flow reactors (i.e., tube-in-tube flow reactor configuration) have been exploited as (i) an efficient analytic tool for gas–liquid solubility and diffusivity measurements and (ii) reliable gas delivery/generation strategy, providing versatile adaptability for a wide range of gas–liquid processes. The tube-in-tube flow reactors have been successfully adopted for rapid exploration of a wide range of gas–liquid reactions (e.g., amination, carboxylation, carbonylation, hydrogenation, ethylenation, oxygenation) using gaseous species both as the reactant and the product, safely handling toxic and flammable gases or unstable intermediate compounds. In this highlight, we present an overview of recent developments in the utilization of such intensified flow reactors within modular flow chemistry platforms for different gas–liquid processes involving carbon dioxide, oxygen, and other gases. We provide a detailed step-by-step guideline for robust assembly and safe operation of tube-in-tube flow reactors. We also discuss the current challenges and potential future directions for further development and utilization of tubular membrane-based flow reactors for gas–liquid processes.

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    Manganese-Catalyzed Synthesis of Quaternary Peroxides: Application in Catalytic Deperoxidation and Rearrangement Reactions

    • Akash S. Ubale
    • Moreshwar B. Chaudhari
    • Moseen A. Shaikh
    • Boopathy Gnanaprakasam*
    • Department of Chemistry, Indian Institute of Science Education and Research, Pune-411008, India.

    Highly efficient, selective and direct C-H peroxidation of 9-substituted fluorenes has been achieved using Mn-2,2’-bipyridine-catalyst via radical-radical cross-coupling. Moreover, this method effectively promote the vicinal bis-peroxidation of sterically hindered various substituted arylidene-9H-fluorene/arylideneindolin-2-one derivatives to afford highly substituted bisperoxides with high selectivity over the oxidative cleavage of C=C bond that usually form ketone of aldehyde. Furthermore, a new approach for the synthesis of (Z)-6-benzylidene-6H-benzo[c]chromene has been achieved via an acid-catalyzed skeletal rearrangement of these peroxides. For the first time, unlike O-O bond cleavage, reductive C-O bond cleavage in peroxides using Pd-catalyst and H2 is described which enables the reversible reaction to afford exclusively deperoxidised products. A detailed mechanism for peroxidation, molecular rearrangement and deperoxidation has been proposed with preliminary experimental evidences.

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    Chemoenzymatic Synthesis of Arabinomannane (AM) Glycoconjugates as Potential Vaccines for Tuberculosis

    • Zhihao Lia
    • Teodora Bavarob
    • Sara Tengattinib
    • Roberta Bernardinic
    • Maurizio Matteic,d
    • Francesca Annunziatae
    • Richard B. Colea
    • Changping Zhenga
    • Matthieu Sollogouba
    • Lucia Tamborinie
    • Marco Terrenib
    • Yongmin Zhanga
    • aSorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire, UMR 8232, 4 Place Jussieu, 75005 Paris, France.
    • bDrug Sciences Department, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy.
    • cItaly Centro Servizi Interdipartimentale – STA, University of Rome “Tor Vergata”, Rome, Italy.
    • dDept. of Biology, University of Rome “Tor Vergata”, Rome, Italy.
    • eDepartment of Pharmaceutical Sciences, University of Milan, via Mangiagalli 25, 20133 Milan, Italy.

    Mycobacteria infection resulting in tuberculosis (TB) is one of the top ten leading causes of death worldwide in 2018, and lipoarabinomannan (LAM) has been confirmed to be the most important antigenic oligosaccharide on the TB cell surface. In this study, a convenient synthetic method has been developed for synthesizing three branched oligosaccharides derived from LAM, in which a core building block was prepared by enzymatic hydrolysis in flow chemistry with excellent yield. After a series of steps of glycosylations, the obtained oligosaccharides were conjugated with recombinant human serum albumin (rHSA) and the ex-vivo ELISA tests were performed using serum obtained from several TB-infected patients, in order to evaluate the affinity of the glycoconjugate products for the human LAM-antibodies. The evaluation results are positive, especially compound 21 that exhibited excellent activity which could be considered as a lead compound for the future development of a new glycoconjugated vaccine against TB.

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    Automation of Synthesis in Medicinal Chemistry: Progress and Challenges

    • Elizabeth Farrant*
    • New Path Molecular Research Ltd, Building 580, Babraham Research Campus, Cambridge CB22 3AT, UK.

    Since the 1990s, concerted attempts have been made to improve the efficiency of medicinal chemistry synthesis tasks using automation. Although impacts have been seen in some tasks, such as small array synthesis and reaction optimization, many synthesis tasks in medicinal chemistry are still manual. As it has been shown that synthesis technology has a large effect on the properties of the compounds being tested, this review looks at recent research in automation relevant to synthesis in medicinal chemistry. A common theme has been the integration of tasks, as well as the use of increased computing power to access complex automation platforms remotely and to improve synthesis planning software. However, there has been more limited progress in modular tools for the medicinal chemist with a focus on autonomy rather than automation.

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    Practical Considerations and Examples in Adapting Amidations to Continuous Flow Processing in Early Development

    • Bryan Li*
    • Gerald A. Weisenburger
    • J. Christopher McWilliams
    • Chemical Research & Development, Pharmaceutical Science Small Molecules Division, Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, United States

    Amidation is among the most frequently executed reactions in pharmaceutical research and development. We have explored the feasibility of adapting amidations to plug flow reactor (PFR) process conditions for the preparation of early development compounds. Among coupling reagents possessing good thermal stability, carbodiimides and T3P have been selected, as they are readily soluble, require no preactivation, offer excellent reaction kinetics, and enable convenient product isolation. A carbodiimide/2-hydroxylpyridine oxide (HOPO) protocol was demonstrated in four case studies with homogeneous feed and reaction streams that were readily adaptable to a PFR design. In a head-to-head comparison, T3P was also found to be readily adaptable to a PFR flow process and gave comparable yields. The EDC/HOPO method works well for amidations that do not involve substrates that are highly sensitive to racemization; its water compatibility makes it the reagent of choice when the amine reactant is in a salt form, since water can be added as a cosolvent to aid solubility. For substrates that are extremely sensitive to racemization, we have shown one successful example of peptide coupling using TBTU or COMU under PFR continuous flow conditions.

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    Two Colour Photoflow Chemistry for Macromolecular Design

    • Matthias Van De Walle
    • Kevin De Bruycker
    • James P. Blinco
    • Christopher Barner-Kowollik
    • Centre for Materials Science, School of Chemistry and Physics, Queensland University of Technology (QUT)2 George St., Brisbane, QLD 4000 (Australia)

    We report a photochemical flow setup that exploits λ‐orthogonal reactions using two different colours of light (λ1=350 nm and λ2=410 nm) in sequential on‐line irradiation steps. Critically, both photochemically reactive units (a visible‐light reactive chalcone and a UV‐activated photo‐caged diene) are present in the reaction mixture. We demonstrate the power of two colour photoflow by the wavelength‐selective end group modification of photo‐caged polymer end groups and the subsequent polymer ring closure driven by a [2+2] cycloaddition. Importantly, we evidence that the high energy gate does not induce the visible light reaction of the chalcone, which attests the true λ‐orthogonal nature of the flow reaction system. For the first time, this study opens the realm of photoflow reactions to λ‐orthogonal photochemistry.

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    Photocatalytic α‐Tertiary Amine Synthesis via C−H Alkylation of Unmasked Primary Amines

    • Alison S. H. Ryder1 William B. Cunningham2
    • George Ballantyne2
    • Tom Mules2
    • Anna G. Kinsella2
    • Jacob Turner-Dore2
    • Catherine M. Alder3
    • Lee J. Edwards3
    • Blandine S. J. McKay3
    • Matthew N. Grayson2
    • Alexander J. Cresswell2
    • 1Centre for Sustainable Chemical Technologies, University of Bath 1 South, Claverton Down, Bath, BA2 7AY (UK)
    • 2Department of Chemistry, University of Bath 1 South, Claverton Down, Bath, BA2 7AY (UK) E-Mail: a.j.cresswell@bath.ac.uk
    • 3Medicines Design, GSK Medicines Research Centre Gunnels Wood Rd, Stevenage, SG1 2NY (UK)

    Catalytic strategies for the α‐C−H functionalisation of primary amines are a major challenge in organic synthesis. A photocatalytic protocol for the α‐C−H alkylation of unprotected primary amines that is amenable to the direct synthesis of α‐tertiary primary amines is reported. This process is readily scalable in continuous flow to provide access to decagram quantities of valuable γ‐lactams and azaspirocycles, for application in drug discovery.

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    Lewis Acid Polymerization Catalyst

    Inventors: Raghuraman, Arjun (Pearland, TX, US), Heath, William H. (Lake Jackson, TX, US), Mukhopadhyay, Sukrit (Midland, MI, US), Spinney, Heather A. (Midland, MI, US), Wilson, David R. (Midland, MI, US)

    • Assignee: Dow Global Technologies LLC (Midland, MI, US)

    A Lewis acid polymerization catalyst has a general formula M(R1)1(R2)1(R3)1(R4)0 or 1, whereas M is boron, R1, R2, R3, and R4 are each independent, R1 is a 3,5-bis(trifluoromethyl)-substituted phenyl group, R2 is the 3,5-bis(trifluoromethyl) substituted phenyl group or a first fluoro-substituted phenyl group selected from Set 1 structures, R3 is independently a second fluoro-substituted phenyl group selected from the Set 1 structures, and optional R4 includes a third functional group or functional polymer group.

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    Automated Glycan Assembly of Plant Cell Wall Oligosaccharides

    • Fabian Pfrengle
    • Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany

    Synthetic cell wall oligosaccharides are promising molecular tools for investigating the structure and function of plant cell walls. Their well-defined structure and high purity prevents misinterpretations of experimental data, and the possibility to introduce chemical handles provides means for easier localization and detection. Automated glycan assembly as emerged has a powerful new method for the efficient preparation of oligosaccharide libraries. We recently made use of this technology to prepare a collection of plant cell wall glycans for cell wall research. In this chapter, detailed experimental procedures for the automated synthesis of oligosaccharides that are ready for use in biological assays are described.

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    Process of Manufacturing Surfactants and Lubricants

    Raghuraman, Arjun (Pearland, TX, US), Heath, William H. (Lake Jackson, TX, US), Hook, Bruce D. (Lake Jackson, TX, US), Yu, Wanglin (Pearland, TX, US), Mukhopadhyay, Sukrit (Midland, MI, US), Spinney, Heather A. (Midland, MI, US), Wilson, David R. (Midland, MI, US), Notestein, Justin M. (Evanston, IL, US), Nguyen, Sonbinh T. (Evanston, IL, US)

    • Dow Global Technologies LLC (Midland, MI, US)
    • Northwestern University (Evanston, IL, US)

    A method of producing an alcohol ethoxylate surfactant or lubricant includes reacting a low molecular weight initiator with ethylene oxide in the presence of a polymerization catalyst, the low molecular weight initiator having a nominal hydroxyl functionality at least 1, and the polymerization catalyst being a Lewis acid catalyst having the general formula M(R1)1(R2)1(R3)1(R4)0 or 1, whereas M is boron, aluminum, indium, bismuth or erbium, R1, R2 and R3 each includes a same fluoroalkyl-substituted phenyl group, and optional R4 includes a functional group or functional polymer group. R1, R2, and R3 are the same fluoroalkyl-substituted phenyl group. The method further includes forming the alcohol ethoxylate surfactant or lubricant having a number average molecular weight of greater than the number average molecular weight of the low molecular weight initiator in the presence of the Lewis acid catalyst.

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    Preparation of Diorganomagnesium Reagents by Halogen–Lithium Exchange of Functionalized Heteroaryl Halides and Subsequent in situ Trapping with MgCl2·LiCl in Continuous Flow

    • Rodolfo Hideki Vicente Nishimuraa
    • Niels Weidmannb
    • Paul Knochel∗b
    • aColegiado de Ciências Farmacêuticas, Universidade Federal do Vale do São Francisco, Avenue José de Sá Maniçoba, Petrolina, 56304-205 Petrolina, Brazil
    • bLudwig-Maximilians-Universität München, Department Chemie, Butenandtstraße 5–13, 81377 München, Germany

    A halogen–lithium exchange in the presence of MgCl2·LiCl on a broad range of heterocyclic scaffolds using a commercial flow set-up with nBuLi as exchange reagent is reported. The resulting diheteroarylmagnesium species were subsequently trapped with various electrophiles, such as ketones, aldehydes, allylic bromides, or disulfides affording functionalized heterocycles. A scale-up was performed by simply increasing the run-time without further optimizations.

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    C(sp3)–H functionalizations of light hydrocarbons using decatungstate photocatalysis in flow

    • Gabriele Laudadio1*
    • Yuchao Deng1,2,3,*
    • Klaas van der Wal1
    • Davide Ravelli4
    • Manuel Nuño5
    • Maurizio Fagnoni4
    • Duncan Guthrie5
    • Yuhan Sun2,3
    • Timothy Noël1,†
    • 1Micro Flow Chemistry and Synthetic Methodology, Department of Chemical Engineering and Chemistry, Eindhoven University of Technology, Eindhoven, Netherlands.
    • 2School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, P. R. China.
    • 3Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, P. R. China.
    • 4PhotoGreen Lab, Department of Chemistry, University of Pavia, Pavia 27100, Italy.
    • 5Vapourtec, Fornham St Genevieve, Bury St Edmunds, Suffolk IP28 6TS, UK.
    • Corresponding author. Email: t.noel@tue.nl
    • *These authors contributed equally to this work.

    Direct activation of gaseous hydrocarbons remains a major challenge for the chemistry community. Because of the intrinsic inertness of these compounds, harsh reaction conditions are typically required to enable C(sp3)–H bond cleavage, barring potential applications in synthetic organic chemistry. Here, we report a general and mild strategy to activate C(sp3)–H bonds in methane, ethane, propane, and isobutane through hydrogen atom transfer using inexpensive decatungstate as photocatalyst at room temperature. The corresponding carbon-centered radicals can be effectively trapped by a variety of Michael acceptors, leading to the corresponding hydroalkylated adducts in good isolated yields and high selectivity (38 examples).

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    Disposable cartridge concept for the on-demand synthesis of turbo Grignards, Knochel–Hauser amides, and magnesium alkoxides

    • Mateo Berton1
    • Kevin Sheehan2
    • Andrea Adamo2
    • D. Tyler McQuade1
    • 1Department of Chemical and Life Sciences Engineering, Virginia Commonwealth University, Biotech Eight, 737 N. 5th St., Box 980100, Richmond, VA 23219, USA
    • 2Zaiput Flow Technologies, 300 2nd Avenue, Waltham, MA 02451, USA

    Magnesium organometallic reagents occupy a central position in organic synthesis. The freshness of these compounds is the key for achieving a high conversion and reproducible results. Common methods for the synthesis of Grignard reagents from metallic magnesium present safety issues and exhibit a batch-to-batch variability. Tubular reactors of solid reagents combined with solution-phase reagents enable the continuous-flow preparation of organomagnesium reagents. The use of stratified packed-bed columns of magnesium metal and lithium chloride for the synthesis of highly concentrated turbo Grignards is reported. A low-cost pod-style synthesizer prototype, which incorporates single-use prepacked perfluorinated cartridges and bags of reagents for the automated on-demand lab-scale synthesis of carbon, nitrogen, and oxygen turbo magnesium bases is presented. This concept will provide access to fresh organomagnesium reagents on a discovery scale and will do so independent from the operator’s experience in flow and/or organometallic chemistry.

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    Flow Chemistry System for Carbohydrate Analysis by Rapid Labeling of Saccharides after Glycan Hydrolysis

    • Wei-Ting Hung1
    • Yi-Ting Chen1
    • Chung-Hsuan Chen1
    • Yuan Chuan Lee2
    • Jim-Min Fang1, 3
    • Wen-Bin Yang1
    • 1The Genomics Research Center, Academia Sinica, Taipei
    • 2Department of Biology, Johns Hopkins University, Baltimore, MD, USA
    • 3Department of Chemistry, National Taiwan University, Taipei

    This study demonstrates the utilization of a flow chemistry system for continuous glycan hydrolysis and saccharide labeling to assist with the existing methods in glycan structural analysis. Acidic hydrolysis of glycans could be accelerated in a flow system. Aldoses and α-ketoacid-type saccharides were effectively labeled with naphthalene-2,3-diamine (NADA) at 60 °C for 10 min to form the fluorescent naphthimidazole (NAIM) and quinoxalinone (QXO) derivatives, respectively. The NADA-labeled derivatives improved the structural determination and composition analysis for their parent saccharides by using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), liquid chromatography mass spectrometry (LC-MS), and nuclear magnetic resonance (NMR). Furthermore, this protocol was applied to determine the SA–Gal–Glc sequence of GM3-sugar out of six possible permutations.

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    Continuous-Flow Approach for the Multi-Gram Scale Synthesis of C2-Alkyl- or β-Amino Functionalized 1,3-Dicarbonyl Derivatives and Ondansetron Drug Using 1,3-Dicarbonyls

    • Nirmala Mohant
    • Krishna Nair
    • Dasharath Vishambar Sutar
    • Boopathy Gnanaprakasam*
    • Department of Chemistry, Indian Institute of Science Education and Research (IISER) Pune, Dr. Homi Bhabha Road, Pune 411008, Maharashtra, (India).

    Continuous-flow chemistry is a modern technology that encompasses the green chemistry principles for the multi-gram synthesis of various API and drugs. Herein, we have developed a highly efficient and environmentally benign metal-free alkylation of 1,3-dicarbonyl compounds using secondary alcohols in the presence of inexpensive Amberlyst®-15 under continuous-flow. This method is broad substrate scope with variety of secondary alcohols and water as a byproduct. The Amberlyst®-15 is recyclable and reusable for the alkylation reaction under batch/continuous-flow technology. Furthermore, a continuous-flow technology driven Mannich reaction is demonstrated under acid free condition. Besides, a continuous-flow Fischer indole strategy for the ondansetron with an improved yield is demonstrated. Additionally, all these reactions were demonstrated with multi-gram scale synthesis without lowering the yield under batch/continuous-flow technology.

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    Preparation of Mono- and Diisocyanates in Flow from Renewable Carboxylic Acids

    • Michael D. Burkar1
    • Thien An Phung Hai1
    • Laurent J. S. De Backer2
    • Nicholas D. P. Cosford2
    • 1Department of Chemistry and Biochemistry and The California Center for Algae Biotechnology, University of California, San Diego, La Jolla, California 92093-0358, United States
    • 2Cancer Metabolism & Signaling Networks Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, United States

    Diisocyanates used in polyurethanes are commonly prepared by phosgenation of petroleum-sourced diamines. This involves highly toxic phosgene and produces corrosive HCl, limiting synthetic applications. In our search for a renewable source for diisocyanates, we have developed a practical methodology for the production of isocyanates from algae-biomass-derived fatty acids or other renewable sources. This technique utilizes flow chemistry to prepare and convert high-energy intermediates, thus mitigating safety concerns. By the use of continuous flow, acyl azides are prepared from hydrazides and subsequently heated to undergo Curtius rearrangement, affording isocyanates in one scalable process. The method is efficient, safe, and sustainable, offers an opportunity to prepare isocyanates and diisocyanates from renewable feedstocks, and is amenable to distributed manufacturing processes.

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    Accelerating Electrochemical Synthesis through Automated Flow: Efficient Synthesis of Chalcogenophosphites

    • Nasser Amri
    • Thomas Wirth*
    • School of Chemistry, Cardiff University, Park Place, Cardiff, CF10 3AT, UK

    Integrated electrochemical reactors in automated flow systems have been utilised for chalcogenophosphite formations. Multiple electrochemical reactions can be performed using a programmed sequence in a fully autonomous way. Differently functionalised chalcogenophosphites have been efficiently synthesised in short reaction times.

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    Rearrangement of 3-Hydroxyazetidines into 2-Oxazolines

    • Ian R. Baxendale1
    • Michele Ruggeri1
    • Amanda W. Dombrowski2
    • Stevan W. Djuric3
    • 1Department of Chemistry, University of Durham, Durham DH1 3LE, United Kingdom
    • 2 Discovery Chemistry and Technology AbbVie Inc., North Chicago, Illinois 60064, United States
    • 3Discovery Chemistry and Technology Consulting LLC, New Bern, North Carolina 28562, United States

    A novel rearrangement sequence of 3-hydroxyazetidines via a Ritter initiated cascade provides highly substituted 2-oxazolines in high yields. The reaction conditions and substrate scope of the transformation have been studied demonstrating the generality of the process. The derived products can also be functionalized in order to undergo further intramolecular cyclization leading to a new class of macrocycle. The final cyclization step was shown to be a transformation amenable to continuous flow processing allowing for a dramatic reduction in the reaction time and simple scale-up.

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    Selective DIBAL‑H Monoreduction of a Diester Using Continuous Flow Chemistry: From Benchtop to Kilo Lab

    • Nick Uhlig1
    • Andrew Martins1
    • Detian Gao2
    • 1Process Development, Gilead Alberta ULC,Edmonton, Alberta T6S 1A1, Canada
    • 2Commercial API Process Optimization, Gilead Alberta ULC, Edmonton, Alberta T6S 1A1, Canada

    Herein we report a selective DIBAL-H-mediated reduction of a heterocyclic diester to the corresponding monoaldehyde using continuous flow chemistry. The use of continuous flow enabled operation at lower temperatures and better control of the reaction time, thereby allowing for a significant increase in reaction selectivity and yield compared with batch conditions. The reaction’s development as a continuous flow process and its scale-up from laboratory gram scale to multikilogram scale are discussed, including design of experiments studies to probe the optimal reaction window.

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    Flow Reactor Synthesis of Bio-Based Polyol from Soybean Oil for the Production of Rigid Polyurethane Foam

    • Kai Guo1
    • Zheng Fang2
    • Wei He2
    • Peng Kang3
    • Jingying Hao4
    • Hao Wu2
    • Yuchen Zhu5
    • 1College of Biotechnology and Pharmaceutical Engineering and State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing 211816, China
    • 2College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, China
    • 3SINOPEC Beijing Research Institute of Chemical Industry, Beijing 100013, China
    • 4The Research Institute of SINOPEC Co., Ltd, Tianjin Branch, Tianjin 10000, China
    • 5School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China

    In this study, a complex ring-opening agent including benzoic acid pentaerythritol ester bearing an aromatic group and pentaerythritol monolaurate bearing a pendant chain was applied in the ring-opening process. Bio-based polyols were obtained through epoxidation in the fixed-bed flow reactor and ring-opening reaction in the flask. Integration of flow chemistry and batch reaction promoted the production of bio-based polyols. The resulting rigid polyurethane foams (PUF) were characterized by scanning electron microscopy, thermogravimetry analysis, and dynamic thermomechanical analysis. Higher mechanical strength and lower thermal conductivity coefficient were obtained when the combination of aromatic alcohol and aliphatic alcohol was applied in the preparation of rigid PUF. Meanwhile, better dimensional stability and higher glass-transition temperature were detected in PUF-bio-3/7. A series of research results demonstrated that rigid PUF derived from this bio-based polyol displayed better properties compared with those of rigid PUF derived from commercially available petroleum-based polyether polyol 4110.

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    Bicyclic quinazolinone derivatives

    Inventors: Jerome HertDaniel, HunzikerChristoph Kuratli, Rainer E. Martin, Patrizio Mattei, Alexander Lee Satz

    • Assignee: Hoffmann La Roche Inc

    The invention provides novel compounds having the general formula (I)

    wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, A1, A2, A3, n and m are as described herein.

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    Ir/Ni Photoredox Dual Catalysis with Heterogeneous Base Enabled by an Oscillatory Plug Flow Photoreactor

    • Wouter Debrouwer,a*
    • Wim Kimpea
    • Ruben Dangreau,a
    • Kevin Huvaere,a
    • Hannes P.L. Gemoets,b
    • Milad Mottaghi,c
    • Simon Kuhn,c
    • Koen Van Akenab
    • aEcoSynth, Industrielaan 12, 9800 Deinze, Belgium
    • bCreaflow, Industrielaan 12, 9800 Deinze, Belgium
    • c Department of Chemical Engineering, KU Leuven, Celestijnenlaan 200F, 3001, Leuven, Belgium

    Continuous flow reactor technology has a proven track record in enabling photochemical transformations. However, transfer of a photochemical batch process to a flow protocol often remains elusive, especially when solid reagents or catalysts are employed. In this work, application of an oscillatory plug flow photoreactor enabled a heterogeneous MacMillan-type C(sp²) – C(sp³) cross-electrophile coupling. Combination of an oscillatory flow regime with static mixing elements imparts exquisite control over mixing intensity and residence time distribution (RTD), pinpointing a mindset shift concerning slurry handling in continuous flow reactors. The C(sp²) – C(sp³) cross-electrophile coupling was successfully transferred from batch to flow, resulting in an intensified slurry process with significantly reduced reaction time and increased productivity (0.87 g/h).

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    Visible Light Mediated N-Desulfonylation of N-Heterocycles using a Heteroleptic Copper (I) Complex as a Photocatalyst

    • Cameron J. Hunter
    • Michael J. Boyd
    • Gregory D. May
    • Robert Fimognari*
    • Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, Massachusetts 02210, United States

    A photoredox protocol that uses a heteroleptic Cu (I) complex [Cu(dq)(BINAP)]BF4 has been developed for the photodeprotection of benzenesulfonyl protected N-heterocycles. A range of substrates were examined, including indazoles, indoles, pyrazoles, and benzimidazole, featuring both electron-rich and electron-deficient substituents, giving good yields of the N-heterocycle products with broad functional group tolerance. This transformation was also found to be amenable to flow reaction conditions.

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    A Flow Process Built upon a Batch Foundation—Preparation of a Key Amino Alcohol Intermediate via Multistage Continuous Synthesis

    • John Jin Lim,*,†
    • Kenneth Arrington,*,†
    • Anna L. Dunn,
    • David C. Leitch,‡,†
    • Ian Andrews,
    • Neil R. Curtis,§
    • Mark J. Hughes,§
    • Daniel R. Tray,§
    • Charles E. Wade,§
    • Matthew P. Whiting,§
    • Charles Goss,
    • Yangmu Chloe Liu,§
    • Brian M. Roesch§
    • Chemical Development, API Chemistry, GlaxoSmithKline, Upper Providence, Pennsylvania 19426, United States
    • Department of Chemistry, University of Victoria, Victoria, BC V8P 5C2, Canada
    • §Chemical Development, API Chemistry, GlaxoSmithKline, Stevenage SG1 2NY, U.K.
    • Chemical Development, Product and Process Engineering, GlaxoSmithKline, Upper Providence, Pennsylvania 19426, United States

    This paper describes recent efforts to apply flow technology in the preparation of the key amino alcohol intermediate 3b so as to address manufacturability issues present in the batch process of a PRMT5 inhibitor. The continuous process, one of the first reported pharmaceutical processes to use aqueous NH4OH in flow, eliminates an isolation and the use of dichloromethane in the workup and improves reaction time >140-fold compared with the batch process to deliver multigram quantities of 3b in 60–65% isolated yield with >99 HPLC area % and >99% ee. While the flow process greatly increases the efficiency compared with the batch process, small-scale batch experiments were crucial in gaining reaction understanding to increase the kinetics and minimize impurity formation. The holistic process design underscores our belief that large-scale flow processes are built upon the knowledge gained through well-chosen small-scale batch experiments.

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    Streamlined Synthesis of Fluoroquinolones

    Gupton, Frank B. (Midlothian, VA, US) Tosso, Perrer N. (Glen Allen, VA, US)

    • VIRGINIA COMMONWEALTH UNIVERSITY (Richmond, VA, US)

    Methods of synthesizing fluoroquinolones such as ciprofloxacin are provided. The methods utilize affordable materials, reduce the number of synthesis steps and provide high yields.

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    Development of a Large-Scale Cyanation Process Using Continuous Flow Chemistry en Route to the Synthesis of Remdesivir

    • Tiago Vieira1*
    • Andrew C. Stevens1*
    • Andrei Chtchemelinine2
    • Detian Gao1
    • Pavel Badalov1
    • Lars Heumann2
    • 1Gilead Alberta ULC, 1021 Hayter Road, Edmonton, Alberta T6S 1A1, Canada
    • 2Gilead Sciences, Inc. 333 Lakeside Drive, Foster City, California 94404, United States

    The implementation of cyanation chemistry at manufacturing scales using batch equipment can be challenging due to the hazardous nature of the reagents employed, and the tight control of reaction parameters, including cryogenic temperatures, that help to afford acceptable selectivity and conversion for the desired reaction. Application of continuous flow chemistry offers a means to mitigate the risk associated with handling large amounts of hazardous reagents and to better control the reaction parameters. A case study describing the cyanation of a glycoside using continuous flow chemistry towards the synthesis of the drug candidate remdesivir is presented.

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    A Metallaphotoredox Method for the Expansion of Benzyl SAR on Electron-Deficient Amines

    • Meghan D. Shea
    • Umar Faruk Mansoor
    • Brett A. Hopkins*
    • Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States

    A metallaphotoredox reaction is described that allows for the efficient exploration of benzyl structure-activity relationships on electron-deficient amines. Typically, accessing a variety of benzyl groups on these substrates can be difficult due to the limited availability of the prerequisite building blocks, namely benzyl halides. However, the use of aryl bromides in this metallaphotoredox reaction allows for greater diversity in the benzyl piece. The reaction scope is discussed herein, including conditions for product scaleup using flow.

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    Tropylium-promoted prenylation reactions of phenols in continuous flow

    • Klaus Omoregbee1,2
    • Kevin N. H. Luc1
    • An H. Dinh1
    • Thanh Vinh Nguyen1
    • 1School of Chemistry, University of New South Wales, Sydney, Australia
    • 2Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Berlin, Germany

    2-Dimethylchroman framework occurs in many complex natural and synthetic compounds which show various types of biological activities such as antitumor, anticancer, antihypertensive, antioxidant and antithrombotic. Herein, we report an organocatalytic approach to the synthesis of 2,2-dimethylchromans where tropylium tetrafluoroborate was used as an organic Lewis acid catalyst for metal-free prenylation reactions of phenols. This method was amenable to continuous flow chemistry to enable an inexpensive pathway to access 2,2-dimethylchromans on multiple-gram scale with short reaction times, high efficiencies and simple product purification.

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    Continuous-Flow Accelerated Sulfation of Heparan Sulfate Intermediates

    • Saurabh Anand
    • Sandhya Mardhekar
    • Rakesh Raigawali
    • Nirmala Mohanta
    • Prashant Jain
    • Chethan D. Shanthamurthy
    • Boopathy Gnanaprakasam*
    • Raghavendra Kikkeri*
    • Indian Institute of Science Education and Research, Dr. Homi Bhabha Road, Pune-411 008, India

    We report for the first time a continuous-flow strategy to execute O-sulfation modification of heparan sulfate (HS) oligosaccharides. A systematic investigation of the influence of the flow parameters on the installation of the sulfate group on glucosamine monosaccharide can aid the development of a comprehensive, quick, and reliable strategy for O-sulfation of HS oligosaccharide precursors. Deprotection of the sulfated heparin intermediates led to the development of a comprehensive biologically inspired oligosaccharide library to understand the crucial structure–function relationship of HS.

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    Electrochemistry in continuous systems

    Thomas P. Nicholls, Christiane Schotten, Charlotte E. Willans

    • School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK

    The use of continuous flow conditions for synthetic electrochemical reactions exhibits many benefits over more traditional batch conditions. This has resulted in many research groups developing continuous electrochemical reactors and their application. The benefits of continuous flow include increased Faradaic efficiencies resulting in reduced energy consumption, higher selectivities, and lower electrolyte loadings which decreases waste streams and simplifies purification. These improvements are largely derived from the smaller interelectrode gaps employed in continuous systems compared to batch protocols. While this may be perceived as a small change in terms of practical reaction setup, it presents many challenges associated with reactor design and development. This perspective will highlight reactor layouts designed to address some of these challenges.

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    Continuous Flow Aminolysis of RAFT Polymers Using Multistep Processing and Inline Analysis

    • Christian H. Hornung*
    • Karin von Känel
    • Ivan Martinez-Botella
    • Maria Espiritu
    • Xuan Nguyen
    • Almar Postma
    • Simon Saubern
    • John Chiefari
    • San H. Thang
    • CSIRO Manufacturing Flagship, Bag 33, Clayton South, Victoria 3169, Australia

    The reversible addition–fragmentation chain transfer (RAFT) method enables the synthesis of polymers with well-defined architecture and narrow molar mass distribution. Simple postpolymerization reactions using amines and Michael acceptors make it possible to conjugate RAFT polymers to a variety of active small molecules and macromolecules. Herein we demonstrate an efficient continuous flow process for aminolysis of RAFT polymers and subsequent Michael addition reactions, using continuous flow reactors, resulting in either thiol- or thioether-terminated polymer chains. After initial reaction optimization we managed to achieve the following: (1) establishment of an integrated flow process, which is capable of producing free thiol containing polymer without the formation of disulfide byproduct; this was achieved by means of an inline, amine scavenging process post-aminolysis using a polymer supported column; (2) the application of UV spectroscopy for inline monitoring of the continuous flow aminolysis reaction; (3) establishment of a simple two-step flow process for the polymerization and subsequent end-group removal by aminolysis; this was achieved by using two continuous reactor units in series in which the residual monomer from the polymerization acted as the Michael acceptor to cap the thiol after aminolysis.

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    Making electrochemistry easily accessible to the synthetic chemist

    • Christiane Schotten*a
    • Thomas P. Nichollsa
    • Richard A. Bourneb
    • Nikil Kapurc
    • Bao N. Nguyena
    • Charlotte E. Willans*a
    • aSchool of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
    • bSchool of Chemical and Process Engineering, University of Leeds, Leeds LS2 9JT, UK
    • cSchool of Mechanical Engineering, University of Leeds, Leeds LS2 9JT, UK

    A significantly renewed interest in synthetic electrochemistry is apparent in the increasing number of publications over the last few years. Electrochemical synthesis offers a mild, green and atom efficient route to interesting and useful molecules, thus avoiding harsh chemical oxidising and reducing agents used in traditional synthetic methods. As such, encouraging broader application of electrochemistry by synthetic chemists should be a priority. Despite the renewed interest there remains a barrier to widespread adoption of this technology derived from the extra knowledge and specialised equipment required. This has led to a knowledge gap between experienced electrochemists and those new in the field. In this tutorial we will bridge the knowledge gap by providing an easily accessible introduction which will enable synthetic chemists new to the field to explore electrochemistry. We will discuss mechanistic considerations, the setup of an electrochemical reaction with all its components, trouble shooting and selected examples from the literature.

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    Scale-up and Optimization of a Continuous Flow Synthesis of an α-Thio-β-chloroacrylamide

    • Olga C. Dennehy1
    • Denis Lynch1
    • Stuart G. Collins1*
    • Anita R. Maguire2*
    • Humphrey A. Moynihan1*
    • 1School of Chemistry, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork, Cork T12 K8AF, Ireland.
    • 2School of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork, Cork T12 K8AF, Ireland

    Use of continuous flow processing to undertake a multistep chlorination cascade has been achieved with effective inline work-up and end-of-line crystallization in batch leading to isolation of α-thio-β-chloroacrylamide Z-3 in pure form from a complex reaction mixture, exploiting the advantage of efficient heat transfer in flow. During the development of a continuous flow strategy for the production of appreciable quantities of the α-thio-β-chloroacrylamides, difficulties surrounding a labour and resource intensive work-up followed by final product isolation were addressed. A greener solvent choice was applied to the chemical synthesis which enabled inline purification and separation, resulting in the crystallization of pure product directly from the reaction mixture. This process was readily scalable and demonstrated control over impurity formation and removal, which is key in an industrial setting.

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    Automated Glycan Assembly in a Variable-Bed Flow Reactor Provides Insights into Oligosaccharide–Resin Interactions

    • Eric T. Sletten1
    • José Danglad-Flores1
    • Manuel Nuño2
    • Duncan Guthrie2
    • Peter H. Seeberger1
    • 1Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany
    • 2Vapourtec, Ltd., Park Farm Business Centre, Fornham St. Genevieve, Bury St. Edmunds, Suffolk IP28 6TS, United Kingdom

    A pressure-based variable-bed flow reactor built for peptide synthesis and capable of real-time monitoring of resin swelling was adapted for automated glycan assembly. In the context of the solid-phase synthesis of several oligosaccharides, the coupling efficiencies, resin growth patterns, and saccharide solvation during the synthesis were determined. The presented work provides the first estimation of on-resin oligosaccharide solvation and an alternative technique to UV–vis monitoring.

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    Photocatalytic α‐Tertiary Amine Synthesis via C–H Alkylation of Unmasked Primary Amines

    • Alison S. H. Rydera
    • William B. Cunninghamb
    • George Ballantyneb
    • Tom Mulesb
    • Anna G. Kinsellab
    • Jacob Turner-Doreb
    • Catherine M. Alderc
    • Lee J. Edwardsc
    • Blandine S. J. McKayc
    • Matthew N. Graysonb
    • Alexander J. Cresswellb*
    • aCentre for Sustainable Chemical Technologies, 1 South, University of Bath, Claverton Down, Bath, BA2 7AY (UK)
    • bDepartment of Chemistry, 1 South, University of Bath, Claverton Down, Bath, BA2 7AY (UK)
    • cMedicines Design, GSK Medicines Research Centre, Gunnels Wood Rd, Stevenage, SG1 2NY (UK)

    A practical, catalytic entry to α,α,α‑trisubstituted (α‑tertiary) primary amines by C–H functionalisation has long been recognised as a critical gap in the synthetic toolbox. We report a simple and scalable solution to this problem that does not require any in situ protection of the amino group and proceeds with 100% atom‐economy. Our strategy, which uses an organic photocatalyst in combination with azide ion as a hydrogen atom transfer (HAT) catalyst, provides a direct synthesis of α‐tertiary amines, or their corresponding γ‑lactams. We anticipate that this methodology will inspire new retrosynthetic disconnections for substituted amine derivatives in organic synthesis, and particularly for challenging α‑tertiary primary amines.

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    Dynamic Crystallization Pathways of Polymorphic Pharmaceuticals Revealed in Segmented Flow with Inline Powder XRD

    • Mark Alan Levenstein1, 2
    • Lois E Wayment3, 4, 5
    • C. Daniel Scott3, 6
    • Ruth A Lunt3, 4
    • Pierre-Baptiste Flandrin3
    • Sarah Day5
    • Chiu Tang5
    • Chick C. Wilson3
    • Fiona C. Meldrum2
    • Nikil Kapur1
    • Karen Robertson3
    • 1School of Mechanical Engineering, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK
    • 2School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK
    • 3Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
    • 4CMAC Future Manufacturing Hub, University of Bath, Claverton Down, Bath BA2 7AY, UK
    • 5Diamond Light Source, Harwell Campus, Didcot, Oxfordshire OX11 0DE, UK
    • 6Centre for Sustainable Chemical Technologies, University of Bath, Claverton Down, Bath BA2 7AY, UK

    Understanding the transitions between polymorphs is essential in the development of strategies for manufacturing and max-imizing the efficiency of pharmaceuticals. However, this can be extremely challenging: crystallization can be influenced by subtle changes in environment such as temperature and mixing intensity or even imperfections in the crystallizer walls. Here, we highlight the importance of in situ measurements in understanding crystallization mechanisms, where a segmented flow crystallizer was used to study the crystallization of the pharmaceuticals urea:barbituric acid (UBA) and carbamazepine (CBZ). The reactor provides highly reproducible reaction conditions, while in situ synchrotron powder X-ray diffraction (PXRD) enables us to monitor the evolution of this system. UBA has two polymorphs of almost equivalent free-energy and so is typically obtained as a polymorphic mixture. In situ PXRD uncovered a progression of polymorphs from UBA III to the thermodynamic polymorph UBA I, where different positions along the length of the tubular flow crystallizer correspond to different reaction times. Addition of UBA I seed crystals modified this pathway such that only UBA I was observed throughout, while transformation from UBA III into UBA I still occurred in the presence of UBA III seeds. Information re-garding the mixing-dependent kinetics of the CBZ form II to III transformation was also uncovered in a series of seeded and unseeded flow crystallization runs, despite atypical habit expression. These results illustrate the importance of coupling controlled reaction environments with in situ XRD to study the phase relationships in polymorphic materials.

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    Management of the Heat of Reaction under Continuous Flow Conditions Using In-Line Monitoring Technologies

    • Masahiro Hosoya
    • Shogo Nishijima
    • Noriyuki Kurose
    • API R&D Laboratory, CMC R&D Division, Shionogi and Co., Ltd., 1-3, Kuise Terajima 2-chome, Amagasaki, Hyogo 660-0813, Japan

    This work presents a guideline for managing process safety under continuous flow conditions. In our previous work, we developed a Grignard reaction for use under such conditions. This reaction was completed in seconds and entailed a large amount of heat generation. To manage the heat of reaction, we quantitatively analyzed the reaction rate using ReactIR with a flow cell. The difference between quantitative values from HPLC and ReactIR was less than 1%, and the reaction rate was 94% in 0.4 second. Based on the reaction rate and the heat of reaction, we simulated the distribution of the internal temperature along the tube length and found the maximum difference from the measured internal temperatures to be 5°C. This accuracy was suitable for evaluating and managing the heat of reaction. Our methodology can facilitate the discussion of process safety under continuous flow conditions.

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    Improving Efficiency by Using Continuous Flow to Enable Cycles: Pseudo-Catalysis, Catalysis and Kinetics

    Ryan Sullivan, Ottawa, Canada

    • Thesis submitted to the University of Ottawa, 2020

    This thesis is centered around the use of flow chemistry to enable cycles in order to increase reaction or process efficiency. Chapter two describes the development of a pseudo-catalytic cycle
    in space; a strategy to achieve formal sub-stoichiometric loading of a chiral auxiliary. By telescoping auxiliary attachment, asymmetric transformation and auxiliary cleavage into one continuous flow process, coupled with separation of product and recovery of auxiliary, the reuse of the auxiliary can be automated by returning the recovered auxiliary back to the start of the process to achieve ‘turn-over.’ An asymmetric hydrogenation mediated by Oppolzer’s sultam is used to demonstrate this concept.

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    Production of Metal-Organic Frameworks

    Rubio Martinez, Marta (Clayton South, AU), Hill, Matthew Roland (Clayton South, AU), Batten, Michael (Clayton South, AU), Lim, Kok Seng (Clayton South, AU), Polyzos, Anastasios (Clayton South, AU), Barton, Timothy Raymond (Clayton South, AU), Hadley, Trevor Deon (Clayton South, AU), Monch, Andreas Alexander (Clayton South, AU)

    • Commonwealth Scientific and Industrial Research Organisation, Acton (AU)

    An apparatus for producing metal organic frameworks, comprising: a tubular flow reactor comprising a tubular body into which, in use, precursor compounds which form the metal organic framework are fed and flow, said tubular body including at least one annular loop.

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    Continuous-Flow Synthesis of Tramadol from Cyclohexanone

    • Timothy M. Monosa
    • Jonathan N. Jaworskia
    • John C. Stephensb, c
    • Timothy F. Jamison*a
    • aDepartment of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
    • bDepartment of Chemistry, Maynooth University, Maynooth, Co. Kildare, Ireland
    • cThe Kathleen Lonsdale Institute of Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland

    A multioperation, continuous-flow platform for the synthesis of tramadol, ranging from gram to decagram quantities, is described. The platform is segmented into two halves allowing for a single operator to modulate between preparation of the intermediate by Mannich addition or complete the fully concatenated synthesis. All purification operations are incorporated in-line for the Mannich reaction. ‘Flash’ reactivity between meta-methoxyphenyl magnesium bromide and the Mannich product was controlled with a static helical mixer and tested with a combination of flow and batch-based and factorial evaluations. These efforts culminated in a rapid production rate of tramadol (13.7 g°h–1) sustained over 56 reactor volumes. A comparison of process metrics including E-Factor, production rate, and space-time yield are used to contextualize the developed platform with respect to established engineering and synthetic methods for making tramadol.

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    Photon Equivalents as a Parameter for Scaling Photoredox Reactions in Flow: Translation of Photocatalytic C−N Cross‐Coupling from Lab Scale to Multikilogram Scale

    • Emily B. Corcoran*a
    • Jonathan P. McMullen*b
    • François Lévesqueb
    • Michael K. Wismerc
    • John R. Naberb
    • aProcess Research & Development, Merck & Co., Inc., Boston, MA 02115 (USA)
    • bProcess Research & Development, Merck & Co., Inc., Rahway, NJ 07065 (USA)
    • cScientific Engineering & Design, Merck & Co., Inc., Kenilworth, NJ 07033 (USA)

    With the development of new photocatalytic methods over recent decades, the translation of these chemical reactions to industrial production scales using continuous flow reactors has become a topic of increasing interest.  In this context, we describe our studies toward elucidating an empirically‐derived parameter for scaling photocatalytic reactions in flow.  By evaluating the performance of a photocatalytic C‐N cross‐coupling across multiple reactor sizes and geometries, it was demonstrated that expressing product yield as a function of the absorbed photon equivalents provided a predictive, empirical scaling parameter.  Through the use of this scaling factor and characterization of the photonic flux within each reactor, the cross‐coupling was scaled successfully from milligram‐scale in batch to a multi‐kilogram reaction in flow.

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    Rapid, Heterogeneous Biocatalytic Hydrogenation and Deuteration in a Continuous Flow Reactor

    • Lisa A. Thompsona
    • Jack S. Rowbothama
    • Jake H. Nicholsona
    • Miguel A Ramireza
    • Ceren Zorb
    • Holly A. Reevea
    • Nicole Grobertb
    • Kylie A. Vincenta*
    • aDepartment of Chemistry, University of Oxford, Inorganic Chemistry Laboratory, South Parks Road, Oxford, OX1 3QR, UK
    • bDepartment of Materials, University of Oxford, Parks Road, Oxford, OX1 3PH, UK

    The high selectivity of biocatalysis offers a valuable method for greener, more efficient production of enantiopure molecules. Operating immobilised enzymes in flow reactors can improve the productivity and handling of biocatalysts, and using H2 gas to drive redox enzymes bridges the gap to more traditional metal‐catalysed hydrogenation chemistry. Herein, we describe examples of H2 ‐driven heterogeneous biocatalysis in flow employing enzymes immobilised on a carbon nanotube column, achieving near‐quantitative conversion in <5 min residence time. Cofactor recycling is carried out in‐situ using H2 gas as a clean reductant, in a completely atom‐efficient process. The flow system is demonstrated for cofactor conversion, reductive amination and ketone reduction, and then extended to biocatalytic deuteration for the selective production of isotopically labelled chemicals.

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    A Continuous Flow Sulfuryl Chloride Based Reaction – Synthesis of a Key Intermediate in a New Route Toward Emtricitabine and Lamivudine

    • Juliana M. de Souza
    • Mateo Berton
    • David R. Snead*
    • D. Tyler McQuade
    • Department of Chemical and Life Science Engineering, Virginia Commonwealth University, Richmond, VA, 23284-3068, USA.

    We demonstrate a continuous two-step sequence where a sulfenyl chloride is formed, trapped by vinyl acetate and chlorinated further via a Pummerer rearrangement. This sequence produces a key intermediate in our new approach to the oxathiolane core used to prepare the anti-retroviral medicines Emtricitabine and Lamivudine. During batch scale-up to tens of grams, we found that the sequence featured a strong exotherm, temperature and pressure sensitivity, and evolution of hydrogen chloride and sulfur dioxide. These reactions are ideal candidates for implementation in a continuous, mesoscale system for the sake of superior control. In addition, we found that fast reagent additions at controlled temperatures decreased byproduct formation. Herein, we discuss the flow implementation and the final reactor design that led to a 141g/h throughput system.

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    Automated Electrochemical Selenenylations

    • Nasser Amri
    • Thomas Wirth
    • School of Chemistry, Cardiff University, Park Place, Cardiff, CF10 3AT, UK

    Integrated electrochemical reactors in automated flow systems were utilised for selenenylation reactions. The automation allowed multiple electrochemical reactions of a programmed sequence to be performed in a fully autonomous way. Many functionalised selenenylated­ products were synthesised in short reaction times in good to high yields.

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    Automated radial synthesis of organic molecules

    • Sourav Chatterjee1
    • Mara Guidi1, 2
    • Peter H. Seeberger1, 2
    • Kerry Gilmore1
    • 1Department of Biomolecular Systems, Max-Planck-Institute of Colloids and Interfaces, Potsdam, Germany
    • 2Freie Universität Berlin, Institute of Chemistry and Biochemistry, Berlin, Germany

    Automated synthesis platforms accelerate and simplify the preparation of molecules by removing the physical barriers to organic synthesis. This provides unrestricted access to biopolymers and small molecules via reproducible and directly comparable chemical processes. Current automated multistep syntheses rely on either iterative1,2,3,4 or linear processes5,6,7,8,9, and require compromises in terms of versatility and the use of equipment. Here we report an approach towards the automated synthesis of small molecules, based on a series of continuous flow modules that are radially arranged around a central switching station. Using this approach, concise volumes can be exposed to any reaction conditions required for a desired transformation. Sequential, non-simultaneous reactions can be combined to perform multistep processes, enabling the use of variable flow rates, reuse of reactors under different conditions, and the storage of intermediates. This fully automated instrument is capable of both linear and convergent syntheses and does not require manual reconfiguration between different processes. The capabilities of this approach are demonstrated by performing optimizations and multistep syntheses of targets, varying concentrations via inline dilutions, exploring several strategies for the multistep synthesis of the anticonvulsant drug rufinamide10, synthesizing eighteen compounds of two derivative libraries that are prepared using different reaction pathways and chemistries, and using the same reagents to perform metallaphotoredox carbon–nitrogen cross-couplings11 in a photochemical module—all without instrument reconfiguration.

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    An Enzymatic Flow-Based Preparative Route to Vidarabine

    • Lucia Tamborini1*
    • Clelia Previtali1
    • Francesca Annunziata1
    • Teodora Bavaro2
    • Marco Terreni2
    • Enrica Calleri2
    • Francesca Rinaldi2
    • Andrea Pinto3
    • Giovanna Speranza4
    • Daniela Ubiali2*
    • Paola Conti1
    • 1Department of Pharmaceutical Sciences, University of Milan, via Mangiagalli 25, 20133 Milano, Italy
    • 2Department of Drug Sciences, University of Pavia, viale Taramelli 12, 27100 Pavia, Italy
    • 3Department of Food, Environmental and Nutritional Sciences, University of Milan, via Celoria 2, 20133 Milano, Italy
    • 4Department of Chemistry, University of Milan, via Golgi 19, 20133 Milano, Italy

    The bi-enzymatic synthesis of the antiviral drug vidarabine (arabinosyladenine, ara-A), catalyzed by uridine phosphorylase from Clostridium perfringens (CpUP) and a purine nucleoside phosphorylase from Aeromonas hydrophila (AhPNP), was re-designed under continuous-flow conditions. Glyoxyl–agarose and EziGTM1 (Opal) were used as immobilization carriers for carrying out this preparative biotransformation. Upon setting-up reaction parameters (substrate concentration and molar ratio, temperature, pressure, residence time), 1 g of vidarabine was obtained in 55% isolated yield and >99% purity by simply running the flow reactor for 1 week and then collecting (by filtration) the nucleoside precipitated out of the exiting flow. Taking into account the substrate specificity of CpUP and AhPNP, the results obtained pave the way to the use of the CpUP/AhPNP-based bioreactor for the preparation of other purine nucleosides.

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    Preparation of 5-Hydroxymethylfurfural from High Fructose Corn Syrup Using Organic Weak Acid in Situ as Catalyst

    • Changqu Lin, Hongli Wu, Junyi Wang, Jinsha Huang, Fei Cao*, Wei Zhuang*, Yanyu Lu, Jiao Chen, Honghua Jia, Pingkai Ouyang
    • College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, 30 South Puzhu Road, Nanjing 211816, P. R. China

    The acidic catalysts play pivotal roles in the dehydration of hexose into 5-hydroxymethylfurfural (HMF). However, these acidic catalysts were usually exogenously added or self-made, which increase the cost of preparation of HMF. Herein, a novel route to prepare HMF from high fructose corn syrup (HFCS-55) using gluconic acid in situ produced by bio-oxidation as a catalyst has been investigated. In the process of bio-oxidation of HFCS-55, the introducing of ε-polylysine (EPL) can effectively improve the acid tolerance of the coimmobilized glucose oxidase and catalase. The immobilized enzymes can keep activity in the existence of a large amount of gluconic acid. Through the chelation of gluconic acid and calcium ions, the degree of gluconic acid ionization was raised and enough protons were released to convert fructose to HMF without the addition of acid. Using 2-methyltetrahydrofuran (2-MeTHF) as an extractor and adding 2 wt % CaCl2, the HMF’s yield reached 85% from fructose–gluconic acid mixture solution at 150 °C for 10 min with 200 W microwave irritations. Furthermore, we also used nuclear magnetic titration to investigate the complexation mechanism of the calcium ion and gluconic acid.

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    Amino Alcohol Acrylonitriles as Activators of the Aryl hydrocarbon Receptor Pathway, An Unexpected MTT Phenotypic Screening Outcome

    • Jennifer Baker 1
    • Cecilia C Russel 1
    • Jayne Gilbert 2
    • Jennette Sakoff 2
    • Adam McCluskey 1
    • 1 The University of Newcastle, Chemistry, University Drive, Callaghan, 2308 Newcastle, AUSTRALIA
    • 2 Calvary Mater Hospital, Medical Oncology, Eidith Street, Waratah, 2298 Newcastle, AUSTRALIA

    Lead (Z)‐N‐(4‐(2‐cyano‐2‐(3,4‐dichlorophenyl)vinyl)phenyl)acetamide, 1 showed MCF‐7 GI50 = 30nM and 400‐fold selective c.f. MCF10A (normal breast tissue). Acetamide moiety modification (13a‐g) to introduce additional hydrophobic moieties was favoured with MCF‐7 breast cancer cell activity enhanced at 1.3 nM. Other analogues were potent against the HT29 colon cancer cell line at 23 nM. Textbook SAR data was observed in the MCF‐7 cell line via the ortho (17a), meta (17b) and para (13f). The amino alcohol ‐OH moiety was pivotal, but no stereochemical preference noted. But, these data did not fit our homology modelling expectations. Aberrant MTT ((3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyl‐tetrazolium bromide) screening results and metabolic interference confirmed by sulforhodamine B (SRB) screening. Interfering analogues resulted in 120 and 80‐fold CYP1A1 and CYP1A2 amplification, with no upregulation of SULT1A1. This is consistent with activation of the AhR pathway. Piperidine per‐deuteration reduced metabolic inactivation. 3‐OH / 4‐OH piperidine analogues showed differential MTT and SRB activity supporting MTT assay metabolic inactivation. Data supports piperidine 3‐OH, but not the 4‐OH, as a CYP substrate. This family of β‐amino alcohol substituted 3,4‐dichlorophenylacetonitriles show broad activity modulated via the AhR pathway. By SRB analysis the most potent analogue was 23b, (Z)‐3‐(4‐(3‐(4‐phenylpiperidin‐1‐yl)‐2‐hydroxypropoxy)phenyl)‐2‐(3,4‐dichlorophenyl)‐acrylonitrile.

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    Continuous flow aminolysis under high temperature and pressure

    • Bryan Li1
    • Scott Bader1, 2
    • Steve M. Guinness1
    • Sally Gut Ruggeri1
    • Cheryl M. Hayward1
    • Steve Hoagland1
    • John Lucas1, 3
    • Ruizhi Li1
    • David Limburg1
    • J. Christopher McWilliams1
    • Jeffrey Raggo1
    • John Van Alsten1, 4
    • 1Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT, 06340, USA
    • 2Celgene Corporation, 556 Morris Ave, Summit, NJ, USA
    • 3Rhodes Technologies, 498 Washington Street, Coventry, RI, USA
    • 4Nitto Denko Avecia Inc, 155 Fortune Blvd., Milford, MA, USA

    Under continuous processing conditions, C-N bond formation via SN2 and SNAr substitutions by amines can be an effective preparative method, especially when volatile amines are used under high pressure and temperature. We have demonstrated SN2 substitution of a 2° mesylate with ammonia and opening of an epoxide with benzylamine, and SNAr substitution of a heteroaryl chloride with aqueous ammonia on multi-kg scales. The homogeneous continuous processes offered better process control, higher efficiency, and comparable or superior reaction profiles and yields to batch conditions.

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    Continuous Flow Photochemistry for the Preparation of Bioactive Molecules

    • Mara Di Filippo, Cormac Bracken, Marcus Baumann*
    • School of Chemistry, University College Dublin, Science Centre South, Belfield, Dublin 4, Ireland

    The last decade has witnessed a remarkable development towards improved and new photochemical transformations in response to greener and more sustainable chemical synthesis needs. Additionally, the availability of modern continuous flow reactors has enabled widespread applications in view of more streamlined and custom designed flow processes. In this focused review article, we wish to evaluate the standing of the field of continuous flow photochemistry with a specific emphasis on the generation of bioactive entities, including natural products, drugs and their precursors. To this end we highlight key developments in this field that have contributed to the progress achieved to date. Dedicated sections present the variety of suitable reactor designs and set-ups available; a short discussion on the relevance of greener and more sustainable approaches; and selected key applications in the area of bioactive structures. A final section outlines remaining challenges and areas that will benefit from further developments in this fast-moving area. It is hoped that this report provides a valuable update on this important field of synthetic chemistry which may fuel developments in the future.

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    Development of a Continuous Flow Photoisomerization Reaction Converting Isoxazoles into Diverse Oxazole Products

    • Cormac Bracken, Marcus Baumann*
    • School of Chemistry, University College Dublin, Science Centre South, Belfield, Dublin 4, Ireland

    A continuous flow process is presented, which directly converts isoxazoles into their oxazole counterparts via a photochemical transposition reaction. This results in the first reported exploitation of this transformation to establish its scope and synthetic utility. A series of various di- and trisubstituted oxazole products bearing different appendages including different heterocyclic moieties were realized through this rapid and mild flow process. Furthermore, the robustness of this approach was demonstrated by generating gram quantities of selected products while also providing insights into likely intermediates.

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    Continuous-Flow Biocatalytic Process for the Synthesis of the Best Stereoisomers of the Commercial Fragrances Leather Cyclohexanol (4-Isopropylcyclohexanol) and Woody Acetate (4-(Tert-Butyl)Cyclohexyl Acetate)

    • Francesca Tentori 1,†
    • Elisabetta Brenna 1,2,*
    • Michele Crotti 1
    • Giuseppe Pedrocchi-Fantoni 2
    • Maria Chiara Ghezzi 1
    • and Davide Tessaro 1
    • 1 Dipartimento di Chimica, Materiali ed Ingegneria Chimica “Giulio Natta”, Politecnico di Milano, Via Mancinelli 7, 20131 Milano, Italy
    • 2 Istituto di Scienze e Tecnologie Chimiche – CNR, Via Mancinelli 7, 20131 Milano, Italy

    Leather cyclohexanol (4-(isopropyl)cyclohexanol) and woody acetate (4-(tert-butyl)cyclohexyl acetate) are commercialized for functional perfumery applications as mixtures of cis- and trans-isomers. The cis-isomers are more potent odorants than the corresponding trans counterparts, but they are the less favoured products in most of the classical synthetic routes. Known stereoselective routes to cis-4-alkylcyclohexanols are characterized by a high environmental burden and/or troublesome reaction work-up. In this work, we examine the use of commercial alcohol dehydrogenases (ADHs) to produce cis-4-alkylcyclohexanols, including the two derivatives with isopropyl and tert-butyl substituents, by the stereoselective reduction of the corresponding ketones. High conversions and diastereoisomeric excess values were achieved with five of the eighteen tested ADHs. To complete the synthetic approach to woody acetate, Candida antarctica A (CALA) was employed as a catalyst for the enzymatic acetylation of cis-4-(tert-butyl)cyclohexanol. In order to provide a technological upgrade to the production of the most odorous isomers of the two commercial fragrances, we designed a continuous-flow process based on the combination of in-line enzymatic steps with in-line work-up, effectively providing samples of cis-leather cyclohexanol and cis-woody acetate with high diastereoisomeric purity.

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    Visible Light-Mediated (Hetero)aryl Amination Using Ni(II) Salts and Photoredox Catalysis in Flow: A Synthesis of Tetracaine

    • Boyoung Y. Park, Michael T. Pirnot andStephen L. Buchwald*
    • Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States

    We report a visible light-mediated flow process for C–N cross-coupling of (hetero)aryl halides with a variety of amine coupling partners through the use of a photoredox/nickel dual catalyst system. Compared to the method in batch, this flow process enables a broader substrate scope, including less-activated (hetero)aryl bromides and electron-deficient (hetero)aryl chlorides, and significantly reduced reaction times (10 to 100 min). Furthermore, scale up of the reaction, demonstrated through the synthesis of tetracaine, is easily achieved, delivering the C–N cross-coupled products in consistently high yield of 84% on up to a 10 mmol scale.

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    In-Line Purification: A Key Component to Facilitate Drug Synthesis and Process Development in Medicinal Chemistry

    • Nopphon Weeranoppanant1, 2, Andrea Adamo3
    • 1Department of Chemical Engineering, Faculty of Engineering, Burapha University, 169 Longhard Bangsaen Road, Muang, Chonburi 02131, Thailand
    • 2School of Biomolecular Science and Engineering, Vidyasirimedhi Institute of Science and Technology (VISTEC), Wangchan Valley 555 Moo 1 Payupnai, Wangchan, Rayong 21210 Thailand
    • 3Zaiput Flow Technologies, 300 Second Avenue, Waltham, Massachusetts 02451, United States

    In-line purification is an important tool for flow chemistry. It enables effective handling of unstable intermediates and integration of multiple synthetic steps. The integrated flow synthesis is useful for drug synthesis and process development in medicinal chemistry. In this article, we overview current states of in-line purification methods. In particular, we focus on four common methods: scavenger column, distillation, nanofiltration, and extraction. Examples of their applications are provided.

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    Preparation of HMF from High Fructose Corn Syrup Using Organic Weak Acid in situ as Catalyst

    • Changqu Lin
    • Hongli Wu
    • Junyi Wang
    • Jinsha Huang
    • Fei Cao*
    • Wei Zhuang*
    • Yanyu Lu
    • Jiao Chen
    • Honghua Jia
    • Pingkai Ouyang
    • College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, 30 South Puzhu Road, Nanjing, 211816 (P. R. China)

    The acidic catalysts play a pivotal role in the dehydration of hexose into 5-hydroxymethylfurfural (HMF). However, these acidic catalysts were usually exogenously added or self-made, which increase the cost of preparation of HMF. Herein, a novel route to prepare HMF from high fructose corn syrup (HFCS-55) using gluconic acid in situ produced by bio-oxidation as catalyst has been investigated. In the process of bio-oxidation of HFCS-55, the introducing of ε-poly-lysine (EPL) can effectively improve the acid tolerance of co-immobilized glucose oxidase and catalase. The immobilized enzymes can keep activity in the existing of large amount of gluconic acid. Through the chelation of gluconic acid and calcium ions, the degree of gluconic acid ionization was raised and enough protons were released to convert fructose to HMF without the addition of acid. Using 2-methyltetrahydrofuran (2-MeTHF) as extractor and adding 2wt% CaCl2, HMF’s yield reached 85% from fructose-gluconic acid mixture solution at 150°C for 10 min with 200W microwave irritations. Furthermore, we also used nuclear magnetic titration to investigate the complexation mechanism of calcium ion and gluconic acid.

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    Continuous flow aminolysis under high temperature and pressure

    • Bryan Li
    • Scott Bader
    • Steve M. Guinness
    • Sally Gut Ruggeri
    • Cheryl M. Hayward
    • Steve Hoagland
    • John Lucas
    • Ruizhi Li
    • David Limburg
    • J. Christopher McWilliams
    • Jeffrey Raggon
    • John Van Alsten
    • Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT, 06340, USA

    Under continuous processing conditions, C-N bond formation via SN2 and SNAr substitutions by amines can be an effective preparative method, especially when volatile amines are used under high pressure and temperature. We have demonstrated SN2 substitution of a 2° mesylate with ammonia and opening of an epoxide with benzylamine, and SNAr substitution of a heteroaryl chloride with aqueous ammonia on multi-kg scales. The homogeneous continuous processes offered better process control, higher efficiency, and comparable or superior reaction profiles and yields to batch conditions.

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    Amino Alcohol Acrylonitriles as Activators of the Aryl hydrocarbon Receptor Pathway, An Unexpected MTT Phenotypic Screening Outcome

    • Jennifer Bakera
    • Cecilia C Russela
    • Jayne Gilbertb
    • Jennette Sakoff*b
    • Adam McCluskey*a
    • aChemistry, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia
    • bExperimental Therapeutics Group, Department of Medical Oncology, Calvary Mater Hospital, Edith Street, Waratah NSW 2298, Australia

    Lead (Z)‐N‐(4‐(2‐cyano‐2‐(3,4‐dichlorophenyl)vinyl)phenyl)acetamide, 1 showed MCF‐7 GI50 = 30nM and 400‐fold selective c.f. MCF10A (normal breast tissue). Acetamide moiety modification (13a‐g) to introduce additional hydrophobic moieties was favoured with MCF‐7 breast cancer cell activity enhanced at 1.3 nM. Other analogues were potent against the HT29 colon cancer cell line at 23 nM. Textbook SAR data was observed in the MCF‐7 cell line via the ortho (17a), meta (17b) and para (13f). The amino alcohol ‐OH moiety was pivotal, but no stereochemical preference noted. But, these data did not fit our homology modelling expectations. Aberrant MTT ((3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyl‐tetrazolium bromide) screening results and metabolic interference confirmed by sulforhodamine B (SRB) screening. Interfering analogues resulted in 120 and 80‐fold CYP1A1 and CYP1A2 amplification, with no upregulation of SULT1A1. This is consistent with activation of the AhR pathway. Piperidine per‐deuteration reduced metabolic inactivation. 3‐OH / 4‐OH piperidine analogues showed differential MTT and SRB activity supporting MTT assay metabolic inactivation. Data supports piperidine 3‐OH, but not the 4‐OH, as a CYP substrate. This family of β‐amino alcohol substituted 3,4‐dichlorophenylacetonitriles show broad activity modulated via the AhR pathway. By SRB analysis the most potent analogue was 23b, (Z)‐3‐(4‐(3‐(4‐phenylpiperidin‐1‐yl)‐2‐hydroxypropoxy)phenyl)‐2‐(3,4‐dichlorophenyl)‐acrylonitrile.

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    Development of a Continuous Flow Photoisomerization Reaction Converting Isoxazoles into Diverse Oxazole Products

    • Cormac Bracken
    • Marcus Baumann
    • School of Chemistry, University College Dublin, Science Centre South, Belfield, Dublin 4, Ireland

    A continuous flow process is presented, which directly converts isoxazoles into their oxazole counterparts via a photochemical transposition reaction. This results in the first reported exploitation of this transformation to establish its scope and synthetic utility. A series of various di- and trisubstituted oxazole products bearing different appendages including different heterocyclic moieties were realized through this rapid and mild flow process. Furthermore, the robustness of this approach was demonstrated by generating gram quantities of selected products while also providing insights into likely intermediates.

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    Visible Light-Mediated (Hetero)aryl Amination Using Ni(II) Salts and Photoredox Catalysis in Flow: A Synthesis of Tetracaine

    • Boyoung Y. Park
    • Michael T. Pirnot
    • Stephen L. Buchwald*
    • Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States

    We report a visible light-mediated flow process for C–N cross-coupling of (hetero)aryl halides with a variety of amine coupling partners through the use of a photoredox/nickel dual catalyst system. Compared to the method in batch, this flow process enables a broader substrate scope, including less-activated (hetero)aryl bromides and electron-deficient (hetero)aryl chlorides, and significantly reduced reaction times (10 to 100 minutes). Furthermore, scale up of the reaction, demonstrated through the synthesis of tetracaine, is easily achieved, delivering the C–N cross-coupled products in consistently high yield of 84% on up to a 10 mmol scale.

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    Use of Immobilized Amine Transaminase from Vibrio fluvialis under Flow Conditions for the Synthesis of (S)‐1‐(5‐Fluoropyrimidin‐2‐yl)‐ethanamine

    • Riccardo Semproli [a]
    • Gianmarco Vaccaro [a],[b]
    • Erica E. Ferrandi [c]
    • Marta Vanoni [c]
    • Teodora Bavaro [a]
    • Giorgio Marrubini [a]
    • Francesca Annunziata [b]
    • Paola Conti [b]
    • Giovanna Speranza [d]
    • Daniela Monti [*c]
    • Lucia Tamborini [*b]
    • Daniela Ubiali [*a]
    • [a] R. Semproli, G. Vaccaro, Dr. G. Marrubini, Dr. T. Bavaro, Prof. D. Ubiali, Department of Drug Sciences, University of Pavia, Viale Taramelli 12, I-27100 Pavia, Italy
    • [b] G. Vaccaro, F. Annunziata, Prof. P. Conti, Prof. L. Tamborini, Department of Pharmaceutical Sciences, University of Milano, Via Mangiagalli 25, I-20133 Milano, Italy
    • [c] Dr. E. E. Ferrandi, M. Vanoni, Dr. D. Monti, Istituto di Scienze e Tecnologie Chimiche "Giulio Natta" (SCITEC) – CNR, Via Bianco 9, I-20131 Milano, Italy
    • [d] Prof. G. Speranza, Department of Chemistry, University of Milano, Via Golgi 19, I-20133 Milano, Italy

    We report on the covalent immobilization of the (S)‐selective amine transaminase from Vibrio fluvialis (Vf‐ATA) and its use in the synthesis of (S)‐1‐(5‐fluoropyrimidin‐2‐yl)‐ethanamine, a key intermediate of the JAK2 kinase inhibitor AZD1480. Immobilized Vf‐ATA on glyoxyl‐agarose (activity recovery: 30%) was used in a packed bed reactor to set‐up a continuous flow biotransformation coupled with a straightforward in‐line purification to circumvent the 2‐step process described in literature for the batch reaction. The newly developed biotransformation was run in a homogeneous system including dimethyl carbonate as a green co‐solvent. Optically pure (S)‐1‐(5‐fluoropyrimidin‐2‐yl)‐ethanamine (ee >99%) was isolated in 35% yield.

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    Continuous Flow Enables Metallaphotoredox Catalysis in a Medicinal Chemistry Setting: Accelerated Optimization and Library Execution of a Reductive Coupling between Benzylic Chlorides and Aryl Bromides

    • Zachary G. Brill, Casey B. Ritts, Umar Faruk Mansoor, Nunzio Sciammetta
    • Department of Discovery Chemistry, MRL, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115 USA

    Continuous flow has been used widely in process chemistry and academic settings for various applications. However, initial reaction discovery has generally remained “batch-exclusive” despite the existence of efficient, reproducible flow systems. We hereby disclose a workflow to bridge the gap between early medicinal chemistry efforts and process-scale development, showcased by the discovery and optimization of a metallaphotoredox-catalyzed cross-coupling between benzylic chlorides and aryl bromides, followed by two library syntheses of complex drug-like compounds.

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    Continuous Flow Synthesis of Methyl Oximino Acetoacetate: Accessing Greener Purification Methods with Inline Liquid-Liquid Extraction and Membrane Separation Technology

    • René Lebl1, 2
    • Trevor Murray3
    • Andrea Adamo3
    • David Cantillo1, 2
    • C. Oliver Kappe1, 2
    • 1Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
    • 2Institute of Chemistry, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
    • 3Zaiput Flow Technologies, 300 2nd Avenue, Waltham, Massachusetts 02451, United States

    A greener continuous flow procedure for the synthesis and purification of methyl oximino acetoacetate, a key intermediate for the generation of several heterocyclic scaffolds, has been established. The synthesis is based on the continuous flow generation of nitrous acid to effect the oximation reaction. Neat reactants and a nearly saturated aqueous NaNO2 solution have provided a methodology with a very low solvent consumption. The extraction of the oxime from the reaction mixture, a challenging process due to the presence of acetic acid in the solution, has been achieved by liquid–liquid extraction in a microreactor and a continuous multistage phase separation platform. Fine-tuning of the output pH by inline monitoring using a flow cell has enabled optimal extraction performance as well as the minimization of the acetic acid residue in the organic phase and the use of very low amounts of extraction solvents. An excellent value for the process mass intensity of 11.1 has been achieved. Moreover, the lack of acetic acid in the product avoids an additional and energy-consuming distillation step.

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    Cellulose fast pyrolysis for platform chemicals: assessment of potential targets and suitable reactor technology

    • Anurag Parihar
    • Sankar Bhattacharya
    • Department of Chemical Engineering, Monash University, Clayton, VIC, Australia

    The cellulosic component of lignocellulosic biomass can be converted to commercially valuable platform chemicals through pyrolysis provided it is effectively controlled and optimized. This review first discusses the underpinning kinetics and mechanism of cellulose pyrolysis to identify target platform chemicals. Platform chemicals like 5‐hydroxymethyl furfural, 5‐chloromethyl furfural, and levoglucosenone, which are potentially amenable to the pyrolytic conversion of cellulose, are then elucidated. There are laboratory and large‐scale reactor technologies available for converting biomass to bio‐oil but they have not been comprehensively investigated for producing platform chemicals through pyrolysis. This review critically evaluates different reactor types available for developing the catalytic pyrolysis process for converting cellulosic component of biomass to platform chemicals. The fluidized bed reactor stands out as the most suitable reactor technology for the catalytic pyrolysis of cellulose to platform chemicals owing to attributes like short residence time, high heating rate, uniform mixing, efficient heat transfer, and scalability of operations. This article provides perspective on the implementation of this technology for the pyrolysis of the cellulosic component of biomass to platform chemicals. © 2019 Society of Chemical Industry and John Wiley & Sons, Ltd

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    Continuous and green microflow synthesis of azobenzene compounds catalyzed by consecutively prepared tetrahedron CuBr

    • Hong Qina,1
    • Chengkou Liua,1
    • Niuniu Lva2
    • Wei Hea
    • Jingjing Menga
    • Zheng Fanga
    • Kai Guoa,b
    • a College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, No. 30 Puzhu South Road, Nanjing, China
    • b State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, 211816, China

    An environmentally friendly and cross-selective process intensification for the continuous synthesis of symmetric aromatic azo compounds by using self-made cuprous bromide as the catalyst under mild conditions in the microreactor was developed. A novel tetrahedron cuprous bromide catalyst which shows outstanding catalytic activity and satisfactory stability has been synthesized in continuous flow microreactor. The online immobilization of self-made cuprous bromide on the catalyst bed achieved oxidative coupling of aromatic amines (oxygen as oxidant) and high-performance gas–liquid–solid three-phase reaction, which strongly limited the possibility of undesired reaction pathways, improving product selectivity and reducing waste generation. Meanwhile, the yield of azo-coupling reaction was up to 98% under optimized condition. As compared with earlier traditional method (diazotization reaction) for synthesizing azobenzene, the designed micro-flow process displays significant advances in terms of selectivity, waste emissions, sustainability and productivity. The combination of online immobilization of self-made cuprous bromide and precise and safe control through the microreactor provides a green solution for the industrial production of valuable aromatic azo compounds.

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    Safe and Scalable Continuous Flow Azidophenylselenylation of Galactal to Prepare Galactosamine Building Blocks

    • Mónica Gubermana,b
    • Bartholomäus Piebera
    • Peter H. Seebergera,b
    • aDepartment of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany
    • bDepartment of Chemistry and Biochemistry, Freie Universitat Berlin, Arnimalle 22, 14195 Berlin, Germany

    Differentially protected galactosamine building blocks are key components for the synthesis of human and bacterial oligosaccharides. The azidophenylselenylation of 3,4,6-tri-O-acetyl-d-galactal provides straightforward access to the corresponding 2-nitrogenated glycoside. Poor reproducibility and the use of azides that lead to the formation of potentially explosive and toxic species limit the scalability of this reaction and render it a bottleneck for carbohydrate synthesis. Here, we present a method for the safe, efficient, and reliable azidophenylselenylation of 3,4,6-tri-O-acetyl-d-galactal at room temperature, using continuous flow chemistry. Careful analysis of the transformation resulted in reaction conditions that produce minimal side products while the reaction time was reduced drastically when compared to batch reactions. The flow setup is readily scalable to process 5 mmol of galactal in 3 h, producing 1.2 mmol/h of product.

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    A practical method for continuous production of sp3-rich compounds from (hetero)aryl halides and redox-active esters

    • Eiichi Watanabea
    • Yiding Chenb
    • Oliver Mayb
    • Steven V. Ley*b
    • aNew Path Molecular Ltd. Building 580, Babraham Research Campus, Cambridge (UK)
    • bDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge (UK)

    A practically useful coupling reaction between aromatic halides and redox‐active esters was realized via nickel catalysis through the use of packed zinc bed column in continuous flow. Multiple reuse of the column showed a negligible decrease in efficiency, affording high space/time yields. A wide range of substrates, including a number of heteroaryl halides and polyfunctional materials were coupled in generally good yields. Longer‐time and larger‐scale experiments further demonstrates the robustness of the system.

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    Metal‐Free Visible‐Light‐Mediated Hydrotrifluoromethylation of Unactivated Alkenes and Alkynes in Continuous Flow

    • Anne‐Laure Barthelemy Guillaume Dagousset Emmanuel Magnier
      • Institut Lavoisier de Versailles, UMR 8180, Université de Versailles‐Saint‐Quentin, 78035 Versailles Cedex, France

      A new versatile protocol for the hydroperfluoroalkylation of alkenes and alkynes using suliflimino iminiums as sources of perfluoroalkyl radicals was developed. This visible‐light‐mediated process is performed in continuous flow with high efficiency (10 min of residence time), and under mild metal‐free conditions.
      We report herein a novel photoredox‐catalyzed hydrotrifluoromethylation of unsaturated systems under continuous flow. This metal‐free method is easily broadened to other perfluoroalkyl groups (RF = CF3, CFCl2, CF2Br, C4F9) thanks to the use of sulfilimino iminiums as sources of ·RF radicals. The mild reaction conditions are compatible with unactivated alkenes bearing a wide range of functionalities, as well as with alkynes for the first time.

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      A new formulation for symbolic regression to identify physico-chemical laws from experimental data

      • Pascal Neumannab
      • Liwei Cao bc
      • Danilo Russob
      • Vassilios S. Vassiliadisb
      • Alexei A.Lapkinbc
      • a Aachener Verfahrenstchnik – Process Systems Engineering, RWTH Aachen University, Aachen, Germany
      • b Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB3 0AS, UK
      • c Cambridge Centre for Advanced Research and Education in Singapore, CARES Ltd., 1 CREATE Way, CREATE Tower #05-05, 138602 Singapore, Singapore

      A modification to the mixed-integer nonlinear programming (MINLP) formulation for symbolic regression was proposed with the aim of identification of physical models from noisy experimental data. In the proposed formulation, a binary tree in which equations are represented as directed, acyclic graphs, is fully constructed for a pre-defined number of layers. The introduced modification results in the reduction in the number of required binary variables and removal of redundancy due to possible symmetry of the tree formulation. The formulation was tested using numerical models and was found to be more efficient than the previous literature example with respect to the numbers of predictor variables and training data points. The globally optimal search was extended to identify physical models and to cope with noise in the experimental data predictor variable. The methodology was proven to be successful in identifying the correct physical models describing the relationship between shear stress and shear rate for both Newtonian and non-Newtonian fluids, and simple kinetic laws of chemical reactions. Future work will focus on addressing the limitations of the present formulation and solver to enable extension of target problems to larger, more complex physical models.

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      Real-Time Monitoring of Solid-Phase Peptide Synthesis Using a Variable Bed Flow Reactor

      • Eric T. Slettena
      • Manuel Nunob
      • Duncan Guthrieb
      • Peter Seebergera,c
      • aDepartment of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany
      • bVapourtec Ltd, Park Farm Business Centre, Fornham St Genevieve, Bury St Edmunds, Suffolk IP28 6TS, U.K
      • cDepartment of Chemistry and Biochemistry, Freie Universität Berlin, Arnimalle 22, 14195, Berlin, Germany

      On-resin aggregation and incomplete amide bond formation are major challenges for solid-phase peptide synthesis that are difficult to be monitored in real-time. Incorporation of a pressure-based variable bed flow reactor into an automated solid-phase peptide synthesizer permitted real-time monitoring of resin swelling to determine amino acid coupling efficiency and on-resin aggregation.

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      Electroorganic Synthesis under Flow Conditions

      • Mohamed Elsherbini
      • Thomas Wirth
      • School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, United Kingdom

      Despite the long history of electroorganic synthesis, it did not participate in the mainstream of chemical research for a long time. This is probably due to the lack of equipment and standardized protocols. However, nowadays organic electrochemistry is witnessing a renaissance, and a wide range of interesting electrochemical transformations and methodologies have been developed, not only for academic purposes but also for large scale industrial production. Depending on the source of electricity, electrochemical methods can be inherently green and environmentally benign and can be easily controlled to achieve high levels of selectivity. In addition, the generation and consumption of reactive or unstable intermediates and hazardous reagents can be achieved in a safe way. Limitations of traditional batch-type electrochemical methods such as the restricted electrode surface, the necessity of supporting electrolytes, and the difficulties in scaling up can be alleviated using electrochemical flow cells. Microreactors offer high surface-to-volume ratios and enable precise control over temperature, residence time, flow rate, and pressure. In addition, efficient mixing, enhanced mass and heat transfer, and handling of small volumes lead to simpler scaling-up protocols and minimize safety concerns. Electrolysis under flow conditions reduces the possibility of overoxidation as the reaction mixture is flown continuously out of the reactor in contrast to traditional batch-type electrolysis cells.

      In this Account, we highlight our contributions in the area of electroorganic synthesis under flow conditions over the past decade. We have designed and manufactured different generations of electrochemical flow cells. The first-generation reactor was effectively used in developing a simple one-step synthesis of diaryliodonium salts and used in proof-of-concept reactions such as the trifluoromethylation of electron-deficient alkenes via Kolbe electrolysis of trifluoroacetic acid in addition to the selective deprotection of the isonicotinyloxycarbonyl (iNoc) group from carbonates and thiocarbonates. The improved second-generation flow cell enabled the development of efficient synthesis of isoindolinones, benzothiazoles, and thiazolopyridines, achieving gram-scale for some of the products easily without changing the reactor design or reoptimizing the reaction parameters. In addition, the same reactor was used in the development of an efficient continuous flow electrochemical synthesis of hypervalent iodine reagents. The generated unstable hypervalent iodine reagents were easily used without isolation in various oxidative transformations in a coupled flow/flow manner and could be easily transformed into bench-stable reagents via quantitative ligand exchange with the appropriate acids. Our second-generation reactor was further improved and commercialized by Vapourtec Ltd. We have demonstrated the power of online analysis in accelerating optimizations and methodology development. Online mass spectrometry enabled fast screening of the charge needed for the cyclization of amides to isoindolinones. The power of online 2D-HPLC combined with a Design of Experiments approach empowered the rapid optimization of stereoselective electrochemical alkoxylations of amino acid derivatives.

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      Lilly Research Award Program (LRAP): A Successful Academia–Industry Partnership Model in the Context of Flow Chemistry for Drug Discovery

      • Mateos, Carlos

      The Lilly Research Award Program (LRAP) provides academic researchers worldwide with a gate to partner with Lilly internal scientists who are working on basic and applied research to collaboratively advance novel impactful projects. The pre-competitive nature of these projects is the most relevant feature as it permits the shared publication of the research outcomes immediately. In this article, this highly successful initiative is reviewed in the context of general academia-industry collaborations and the lessons learned from different shared projects, in the area of innovative continuous flow chemistry, will be discussed.

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      In situ non-invasive Raman spectroscopic characterisation of succinic acid polymorphism during segmented flow crystallisation

      • Anuradha R. Pallipuratha
      • Pierre-Baptiste Flandrina
      • Lois E. Waymenta, b, c
      • Chick C. Wilsona, b
      • Karen Robertsona
      • aDepartment of Chemistry, University of Bath, Claverton Down, BA2 7AY, UK
      • bCMAC Future Manufacturing Hub, University of Bath, Claverton Down, Bath BA2 7AY, UK
      • c.Diamond Light Source, Harwell Campus, Didcot, Oxfordshire OX11 0DE, UK

      The kinetically regulated automated input crystalliser for Raman spectroscopy (KRAIC-R) combines highly controlled crystallisation environments, via tri segmented flow, with non-invasive confocal Raman spectroscopy. Taking advantage of the highly reproducible crystallisation environment within a segmented flow crystalliser and the non-invasive nature of confocal spectroscopy, we are able to shine light on the nucleation and growth of Raman active polymorphic materials without inducing unrepresentative crystallisation events through our analysis technique. Using the KRAIC-R we have probed the nucleation and subsequent growth of succinic acid. Succinic acid typically crystallises as β-SA from solution-based crystallisation although some examples of a small proportion of α-SA have been reported in the β-SA product. Here we show that α-SA and β-SA nucleate concomitantly but undergo Ostwald ripening to a predominantly β-SA product.

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      Trypanosomes inhibitors

      Inventors: Maude Giroud, Wolfgang Haap, Bernd Kuhn, Rainer E. Martin

      • Assignee: Hoffmann La Roche Inc

      The invention relates to a compound of formula (I)

      wherein R1 and R2 are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.

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      Microfluidic synthesis of fatty acid esters: Integration of dynamic combinatorial chemistry and scale effect

      • Wei He a,1
      • Yuan Gao a,1
      • Guiqin Zhu a
      • Hao Wu a
      • Zheng Fang a
      • Kai Guo a,b
      • a College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, PR China
      • b State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing 210009, PR China

      Integration of dynamic combinatorial chemistry and scale effect was designed to realize the efficient synthesis of bioactive compounds. Synthetic efficiency in the esterification reaction and combinatorial synthesis was significantly improved in smaller characteristic scale. Obvious increase in yield was observed when the reaction was conducted in the capillary with smaller diameters. More kinds of fatty acid esters were detected in the fixed bed flow reactor compared with the results in the flask. Based on the interaction of bioactive compounds and targets, the synthesis of compounds with high binding activity was intensified along with the dynamic shift of reaction equilibrium verified by gas chromatography. Uniform distribution of flow field would be beneficial to the mixing process, resulting in better mass transfer efficiency.

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      MnO2@Fe3O4 Magnetic Nanoparticles as Efficient and Recyclable Heterogeneous Catalyst for Benzylic sp3 C−H Oxidation

      • Akanksha M. Pandeya
      • Dr. Sandip G. Agalavea
      • Dr. Chathakudath P. Vinodb
      • Dr. Boopathy Gnanaprakasama
      • aDepartment of Chemistry, Indian Institute of Science Education and Research, Pune-, 411008 India
      • bCSIR-NCL Catalysis and Inorganic Chemistry Division, Pune, India

      A highly chemoselective and efficient heterogeneous MnO2@Fe3O4 magnetic nanoparticle catalyst for the oxidation of benzylic sp3 C−H group to afford ester and ketone derivatives in high yield under batch and continuous flow modules is reported.

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      Development of a continuous flow synthesis of propranolol: tackling a competitive side reaction

      • Sonia De Angelis1, 2
      • Paolo Celestini3
      • Rosa Purgatorio1
      • Leonardo Degennaro1, 2
      • Gabriele Rebuzzini3
      • Renzo Luisi1, 2
      • Claudia Carlucci1, 2
      • 1Department of Pharmacy - Drug Sciences, University of Bari "A. Moro" Via E. Orabona 4, Bari, Italy
      • 2Flow Chemistry and Microreactor Technology FLAME-Lab, Bari, Italy
      • 3COSMA S.p.A, Ciserano Italy

      This work reports the preparation of propranolol according to a flow process. Propranolol has been prepared paying attention to tackle the formation of the by-product tertiary amine, resulting from an additional ring opening of the starting epoxide. Remarkably, the use of catalytic amount of water resulted beneficial for the yield and purity of the desired propranolol, and to substantially reducing the amount of tertiary amine byproduct. The high concentration of the solutions allowed for a productivity of several grams/h.

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      Photochemical flow synthesis of 3‐hydroxyazetidines

      • Michele Ruggeri1
      • Amanda Worthy Dombrowski2
      • Stevan W. Djuric2
      • Ian Richard Baxendale1
      • 1University of Durham, Department of Chemistry, South Road, DH1 3LE Durham, UNITED KINGDOM
      • 2AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064 Chicago, UNITED STATES

      A photo‐flow Norrish‐Yang cyclisation has been devised that delivers 3‐hydroxyazetidines in good yields. The high reproducibility and short residence times of the flow process enables easy scaling of the transformation allowing access to these valuable chemical entities at synthetically useful multi‐gram scales. A systematic exploration of the constituent structural components was undertaken allowing an understanding of the reactivity and functional group tolerance of the transformation.

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      Flow nanoprecipitation of size-controlled D-leucine nanoparticles for spray-drying formulations

      • Bruno Cerra, Gabriele Mosca, Maurizio Ricci, Aurélie Schoubben and Antimo Gioiello
      • Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, I-06122 Perugia, Italy

      The increasing interest in the use of nanoparticles for biomedical applications has resulted in a growing demand for efficient and scalable methods that enable their preparation with a fine control over particle size, distribution and morphology. In this work we report a novel flow-based method for the flash nanoprecipitation of size-controlled D-leucine nanoparticles for spray-drying formulations. Preliminary experiments were conducted in batch to define best flowable conditions that were then optimized considering nanoparticle size and distribution using a mesofluidic flow system. The method was applied to the streamilined preparation of D-leucine nanoparticles readily nebulized by mini and nano spray-dryer devices and characterized by SEM analysis. Finally, the D-leucine atomized powder was used as glidant in dry powder for inhalation with micronized budesonide, a poorly water-soluble and low flowable anti-asthma drug.

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      Visible‐Light‐Mediated Cross‐Couplings and C–H Activation via Dual Photoredox/Transition‐Metal Catalysis in Continuous‐Flow Processes

      • Soo Dong Kim
      • Jonghyun Lee
      • Nam-Jung Kim
      • Boyoung Park
      • Kyung Hee University, Department of Pharmacy, Kyungheedaero 26, 02447 Seoul, Republic of Korea

      Here we review dual photoredox/transition‐metal catalysis for C–C/C–N cross‐couplings and C–H activation in continuous‐flow processes. Compared to conventional transition‐metal catalysis for these reactions, a visible‐light‐mediated synergistic catalysis enables the use of relatively mild and environmentally friendly reaction conditions by decreasing the activation energy and using a renewable energy source. However, photochemical transformations in batch processing have limitations such as reactivity, reaction time, substrate scope, and scalability due to light attenuation as represented by the Beer‐Lambert law. In this review article, we therefore summarize and discuss several examples of cross‐couplings and C–H activation in continuous‐flow processes that overcome these problems in batch processing.

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      A flow platform for degradation-free CuAAC bioconjugation

      • Marine Z. C. Hatit1
      • Linus F. Reichenbach1
      • John M. Tobin2, Filipe Vilela2
      • Glenn A. Burley1
      • Allan J. B. Watson3
      • 1Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, UK
      • 2Chemical Sciences, Heriot-Watt University, Edinburgh EH14 4AS, UK
      • 3School of Chemistry, University of St Andrews, North Haugh, St Andrews

      The Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is a cornerstone method for the ligation of biomolecules. However, undesired Cu-mediated oxidation and Cu-contamination in bioconjugates limits biomedical utility. Here, we report a generic CuAAC flow platform for the rapid, robust, and broad-spectrum formation of discrete triazole bioconjugates. This process leverages an engineering problem to chemical advantage: solvent-mediated Cu pipe erosion generates ppm levels of Cu in situ under laminar flow conditions. This is sufficient to catalyze the CuAAC reaction of small molecule alkynes and azides, fluorophores, marketed drug molecules, peptides, DNA, and therapeutic oligonucleotides. This flow approach, not replicated in batch, operates at ambient temperature and pressure, requires short residence times, avoids oxidation of sensitive functional groups, and produces products with very low ppm Cu contamination.

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      Batch Versus Flow Lithiation‐Substitution of 1,3,4‐Oxadiazoles: Exploitation of Unstable Intermediates Using Flow Chemistry

      • Jeff Y. F. Wong
      • John M. Tobin
      • Filipe Vilela
      • Graeme Barker
      • Institute of Chemical Sciences, Heriot-Watt University, Edinburgh EH11 4AS, Scotland, UK

      1,3,4‐Oxadiazoles are a common motif in pharmaceutical chemistry, but few convenient methods for their modification exist. A fast, convenient, high yielding and general α‐substitution of 1,3,4‐oxadiazoles has been developed using a metalation‐electrophilic trapping protocol both in batch and under continuous flow conditions in contradiction to previous reports which suggest that α‐metalation of this ring system results in ring fragmentation. In batch, lithiation is accomplished at an industrially convenient temperature, –30 °C, with subsequent trapping giving isolated yields of up to 91%. Under continuous flow conditions, metalation is carried out at room temperature, and subsequent in flow electrophilic trapping gave up to quantitative isolated yields. Notably, lithiation in batch at room temperature results only in ring fragmentation and we propose that the superior mixing in flow allows interception and exploitation of an unstable intermediate before decomposition can occur.

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      A Photoredox Coupling Reaction of Benzylboronic Esters and Carbonyl Compounds in Batch and Flow

      • Yiding Chen
      • Oliver May
      • David C. Blakemore
      • and Steven V. Ley†*
      • Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
      • †‡ Medicine Design, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, United States

      Mild cross-coupling reaction between benzylboronic esters with carbonyl compounds and some imines was achieved under visible-light-induced iridium-catalyzed photoredox conditions. Functional group tolerance was demonstrated by 51 examples, including 13 heterocyclic compounds. Gram-scale reaction was realized through the use of computer-controlled continuous flow photoreactors.

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      Heumann Indole Flow Chemistry Process

      • Cynthia Crifar, Fenja Leena Dücker, Sacha Nguyen Thanh, Vanessa Kairouz, William D. Lubell
      • Department of Chemistry, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montreal, Quebec H3C 3J7, Canada

      Continuous flow chemistry has improved efficiency in the Heumann indole process. 3-Substituted indoles were prepared by three flow steps performed in succession in better overall yield and shorter reaction times relative to their batch counterparts. Novel 3-alkyl and 3-methoxyindoles were synthesized from their corresponding amino ketone and ester precursors by flow sequences featuring base-free alkylation with methyl bromoacetate in DMF, saponification, and cyclization with acetic anhydride and Et3N.

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      Integrated plug flow synthesis and crystallisation of pyrazinamide

      • C. Daniel Scotta
      • Ricardo Labesb
      • Martin Depardieuc
      • Claudio Battilocchiob
      • Matthew G. Davidsona
      • Steven V. Leyb
      • Chick C. Wilsonad
      • and Karen Robertson*c
      • a Centre for Sustainable Chemical Technologies, Department of Chemistry, University of Bath, UK
      • b Department of Chemistry, University of Cambridge, UK
      • c Department of Chemistry, University of Bath, UK
      • d EPSRC Future Continuous Manufacturing and Advanced Crystallisation Research Hub, University of Bath, UK

      We report the integration of flow chemistry with plug flow crystallisation. Catalytic flow hydration of pyrazinecarbonitrile to pyrazinamide was performed in a packed bed column of MnO2. The effluent of this flow reactor was directly linked to a tri-segmented tubular crystalliser (KRAIC), providing a seamless transition from flow synthesis to crystallisation, with control over solid form and particle characteristics.

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      Conjugated porous polymers for photocatalytic applications

      • Y. L. Wonga
      • J. M. Tobinb
      • Z. Xua
      • F. Vilela*b
      • aDepartment of Biology and Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong
      • bSchool of Engineering and Physical Sciences, Heriot Watt University, Edinburgh, UK

      Conjugated porous polymers (CPPs) are a class of fully crosslinked polymers defined by high surface area and porosity in the nanometer range, having been traditionally developed for applications such as gas storage, sensing and (photo)catalysis. As these materials are comprised of extended π-conjugation, their ability to act as light harvesters, and in turn photocatalysts, has come to prominence. The insoluble nature of CPPs allows them to be employed as photocatalysts under heterogeneous conditions, replacing traditional homogeneous systems. This Perspective highlights the current state-of-the-art CPPs along with a view to their applications as heterogeneous photocatalysts for a wide range of chemical transformations including hydrogen production, organic synthesis and photopolymerization, just to name but a few.

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      In-Flow Flash Nanoprecipitation of Size-Controlled D-Leucine Nanoparticles for Spray-Drying Formulations

      Bruno Cerraa, Gabriele Moscaa, Maurizio Riccia, Aurélie Schoubbena, Antimo Gioielloa

      • aDepartment of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, I-06122 Perugia, Italy.

      In this work we report the development of a cheap and scalable flow-based flash nanoprecipitation approach to prepare D-leucine nanoparticles particularly useful as glidants in dry powder for inhalation. Starting from preliminary batch screens, the process was successfully optimized and scaled-up under mesofluidic conditions. The nebulization with both mini and nano spray-dryer, the SEM analysis of nanoparticles and the aerodynamic evaluation of a formulation obtained by physical mixing of atomized D-leucine powders with budenoside showed an excellent decrease in particle size without altering the morphology, and a marked improvement in the aerodynamic properties of the drug. This simple and economic method by physical mixing of leucine with micronized active pharmaceutical ingredients can represent a valid alternative to co-spray-drying.

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      The Role of Single-Atom Catalysis in Potentially Disruptive Technologies

      • Mario Pagliaro
      • Instituto per lo Studio dei Materiali Nanostrutturati, CNR, Palermo, Italy

      Single-atom catalysis holds significant potential as a disruptive chemical technology. The production of a number of key chemical products, including solar hydrogen, ammonia, and hydrogen peroxide, could be shortly reshaped by the commercialization of new single-atom catalysts and the related new decentralized chemical manufacturing processes. This chapter focuses on four potential applications of single-atom catalysts that may soon significantly impact the chemical and energy sectors central to the current and future industrial societies: synthetic organic chemistry, ammonia and solar hydrogen manufacturing, and hydrogen utilization in low-cost fuel cells.

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      A Simple and Efficient Flow Preparation of Pyocyanin a Virulence Factor of Pseudomonas aeruginosa

      • Frederik B. Mortzfelda,b
      • Jörg Pietruszkab
      • Ian R. Baxendale*a
      • aDepartment of Chemistry, University of Durham, South Road, Durham, Durham, DH1 3LE, UK
      • bInstitut für Bioorganische Chemie, Heinrich‐Heine‐Universität Düsseldorf im Forschungszentrum Jülich, 52425, Jülich, Deutschland

      The synthesis of the naturally occurring toxin pyocyanin has been realized in a short 4 step sequence. The key photochemical reaction and isolation of the final product have been facilitated by the use of flow chemistry techniques and immobilised reagents. Using these procedures gram quantities of pyocyanin were easily prepared in high yield and purity.

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      Electrophilic Bromination in Flow: A Safe and Sustainable Alternative to the Use of Molecular Bromine in Batch

      • Reinout Van Kerrebroeck
      • Pieter Naert
      • Thomas S. A. Heugebaert
      • Matthias D'hooghe
      • Christian V. Stevens*
      • SynBioC research Group, Department of Green Chemistry and Technology, Ghent University, Coupure Links 653, 9000 Ghent, Belgium

      Bromination reactions are crucial in today’s chemical industry since the versatility of the formed organobromides makes them suitable building blocks for numerous syntheses. However, the use of the toxic and highly reactive molecular bromine (Br2) makes these brominations very challenging and hazardous. We describe here a safe and straightforward protocol for bromination in continuous flow. The hazardous Br2 or KOBr is generated in situ by reacting an oxidant (NaOCl) with HBr or KBr, respectively, which is directly coupled to the bromination reaction and a quench of residual bromine. This protocol was demonstrated by polybrominating both alkenes and aromatic substrates in a wide variety of solvents, with yields ranging from 78% to 99%. The protocol can easily be adapted for the bromination of other substrates in an academic and industrial environment.

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      Microfluidic process intensification for synthesis and formulation in the pharmaceutical industry

      • Aliaa I. Shallana,b,*
      • Craig Priesta,c
      • aFuture Industries Institute, University of South Australia, Mawson Lakes, SA, 5095, Australia
      • bFaculty of Pharmacy, Helwan University, Cairo, 11795, Egypt
      • cSchool of Engineering, University of South Australia, Mawson Lakes, SA, 5095, Australia

      Process intensification has had an enormous impact on industrial strategy over the last century, with good outcomes for efficiency, safety, environment, and financial cost. Microfluidics offers a relatively new approach that has been studied for 30 years and has become a realistic tool for process intensification in important areas, including pharmaceutical industry. Drug manufacturing and development are expensive, highly regulated, and of great importance to society, due to the health care application. It is therefore a natural target for new technologies that can make pharmaceuticals simultaneously cheaper, more effective, and more accessible, without adverse impact on the environment and health of the workforce. Much work has been done, so this review will necessarily focus on improved pharmaceutical synthesis and drug delivery systems. This review also highlights examples of process intensification and future directions.

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      Continuous Flow Chemo-Enzymatic Baeyer–Villiger Oxidation with Superactive and Extra-Stable Enzyme/Carbon Nanotube Catalyst: An Efficient Upgrade from Batch to Flow

      • Anna Szelwickaa
      • Przemysław Zawadzkib
      • Magdalena Sitkoa
      • Sławomir Boncelc
      • Wojciech Czardybonb
      • Anna Chrobok*a
      • aDepartment of Chemical Organic Technology and Petrochemistry, Silesian University of Technology, Krzywoustego 4, 44-100 Gliwice, Poland
      • bSelvita S.A., Bobrzynskiego 14, 30-348 Cracow, Poland
      • cDepartment of Organic Chemistry, Bioorganic Chemistry, and Biotechnology, Silesian University of Technology, Krzywoustego 4, 44-100 Gliwice, Poland

      Continuous flow chemo-enzymatic Baeyer–Villiger oxidation in the presence of exceptionally active Candida antarctica lipase B immobilized via simple physical adsorption on multiwalled carbon nanotubes has been investigated. The nanobiocatalyst was used to generate peracid in situ from ethyl acetate and 30 wt % aq. hydrogen peroxide as the primary oxidant. Application of the highly stable and active nanobiocatalyst in the Baeyer–Villiger oxidation of 2-methylcyclohexanone to 6-methyl-ε-caprolactone after 8 h at 40 °C led to a high product yield (87%) and selectivity (>99%). Environmentally friendly ethyl acetate was applied as both solvent and the peracid precursor. To determine the most favorable reaction conditions, a series of experiments using various parameters was performed. The main contribution of this work is that it describes the first application of the nanobiocatalyst in a chemo-enzymatic Baeyer–Villiger oxidation in a flow system. Since the process was performed in a flow reactor, many improvements were achieved. First of all, substantially shorter reaction times as well as a significant increase in the product yield were obtained as compared to the batch process. Since peracids are unstable, a large increase in the safety of the process was demonstrated under mild conditions in this work. In summary, this work shows a particularly efficient upgrade in the studied processes by transfer from a batch to a flow system.

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      Synthetic Route Design of AZD4635, an A2AR Antagonist

      • Mairi M. Littleson *†, Andrew D. Campbell , Adam Clarke , Mark Dow , Gareth Ensor , Matthew C. Evans , Adam Herring ,Bethany A. Jackson , Lucinda V. Jackson , Staffan Karlsson , David J. Klauber , Danny H. Legg §, Kevin W. Leslie , Štefan Moravcí̌k , Chris D. Parsons §, Thomas O. Ronson , Rebecca E. Meadows
      • Chemical Development, Pharmaceutical Technology and Development, AstraZeneca, Macclesfield Campus, SK10 2NA, Macclesfield, U.K.
      • Early Chemical Development, Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, SE-431 83 Mölndal, Sweden
      • § Early Chemical Development, Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca, Macclesfield Campus, SK10 2NA, Macclesfield, U.K.

      The AstraZeneca approach to synthetic Route Design is exemplified through our AZD4635 chemical development program. The identification of possible new route concepts is presented, as well as their subsequent prioritization for practical exploration based on project objectives. Selected ideas were tested to demonstrate proof of concept for the bond formation strategy and, where successful, were fed into a decision tool based on key SELECTion principles.

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      Continuous flow knitting of a triptycene hypercrosslinked polymer

      • Cher Hon Lau *a
      • Tian-dan Lu b
      • Shi-Peng Sun b
      • Xianfeng Chen a
      • Mariolino Carta c
      • Daniel M. Dawson d
      • a School of Engineering, The University of Edinburgh, Robert Stevenson Road,Edinburgh EH9 3FB, UK
      • b State Key Laboratory of Materials-Oriented Chemical Engineering, College of Chemical Engineering, Nanjing Tech. University, Nanjing 210009, China
      • c Department of Chemistry, College of Science, Swansea University, Grove Building, Singleton Park, Swansea SA2 8PP, UK
      • d School of Chemistry, EaStCHEM and Centre of Magnetic Resonance, University of St. Andrews, KY16 9ST, UK

      By replacing Lewis acids with Brønsted acids as catalysts, continuous flow synthesis of hypercrosslinked polymers is achieved within 10% of the time required for a typical batch reaction. Compared with batch-synthesised polymers, the flow-produced materials take up 24% more CO2, precluding the need for lengthy reaction protocols to yield high-performance hypercrosslinked polymers for carbon capture.

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      Transaminase‐catalyzed continuous synthesis of biogenic aldehydes

      • Martina L. Contente a
      • Francesca Paradisi *a,b
      • a School of Chemistry, University of Nottingham, University Park, Nottingham, NG7, 2RD, United Kingdom
      • b Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, 3012 Bern

      The physiological role of biogenic aldehydes such as Dopal and Dopegal has been associated with cardiovascular and neurodegenerative disorders. The availability of these substrates is limited and robust synthetic methodologies would greatly facilitate further biological studies. Here we report on transaminase mediated single‐step process in continuous mode which leads to excellent product yields (90‐95%). Co‐immoblization of the PLP cofactor eliminated the need of exogenous addition of this reagent without affecting the longevity of the system, delivering a truly self‐sufficient process.

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      Optimisation by Design of Experiment of Benzimidazol-2-One Synthesis under Flow Conditions

      Serena Mostarda1,2, Tugçe Gür Maz3, Alessandro Piccinno1, Bruno Cerra1, Erden Banoglu3

      • 1Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06123 Perugia, Italy
      • 2Current affiliation: Novartis Pharma AG, CH-4002 Basel, Switzerland
      • 3Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Etiler, 06560 Ankara, Turkey

      A novel flow-based approach for the preparation of benzimidazol-2-one (1) scaffold by the 1,1′-carbonyldiimidazole (CDI)-promoted cyclocarbonylation of o-phenylenediamine (2) is reported. Starting from a preliminary batch screening, the model reaction was successfully translated under flow conditions and optimised by means of design of experiment (DoE). The method allowed the efficient preparation of this privileged scaffold and to set up a general protocol for the multigram-scale preparation in high yield, purity, and productivity, and was successfully applied for the multigram flow synthesis of N-(2-chlorobenzyl)-5-cyano-benzimidazol-2-one, which is a key synthon for hit-to-lead explorations in our anti-inflammatory drug discovery program.

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      A Novel and Efficient Continuous-Flow Route To Prepare Trifluoromethylated N‑Fused Heterocycles for Drug Discovery and Pharmaceutical Manufacturing

      • Lara Amini-Rentsch1,2
      • Ennio Vanoli2
      • Sylvia Richard-Bildstein1
      • Roger Marti2
      • Gianvito Vilé1
      • 1 Idorsia Pharmaceuticals Ltd., Chemistry Technologies & Lead Discovery, Department of Drug Discovery Chemistry, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
      • 2 University of Applied Sciences Western Switzerland (HES-SO), Haute Ecole d’Ingénierie et d’Architecture de Fribourg, Institute of Chemical Technology, 80 boulevard de Pérolles, CH-1700 Fribourg, Switzerland

      Continuous-flow processing has become one of the fastest-growing research areas in chemistry in the last 10 years. Herein we disclose an automated and scalable continuous-flow route for the quick introduction of trifluoromethyl groups on a variety of heterocycles, with application in drug discovery and manufacturing. This involves the direct alkylation-cyclization of amines in the presence of trifluoroacetic acid or anhydride, cheap and readily available CF3-containing building blocks.
      Compared to traditional batch reactions involving an intermediate purification step, the continuous-flow reactions occurred quickly and at mild conditions, with high yield and broad functional-group tolerance. The practical utility of the method was demonstrated by a gram-scale synthesis and by the estimation of modern green metrics.

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      A robust and scalable continuous flow process for glycerol carbonate

      Seger Van Mileghema,b, Wim M. De Borggraeveb, Ian R. Baxendalea

      • aUniversity of Durham, Department of Chemistry, South Road, DH1 3LE Durham, UK
      • bKU Leuven, Division of Molecular Design and Synthesis, Department of Chemistry, Celestijnenlaan 200F, 3001 Heverlee, Belgium

      With glycerol being a bulk waste product, the interest in converting it to other value-added products is steadily increasing. A scalable continuous flow process was developed for the synthesis of glycerol carbonate (2-GLC) from glycerol and dimethyl carbonate on a hydroxide functional resin. High conversion and selectivity were obtained while the residence times were typically shorter than 10 min. Continuous production of 2-GLC was achieved in high throughput and with improved processing metrics, creating the foundations for a production level process.

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      Flow Hydrodediazoniation of Aromatic Heterocycles

      • Liesa Röder1
      • Alexander J. Nicholls2
      • Ian R. Baxendale2
      • 1 Department of Biology, Chemistry, and Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany
      • 2 Department of Chemistry, University of Durham, South Road, Durham, DH1 3LE, UK

      Continuous flow processing was applied for the rapid replacement of an aromatic amino group with a hydride. The approach was applied to a range of aromatic heterocycles, confirming the wide scope and substituent-tolerance of the processes. Flow equipment was utilized and the process optimised to overcome the problematically-unstable intermediates that have restricted yields in previous studies relying on batch procedures. Various common organic solvents were investigated as potential hydride sources. The approach has allowed key structures, such as amino-pyrazoles and aminopyridines, to be deaminated in good yield using a purely organic-soluble system.

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      Continuous‐Flow Electrochemical Generator of Hypervalent Iodine Reagents: Synthetic Applications

      • Dr Mohamed Elsherbini
      • Bethan Winterson
      • Haifa Alharbi
      • Ana A. Folgueiras-Amador
      • Clina Gnot
      • Thomas Wirth
      • School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT UK

      An efficient and reliable electrochemical generator of hypervalent iodine reagents has been developed. In the anodic oxidation of iodoarenes to hypervalent iodine reagents under flow conditions, the use of electricity replaces hazardous and costly chemical oxidants. Unstable hypervalent iodine reagents can be prepared easily and coupled with different substrates to achieve oxidative transformations in high yields. The unstable, electrochemically generated reagents can also easily be transformed into classic bench‐stable hypervalent iodine reagents through ligand exchange. The combination of electrochemical and flow‐chemistry advantages largely improves the ecological footprint of the overall process compared to conventional approaches.

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      Definitive screening designs for multistep kinetic models in flow

      • Christopher A. Honea
      • Alistair Boydb
      • Anne O’Kearney-McMullanb
      • Richard A. Bournea*
      • Frans L. Mullera*
      • a Institute of Process Research and Development (iPRD), School of Chemistry and School of Chemical and Process Engineering, University of Leeds, LS2 9JT, UK
      • b Global Development, AstraZeneca, Macclesfield, Cheshire, UK, SK10 2NA, UK

      Currently, rate-based understanding of organic reactions employed in the manufacture of active pharmaceutical ingredients (APIs) is often not obtained. In many cases, the generation of kinetic models is still seen as a specialised and time intensive activity, which can only be justified at certain instances in development. In this Communication, we report the application of a definitive screening design (DSD) in combination with reaction profiling for the efficient collection of kinetic data. The experimental data (10 profiles, 40 experimental data points) were collected within a short time frame (<1 week) within a continuous flow reactor. The data were fitted to a multistep kinetic model consisting of 3 fitted rate constants and 3 fitted activation energies. The approach is demonstrated on a Friedel-Crafts type reaction used in the synthesis of an important API. Our approach enables early identification of the sensitivity of product quality to parameter changes and the early use of process models to identify optimal process-equipment combinations in silico, significantly reducing development time and scale-up risks.

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      Visible light‐promoted Fe‐catalyzed Csp2‐Csp3 Kumada cross‐coupling in flow

      • Xiao-Jing Weia
      • Irini Abdiajb
      • Carlo Sambiagioa
      • Chenfei Lic
      • Eli Zysman-Colmanc
      • Jesús Alcázarb
      • Timothy Noëla
      • a Department of Chemical Engineering and Chemistry Micro Flow Chemistry and Synthetic Methodology Eindhoven University of Technology Den Dolech 2, 5612 AZ Eindhoven (The Netherlands)
      • b Discovery Sciences, Janssen Research and Development Jannsen-Cilag, S.A. Jarama 75A, 45007 Toledo (Spain)
      • c Organic Semiconductor Center, EaStCHEM School of ChemistryUniversity of St Andrews, St Andrews, Fife, KY16 9ST (UK).

      A continuous‐flow, visible light‐promoted method has been developed to overcome the limitations of Fe‐catalyzed Kumada‐Corriu cross‐couplings. A variety of strongly electron‐rich aryl chlorides, previously hardly reactive, could be efficiently coupled with aliphatic Grignard reagents at room temperature, in high yields and within a few minutes residence time, considerably enhancing the applicability of this Fe‐catalyzed reaction. The robustness of this protocol was demonstrated on the multi‐gram scale, providing the potential for future pharmaceutical application.

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      Experimental Methods in Chemical Engineering: Micro‐Reactors

      • Arturo Macchi a
      • Patrick Plouffe a
      • Gregory S. Patience b
      • Dominique M. Roberge c
      • a Centre for Catalysis Research and Innovation, Department of Chemical and Biological Engineering, University of Ottawa, Ottawa, ON, K1N 6N5 Canada
      • b Department of Chemical Engineering ‐ Ecole Polytechnique de Montreal, QC, H3C 3A7 Canada
      • c Chemical Manufacturing Technologies, Lonza AG, CH‐, 3930 Visp, Switzerland

      Whereas the bulk chemical industry has historically sought economic advantage through economies of scale, a paradigm shift has researchers developing systems on smaller scales. Nano‐cages and nano‐actuators increase selectivity and robustness at the molecular scale. In parallel, micro‐contactors with sub‐millimeter lateral dimensions are decreasing boundary layers that restrict heat and mass transfer and thus meet the objectives of process intensification with great increases in productivity with a smaller footprint. These contactors continue to serve chemical engineers and chemists to synthesize fine chemicals and characterize catalysts, however, now have been adopted for sensors in biological and biochemical systems. A bibliometric analysis of articles indexed in the Web of Science in 2016 and 2017 identified five major clusters of research: catalysis and bulk chemicals; nanoparticles; organic synthesis and flow chemistry; systems and micro‐fluidics applied to biochemistry; and micro‐channel reactors and mass transfer. In the early 1990s, less than 100 articles a year mentioned micro‐reactors, while over 943 articles mentioned it in 2017. Here, we introduce micro‐reactors and their role in the continuous synthesis of fine chemicals across the various scales to commercialization.

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      Continuous Flow Synthesis of Highly Substituted Tetrahydrofurans

      • Patrick Hoffmeyer, Christoph Schneider
      • Institute of Organic Chemistry, University of Leipzig, Johannisallee 29, D, ‐04103 Leipzig Germany

      Under continuous flow conditions, the diastereoselective synthesis of a broad range of 2,3,5‐trisubstituted tetrahydrofurans has been developed. Compared to the initial batch synthesis both yields and selectivities with respect to different substituents in the 2,5‐position were improved and reaction times significantly reduced.

      The highly diastereoselective synthesis of multiply substituted tetrahydrofurans was achieved in a sequential process under continuous flow conditions. Greatly reduced reaction times, improved selectivities and enhanced yields are the benefits of this approach in comparison to the initial batch synthesis. Moreover, gram amounts of product were produced in the flow reactor likewise due to facile upscaling. In addition, employing a novel bis(silyl)dienediolate tetrasubstituted tetrahydrofurans were made accessible as well.

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      Peroxidation of 2-oxindole and barbituric acid derivatives under batch and continuous flow using an eco-friendly ethyl acetate solvent

      • Moreshwar B. Chaudhari a
      • Nirmala Mohanta a
      • Akanksha M. Pandey a
      • Madhusoodhanan Vandana b
      • Krishanpal Karmodiya b
      • Boopathy Gnanaprakasam*a
      • a Department of Chemistry, Indian Institute of Science Education and Research (IISER) Pune, Dr. Homi Bhabha Road, Pune 411008, India
      • b Department of Biology, Indian Institute of Science Education and Research (IISER) Pune, Dr. Homi Bhabha Road, Pune 411008, India

      The C(sp3)–H peroxidation of 2-oxindole and barbituric acid derivatives using aliphatic peroxides under continuous flow and their antimalarial evaluation in vitro have been explored using magnetic iron oxide nanoparticles. This transformation uses less toxic, low cost, and eco-friendly ethyl acetate as a solvent. To show the robustness, supported catalysis integrated with continuous-flow was employed as a process development tool for the expeditious synthesis of quaternary peroxide derivatives with a residence time of 7.9 minutes. Additionally, the explosive hazards of TBHP (tert-butyl hydroperoxide) were also minimized during peroxidation in a continuous-flow process by controlled addition.

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      Rapid and Multigram Synthesis of Vinylogous Esters under Continuous Flow: An Access to Transetherification and Reverse Reaction of Vinylogous Esters

      • Nirmala Mohanta
      • Moreshwar B. Chaudhari
      • Naveen Kumar Digrawal
      • Boopathy Gnanaprakasam*
      • Department of Chemistry, Indian Institute of Science Education and Research, Pune 411008, India

      An environmentally benign approach for the synthesis of vinylogous esters from 1,3-diketone and its reverse reaction under continuous-flow has been developed with alcohols in the presence of inexpensive Amberlyst-15 as a catalyst. This methodology is highly selective and general for a range of cyclic 1,3-dicarbonyl compounds which gives a library of linear alkylated and arylated vinylogous esters in good to excellent yield under solvent and metal free condition. Furthermore, the long-time experiment in a continuous-flow up to 40 h afforded 8.0 g of the vinylogous ester with turnover number (TON) = 28.6 and turnover frequency (TOF) = 0.715 h–1 using Amberlyst-15 as a catalyst. Furthermore, a continuous-flow sequential transetherification of vinylogous esters with various alcohols has been achieved in high yield. Reversibly, this vinylogous ester was deprotected or hydrolyzed into ketone using environmentally benign water as a solvent and Amberlyst-15 as a catalyst under continuous-flow process.

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      Continuous manufacturing – the Green Chemistry promise?

      • Luke Rogers and Klavs F. Jensen
      • Department of Chemical Engineering, MIT, 77 Massachusetts Avenue, Cambridge, MA 02139-4307, USA

      Continuous manufacturing and Green Chemistry, are two promising approaches to synthesis with underutilized potential that are gaining traction by the wider pharmaceutical community. We review Green Chemistry advances resulting when transitioning to continuous manufacturing with focus on Green Chemistry elements inherent in flow chemistry and related separation processes. Case studies of continuous manufacturing represented by the F3 (Flexible, Fast, and Future) project, cGPM manufacturing at Eli Lilly, and the MIT pharmaceuticals on demand projects provide examples of Green Chemistry advances realised. Throughout the review, Green Chemistry advances are identified in terms of the pertinent principles of Green Chemistry. A count of the occurrences of the different principles of Green Chemistry reveals that the principle of prevention greatly overshadows all other principles.

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      Practical and regioselective amination of arenes using alkyl amines

      • Alessandro Ruffoni 1
      • Fabio Juliá 1
      • Thomas D. Svejstrup 1
      • Alastair J. McMillan 1
      • James J. Douglas 2
      • Daniele Leonori 1
      • 1 School of Chemistry, University of Manchester, Manchester, UK.
      • 2 Early Chemical Development, Pharmaceutical Sciences, IMED Biotech Unit,AstraZeneca, Macclesfield, UK

      The formation of carbon–nitrogen bonds for the preparation of aromatic amines is among the top five reactions carried out globally for the production of high-value materials, ranging from from bulk chemicals to pharmaceuticals and polymers. As a result of this ubiquity and diversity, methods for their preparation impact the full spectrum of chemical syntheses in academia and industry. In general, these molecules are assembled through the stepwise introduction of a reactivity handle in place of an aromatic C–H bond (that is, a nitro group, halogen or boronic acid) and a subsequent functionalization or cross-coupling. Here we show that aromatic amines can be constructed by direct reaction of arenes and alkyl amines using photocatalysis, without the need for pre-functionalization. The process enables the easy preparation of advanced building blocks, tolerates a broad range of functionalities, and multigram scale can be achieved via a batch-to-flow protocol. The merit of this strategy as a late-stage functionalization platform has been demonstrated by the modification of several drugs, agrochemicals, peptides, chiral catalysts, polymers and organometallic complexes.

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      The Influence of Residence Time Distribution on Continuous-Flow Polymerization

      • Marcus H. Reis
      • Travis P. Varner
      • Frank A. Leibfarth
      • Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

      Continuous-flow chemistry is emerging as an enabling technology for the synthesis of precise polymers. Despite recent advances in this rapidly growing field, there remains a need for a fundamental understanding of how fluid dynamics in tubular reactors influence polymerizations. Herein, we report a comprehensive study of how laminar flow influences polymer structure and composition. Tracer experiments coupled with in-line UV-vis spectroscopy demonstrate how viscosity, tubing diameter, and reaction time affect the residence time distribution (RTD) of fluid in reactor geometries relevant for continuous-flow polymerizations. We found that the breadth of the RTD has strong, statistical correlations with reaction conversion, polymer molar mass, and dispersity for polymerizations conducted in continuous flow. These correlations were demonstrated to be general to a variety of different reaction conditions, monomers, and polymerization mechanisms. Additionally, these findings inspired the design of a droplet flow reactor that minimizes the RTD in continuous-flow polymerizations and enables the continuous production of well-defined polymer at a rate of 1.4 kg/day.

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      Additive manufacturing of photoactive polymers for visible light harvesting

      • Adilet Zhakeyevac
      • John Tobina
      • Huizhi Wangb
      • Filipe Vilelaa
      • Jin Xuanac
      • a School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS, UK
      • b Department of Mechanical Engineering, Imperial College London, Exhibition Road, South Kensington Campus, London, SW7 2AZ, UK
      • c Department of Chemical Engineering, Loughborough University, Loughborough, UK

      In recent years, 3D printing has gained a great deal of attention in the energy field, with numerous reports demonstrating its application in fabrication of electrochemical devices. The near-complete freedom of design offered by 3D printing technologies make them very appealing, since complex 3D parts can be directly fabricated. However, its application in photochemistry and solar energy harvesting remains, so far, an uncharted territory. In this work, a photoactive monomer was incorporated into commercially available 3D printing resin, which was subsequently used to successfully fabricate 3D photosensitizing structures for singlet oxygen generation. Results indicate that the SLA fabricated small-scale (0.1 ml) photoactive continuous flow reactor shows activity in singlet oxygen synthesis reaction under visible light irradiation (420 nm).

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      Modeling and Design of a Flow-Microreactor-Based Process for Synthesizing Ionic Liquids

      • Yuichi Nakahara *†⊥
      • Bert Metten
      • Osamu Tonomura §⊥
      • Aiichiro Nagaki ∥⊥
      • Shinji Hasebe §⊥
      • Jun-ichi Yoshida ⊥#
      • Francesco Molinari 1
      • New Frontiers Research Group, Frontier Research Laboratories, Institute For Innovation, Ajinomoto Co., Inc., 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki, Kanagawa 210-8681, Japan
      • Ajinomoto Bio Pharma Services, Cooppallaan 91, B-9230 Wetteren, Belgium
      • § Department of Chemical Engineering, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto 615-8510, Japan
      • Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto 615-8510, Japan
      • Micro Chemical Production Study Consortium in Kyoto University, Kyoto University, Nishikyo-ku, Kyoto 615-8510, Japan
      • # National Institute of Technology, Suzuka College, Shiroko-cho, Suzuka, Mie 510-0294, Japan

      A synthesis process for the ionic liquid (IL) 1-butyl-3-methylimidazolium chloride (BMIM.Cl) was developed using a flow microreactor (FMR) in this study. After the reaction rate analysis, the FMR was efficiently designed using computational fluid dynamics simulation, which can shorten the process development time by reducing trial-and-error experimentation. The designed FMR is composed of a V-shaped mixer and a tubular reactor having a millimeter-scale inner diameter. From the viewpoint of process operation and control, reactors with larger inner diameter are basically preferable. The influence of three inner diameters, 0.75, 2.16, and 4.35 mm, that satisfy temperature constraints on product quality, product yield, and production volume was investigated. It was found that as the inner diameter becomes large, the product yield becomes low because the mass transfer approaches the rate-limiting step of the reaction process. To avoid this problem, it was proposed that static mixers should be built in the reactor having the inner diameter of 4.35 mm. As a result, its production volume, without lowering the product yield, could be improved about 39 times compared with the conventional one.

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      Synthesis of a Renewable Macrocyclic Musk: Evaluation of Batch, Microwave, and Continuous Flow Strategies

      • Émilie Morin §
      • Johann Sosoe §
      • Michaël Raymond §
      • Benjamin Amorelli †*
      • Richard M. Boden
      • Shawn K. Collins
      • § Department of Chemistry and Centre for Green Chemistry and Catalysis, Université de Montréal, CP 6128 Station Downtown, Montréal, Québec, Canada H3C 3J7
      • Research & Development, International Flavors & Fragrances Inc., 1515 State Route 36, Union Beach, New Jersey, 07735, United States

      The renewable macrocyclic musk 3-methylcyclohexadec-6-enone was prepared via macrocyclic olefin metathesis on gram scale using two different protocols: a room temperature batch process which afforded a 57% yield of the desired macrocycle, but required long reaction times (5 d). In contrast, a continuous flow strategy provided a lower yield of 32% of macrocycle, although the short reaction times (150 °C, 5 min) improve throughput (1 g/4.8 h). Batch and continuous flow protocols were also tested on other macrocyclizations involving substrates bearing trisubstituted olefins.

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      Bioprocess Intensification Using Flow Reactors: Stereoselective Oxidation of Achiral 1,3-diols with Immobilized Acetobacter Aceti

      • Valerio De Vitis 1
      • Federica Dall’Oglio 2
      • Francesca Tentori 3
      • Martina Letizia Contente 4
      • Elisabetta Brenna 3
      • Lucia Tamborini 2
      • Francesco Molinari 1
      • 1 Department of Food, Environmental and Nutritional Sciences (DeFENS), Università degli Studi di Milano, Via Celoria 2, 20133 Milan, Italy
      • 2 Department of Pharmaceutical Sciences (DISFARM), Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy
      • 3 Dipartimento di Chimica, Materiali ed Ingegneria Chimica “Giulio Natta” Politecnico di Milano, Via Mancinelli 7, I-20131 Milan, Italy
      • 4 School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK

      Enantiomerically enriched 2-hydroxymethylalkanoic acids were prepared by oxidative desymmetrisation of achiral 1,3-diols using immobilized cells of Acetobacter aceti in water at 28 °C. The biotransformations were first performed in batch mode with cells immobilized in dry alginate, furnishing the desired products with high molar conversion and reaction times ranging from 2 to 6 h. The biocatalytic process was intensified using a multiphasic flow reactor, where a segmented gas–liquid flow regime was applied for achieving an efficient O2-liquid transfer; the continuous flow systems allowed for high yields and high biocatalyst productivity.

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      Reversible chemoselective transetherification of vinylogous esters using Fe-catalyst under additive free conditions

      • Nenavath Parvathalu, Sandip G. Agalave, Nirmala Mohanta and Boopathy Gnanaprakasam
      • Department of Chemistry, Indian Institute of Science Education and Research, Pune-411008, India

      An additive/Brønsted acid/base free, highly efficient and chemoselective transetherification of electron deficient vinylogous esters and water mediated de-alkylation using an earth-abundant Fe-catalyst under very mild reaction conditions is described. This reaction is highly selective to primary alcohols over secondary alcohols, has good functional group tolerance, is scalable to gram scale and a purification free sequential transetherification in a continuous flow mode is demonstrated.

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      Investigation of a Weak Temperature–Rate Relationship in the Carbamoylation of a Barbituric Acid Pharmaceutical Intermediate

      • Alexander G. O’Brien *†
      • Yangmu Chloe Liu *†
      • Mark J. Hughes
      • John Jin Lim
      • Neil S. Hodnett
      • Nicholas Falco
      • GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States
      • GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom

      The rate of reaction between N,N′-dicyclohexylbarbituric acid 1 and ethyl 2-isocyanatoacetate 2 is invariant with temperature. Positive orders in each reactant and dissociation of triethylammonium salts of 1 and product 3 at elevated temperature indicate that reaction occurs via a catalytic mechanism where changes to the positions of equilibria negate changes in the rate of the turnover-limiting step. A model for the consumption of 1 in a flow reactor accurately predicted the outcome of a laboratory-scale multivariate study.

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      Protection‐Group‐Free Synthesis of Sequence‐Defined Macromolecules via Precision λ‐Orthogonal Photochemistry

      • Waldemar Konrad1,2
      • Christian Fengler1,2
      • Sarrah Putwa1
      • Christopher Barner-Kowollik1,2
      • 1Macromolecular Architectures, Institut für Technische Chemie und Polymerchemie, Karlsruhe Institute of Technology (KIT), Engesserstr. 18, 76131 Karlsruhe, Germany
      • 2School of Chemistry, Physics and Mechanical Engineering, Queensland University of Technology (QUT), 2 George Street, QLD, 4000 Brisbane, Australia

      An advanced light‐induced avenue to monodisperse sequence‐defined linear macromolecules via a unique photochemical protocol is presented that does not require any protection‐group chemistry. Starting from a symmetrical core unit, precision macromolecules with molecular weights up to 6257.10 g mol−1 are obtained via a two‐monomer system: a monomer unit carrying a pyrene functionalized visible light responsive tetrazole and a photo‐caged UV responsive diene, enabling an iterative approach for chain growth; and a monomer unit equipped with a carboxylic acid and a fumarate. Both light‐induced chain growth reactions are carried out in a λ‐orthogonal fashion, exciting the respective photosensitive group selectively and thus avoiding protecting chemistry. Characterization of each sequence‐defined chain (size‐exclusion chromatography (SEC), high‐resolution electrospray ionization mass spectrometry (ESI‐MS), and NMR spectroscopy), confirms the precision nature of the macromolecules.

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      Decarboxylative Intramolecular Arene Alkylation Using N-(Acyloxy)phthalimides, an Organic Photocatalyst, and Visible Light

      • Trevor C. Sherwood*†
      • Hai-Yun Xiao*†
      • Roshan G. Bhaskar
      • Eric M. Simmons
      • Serge Zaretsky
      • Martin P. Rauch§
      • Robert R. Knowles§
      • T. G. Murali Dhar
      • Research and Development, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, New Jersey 08543-4000, United States
      • Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States
      • §Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States

      An intramolecular arene alkylation reaction has been developed using the organic photocatalyst 4CzIPN, visible light, and N-(acyloxy)phthalimides as radical precursors. Reaction conditions were optimized via high-throughput experimentation, and electron-rich and electron-deficient arenes and heteroarenes are viable reaction substrates. This reaction enables access to a diverse set of fused, partially saturated cores which are of high interest in synthetic and medicinal chemistry.

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      Flow Electrochemical Cyclizations via Amidyl Radicals: Easy Access to Cyclic Ureas

      Nisar Ahmeda,b*, Aggeliki Vgenopouloua

      • a School of Chemistry, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
      • b School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK

      Flow chemistry has advantages over batch processes and can achieve the synthesis of substances in high yield under safe working conditions. The combination of electrochemistry and flow microreactor technology has made chemical transformations possible without the use of oxidants or catalysts. Herein, we report flow electrosynthesis of cyclic ureas via oxyamination of N-allylic ureas. We have found that continuous flow is able to outperform its batch counterpart, producing cyclic ureas in excellent yields.

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      Efficient Flow Electrochemical Alkoxylation of Pyrrolidine-1-Carbaldehyde

      • Nasser Amria
      • Ryan A. Skiltonb
      • Duncan Guthrieb
      • Thomas Wirth*a
      • a School of Chemistry, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
      • b Vapourtec Ltd., 21 Park Farm Business Centre, Bury St Edmunds, IP28 6TS, UK

      We report on the optimization of the alkoxylation of pyrrolidine-1-carbaldehyde by using a new electrochemical microreactor. Precise control of the reaction conditions permits the synthesis of either mono- or dialkoxylated reaction products in high yields.

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      Overcoming Water Insolubility in Flow: Enantioselective Hydrolysis of Naproxen Ester

      • David Roura Padrosa1
      • Valerio De Vitis2
      • Martina Letizia Contente1*
      • Francesco Molinari2
      • Francesca Paradisi1*
      • 1 School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
      • 2 Department of Food, Environmental and Nutritional Sciences (DeFENS), Università degli studi di Milano, Via Mongiagalli 25, 20133 Milan, Italy;

      Hydrolytic enantioselective cleavage of different racemic non-steroidal anti-inflammatory drugs (NSAIDs) ester derivatives has been studied. An engineered esterase form Bacillus subtilis (BS2m) significantly outperformed homologous enzymes from Halomonas elongata (HeE) and Bacillus coagulants (BCE) in the enantioselective hydrolysis of naproxen esters. Structural analysis of the three active sites highlighted key differences which explained the substrate preference. Immobilization of a chimeric BS2m-T4 lysozyme fusion (BS2mT4L1) was improved by resin screening achieving twice the recovered activity (22.1 ± 5 U/g) with respect to what had been previously reported, and was utilized in a packed bed reactor. Continuous hydrolysis of α-methyl benzene acetic acid butyl ester as a model substrate was easily achieved, albeit at low concentration (1 mM). However, the high degree of insolubility of the naproxen butyl ester resulted in a slurry which could not be efficiently bioconverted, despite the addition of co-solvents and lower substrate concentration (1 mM). Addition of Triton® X-100 to the substrate mix yielded 24% molar conversion and 80% e.e. at a 5 mM scale with 5 min residence time and sufficient retention of catalytic efficiency after 6 h of use.

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      A solid-supported arylboronic acid catalyst for direct amidation

      • Yihao Dua,
      • Thomas Barbera,
      • Sol Ee Lima,
      • Henry S. Rzepab,
      • Ian R. Baxendale*a,
      • Andrew Whiting*a,
      • a Centre for Sustainable Chemical Processes, Department of Chemistry, Durham University, Science Laboratories, South Road, Durham, UK
      • a Department of Chemistry, Imperial College, South Kensington Campus, London, UK

      An efficient heterogeneous amidation catalyst has been prepared by co-polymerisation of styrene, DVB with 4-styreneboronic acid, which shows wide substrate applicability and higher reactivity than the equivalent homogeneous phenylboronic acid, suggesting potential cooperative catalytic effects. The catalyst can be easily recovered and reused; suitable for use in packed bed flow reactors.

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      Visible Light‐Promoted Beckmann Rearrangements: Separating Sequential Photochemical and Thermal Phenomena in a Continuous Flow Reactor

      • Yuesu Chen
      • David Cantillo
      • C. Oliver Kappe
      • Karl-Franzens-Universitat Graz, Institute of Chemistry, 8010 Graz, AUSTRIA

      The Beckmann rearrangement of oximes to amides typically requires strong acids or highly reactive, hazardous electrophiles and/or high tempertatures to proceed. A very attractive alternative is the in situ generation of Vilsmeier‐Haack reagents, by means of photoredox catalysis, as promoters for the thermal rearrangement. Investigation of the reaction parameters for this light induced method using a one‐pot strategy has shown that the reaction is limited by the different temperatures required for each of the two sequential steps. Using a continuous flow reactor, the photochemical and thermal processes have been separated by integrating a flow photoreactor unit at low temperature for the electrophile generation with a second reactor unit, at high temperature, where the rearrangement takes place. This strategy has enabled excellent conversions and yields for a diverse set of oximes, minimizing all side products that were being obtained with the original one‐pot method.

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      A Consolidated and Continuous Synthesis of Ciprofloxacin from a Vinylogous Cyclopropyl Amide

      • N. Perrer Tosso, Bimbisar K. Desai, Eliseu De Oliveira, Juekun Wen, John Tomlin, and B. Frank Gupton*
      • Department of Chemistry and Department of Chemical and Life Science Engineering, Virginia Commonwealth University, 601 West Main Street, Richmond, Virginia 23220, United States

      Ciprofloxacin is a broad-spectrum antibiotic that is recognized as one of the World Health Organization’s Essential Medicines. It is particularly effective in the treatment of Gram-negative bacterial infections associated with urinary, respiratory, and gastrointestinal tract infections. A streamlined and high yielding continuous synthesis of ciprofloxacin has been developed, which employs a chemoselective C-acylation step that precludes the need for intermediate isolations, extractions, or purifications. The end-to-end process has a residence time of 4.7 min with a 15.8 g/h throughput at laboratory scale and an overall isolated yield of 83%.

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      Emerging Trends in Flow Chemistry and Applications to the Pharmaceutical Industry

      • Andrew R Bogdan
      • Amanda W Dombrowski
      • Discovery Chemistry and Technologies, AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States

      The field of flow chemistry has garnered considerable attention over the past two decades. This perspective highlights many recent advances in the field of flow chemistry and discusses applications to the pharmaceutical industry, from discovery to manufacturing. From a synthetic perspective, a number of new enabling technologies are providing more rationale to run reactions in flow over batch techniques. Additionally, highly automated flow synthesis platforms have been developed with broad applicability across the pharmaceutical industry, ranging advancing medicinal chemistry programs to self-optimizing synthetic routes. A combination of simplified and automated systems is discussed, demonstrating how flow chemistry solutions can be tailored to fit the specific needs of a project.

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      Towards a Scalable Synthesis of 2‐Oxabicyclo[2.2.0]hex‐5‐en‐3‐one Using Flow Photochemistry

      • Jason D. Williamsa,b
      • Yuma Otakea
      • Guilhem Coussanesc
      • Iakovos Saridakiscc
      • Nuno Maulidecc
      • C. Oliver Kappeaa,b
      • a Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
      • b Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria
      • c Institute of Organic Chemistry, University of Vienna, Währinger Strasse 38, 1090 Vienna, Austria

      Cyclobutene lactones hold great potential as synthetic building blocks, yet their preparation by photochemical rearrangement in batch can often be a bottleneck in synthetic studies. We report the use of flow photochemistry as a tool to enable a higher‐throughput approach to the synthesis of 2‐oxabicyclo[2.2.0]hex‐5‐en‐3‐one, which reduces reaction times from 24 hours to 10 minutes. Accordingly, a significantly improved throughput of 144 mg/h (vs 14‐21 mg/h in batch) was achieved. Scale‐out experiments showed problematic reactor fouling, whereby steps were taken to explore and minimize this effect.

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      Continuous flow processing as a tool for the generation of terpene-derived monomer libraries

      • Renan Galavernaa
      • Lucas P. Fernandesa
      • Duncan L. Browneb
      • Julio C. Pastrea
      • a Institute of Chemistry, University of Campinas – UNICAMP, Campinas, Brazil
      • b School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK

      We report the development of a continuous flow approach for the preparation of two bio-derived monomer libraries. A small range of terpenes (ocimene, myrcene, α-terpinene, α-phellandrene, isoprene, and farnesene) have been used as the base set for the library, with the first library derived from a Diels–Alder reaction with the platform chemical maleic anhydride. The second library requires the derivatization of the first through a hydrogenation reaction. The potential for scale-up of both libraries has been demonstrated, with the Diels–Alder process delivering 10.5 grams of the product in 3 hours and the hydrogenation process delivering 10 grams of the material in 16 hours.

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      Rapid Photochemical Reaction Studies under Continuous-flow Conditions in the Vapourtec UV-150 Reactor-A Technical Note

      • Richard Huntera
      • Sam Joslanda
      • Joseph Mooreb
      • Duncan Guthrieb
      • Mark J. Robertsona
      • Michael Oelgemöllera
      • a College of Science and Engineering, James Cook University, Townsville, QLD 4911, Australia
      • b Vapourtec Ltd, Park Farm Business Centre, Fornham St Genevieve, Bury St Edmunds, Suffolk, IP28 6TS, UK

      Five different model reactions (photodecarboxylation, inter- and intramolecular [2+2] cycloadditions, TiO2 photocatalytic reduction and type II photooxygenation) were investigated in the advanced Vapourtec UV-150 photo reactor with their conversion and throughput potentials reported. Compared to known batch reactions in laboratory reactors, significantly higher calculated productivities were achieved despite a rather small 10 mL reactor coil. The device enables rapid, convenient, reliable and reproducible flow photochemistry studies across the entire wavelengths spectrum and on flexible scales.

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      Enabling synthesis in fragment-based drug discovery by reactivity mapping: photoredox-mediated cross-dehydrogenative heteroarylation of cyclic amines

      • Rachel Grainger*a
      • Tom D. Heightmana
      • Steven V. Leyb
      • Fabio Limab,c
      • Christopher N. Johnson*a
      • a Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, UK
      • b Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
      • c Novartis Pharma AG, Novartis Campus, 4002 Basel, Switzerland

      In fragment-based drug discovery (FBDD), a weakly binding fragment hit is elaborated into a potent ligand by bespoke functionalization along specific directions (growth vectors) from the fragment core in order to complement the 3D structure of the target protein. This structure-based design approach can present significant synthetic challenges, as growth vectors often originate on sp2 or sp3 ring carbons which are not the most synthetically accessible points on the fragment. To address this issue and expedite synthesis in FBDD, we established a nanogram-to-gram workflow for the development of enabling synthetic transformations, such as the direct C–H functionalization of heterocycles. This novel approach deploys high-throughput experimentation (HTE) in 1536-well microtiter plates (MTPs) facilitated by liquid handling robots to screen reaction conditions on the nanomolar scale; subsequently the reaction is upscaled in a continuous flow to generate gram-quantities of the material. In this paper, we disclose the use of this powerful workflow for the development of a photoredox-mediated cross-dehydrogenative coupling of fragments and medicinally relevant heterocyclic precursors via Minisci-type addition of α-amino radicals to electron-deficient heteroarenes. The optimized reaction conditions were employed on the milligram-scale on a diverse set of 112 substrates to map out structure–reactivity relationships (SRRs) of the transformation. The coupling exhibits excellent tolerance to a variety of functional groups and N-rich heteroarenes relevant to FBDD and was upscaled in a continuous flow to afford gram-quantities of pharmaceutically relevant sp2–sp3 privileged architectures.

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      Enhanced mixing of biphasic liquid-liquid systems for the synthesis of gem-dihalocyclopropanes using packed bed reactors

      • T von Keutz1,2
      • D Cantillo1,2
      • CO Kappe1,2
      • 1 Center for Continuous Flow Synthesis and Processing (CCFLOW) Research Center Pharmaceutical Engineering GmbH (RCPE) Graz, Austria
      • 2 Institute of Chemistry, NAWI Graz, University of Graz, Graz, Austria

      A continuous flow procedure for the gem-dichlorocyclopropanation of alkenes has been developed. The method is based on the generation of dichlorocarbene utilizing the classical biphasic aqueous sodium hydroxide/chloroform system. This reaction typically requires vigorous stirring for several hours in batch for completion. Tarry materials precipitate due to partial polymerization of dichlorocarbene and the process is difficult to scale. To overcome these problems and achieve very efficient mixing during the flow process a column reactor packed with PTFE beads as inert filling material has been used. PTFE beads have been found to be the optimal material to obtain fine dispersions of the aqueous phase in the organic solution. By heating the packed-bed reactor at 80 °C excellent conversions have been achieved after a residence time of only 4 min. The process has been applied for the synthesis of Ciprofibrate, a dichlorocyclopropane-containing drug used as treatment for several diseases associated with high lipid content in blood.

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      Deprotection of N-Boc Groups Under Continuous Flow High Temperature Conditions

      • Bryan Li
      • Ruizhi Li
      • Peter Dorff
      • James Christopher McWilliams
      • Robert M Guinn
      • Steven M. Guinness
      • Lu Han
      • Ke Wang
      • Shu Yu
      • Medicinal Science, Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, United States

      The scope of thermolytic, N-Boc deprotection was studied on 26 compounds from the Pfizer compound library, representing a diverse set of structural moieties. Among these compounds, 12 substrates resulted in clean (≥95% product) deprotection, and an additional three compounds gave ≥90% product. The thermal de-Boc conditions were found to be compatible with a large number of functional groups. A combination of computational modeling, statistical analysis, and kinetic model fitting was used to support an initial, slow, and concerted proton transfer with release of isobutylene, followed by a rapid decarboxylation. A strong correlation was found to exist between the electrophilicity of the N-Boc carbonyl group and the reaction rate.

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      A Laser Driven Flow Chemistry Platform for Scaling Photochemical Reactions with Visible Light

      • Kaid C. Harper
      • Eric G. Moschetta
      • Shailendra V. Bordawekar
      • Steven J. Wittenberger
      • Process Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States

      Visible-light-promoted organic reactions can offer increased reactivity and selectivity via unique reaction pathways to address a multitude of practical synthetic problems, yet few practical solutions exist to employ these reactions for multikilogram production. We have developed a simple and versatile continuous stirred tank reactor (CSTR) equipped with a high-intensity laser to drive photochemical reactions at unprecedented rates in continuous flow, achieving kg/day throughput using a 100 mL reactor. Our approach to flow reactor design uses the Beer–Lambert law as a guideline to optimize catalyst concentration and reactor depth for maximum throughput. This laser CSTR platform coupled with the rationale for design can be applied to a breadth of photochemical reactions.

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      De novo design of organic photocatalysts: bithiophene derivatives for the visible‐light induced C‐H functionalization of heteroarenes

      • Cecilia Bottecchia1
      • Raul Martin2
      • Irini Abdiaj3
      • Ettore Crovini4
      • Jesus Alcazar3
      • Jesus Jorduna
      • Maria Blesa
      • Jose Carrillo3
      • Pilar Prieto
      • Timothy Noel1
      • 1 TU Eindhoven, Netherlands
      • 2 Universidad de Castilla-La Mancha Facultad de Ciencias y Tecnologias Quimicas de Ciudad Real, Spain
      • 3 Janssen Research and Development, Spain
      • 4 University of Saint Andrews School of Chemistry, United Kingdom

      Herein, we report the de novo synthesis and characterization of a series of substituted bithiophene derivatives as novel and inexpensive organic photocatalysts. DFT calculations were used to predict a priori their absorption spectra and redox potentials, which were then confirmed with empirical data. The photocatalytic activity of this novel class of organic photoredox catalyst was demonstrated in two visible‐light mediated strategies for the C‐H functionalization of heteroarenes. The implementation of these strategies in a continuous‐flow photo‐microreactor afforded moderate to excellent yields within few minutes of reaction time. Due to their straightforward synthesis, low cost and good photocatalytic properties we believe that the proposed bithiophene derivatives could be employed as a new class of organic photoredox catalysts.

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      Integrating reactive distillation with continuous flow processing

      • Marcus Baumann
      • School of Chemistry, University College Dublin, Science Centre South, Belfield, Dublin 4, Ireland

      A continuous flow process for the synthesis of trifluoromethylthioethers is reported. The palladium-catalyzed C-H trifluoromethylthiolation of amides derived from the 8-aminoquinoline using N-[(trifluoromethyl)thio]phthalimide produced the desired products in moderate to good yields with a residence time of 20 min. In comparison with the batch process, the reaction time was decreased by a factor of 100 to 200, demonstrating the positive effect of continuous flow processes for this type of reaction.

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      Enabling tools for continuous-flow biphasic liquid–liquid reaction

      • Nopphon Weeranoppanant a
      • a Department of Chemical Engineering, Faculty of Engineering, Burapha University, 169 Longhard Bangsaen, Saensook, Muang, Thailand

      Flow chemistry has attracted considerable attention as it offers several advantages over conventional batch chemistry. Several multiphase reactions, including liquid–liquid reactions, are more efficient in flow due to intensified mass transfer. This observation has led to many developments of enabling tools in recent years. In this minireview, an up-to-date overview of such tools will be highlighted. In addition, interesting examples of the integrated continuous-flow process with liquid–liquid reactions will also be presented.

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      High-Throughput Template-Free Continuous Flow Synthesis of Polyaniline Nanofibers

      • Rekha Singh†#
      • Karuna Veeramani†‡#
      • Rishab Bajpai
      • Anil Kumar*†‡§
      • Department of Chemistry, IITB-Monash Research Academy,§ National Centre for Excellence in Technologies for Internal Security (NCETIS), Indian Institute of Technology Bombay, Powai, Mumbai, 400076, India

      The large-scale and high-throughput synthesis of conjugated polymer based nanofibers always remain a challenge for the chemists due to the issues related to secondary nucleation in traditional batch processes. Typically polyaniline (PANI) nanofibers are synthesized under highly dilute conditions resulting in a very low throughput of few hundred milligrams per hour and a low space-time yield (STY) of 1–2 g·L–1·h–1. In this manuscript, we report the continuous flow synthesis of PANI nanofibers which results in high throughput (17–30 g·h–1) and high space-time yield (140–450 g·L–1·h–1). These polyaniline nanofibers show high surface area (42 m2·g–1), high specific capacitance (577 F·g–1), and high crystallinity. Finally, the present method is generic in nature and, in principle, can be extended for the synthesis of nanofibers of other conjugated polymers via oxidative polymerization.

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      A Continuous Flow Strategy for the Facile Synthesis and Elaboration of Semi‐Saturated Heterobicyclic Fragments

      • Nicola Luise
      • Eleanor Wyatt
      • Gary Tarver
      • Paul Graham Wyatt
      • University of Dundee, School of Life Sciences, DD1 5EH Dundee, UNITED KINGDOM

      An efficient hydrogenation protocol under continuous flow conditions was developed for the synthesis of underrepresented semi‐saturated bicyclic fragments containing highly sp3‐rich skeletons for fragment‐based drug discovery (FBDD) programs. Excellent yields were generally achieved by using Pd/C (10% w/w) and RaNi at 25‐150 °C under 4‐100 bar of hydrogen pressure. The generated fragments, with appropriate physicochemical properties, present diverse hydrogen‐bonding pharmacophores and useful vectors for their synthetic elaboration in the optimization stage. Successive, simple functionalizations in continuous flow were accomplished to demonstrate the opportunity to develop multi‐step continuous flow synthesis of valuable starting points for FBDD campaigns. A conclusive quality control (QC) was essential to discard those structures that do not fit typical fragment library parameters.

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      Continuous Flow Chlorination of Alkenyl Iodides Promoted by Copper Tubing

      • Antoine Niteleta
      • Vanessa Kairouzb
      • Hélène Lebelb
      • André B. Charetteb
      • Gwilherm Evanoa
      • a  Laboratoire de Chimie Organique, Service de Chimie et Physico, Chimie Organiques, Université libre de Bruxelles (ULB), Avenue F. D. Roosevelt 50, CP160/06, 1050 Brussels, Belgium
      • b  Centre in Green Chemistry and Catalysis, Faculty of Arts and Sciences, Department of Chemistry, Université de Montréal, P.O. Box 6128, Station Downtown, Montréal, Québec, H3C 3J7, Canada

      A simple continuous flow synthesis of alkenyl chlorides from the corresponding readily available alkenyl iodides in copper reactor tubing is described. A variety of alkenyl chlorides were obtained in good to excellent yields with full retention of the double bond geometry. The reaction time was reduced by a factor of 24–48 compared to the batch process.

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      Continuous flow palladium-catalyzed trifluoromethylthiolation of C-H bonds

      • Alexanne Bouchard 1
      • Vanessa Kairouz 1
      • Maxime Manneveau 2
      • Heng-Ying Xiong 2
      • Tatiana Besset 2
      • 1 Department of Chemistry and Continuous Flow Synthesis Laboratory, Université de Montréal, Montréal, Canada
      • 2 INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), Normandie Université, Rouen, France

      A continuous flow process for the synthesis of trifluoromethylthioethers is reported. The palladium-catalyzed C-H trifluoromethylthiolation of amides derived from the 8-aminoquinoline using N-[(trifluoromethyl)thio]phthalimide produced the desired products in moderate to good yields with a residence time of 20 min. In comparison with the batch process, the reaction time was decreased by a factor of 100 to 200, demonstrating the positive effect of continuous flow processes for this type of reaction.

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      Continuous preparation for rifampicin

      • Xin Li 1
      • Zhuang Liu 1
      • Zheng Fang 1
      • Hao Qi 1
      • Siyu Huang 1
      • Shanshan Miao 1
      • Kai Guo 1,2
      • 1 College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, China
      • 2 State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, China

      To reduce the cost and improve the efficiency for rifampicin preparation, a continuous flow synthesis of rifampicin starting from rifamycin S and tert-butylamine was studied in a microreactor. Two reaction steps and one purification step were coupled in a microreactor, and rifampicin was obtained with 67% overall yield. This method used 25% less 1-amino-4-methyl piperazine and got 16% higher overall yield without changing solvent and purification process between steps. This method has a good potential for further industrial application.

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      Using Carbon Dioxide as a Building Block in Continuous Flow Synthesis

      • Hyowon Seo
      • Long V. Nguyen
      • Timothy F. Jamison
      • Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts

      Carbon dioxide (CO2) is an attractive building block for organic synthesis that is environmentally friendly. Continuous flow technologies have enabled C−O and C−C bond forming reactions with CO2 that previously were either low‐yielding or impossible in batch to afford value‐added chemicals. This review describes recent advances in continuous flow as an enabling strategy in utilizing CO2 as a C1 building block in chemical synthesis.

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      Chemoselective Synthesis of Amines from Ammonium Hydroxide and Hydroxylamine in Continuous Flow

      • Clément Audubert
      • Alexanne Bouchard
      • Gary Mathieu
      • Hélène Lebel
      • Department of Chemistry and Centre in Green Chemistry and Catalysis (CGCC), Université de Montréal, P.O. Box 6128, Station Downtown, Montréal, QC H3C 3J7, Canada

      The chemoselective amination of alkyl bromides and chlorides with aqueous ammonia and hydroxylamine was achieved in continuous flow to produce primary ammonium salts and hydroxylamines in high yields. An in-line workup was designed to isolate the corresponding primary amine, which was also telescoped in further reactions, such as acylation and Paal–Knorr pyrrole synthesis. Monosubstituted epoxides are also compatible with the reaction conditions.

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      Enantiospecific cyclization of methyl N-(tert-butoxycarbonyl)-N-(3-chloropropyl)-D-alaninate to 2-methylproline derivative via ‘memory of chirality’ in flow

      • Gianvito Vilé 1
      • Gunther Schmidt 2
      • Sylvia Richard-Bildstein 1
      • Stefan Abele 2
      • 1 Drug Discovery Chemistry, Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland
      • 2 Chemical Development, Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland

      We report for the very first time a continuous-flow route to perform the intramolecular cyclization of haloalkyl-substituted α-amino esters via memory of chirality (MoC), using lithium bis(trimethylsilyl)amine as a base and methyl N-(tert-butoxycarbonyl)-N-(3-chloropropyl)-D-alaninate as a model reactant. The various reaction parameters, such as temperature, residence time, reactant stoichiometry, or type and concentration of the base were optimized to maximize the yield of the cyclized product and its enantiomeric excess. At the conditions identified, the reaction was eventually scaled up, reaching a productivity of 11 g h−1. Compared to the standard batch protocols available in the literature, the use of a microreactor enables a better control of the exothermicity associated with the addition of the organolithium reagent to the reaction mixture, resulting in operations at more practical temperatures, with high enantiospecificity and full conversion of the reactive amino ester within a few seconds of residence time.

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      Mg-Catalyzed OPPenauer Oxidation—Application to the Flow Synthesis of a Natural Pheromone

      • Virginie Liautard
      • Mélodie Birepinte
      • Camille Bettoli
      • Mathieu Pucheault
      • Institut des Sciences Moléculaires (ISM), UMR 5255 CNRS—Université de Bordeaux, 351 Cours de la Libération, 33405 Talence CEDEX, France

      The so-called OPPenauer oxidation is well known for its ability to oxidize valuable alcohols into their corresponding aldehydes or ketones. In particular, it has proven to be extremely successful in the oxidation of sterols. On the other hand, its application—in the original formulation—to the obtainment of ketones outside the field of steroids met a more limited success because of less favorable thermodynamics and side reactions. To circumvent these issues, the first example of magnesium-catalyzed OPPenauer oxidation is described. The oxidation of primary and secondary alcohol was performed using pivaldehyde or bromaldehyde as the oxidant and cheap magnesium tert-butoxide as catalyst. Decent to excellent yields were obtained using reasonable catalytic charge. The synthesis of a pheromone stemming from the Rhynchophorus ferrugineus was obtained by tandem addition-oxidation of 2-methylpentanal and the process was successfully applied to continuous flow on a multigram scale.

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      Dehydration of an Insoluble Urea Byproduct Enables the Condensation of DCC and Malonic Acid in Flow

      • Alexander G. O’Brien
      • Eric M. Ricci
      • Michel Journet
      • GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States

      A procedure for the preparation of N,N′-dicyclohexylbarbituric acid from DCC and malonic acid is described. Addition of phosphorus oxychloride to the reaction mixture facilitates dehydration of the insoluble byproduct N,N′-dicyclohexyl urea, enabling operation in continuous flow. A development approach based on in situ monitoring of batch reactions was used, which supported screening and determination of reaction conditions at small scale prior to scaleup in flow. Additional mechanistic understanding and control of impurity formation are presented.

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      Self-Sufficient Flow-Biocatalysis by Coimmobilization of Pyridoxal 5′-Phosphate and ω-Transaminases onto Porous Carriers

      • Ana I. Benítez-Mateos
      • Martina L. Contente §
      • Susana Velasco-Lozano
      • Francesca Paradisi
      • Fernando López-Gallego *⊥‡
      • Heterogeneous Biocatalysis Laboratory, CICbiomaGUNE, Paseo Miramón 182, Edificio empresarial C”, 20014 San Sebastián, Spain
      • § School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, U.K
      • Heterogeneous biocatalysis laboratory, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH−CSIC), University of Zaragoza, C/Pedro Cerbuna 12, 50009 Zaragoza, Spain
      • ARAID, Aragon I+D foundation, Zaragoza, Spain

      We expanded the application of self-sufficient heterogeneous biocatalysts containing coimmobilized ω-transaminases and pyridoxal 5′-phosphate (PLP) to efficiently operate packed-bed reactors in continuous flow. Using a ω-transaminase from Halomonas elongata coimmobilized with PLP onto porous methacrylate-based carriers coated with polyethylenimine, we operated a packed-bed reactor continuously for up to 50 column volumes at 1.45 mL × min–1 in the enantioselective deamination of model amines (α-methylbenzyl amine), yielding >90% conversion in all cycles without exogenous addition of cofactor. In this work, we expanded the concept of self-sufficient heterogeneous biocatalysts to other ω-transaminases such as the ones from Chromobacterium violaceum and Pseudomonas fluorescens. We found that enzymes with lower affinities toward PLP present lower operational stabilities in flow, even when coimmobilizing PLP. Furthermore, ω-transaminases coimmobilized with PLP were successfully implemented for the continuous synthesis of amines and the sustainable metrics were assessed. These results give some clues to exploit PLP-dependent ω-transaminases under industrially relevant continuous operations in a more cost-effective and environmentally friendly process.

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      A Convergent Continuous Multistep Process for the Preparation of C4-Oxime-Substituted Thiazoles

      • Edouard Godineau *†
      • Claudio Battilocchio †‡
      • Matthias Lehmann
      • Steven V. Ley
      • Ricardo Labes
      • Letitia Birnoschi
      • Srinivas Subramanian §
      • C.S Prasanna §
      • Amol Gorde §
      • Mahesh Kalbagh §
      • Vivek Khade §
      • Anton Scherrer
      • Anthony C. O’Sullivan
      • Syngenta Crop Protection, Process Research, Schaffhauserstrasse 101, CH-4332, Switzerland
      • Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, UK
      • § Syngenta Research and Technology Centre, Santa Monica Works, Corlim, Goa India, 403110

      We report a strategy designed for the rapid and convergent assembly of C4-oxime substituted thiazoles. Our approach relied on 3-bromo-2-oxopropanal O-methyl oxime 7 as a key building block. A three-step sequence to 7 was designed, which, for safety concerns, could only be operated in batch mode on limited scales (≪100 g). We describe herein how we addressed such a limitation, by designing a multistep continuous synthesis of this intermediate and further demonstrate the advantages of flow reactor configuration upon scaling up.

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      Additive Free Fe-Catalyzed Conversion of Nitro to Aldehyde under Continuous Flow Module

      • Sandip G. Agalave
      • Moreshwar B. Chaudhari
      • Girish Singh Bisht
      • Boopathy Gnanaprakasam*
      • Department of Chemistry, Indian Institute of Science Education and Research Pune-411008, India

      Fe-catalyzed direct transformation of nitro compounds to aldehyde under batch/continuous flow module is reported. This catalytic transformation is highly selective for syntheses of various aldehydes and does not require any additional additives such as bases and oxidants. Furthermore, the heterogeneous Fe–zeolite catalyst is recoverable and reusable for more than five cycles and offers gram-scale synthesis without the loss of catalytic efficiency. This heterogeneous catalyst has a maximum TOF of 5.93 h–1.

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      Recent Advances in Photodecarboxylations Involving Phthalimides

      • Saira Mumtaz
      • Mark J. Robertson
      • Michael Oelgemöller
      • James Cook University, College of Science and Engineering, Townsville, Qld 4811, Australia.

      Owing to their favourable photophysical and electrochemical properties, phthalimides undergo a variety of highly efficient photodecarboxylation reactions. These transformations have been applied to the synthesis of macrocyclic compounds as well as bioactive addition adducts. N-Acetoxyphthalimides are versatile precursors to imidyl and alkyl radicals through photodecarboxylation and have subsequently been used for a variety of coupling reactions. The generally mild reaction conditions make these reactions attractive for green chemical applications. The process protocols were successfully transferred to novel photoreactor devices, among these falling film or continuous flow reactors.

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      C–H functionalisation of aldehydes using light generated, non-stabilised diazo compounds in flow

      • Paul Dingwall a
      • Andreas Greb a
      • Lorène N. S. Crespin a
      • Ricardo Labes a
      • Biagia Musio a
      • Jian-Siang Poh a
      • Patrick Pasau b
      • David C. Blakemore c
      • Steven V. Ley *a
      • a Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
      • b UCB Biopharma SPRL, Chemical Research R5, Chemin du Foriest 1420, Braine-L’Alleud, Belgium
      • c Medicine Design, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, USA

      The difficulty in accessing and safely utilising non-stabilised diazo species has in the past limited the application of this class of compounds. Here we explore further the use of oxadiazolines, non-stabilised diazo precursors which are bench stable, in direct, non-catalytic, aldehyde C–H functionalisation reactions under UV photolysis in flow and free from additives. Commercially available aldehydes are coupled to afford unsymmetrical aryl–alkyl and alkyl–alkyl ketones while mild conditions and lack of transition metal catalysts allow for exceptional functional group tolerance. Examples are given on small scale and in a larger scale continuous production.

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      Catalytic Static Mixers for the Continuous Flow Hydrogenation of a Key Intermediate of Linezolid (Zyvox)

      • James Gardiner a*
      • Xuan Nguyen a
      • Charlotte Genet a
      • Mike D. Horne b
      • Christian Hornung a
      • John Tsanaktsidis a
      • a CSIRO Manufacturing Flagship, Bayview Avenue, Clayton, Australia
      • b CSIRO Mineral Resources, Bayview Avenue, Clayton, VIC 3169, Australia

      Catalytic static mixers (CSMs) were used for the efficient preparation of a key intermediate of the antimicrobial drug linezolid (Zyvox). The approach combines 3D printing and additive manufacturing techniques with continuous flow processing to produce a general method for catalytic hydrogenations and the rapid production of the target molecule without the need for catalyst removal or recovery.

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      Photoinduced Palladium Negishi Cross-Coupling Through Visible Light Absorption of Palladium-Organozinc complexes

      • Irini Abdiaj a
      • Lena Huck a,b
      • José Miguel Mateo b
      • Antonio de la Hoz b
      • M. Victoria Gomez c
      • Angel Díaz-Ortiz b
      • Jesús Alcázar a
      • a Lead Discovery, Janssen Research and Development, Janssen-Cilag, S.A., Jarama 75A, 45007 Toledo, Spain
      • b Facultad de Ciencias y Tecnologías Químicas, Universidad de Castilla-La Mancha, Av. Camilo José Cela 10, 13071 Ciudad Real, Spain
      • c Instituto Regional de Investigación Científica Aplicada, Universidad de Castilla-La Mancha, Av. Camilo José Cela, sn, 13071 Ciudad Real, Spain

      A visible‐light‐induced Negishi cross‐coupling is enabled by the activation of a Pd0–Zn complex. With this photocatalytic method, the scope of deactivated aryl halides that can be employed in the Negishi coupling was significantly expanded. NMR experiments conducted in the presence and absence of light confirmed that the formation of the palladium–zinc complex is key for accelerating the oxidative addition step.

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      Three-Component Assembly of Multiply Substituted Homoallylic Alcohols and Amines Using a Flow Chemistry Photoreactor

      • Yiding Chen
      • David Blakemore
      • Patrick Pasau §
      • Steven V. Ley
      • Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
      • Medicine Design, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, United States
      • § UCB Biopharma SPRL, Chemical Research R5, Chemin du Foriest, 1420 Braine-L’Alleud, Belgium

      Oxadiazolines are bench-stable diazo precursors, which are activated under UV radiation in the presence of vinylboronic acids and aldehydes to enable a one-step three-component assembly of densely functionalized homoallylic alcohols. Substitution on all positions of the homoallylic alcohol product were achieved with high functional group tolerance. No catalyst or other additive was required to effect the reaction, which proceeds at 20 °C over 40 min. Imines and indoles were also incorporated, giving access to homoallylic amines.

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      Mild Homologation of Esters via Continuous Flow Chloroacetate Claisen Reactions

      • Maximilian A. Ganiek
      • Maria V. Ivanova
      • Benjamin Martin*
      • Paul Knochel*
      • Department of Chemistry, Ludwig-Maximilians-Universität Munich, Butenandtstr. 5 – 13, 81377 Munich, Germany

      The selective chloromethylenation of functionalized esters using chloroacetic acid (CA) and LiHMDS (HMDS = hexamethyldisilazide) in a continuous flow setup is reported. This Claisen homologation is for the first time extended to bis-chloromethylenation using dichloro-acetic acid (DCA), thus giving access to under-explored α,α’-bis-chloroketones. The use of flow conditions enables an efficient generation and reaction of the unstable chloroacetate dianion intermediates, leading to unprecedented mild and scalable reaction conditions at an economic reagent stoichiometry ( 10 °C, < 1 min, 1.0-2.4 equiv. dianion). The clean reaction profiles allows the subsequent use of the unpurified crude products, which is demonstrated in the synthesis of various heterocycles of broad interest. Furthermore, we report a novel, catalyst-free substitution of the obtained monochloro ketone products with (hetero)aryl zinc enolates leading to valuable 1,4-diketones.

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      Regioselective Chlorination of Quinoline Derivatives via Fluorine Mediation in a Microfluidic Reactor

      • Hao Qi
      • Xin Li
      • Zhuang Liu
      • Shan‐Shan Miao
      • Prof. Zheng Fang, Lin Chen, Zheng Fang, Prof. Kai Guo
      • College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, China State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, China

      A novel green and efficient reaction route for the synthesis of 2‐chloroquinoline via N‐fluoride fluorinated by 1‐Chloromethyl‐4‐fluoro‐1,4‐diazoniabicyclo [2.2.2] octane bis(tetrafluoroborate) (Selectfluor) with 1,3‐Dichloro‐5,5‐dimethylhydantoin (DCDMH) in Vapourtec reactor has been developed. In addition, a series of C2 heterocyclic derivative products are obtained in moderate to good yields under no metal conditions.

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      Molecular machines

      Inventors: Colin Scott, Carol HARTLEY, Charlotte Williams, Quentin CHURCHES, Judith SCOBLE, Nicholas Turner, Nigel French

      • Assignee: Commonwealth Scientific and Industrial Research Organization CSIRO

      The present disclosure relates to isolated enzyme complexes comprising a tethered cofactor and at least two enzymes paired to catalyse an enzymatic reaction and recycle the cofactor.

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      Continuous flow synthesis of a carbon-based molecular cage macrocycle via a three-fold homocoupling reaction

      • Melanie Kitchinab
      • Kristina Konstasa
      • Christopher J. Sumbyb
      • Milena L. Czyza
      • Peter Valenteb
      • Matthew R. Hill*ab
      • Anastasios Polyzos*ac
      • Christian J. Doonan*ab
      • * Corresponding authors
      • a CSIRO Manufacturing Flagship, Bayview Avenue, Clayton, Australia
      • b Centre for Advanced Nanomaterials and the School of Physical Sciences, The University of Adelaide, Adelaide, Australia

      The facile synthesis of the cage molecule (C110H56Br2) via a remarkable three-fold homo-coupling macrocyclization reaction using continuous flow methodology is reported. Synthesis via continuous flow chemistry improves the residence time, safety, and environmental profile of this synthetically challenging reaction. Further, the new cage possesses halogen atoms at its apex that serve to expand the potential reaction space of these intrinsically porous, all carbon–carbon bonded molecular cage molecules.

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      Flow-based biocatalysis: Application to peracetylated arabinofuranosyl-1,5-arabinofuranose synthesis

      • Teodora Bavaroa
      • Andrea Pintob
      • Federica Dall’Oglioc
      • María J. Hernáizd
      • Carlo F. Morellie
      • Paolo Zambellib
      • Carlo De Michelic
      • Paola Contic
      • Lucia Tamborinic
      • Marco Terrenia
      • a Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy
      • b Department of Food Environmental and Nutritional Science (DeFENS), University of Milan, Via Mangiagalli 25, 20133 Milan, Italy
      • c Department of Pharmaceutical Sciences (DISFARM), University of Milan, Via Mangiagalli 25, 20133 Milan, Italy
      • d Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Complutense University of Madrid, Plaza de Ramón y Cajal s/n, 28040 Madrid, Spain
      • e Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milan, Italy

      The lipase-catalyzed regioselective hydrolysis of peracetylated arabinose was performed in a packed bed flow reactor (PBR). In particular, the hydrolysis of the α  anomer of peracetylated arabinose catalyzed by Novozym® 435 resulted in the monodeprotection of C5 in only 5 min and 91% yield. By using the immobilized Pseudomonas stutzeri lipase, the regioselective hydrolysis of the β  anomer was also accomplished affording the C1 deacetylated derivative in 30 min with good yields. The high local concentration of the immobilized biocatalyst in the PBR allow for a significant reduction of the reaction time; moreover, repeated re-use, and easy downstream processing increase the efficiency and the productivity of the process, if compared to the classical batch procedure. In fact, under optimized conditions, the specific reaction rate of the biocatalyzed flow reaction showed an increase of more than 300 times compared to the batch one. The obtained building blocks were prepared in gram scale and then used for the synthesis of peracetylated arabinofuranosyl-1,5-arabinofuranose.

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      Continuous Flow Photochemical Benzylic Bromination of a Key Intermediate in the Synthesis of a 2‐Oxazolidinone

      • Yuesu Chena, b
      • Oscar de Frutosc
      • Carlos Mateosc
      • Juan A. Rinconc
      • David Cantillo*a, b
      • C. Oliver Kappe*a, b
      • a Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz (Austria)
      • b Institute of Chemistry, University of Graz, Heinrichstrasse 28, 8010, Graz (Austria)
      • c Centro de Investigacin Lilly S. A. Avda. de la Industria 30, 28108 Alcobendas-Madrid (Spain)

      A continuous flow protocol for the benzylic photobromination of methyl N,N‐bis(tert‐butoxycarbonyl) phenylalaninate (3) is presented. This photochemical transformation generating brominated intermediate 4 is the critical step in synthesis of oxazolidinone 5, a key intermediate for the preparation of active pharmaceutical ingredients. The reaction was optimized in three continuous flow photoreactors: a self‐made reactor based on a T5 8 W black light lamp, as well as the commercially available VapourTec® UV‐150 and Corning® Advanced‐Flow™ reactors, both equipped with LED light sources. Under optimal conditions, concentrated solutions (95 g/L) of the starting material could be processed on multi‐gram scale, providing high conversion (96%) within 7 min at 30 °C, using 2 equivalents of N‐bromosuccinimide (NBS).

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      Native Chemical Ligation–Photodesulfurization in Flow

      • Timothy S. Chisholm
      • Daniel Clayton
      • Luke J. Dowman
      • Jessica Sayers
      • Richard J. Payne
      • School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia
      Native Chemical Ligation–Photodesulfurization in Flow

      Native chemical ligation (NCL) combined with desulfurization chemistry has revolutionized the way in which large polypeptides and proteins are accessed by chemical synthesis. Herein, we outline the use of flow chemistry for the ligation-based assembly of polypeptides. We also describe the development of a novel photodesulfurization transformation that, when coupled with flow NCL, enables efficient access to native polypeptides on time scales up to 2 orders of magnitude faster than current batch NCL–desulfurization methods. The power of the new ligation–photodesulfurization flow platform is showcased through the rapid synthesis of the 36 residue clinically approved HIV entry inhibitor enfuvirtide and the peptide diagnostic agent somatorelin.

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      Continuous flow biocatalysis

      • Joshua Britton
      • Sudpta Majumdar
      • Gregory A. Weiss
      • Department of Chemistry, Molecular Biology and Biochemistry, University of California, Irvine, USA

      The continuous flow synthesis of active pharmaceutical ingredients, value-added chemicals, and materials has grown tremendously over the past ten years. This revolution in chemical manufacturing has resulted from innovations in both new methodology and technology. This field, however, has been predominantly focused on synthetic organic chemistry, and the use of biocatalysts in continuous flow systems is only now becoming popular. Although immobilized enzymes and whole cells in batch systems are common, their continuous flow counterparts have grown rapidly over the past two years. With continuous flow systems offering improved mixing, mass transfer, thermal control, pressurized processing, decreased variation, automation, process analytical technology, and in-line purification, the combination of biocatalysis and flow chemistry opens powerful new process windows. This Review explores continuous flow biocatalysts with emphasis on new technology, enzymes, whole cells, co-factor recycling, and immobilization methods for the synthesis of pharmaceuticals, value-added chemicals, and materials.

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      Reductive aminations using a 3D printed supported metal(0) catalyst system

      • Charlotte Genet1
      • Xuan Nguyen1
      • Bita Bayatsarmadi2
      • Mike D. Horne2
      • James Gardiner1
      • Christian H. Hornung1
      • 1 CSIRO Manufacturing, Clayton, South Australia
      • 2 CSIRO Minerals Resources, Clayton, South Australia

      Additively manufactured catalytic static mixers were used for the intensified reductive amination of aldehydes and ketones inside a continuous flow reactor. This efficient synthesis method is enabled by the use of tubular reactors fitted with 3D printed metal static mixers which are coated with a catalytically active layer, either Pd or Ni. The 3D printing process allows for maximum design flexibility for the mixer scaffold and is compatible with a range of deposition methods including electroplating and metal cold spraying. Single- and multi-stage continuous flow processing yielded high to full conversion and has the potential to scale-up these operations without the need for manual handling of reactive imine intermediates.

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      Flow Synthesis of Coumalic Acid and its Derivatization

      • Laura K. Smith and Ian R. Baxendale
      • Department of Chemistry, University of Durham, South Road, Durham, DH1 3LE, UK.

      Coumalic acid is a valuable platform compound which can be prepared from malic acid, a biorenewable feedstock readily derived from the fermentation of glucose. Current batch procedures to synthesise coumalic acid have several drawbacks, which we address with the aid of tubular flow systems and a simple heated rotating flow reactor. The prepared coumalate derivatives can be further used in inverse electron demand Diels-Alder reactions to synthesise compounds with many applications including molecular electronics, with the added advantage of providing metal-free preparations.

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      Production of metal-organic frameworks

      Inventors:, Marta RUBIO MARTINEZ, Matthew Roland Hill, Michael Batten, Kok Seng Lim, Anastasios POLYZOS, Timothy Raymond Barton, Trevor Deon HADLEY, Andreas Alexander MONCH

      • Assignee: Commonwealth Scientific and Industrial Research Organization CSIRO

      An apparatus for producing metal organic frameworks, comprising: a tubular flow reactor comprising a tubular body into which, in use, precursor compounds which form the metal organic framework are fed and flow, said tubular body including at least one annular loop.

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      Combining CH functionalisation and flow photochemical heterocyclic metamorphosis (FP-HM) for the synthesis of benzo [1, 3] oxazepines

      • Jasraj S. Babra, Andrew T. Russell, Christopher D. Smith, Yuxiong Zhang
      • Department of Chemistry, University of Reading, Whiteknights, Reading, RG6 6AD, UK

      C-H Activation/functionalisation and Flow Photochemical Heterocyclic Metamorphosis (FP-HM) have been combined to synthesize a library of benzo [1,3]oxazepines, a rarely described heterocyclic family. This combined protocol allows a range of arylated products to be made from simple starting materials, and the cheap flow photochemical system has proven effective for rapid synthesis of gram-quantities of benzo [1,3]oxazepines.

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      Studies toward the scaling of gas‐liquid photocycloadditions

      Dr. Emily B. Corcoran, Dr. François Lévesque, Dr. Jonathan P. McMullen, Dr. John R. Naber

      • Department of Process Research and Development, Merck Sharp & Dohme Corp., Rahway, USA

      The gas‐liquid biphasic photochemical [2+2] cycloaddition of maleic anhydride with ethylene was identified as a desirable strategy for the divergent synthesis of cyclobutane derivatives. To address the challenge of utilizing this transformation on a larger scale, studies toward the development of a stable process with sufficient productivity were undertaken. These studies revealed the importance of several reaction parameters to enhance both the gas solubility in solution and the efficient utilization of photons from various types of light sources.

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      Photooxygenation in an advanced led-driven flow reactor module: Experimental investigations and modelling

      • Robbie Radjagobalouab
      • Jean-François Blancoa
      • Odile Dechy-Cabaretb
      • Michael Oelgemöllerc
      • Karine Loubièrea
      • a Laboratoire de Génie Chimique LGC, Université de Toulouse, CNRS, Toulouse, France
      • b Laboratoire de Chimie de Coordination LCC, CNRS, Toulouse, France
      • c James Cook University, College of Science and Engineering, Townsville, Queensland 4811, Australia

      The photooxygenation of  α-terpinene was investigated as a benchmark reaction in an advanced LED-driven flow reactor module, both from an experimental and modelling point of view. Ethanol was used as a green solvent and rose Bengal was chosen as a cheap sensitizer of industrial importance. Firstly, the kinetic law based on all mechanistic steps was established for the chosen photooxygenation. From this, the set of operating parameters potentially influencing the photoreaction rate were identified. Subsequently, experiments were carried out under continuous-flow conditions to screen these operating parameters, namely concentration of α-terpinene, concentration of photosensitizer, residence time, structure of the segmented gas-liquid flow and nature of the reagent gas phase (air versus pure oxygen). Finally, the conditions enabling minimization of sensitizer bleaching were established. It was also shown that the hydrodynamic characteristics of the gas-liquid flow can have an effect on the conversion levels. From this, a simplified model was proposed to predict the conversion at the reactor’s outlet when pure oxygen was used.

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      P‐121: Successive and scalable synthesis of highly stable Cs4PbBr6 perovskite microcrystal by microfluidic system and their application in backlight display

      Hung-Chia Wang1, Zhen Bao1, Ru-Shi Liu1,2

      • 1 Department of Chemistry, National Taiwan University, Taipei, Taiwan
      • 2 Department of Mechanical Engineering and Graduate Institute of Manufacturing Technology, National Taipei University of Technology, Taipei, Taiwan

      All Inorganic CsPbX3 (X = I, Br, Cl) perovskite nanocrystal have attracted immense research interest in recent years, due to their high photoluminescence quantum yield (PLQY). These fascinating features of inorganic nanocrystals have been utilized in light emitting diodes (LEDs) device. However, maintaining the high PLQY in the solid state remains a big challenge. Inorganic mesoporous silica encapsulation of NCs has moderate improvements, but it remains an unsolved problem. Robust and air‐stable Cs4PbBr6microcrystal was another choice in perovskite solid. In this study, we report mass production of Cs4PbBr6 perovskite microcrystal by microfluidic system. To demonstrate the potential application of Cs 4PbBr6 perovskite microcrystal, we fabricated white‐light LEDs based on Cs4PbBr6 and K2SiF6:Mn4+ phosphor. Our white light LED device for backlight display having the NTSC value is 115%.

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      Self-sustaining closed-loop multienzyme-mediated conversion of amines into alcohols in continuous reactions

      Martina L. Contente, Francesca Paradisi

      • School of Chemistry, University of Nottingham, Nottingham, United Kingdom

      The synthesis of alcohols from amine starting materials is an excellent yet challenging strategy for the preparation of pharmaceuticals and polymers. Here we developed a versatile, self-sustaining closed-loop multienzymatic platform for the biocatalytic synthesis of a large range of non-commercially available products in a continuous flow with excellent yields (80 to >99%), reaction times and optical purity of secondary alcohols (>99 enantiomeric excess). This process was also extended to the conversion of biogenic amines into high-value alcohols, such as the powerful antioxidant hydroxytyrosol, and the synthesis of enantiopure 2-arylpropanols via the dynamic kinetic resolution of commercially affordable racemic amines. The system exploits the in situ immobilization of transaminases and redox enzymes which were combined to cater for a fully automated, ultra-efficient synthetic platform with cofactor recycling, in-line recovery of benign by-products and recirculation of the aqueous media that contains the recycled cofactors in catalytic amounts, which increases the efficiency of the system by over 20-fold.

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      Dichlorophenylacrylonitriles as AhR Ligands displaying selective breast cancer cytotoxicity in vitro

      Jennifer R Baker1, Jayne Gilbert2, Stefan Paula3, Xiao Zhu3, Jennette A Sakoff2, Adam McCluskey1

      • 1 The University of Newcastle, Chemistry, Newcastle, Australia
      • 2 Calvary Mater Hospital, Medical Oncology, Newcastle, Australia
      • 3 Purdue University, Chemistry, West Lafayette, United States

      Knoevenagel condensation of 3,4‐dichloro‐ and 2,6‐dichloro‐ phenylacetonitriles gave a library of dichlorophenylacrylonitriles. Our leads 5 and 6 displayed 0.56±0.03 and 0.127±0.04 μM growth inhibition (GI₅₀) and 260‐fold selectivity for the MCF‐7 breast cancer cell line. A 2,6‐dichlorophenyl moiety saw a 10‐fold potency loss; additional nitrogen moieties (‐NO₂) enhanced activity (26 and 27), with the corresponding ‐NH₂ analogues (29 and 30) more potent. Despite this, both 29 (2.8±0.03 μM) and 30 (2.8±0.03 μM) were 10‐fold less cytotoxic than 6. A bromine moiety effected a 3‐fold enhancement in solubility with 18 relative to 5 at 211 μg mL‐1. Modelling led synthesis saw the introduction of 4‐aminophenyl substituent gave 35 and 38, 0.030±0.014 and 0.034±0.01 μM potent, respectively. Other analogues, e.g. 35 and 36, were sub‐micromolar potent against our cell line panel (HT29, colon; U87 and SJ‐G2, glioblastoma; A2780, ovarian; H460, lung; A431, skin; Du145, prostate; BE2‐C neuroblastoma; MIA, pancreas and SMA murine glioblastoma) except 35 against U87. A more extensive evaluation of 38 ((Z)‐N‐(4‐(2‐cyano‐2‐(3,4‐dichlorophenyl)vinyl)phenyl)acetamide), in a panel of drug resistant breast carcinoma cell lines showed 10‐206 nM potency against MDAMB468, T47D, ZR‐75‐1, SKBR3 and BT474. MOE docking scores showed a good correlation between predicted binding efficiencies and observed MCF‐7 cytotoxicity. This supports the use of this model in developing breast cancer specific drugs.

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      Combining C-H functionalisation and flow photochemical heterocyclic metamorphosis (FP-HM) for the synthesis of benzo[1,3]oxazepines

      • Jasraj S. Babra, Andrew T. Russell, Christopher D. Smith, Yuxiong Zhang
      • Department of Chemistry, University of Reading, Whiteknights, Reading, RG6 6AD, UK

      C-H Activation/functionalisation and Flow Photochemical Heterocyclic Metamorphosis (FP-HM) have been combined to synthesize a library of benzo [1,3]oxazepines, a rarely described heterocyclic family. This combined protocol allows a range of arylated products to be made from simple starting materials, and the cheap flow photochemical system has proven effective for rapid synthesis of gram-quantities of benzo [1,3]oxazepines.

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      Multistep Continuous-Flow Processes for the Preparation of Heterocyclic Active Pharmaceutical Ingredients

      Romaric Gérardy, Jean-Christophe M. Monbaliu

      • Center for Integrated Technology and Organic Synthesis, Department of Chemistry, University of Liège, Liège, Belgium

      Flow chemistry has many fascinating facets, among which the most challenging is arguably the implementation of complex multistep processes within one uninterrupted fluidic network. This document provides a thorough overview of some of the most representative examples of multistep continuous-flow strategies in the specific context of preparing heterocyclic active pharmaceuticals. Selected examples emphasizing the implementation of multistep sequences, including various combinations of chemical transformations, purifications, or in-line analysis, are discussed.

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      Flow Chemistry Approaches Applied to the Synthesis of Saturated Heterocycles

      Marcus Baumann, Ian R. Baxendale

      • Department of Chemistry, University of Durham, Durham, UK

      Continuous-flow processing approaches are having a significant impact on the way we devise and perform chemical synthesis. Flow chemistry has repeatedly demonstrated numerous improvements with respect to synthesis efficiency, process safety and ease of reaction scale-up. In recent years flow chemistry has been applied with remarkable success to the generation of valuable target structures across a range of industries from basic bulk chemical manufacture and materials development to flavours, food and cosmetic applications. However, due to its earlier implementation, it has found so far many more advocates in areas of medicinal and agrochemical research and manufacture. In this review article, we summarise the key developments that continuous-flow synthesis has had in the area of saturated heterocycles, specifically focusing on approaches that generate these important entities from acyclic precursors.

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      An efficient benzoxaborole one‐pot synthesis by SiliaCat DPP‐Pd heterogeneous catalysis using diboronic acid

      • Kana kunihiro1
      • Laurence Dumais2
      • Guillaume Lafitte2
      • Emeric Varvier2
      • Loïc Tomas2
      • Craig Harris2
      • 1 Ecole Nationale Supérieure des Ingenieurs en Arts Chimiques et Technologiques, France
      • 2 Nestlé Skin Health, Galderma R&D, France

      Organoboron compounds are valuable molecules of increasing interest in organic synthesis, catalysis, biology and medicine. Among them, benzoxaboroles emerged as promising building blocks for numerous research programs. In this letter, we communicate the development of new conditions for the one‐pot benzoxaborole synthesis by SiliaCat DPP‐Pd catalysis using diboronic acid as the boron source. This low cost and sustainable strategy permitted the preparation of a useful range of benzoxaborole building blocks. Finally, the transformation was extended to a continuous flow process using our Vapourtec system.

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      Total Synthesis of Neomarchantin A: Key Bond Constructions Performed Using Continuous Flow Methods

      • Émilie Morin, Michaël Raymond, Amaury Dubart, and Shawn K. Collins
      • Department of Chemistry and Centre for Green Chemistry and Catalysis, Université de Montréal, CP 6128 Station Downtown, Montréal, Québec, Canada H3C 3J7

      A synthesis of neomarchantin A has been achieved wherein key bond constructions involving C–O or C–C bond formations were augmented via continuous flow techniques. Of note, the synthesis of neomarchantin A represents the first demonstration of catalytic macrocyclic olefin metathesis as a key step for the synthesis of a macrocyclic bisbibenzyl natural product.

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      In situ epoxide generation by dimethyldioxirane oxidation and the use of epichlorohydrin in the flow synthesis of a library of β-amino alcohols

      Peter J. Cossar, Jennifer R. Baker, Nicholas Cain, Adam McCluskey

      • Chemistry, The University of Newcastle, University Drive Callaghan, New South Wales 2308, Australia

      The flow coupling of epichlorohydrin with substituted phenols, while efficient, limits the nature of the epoxide available for the development of focused libraries of β-amino alcohols. This limitation was encountered in the production of analogues of 1-(4-nitrophenoxy)-3-((2-((4-(trifluoromethyl)pyrimidin-2-yl)amino)ethyl)amino)propan-2-ol 1, a potential antibiotic lead. The in situ (flow) generation of dimethyldoxirane (DMDO) and subsequent flow olefin epoxidation abrogates this limitation and afforded facile access to structurally diverse β-amino alcohols. Analogues of 1 were readily accessed either via (i) a flow/microwave hybrid approach, or (ii) a sequential flow approach. Key steps were the in situ generation of DMDO, with olefin epoxidation in typically good yields and a flow-mediated ring opening aminolysis to form an expanded library of β-amino alcohols 1 and 10a–18g, resulting in modest (11a, 21%) to excellent (12g, 80%) yields. Alternatively flow coupling of epichlorohydrin with phenols 4a–4m (22%–89%) and a Bi(OTf)3catalysed microwave ring opening with amines afforded a select range of β-amino alcohols, but with lower levels of aminolysis regiocontrol than the sequential flow approach.

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      Safe Use of Hazardous Chemicals in Flow

      MT Rahman1, T Wirth2

      • 1 School of Chemistry and Chemical Engineering, Queen’s University Belfast, Belfast, UK
      • 2 School of Chemistry, Cardiff University, Cardiff, UK

      Flow chemistry has evolved into an excellent toolkit for handling challenging chemical transformations during the past decade. Highly exothermic and kinetically fast reactions are difficult to handle even on a small scale, whereas any scale-up poses significant risks when conventional reactors are considered. Flow chemistry enables exquisite control over mixing sequences, reaction time and quenching that ultimately paves the way for the fine-tuning of chemical reactivity in ‘space and time’. This chapter describes recent advances of flow chemistry in controlling and even discovering new reactivities of highly hazardous chemical species and unstable intermediates. This chapter compiles intriguing recent examples manifesting the power of flow chemistry to perform commonly known‚ cryogenic reactions at or near room temperature, safe-handling and in situ production of hazardous or toxic reagents for chemical transformations that are generally considered unsafe in conventional reactors.

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      Photochemical Synthesis of Heterocycles: Merging Flow Processing and Metal-Catalyzed Visible Light Photoredox Transformations

      T Glasnov

      • Institute of Chemistry, University of Graz, Graz, Austria

      The ubiquitous presence of heterocyclic moieties in everyday life justifies the ongoing intensive research within the synthetic community to discover effective methodologies for their construction. As the social concern regarding environmental protection gains importance, the use of light as the ultimate green promoter for chemical reactions has been revived in the scientific community. Specifically, visible-light photoredox processes based on metal- and organic photosensitizer are attracting significant attention and have seen an exceptional advance recently.

      Additionally, continuous-flow processing has enabled a safer and more efficient generation of various heterocycles, whilst allowing their syntheses in a scalable manner. In this chapter, recent achievements in the area of continuous-flow aided photoredox synthesis are covered, including some general remarks on instrumentation, theoretical background and selected flow UV-photochemistry examples.

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      Flow Chemistry as a Drug Discovery Tool: A Medicinal Chemistry Perspective

      Andrew R. Bogdan1, Michael G. Organ2

      • 1 Discovery Chemistry and Technology, AbbVie Inc., North Chicago, USA
      • 2 Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Canada

      The applications of flow chemistry in a drug discovery environment are discussed within. The development of integrated synthesis–bioassay platforms is discussed in the context of enabling medicinal chemistry programs, as is the use of flow chemistry to facilitate intermediate scale-up in a lead optimization setting. Emerging chemical technologies are also discussed, highlighting the use of high temperatures, hazardous gases, and photochemistry in flow to support medicinal chemistry efforts.

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      Copper mediated, heterogeneous, enantioselective intramolecular Buchner reactions of α-diazoketones using continuous flow processing

      • DC Crowley
      • D Lynch
      • AR Maguire
      • School of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Cork T12 K8AF, Ireland
      • School of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork, Cork T12 K8AF, Ireland

      Enantioselective intramolecular Buchner reactions of α-diazoketones can be effected using heterogeneous copper–bis(oxazoline) catalysts in batch or using continuous flow processing in up to 83% ee. The catalyst can be reused up to 7 times without loss of activity. For α-diazoketones 3 and 4, the enantioselection achieved in flow with the immobilized catalyst was comparable with the standard homogeneous catalyzed process.

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      Functionalization of Heteroarenes Under Continuous Flow

      Joachim Demaerel, Vidmantas Bieliũnas, Wim M. De Borggraeve

      • Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Leuven, Belgium

      Aromatic heterocycles are omnipresent motifs in pharmaceutical and agrochemical structures. Functionalization of these ring systems is an important part of many synthetic procedures. In this chapter, an overview is given of how microflow technology has been employed as a powerful tool for the diversification of heteroarenes. An emphasis is put on fine chemical synthesis, although reactor design and problem solving will be discussed when relevant, as it comprises an important part of the research field. Pragmatic translations to microflow are reviewed for existing functionalization protocols, and a few elusive reactions are highlighted that cannot be performed satisfyingly in batch mode.

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      Photoredox Iridium–Nickel Dual-Catalyzed Decarboxylative Arylation Cross-Coupling: From Batch to Continuous Flow via Self-Optimizing Segmented Flow Reactor

      • Hsiao-Wu Hsieh
      • Connor W. Coley
      • Lorenz M. Baumgartner
      • Klavs F. Jensen*‡
      • Richard I. Robinson*†
      • Global Discovery Chemistry − Chemical Technology Group, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
      • Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States

      Photoredox decarboxylative cross-coupling via iridium–nickel dual catalysis has emerged as a valuable method for C(sp2)–C(sp3) bond formation. Herein we describe the application of a segmented flow (“microslug”) reactor equipped with a newly designed photochemistry module for material-efficient reaction screening and optimization. Through the deployment of a self-optimizing algorithm, optimal flow conditions for the model reaction were rapidly developed, simultaneously accounting for the effects of continuous variables (temperature and time) and discrete variables (base and catalyst). Temperature was found to be a critical parameter with regard to reaction rates and hence productivity in subsequent scale-up in flow. The optimized conditions identified at microscale were found to directly transfer to a Vapourtec UV-150 continuous flow photoreactor, enabling predictable scale-up operation at a scale of hundreds of milligrams per hour. This optimization approach was then expanded to other halide coupling partners that were low-yielding in batch reactions, highlighting the practical application of this optimization platform in the development of conditions for photochemical synthesis in continuous flow.

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      A combination of flow and batch mode processes for the efficient preparation of mGlu2/3 receptor negative allosteric modulators (NAMs)

      • Raveendra Panickar Dhanya, Ananda Herath, Douglas J. Sheffler, Nicholas D.P. Cosford
      • Cancer Metabolism and Signaling Networks Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA

      Benzodiazepinones are privileged scaffolds with activity against multiple therapeutically relevant biological targets. In support of our ongoing studies around allosteric modulators of metabotropic glutamate receptors (mGlus) we required the multigram synthesis of a β-ketoester key intermediate. We report the continuous flow synthesis of tert-butyl 3-(2-cyanopyridin-4-yl)-3-oxopropanoate and its transformation to potent mGlu2/3 negative allosteric modulators (NAMs) in batch mode.

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      On-demand synthesis of organozinc halides under continuous flow conditions

      Mateo Berton, Lena Huck, Jesús Alcázar

      • Lead Discovery, Janssen Research and Development, Janssen-Cilag, S.A., Toledo, Spain

      Organozinc reagents are versatile building blocks for introducing C(sp2)-C(sp3) and C(sp3)-C(sp3) bonds into organic structures. However, despite their ample synthetic versatility and broad functional group tolerance, the use of organozinc reagents in the laboratory is limited because of their instability, exothermicity and water sensitivity, as well as their labor-intensive preparation. Herein, we describe an on-demand synthesis of these useful reagents under continuous flow conditions, overcoming these primary limitations and supporting widespread adoption of these reagents in synthetic organic chemistry. To exemplify this procedure, a solution of ethyl zincbromoacetate is prepared by flowing ethyl bromoacetate through a column containing metallic zinc. The temperature of the column is controlled by a heating jacket and a thermocouple in close contact with it. Advice on how to perform the procedure using alternative equipment is also given to allow a wider access to the methodology. Here we describe the preparation of 50 ml of solution, which takes 1 h 40 min, although up to 250–300 ml can be prepared with the same column setup at a rate of 30 ml per h. The procedure provides the reagent as a clean solution with reproducible concentration. Organozinc solutions generated in flow can be coupled to a second flow reactor to perform a Reformatsky reaction or can be collected over a flask containing the required reagents for a batch Negishi reaction.

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      Generation of Diversity Sets with High sp3 Fraction Using the Photoredox Coupling of Organotrifluoroborates and Organosilicates with Heteroaryl/Aryl Bromides in Continuous Flow

      • Kevin D Raynor, Gregory D May, Upul K. Bandarage, and Michael J. Boyd
      • Vertex Pharmaceuticals Inc., 50 Nothern Avenue, Boston, Massachusetts 02210, United States

      The photoredox cross-coupling of aryl halides and potassium alkyl trifluoroborates is a very effective means to form Csp3-Csp2 bonds. However, this transformation is inefficient for the coupling of unactivated primary trifluoroborates. We have developed a generally useful, continuous flow Csp3-Csp2 coupling procedure for the synthesis of diverse product sets that is compatible with both trifluoroborates and silicate reagents. This universal protocol provides diversity sets from both primary and secondary coupling partners. This easily scalable procedure widens the substrate scope of the coupling reaction and is efficient for producing a greater range of analogues bearing a high sp3 fraction.

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      Iron-Catalyzed Batch/Continuous Flow C-H Functionalization Module for the Synthesis of Anticancer Peroxides

      • Moreshwar Bhagwan Chaudhari, Suresh Moorthy, Sohan Patil, Girish Singh Bisht, Haneef Mohamed, Sudipta Basu, and Boopathy Gnanaprakasam
      • Department of Chemistry, Indian Institute of Science Education and Research, Pune 411008, India

      Iron-catalyzed dehydrogenative cross-coupling of carbonyl compounds with aliphatic peroxide was developed under mild conditions. A library of linear alkylated and arylated peroxides are synthesized in good to excellent yield. This method is highly selective and general for a range of biologically important derivatives of 2-oxindole, barbituric acid, and 4-hydroxy coumarin with a good functional group tolerance and without the cleavage of the peroxide bond. This peroxidation reaction is upscalable to grams and also synthesizable in continuous flow with increased safety in short duration. Mechanistic investigation reveals Fe-(II) undergoes redox type process to generate the radical intermediates, which subsequently recombine selectively to form the stable peroxides. The potential of peroxides is evaluated by cell viability assay and found to exhibit the good anticancer activity with minimum IC50= 5.3 μM.

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      5′-substituted nucleoside compounds

      Inventors: Guillermo S CORTEZ, Zahid Quyoom BONDAY

      • Assignee: Eli Lilly and Co

      The present invention relates to novel 5′-substituted nucleoside compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds to treat cancer, more particularly for the treatment of cancer, in particular glioblastomas, melanoma, sarcomas, gastric cancer, pancreatic cancer, cholangiocarcinoma, bladder cancer, breast cancer, non-small cell lung cancer, leukemias including acute myeloid leukemia, and lymphomas.

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      Selective N-monomethylation of primary anilines with dimethyl carbonate in continuous flow

      • Hyowon Seo, Anne-Catherine Bédard, Willie P. Chen, Robert W. Hicklin, Alexander Alabugin, Timothy F. Jamison
      • Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139, USA

      Selective N-monomethylation of anilines has been achieved under continuous flow conditions using dimethyl carbonate as a green methylating agent in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene. Our methodology takes advantage of the expanded process windows available in the continuous flow regime to safely induce monomethylation in superheated solvents at high pressure. We propose selective N-monomethylation is achieved via an in situ protection-deprotection pathway, which is supported by the observed reactivities of several putative reaction intermediates. The robust and scalable method was applicable to a broad range of primary aniline substrates including ortho-, meta-, and para-substituted anilines, as well as electron-rich and electron-deficient anilines. The synthetic precursor of diazepam, 5-chloro-2-(methylamino)benzophenone, was selectively synthesized under our optimized conditions.

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      Continuous flow multistep synthesis of α-functionalized esters via lithium enolate intermediates

      • Timo von Keutza,b
      • Franz J. Straussb
      • David Cantilloa,b
      • C. Oliver Kappea,b
      • a Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
      • b Institute of Chemistry, NAWI Graz, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria

      This manuscript describes a continuous flow protocol for the α-alkylation of esters. The method is based on the generation of lithium enolate intermediates from the esters and in situ delivered LDA. The process is then integrated with the electrophilic addition step and a quench in line. A series of α-functionalized ester have been prepared using this procedure with moderate to good yields. Key reaction parameters such as temperature and residence time and their influence on the reaction outcome are discussed in detail.

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      A concise flow synthesis of indole-3-carboxylic ester and its derivatisation to an auxin mimic

      Marcus Baumann, Ian R. Baxendale and Fabien Deplante

      • Department of Chemistry, University of Durham, South Road, Durham, Durham, DH1 3LE, UK

      An assembled suite of flow-based transformations have been used to rapidly scale-up the production of a novel auxin mimic-based herbicide which was required for preliminary field trials. The overall synthetic approach and optimisation studies are described along with a full description of the final reactor configurations employed for the synthesis as well as the downstream processing of the reaction streams.

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      Synthesis, physicochemical properties, and biological activity of bile acids 3-glucuronides: Novel insights into bile acid signalling and detoxification

      • Serena Mostardaa
      • Daniela Passerib
      • Andrea Carottia,1
      • Bruno Cerraa
      • Carolina Collivab
      • Tiziana Benicchib
      • Antonio Macchiaruloa
      • Roberto Pellicciarib
      • Antimo Gioielloa
      • a Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo, 1, 06123 Perugia, Italy
      • b TES Pharma, Corso Vannucci, 47, 06121 Perugia, Italy

      Glucuronidation is considered an important detoxification pathway of bile acids especially in cholestatic conditions. Glucuronides are less toxic than the parent free forms and are more easily excreted in urine. However, the pathophysiological significance of bile acid glucuronidation is still controversial and debated among the scientific community. Progress in this field has been strongly limited by the lack of appropriate methods for the preparation of pure glucuronides in the amount needed for biological and pharmacological studies. In this work, we have developed a new synthesis of bile acid C3-glucuronides enabling the convenient preparation of gram-scale quantities. The synthesized compounds have been characterized in terms of physicochemical properties and abilities to modulate key nuclear receptors including the farnesoid X receptor (FXR). In particular, we found that C3-glucuronides of chenodeoxycholic acid and lithocholic acid, respectively the most abundant and potentially cytotoxic species formed in patients affected by cholestasis, behave as FXR agonists and positively regulate the gene expression of transporter proteins, the function of which is critical in human conditions related to imbalances of bile acid homeostasis.

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      5,6-dihydro-imidazo[1,2-a]pyrazin-8-ylamine derivatives useful as inhibitors of beta-secretase (BACE)

      Inventors: Andrés Avelino Trabanco-Suárez, Francisca Delgado-Jiménez, Juan Antonio Vega Ramiro, Gary John Tresadern, Henricus Jacobus Maria Gijsen, Daniel Oehlrich,

      • Assignee: Janssen Pharmaceutica NV Janssen Cilag SA

      The present invention relates to novel 5,6-dihydro-imidazo[1,2-a]pyrazin-8-ylamine inhibitors of beta-secretase, having the structure shown in Formula (I)

      wherein R1, R2, R3, R4, X1, X2, X3, X4, L and Ar are defined in the specification. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which beta-secretase is involved, such as Alzheimer’s disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies, cerebrovascular amyloid angiopathy, multi-infarct dementia, Down’s syndrome, dementia associated with stroke, dementia associated with Parkinson’s disease or dementia associated with beta-amyloid.

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      Conjugated polymers via direct arylation polymerization in continuous flow: minimizing the cost and batch-to-batch variations for high-throughput energy conversion

      Nemal S. Gobalasingham1, Jon E. Carlé2, Frederik C. Krebs2, Barry C. Thompson1, Eva Bundgaard2, Martin Helgesen*,2

      • 1 Department of Chemistry and Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, California, 90089-1661
      • 2 DTU Energy, Technical University of Denmark, Roskilde, DK-4000, Denmark

      Continuous flow methods are utilized in conjunction with direct arylation polymerization (DArP) for the scaled synthesis of the roll-to-roll compatible polymer, poly[(2,5-bis(2-hexyldecyloxy)phenylene)-alt-(4,7-di(thiophen-2-yl)-benzo[c][1,2,5]thiadiazole)] (PPDTBT). PPDTBT is based on simple, inexpensive, and scalable monomers using thienyl-flanked benzothiadiazole as the acceptor, which is the first β-unprotected substrate to be used in continuous flow via DArP, enabling critical evaluation of the suitability of this emerging synthetic method for minimizing defects and for the scaled synthesis of high-performance materials. To demonstrate the usefulness of the method, DArP-prepared PPDTBT via continuous flow synthesis is employed for the preparation of indium tin oxide (ITO)-free and flexible roll-coated solar cells to achieve a power conversion efficiency of 3.5% for 1 cm2 devices, which is comparable to the performance of PPDTBT polymerized through Stille cross coupling. These efforts demonstrate the distinct advantages of the continuous flow protocol with DArP avoiding use of toxic tin chemicals, reducing the associated costs of polymer upscaling, and minimizing batch-to-batch variations for high-quality material.

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      Recent advances of microfluidics technologies in the field of medicinal chemistry

      László Ürge*, Jesus Alcazar, Lena Huck, György Dormán

      • * DBH Group, Budapest, Hungary
      • Janssen Research and Development, Toledo, Spain
      • Innostudio Inc., Budapest, Hungary

      Microfluidics, mesofluidics, and lab-on-a-chip technologies have been extensively researched in the pharma and life science industry over the last two decades, including synthesis of novel compounds and building blocks, medicinal chemistry support, biological screening, DMPK studies, and formulation and manufacturing of APIs and final products. These technologies can provide significant advantages over traditional methods and have the potential to revolutionize certain aspects of pharma R&D. The recent developments on the application of these novel techniques, their penetration in the industry, and their barriers for the further adaptation will be extensively discussed in this overview.

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      Sustainable flow synthesis of a versatile cyclopentenone building block

      • Marcus Baumann
      • Ian R. Baxendale
      • Paolo Filipponi
      • Te Hu
      • Department of Chemistry, University of Durham, South Road, DH1 3LE Durham, U.K
      • Novartis Pharma AG, Fabrikstrasse 14, 4002 Basel, Switzerland

      A flow based multistep processing sequence to reliably provide the delivery of a highly functional cyclopentenone is described. The exemplification of employing solid dosing of reagents and in-line aqueous extraction has enabled an integrated workflow in a highly automated reactor setup.

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      Method and apparatus for the synthesis of dihydroartemisinin and artemisinin derivatives

      Inventors: Daniel Kopetzki, David Tyler McQuade, Peter H. Seeberger, Kerry Gilmore

      • Assignee: Max-Planck-Gesellschaft zur Forderung der Wissenschaften

      The present invention is directed to a method for continuous production of dihydroartemisinin and also artemisinin derivatives derived from dihydroartemisinin by using artemisinin or dihydroartemisinic acid (DHAA) as starting material as well as to a continuous flow reactor for producing dihydroartemisinin as well as the artemisinin derivatives. It was found that the reduction of artemisinin to dihydroartemisinin in a continuous process requires a special kind of reactor and a special combination of reagents comprising a hydride reducing agent, at least one activator such as an inorganic activator, at least one solid base, at least one aprotic solvent and at least one C1-C5 alcohol.

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      Auto-Tandem Catalysis: Pd(II)-Catalysed Dehydrogenation/Oxidative Heck of Cyclopentane-1,3-diones

      Claire J C Lamb, Bryan G Nderitu, Gemma McMurdo, John MTobin, Filipe Vilela, and Ai-Lan Lee

      • Institute of Chemical Sciences, Heriot-Watt University, Edinburgh EH14 4AS, United Kingdom

      A Pd(II) catalyst system has been used to successfully catalyse two mechanistically distinct reactions in a one-pot procedure: dehydrogenation of 2,2-disubstituted cyclopentane-1,3-diones and
      the subsequent oxidative Heck coupling. This auto-tandem catalytic reaction is applicable to both batch and continuous flow processes, with the latter being the first example of a tandem aerobic dehydrogenation/oxidative Heck in flow. In addition, a telescoped reaction involving enantioselective desymmetrisation of the all-C quaternary centre was successfully achieved.

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      Exploring effects of intermittent light upon visible light promoted water oxidations

      Dominic Walsh*a, Pascaline Patureaua, Karen Robertsona, Shaun Reekstingb, Anneke Lubbenb, Salvador Eslavac, Mark T. Welleraa

      • a Department of Chemistry, University of Bath, Bath, BA2 7AY, UK. E-mail: d.walsh2@bath.ac.uk
      • b Chemical Characterization and Analysis Facility, University of Bath, Bath, BA2 7AY, UK
      • c Department of Chemical Engineering, University of Bath, BA2 7AY, UK

      Visible light promoted photocatalytic water oxidations for potential solar fuel production have been studied widely, with many reports on optimization of reagent components. Here we report an exploration on the effects upon ongoing reactions of daylight equivalent light intensity illumination with regulated short dark periods of a few seconds duration as compared to standard continuous illumination. Comparison was made with systems employing synthesized low cost earth abundant iron oxide, calciumoxomanganite and cobalt oxide nanoparticulate catalysts together with a [Ru(bpy)3] 2+ light harvesting dye and an electron acceptor. Yields of gaseous O2 and proton production were measured in situ and in real time. The study found that low cost catalysts could give very significantly increased O2 yields, turn over frequency and improved reaction profiles by use of simple on/off illumination. A range of timings with identical overall photon flux were tested and an optimum determined. Analysis of effects upon the light sensitizer under the range of lighting conditions (through mass spectrometry and UV-vis measurements), together with implementation of a continuous flow system as comparison to the batch reactions, were all employed to help elucidate the mechanisms for the clear improvements in reaction yields observed. These are believed to stem from reduction in self-decomposition of excess oxidized sensitizer and better synchronization of cyclic sensitizer oxidation/reductions with water oxidation at the
      metal oxide surface at specific light on : off timing.

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      Telescoped continuous flow generation of a library of highly substituted 3-thio-1,2,4-triazoles.

      Mariana C. F. C. B. Damiãoa, Renan Galavernaa, Alan P. Kozikowskib, James Eubanksc, Julio C. Pastrea

      • a Institute of Chemistry, University of Campinas - UNICAMP, PO Box 6154 - Zip Code 13083-970, Campinas, SP, Brazil
      • b StarWise Therapeutics LLC - University Research Park – Zip Code 53719-1235, Madison, Wisconsin, USA
      • c Division of Genetics and Development - Krembil Research Institute – Zip Code M5T 2S8, Toronto, Ontario, Canada

      We report herein the successful application of continuous flow micro reactors to prepare important building blocks based on the 3-thio-1,2,4-triazole core. A telescoped continuous flow process was developed based on the condensation of hydrazides and isothiocyanates to deliver an in situ stream of a thiosemicarbazide, which subsequently was cyclized under basic conditions. The obtained 1,2,4-triazole-3-thiol was further alkylated with benzyl/alkyl halides. In addition, we evaluated the scope of heterocycle formation and alkylation using different hydrazides, isothiocyanates, and aryl/alkyl chlorides, bromides and iodides. We were able to synthesize a small library of 18 compounds in 48 minutes of residence time for each synthesis, and in moderate to excellent yields, in a telescoped fashion. The fully integrated synthesis flow platform enables the fast generation of compound libraries, reducing the time consumed in preliminary stages of a drug discovery process.

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      Targeting a mirabegron precursor by BH3-mediated continuous flow reduction process

      • Sonia De Angelisa
      • Claudia Carluccia
      • Modesto de Candiaa
      • Gabriele Rebuzzinib
      • Paolo Celestinib
      • Massimiliano Riscazzib
      • Renzo Luisia
      • Leonardo Degennaroa
      • a FLAME-Lab − Flow Chemistry and Microreactor Technology Laboratory, Department of Pharmacy — Drug Sciences, University of Bari “A. Moro” Via E. Orabona 4, Bari 70125, Italy
      • b COSMA S.p.A, Via Colleoni 15/17, Ciserano, BG 24040, Italy

      A continuous-flow reduction of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide, involved in the synthetic pathway of Mirabegron, has been developed. This study demonstrated the possibility to safely handling BH3 complexes within microfluidic reactors using 2-MeTHF as greener alternative to traditional solvents, and without requiring any additive such as DMI. In addition, NMR and HPLC purity analysis revealed that the sole by-product of this process is the diamine 3, which wouldn’t affect the following synthetic steps towards Mirabegron.

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      In Situ Preparation and Consumption of O-Mesitylsulfonylhydroxylamine (MSH) in Continuous Flow for the Amination of Pyridines

      Cara E. Brocklehurst*, Guido Koch, Stephanie Rothe-Pöllet, Luigi La Vecchia

      • Synthesis and Technologies, Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Klybeckstrasse 141, 4057 Basel, Switzerland

      The paper demonstrates a safe method in which highly unstable O-mesitylsulfonylhydroxylamine (MSH) can be prepared and consumed in continuous flow. MSH was prepared in situ and used for the flow amination of a range of pyridines, which were subsequently transformed into useful pyrazolopyridine building blocks.

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      Highly efficient oxidation of amines to aldehydes with flow-based biocatalysis

      Dr. Martina L. Contente1,2, Federica Dall'Oglio3, Dr. Lucia Tamborini3, Prof. Francesco Molinari4, Prof. Francesca Paradisi1,2

      • 1 School of Chemistry, University of Nottingham, Nottingham, UK
      • 2 UCD School of Chemistry, University College Dublin, Dublin, Ireland
      • 3 Department of Pharmaceutical Sciences, DISFARM, University of Milan, Milan, Italy
      • 4 Department of Food, Environmental and Nutritional Science, DeFENS, University of Milan, Milan, Italy

      A new mild and efficient process for the aqueous preparation of aldehydes, which are employed as flavour and fragrance components in food, beverage, cosmetics, as well as in pharmaceuticals, was developed using a continuous-flow approach based on an immobilised pure transaminase-packed bed reactor. HEWT, an ω-transaminase from the haloadapted bacterium Halomonas elongata, has been selected for its excellent stability and substrate scope. Sixteen different amines were rapidly (3–15 min) oxidised to the corresponding aldehydes (90 to 99 %) with only 1 to 5 equivalents of sodium pyruvate. The process was fully automated, allowing for the in-line recovery of the pure aldehydes (chemical purity >99 % and isolated yields above 80 %), without any further work-up procedure.

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      Novel Polystyrene-Immobilized Chiral Amino Alcohols as Heterogeneous Ligands for the Enantioselective Arylation of Aldehydes in Batch and Continuous Flow Regime

      • José AugustoForni, Luiz Fernando Toneto, Novaes, Renan Galaverna, Julio C.Pastre
      • Institute of Chemistry, University of Campinas – UNICAMP, PO Box 6154, 13083-970, Campinas, SP, Brazil

      Six different ligands derived from (S)-proline, (2S,4R)-4-hydroxyproline, (S)-tyrosine and (S)-phenylalanine were synthesized and screened in homogeneous phase for the enantioselective arylation of aldehydes using mixed organozinc reagents. The best ligands were immobilized on the Merrifield resin and evaluated in batch and continuous flow regimes. In batch, up to 89% yield and 90:10 enantiomeric ratio were obtained. In continuous flow regime, we explored the examples that were more challenging in batch, being able to obtain the desired product in 88% yield and 94:6 of enantiomeric excess in residence time as low as 1.5 min.

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      An efficient and green pathway for continuous Friedel-Crafts acylation over α-Fe2O3 and CaCO3 nanoparticles prepared in the microreactors

      Zheng Fanga1, Wei Heb1, Tao Tub, Niuniu Lva, Chuanhong Qiua, Xin Lia, Ning Zhua, Li Wana, Kai Guoac

      • a College of Biotechnology and Pharmaceutical Engineering, Nanjing Technology University, No. 30 Puzhu South Road, Nanjing, 211816, PR China
      • b Department of Chemistry, Fudan University, No. 220 Handan Road, Shanghai, 200433, PR China
      • c State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Technology University, No. 30 Puzhu South Road, Nanjing, 211816, PR China

      α-Fe2O3 nanoparticles were prepared by using a continuous precipitation method with a valve assisted micromixer in the presence of iron (III) sulfate and ammonia water. The resulting nanoparticles were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM). Meanwhile, CaCO3 nanoparticles were synthesized in a tube-in-tube flow reactor AF-2400. The acylation process catalyzed by modified lipophilic α-Fe2O3 and CaCO3 nanoparticles in the flow reactor were systematically investigated. Under the optimal conditions, a yield of 97.8% was obtained. Addition of CaCO3 nanoparticles resulted in higher catalytic efficiency compared with pure modified α-Fe2O3 nanoparticles. Moreover, this novel acylation also worked well for other substrates.

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      A nanoporous graphene analog for superfast heavy metal removal and continuous-flow visible-light photoredox catalysis

      Ran Xiaoa, John Michael Tobinb, Meiqin Zhaa, Yunlong Houa, Jun Hec, Filipe Vilela*b, Zhengtao Xu*a

      • a Department of Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong
      • b School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, UK
      • c School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou 510006, China

      We report a highly recyclable, 2D aromatic framework that offers a unique and versatile combination of photocatalytic activity and heavy metal uptake capability, as well as other attributes crucial for green and sustainable development technologies. The graphene-like open structure consists of fused tritopic aromatic building blocks (i.e., hexahydroxytriphenylene and hexaazatrinaphthylene) that can be assembled from readily available industrial materials without the need for transition metal catalysts. Besides fast and strong binding for Pb(II) ions (e.g., removing aqueous Pb ions below the drinkable limit within minutes), the alkaline N-heterocycle units of the robust and porous host are able to quantitatively catalyse Knoevenagel reactions in water. Furthermore, the fused donor–acceptor aromatic π-systems enable environmentally friendly photoredox catalysis (PRC) utilizing the safe and abundant visible light in a commercial flow reactor. Also discussed is a new metric for benchmarking the kinetic performance of sorbents in the context of heavy metal removal from drinking water.

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      A novel micro-flow system under microwave irradiation for continuous synthesis of 1, 4-dihydropyridines in the absence of solvents via Hantzsch reaction

      Wei Hea,b, Zheng Fangb, Kai Zhangb, Tao Tua, Niuniu Lvb, Chuanhong Qiub, Kai Guob,c

      • a Department of Chemistry, Fudan University, No. 220 Handan Road, Shanghai, 200433, PR China
      • b College of Biotechnology and Pharmaceutical Engineering, Nanjing Technology University, No. 30 Puzhu South Road, Nanjing, 211816, PR China
      • c State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Technology University, No. 30 Puzhu South Road, Nanjing, 211816, PR China

      γ-Fe2O3 nanoparticles were synthesized in the valve-assisted micromixer. The resulting nanoparticles were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM). In the packed bed flow reactor, the investigation concerning the comparison of different heating methods demonstrated that microwave irradiation displayed the best reaction efficiency compared with air heating and oil-bath heating. A novel micro-flow system under microwave irradiation was designed and employed in the condensation of aldehyde, ethyl acetoacetate and ammonia. Under optimized conditions, Hantzsch reaction conducted well, resulting in a yield of 98.7% and excellent selectivity. In addition, this novel process worked well for other substrates.

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      Methanolysis of epoxidized soybean oil in continuous flow conditions

      Vincenzo Pantonea, Amelita Grazia Laurensab, Cosimo Annesec, Francesco Fracassib, Caterina Fuscob, Angelo Naccib,c, Antonella Russoa, Lucia D’Accoltib,c

      • a Greenswitch s.r.l., Ferrandina MT, Italy
      • b Dipartimento di Chimica, Università di Bari Aldo Moro, Via E. Orabona 4, 70126 Bari, Italy
      • c ICCOM-CNR, SS Bari, Via E. Orabona 4, 70126 Bari, Italy

      Bio-polyols synthesized from vegetables oils are a great alternative to petrochemical polyols for polyurethanes industry. The simplest approach to bio-polyols synthesis involves epoxidation of carbon–carbon double bond of unsaturated fatty ester moieties and subsequent epoxide ring-opening by nucleophilic reagents. In order to improve the latter process by increasing both productivity and product quality, the advantages of flow chemistry were exploited, such as facile automation, reproducibility, improved safety and process reliability, investigating for the first time in the literature the methanolysis reaction of epoxidized soybean oil (ESO) in a continuous flow mode.

      Compared with batch reaction, flow mode allowed the cut of the reaction time from 30 min to 2 min, and the reduction of catalyst concentration by an order of magnitude, which brought significant benefits in terms of cost efficiency and eco-sustainability, rendering the method suitable for industrial applications.

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      Visible-light-induced trifluoromethylation of highly functionalized arenes and heteroarenes in continuous flow

      Irini Abdiaja, Cecilia Bottecchiab, Jesus Alcazar*a, Timothy Noёl*b

      • a Janssen Research & Development, Jarama 75A, 45007 Toledo, Spain
      • b Department of Chemical Engineering and Chemistry, Micro Flow Chemistry & Process Technology, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands

      We report a continuous-flow protocol for the trifluoromethylation of arenes, heteroarenes, and benzofused heterocycles. This photoredox methodology relies on the use of solid sodium trifluoromethanesulfinate (CF3SO2Na) as the trifluoromethylating agent and the iridium complex [Ir{dF(CF3)ppy}2](dtbpy)]PF6 as the photoredox catalyst. A diverse set of highly functionalized heterocycles proved compatible with the methodology, and moderate to good yields were obtained within 30 minutes of residence time.

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      Continuous preparation and use of dibromoformaldoxime as a reactive intermediate for the synthesis of 3- bromoisoxazolines

      • Claudio Battilocchioa*
      • Francesco Bosicaa
      • Sam M. Rowea
      • Bruna L. Abreua
      • Edouard Godineaub*
      • Matthias Lehmannb
      • Steven V. Leya
      • a Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
      • b Syngenta Crop Protection AG, Crop Protection Research, Schaffhauserstrasse 101, CH-4332 Stein, Switzerland

      We report the multistep continuous process for the preparation of dibromoformaldoxime (DBFO) as a precursor to generate bromoisoxazolines. We also report process improvements that afford a productivity of over 620 mmol h-1 of DBFO.

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      Treatment of alcohols

      Inventors: Thomas Mark Douglas, Andrew John Hogben, David John Law, John Glenn Sunley, Thomas Giles Parsons

      • Assignee: Technip E&C Ltd

      Process for treating an alcohol composition containing nitrogen-containing contaminants by contacting the alcohol composition with an adsorbent in an adsorption zone. The adsorbent is a transition metal-loaded solid porous material selected from aluminosilicates, silica-aluminas, silicates and aluminas, and the alcohol composition is contacted with the adsorbent either alone or in the presence of an inert carrier gas.

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      Chemoenzymatic synthesis in flow reactors: a rapid and convenient preparation of captopril

      • Dr. Valerio De Vitis1
      • Dr. Federica Dall'Oglio1
      • Dr. Andrea Pinto2
      • Prof. Carlo De Micheli2
      • Prof. Francesco Molinari1
      • Prof. Paola Conti2
      • Dr. Diego Romano1
      • Dr. Lucia Tamborini2
      • 1 Department of Food Environmental and Nutritional Science, University of Milan, Milan, Italy
      • 2 Department of Pharmaceutical Sciences, University of Milan, Milan, Italy

      The chemoenzymatic flow synthesis of enantiomerically pure captopril, a widely used antihypertensive drug, is accomplished starting from simple, inexpensive, and readily available reagents. The first step is a heterogeneous biocatalyzed regio- and stereoselective oxidation of cheap prochiral 2-methyl-1,3-propandiol, performed in flow using immobilized whole cells of Acetobacter aceti MIM 2000/28, thus avoiding the use of aggressive and environmentally harmful chemical oxidants. The isolation of the highly hydrophilic intermediate (R)-3-hydroxy-2-methylpropanoic acid is achieved in-line by using a catch-and-release strategy. Then, three sequential high-throughput chemical steps lead to the isolation of captopril in only 75 min. In-line quenching and liquid–liquid separation enable breaks in the workflow and other manipulations to be avoided.

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      Preparation of polyfunctional diorgano-magnesium and – zinc reagents using in situ trapping halogen-lithium exchange of highly functionalized (hetero)aryl halides in continuous flow

      Marthe Ketels, Maximilian Andreas Ganiek, Niels Weidmann, Paul Knochel

      • LMU München, Department of Chemistry, München, Germany

      We report a halogen-lithium exchange performed in the presence of various metal salts (ZnCl2, MgCl2·LiCl) on a broad range of sensitive bromo- or iodo-(hetero)arenes using BuLi or PhLi as exchange reagent and a commercially available continuous flow setup. The resulting diarylmagnesium or diarylzinc species were trapped with various electrophiles resulting in the formation of polyfunctional (hetero)arenes in high yields. This methodology enabled the functionalization of (hetero)arenes containing highly sensitive groups such as an isothiocyanate, nitro, azide or ester. A straightforward scale-up was possible without further optimization.

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      Flow assisted synthesis: a key fragment of SR 142948A

      • Matthew Oliver Kitching, Olivia E Dixon, Marcus Baumann, Ian Richard Baxendale
      • University of Durham, Chemistry, Durham, UK

      We report a series of multi-step flow operations to deliver an advanced hydrazine intermediate used in the assembly of the Neurotensin modulator SR142948A. Several new reactor configurations have enabled chemical transformations that would be otherwise difficult or dangerous to perform at scale. Overall the flow approach has allowed the preparation of kilogram quantities of the required hydrazine via a short and efficient route.

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      Singlet oxygen oxidations in homogeneous continuous flow using a gas–liquid membrane reactor

      Antonia Kouridaki, Kevin Huvaere

      • EcoSynth NV, Industrielaan 12, 9800 Deinze, Belgium

      A flow chemistry reactor system for scalable photooxygenation reactions was developed using a gas–liquid reactor as key feature. Herein oxygen gas is dissolved under pressure in the reaction mixture to give a homogeneous flow regime prior to irradiation. The system enables safe mass transport of oxygen in an accurate manner simply by adjusting liquid flow rate, membrane temperature, and gas pressure as concluded after characterization of reactor behaviour. Quantification of oxygen supply as function of liquid flow rate and membrane temperature showed that 50 mM and 58 mM of oxygen were supplied to methanol and acetonitrile at 1 mL min−1 flow rate and 110 °C membrane temperature. With 100 mM measured at 90 °C, dichloromethane was most effective for oxygen uptake. Photooxidation of a model system, the furan derivative ethyl 3-(2-furyl)propanoate, was elaborated to validate the system for singlet oxygen chemistry, with reactor parameters being further optimized for maximum conversion. Scope of the system was demonstrated by performing a set of representative photochemical oxidations, including reaction with citronellol as first step in the synthesis of rose oxide.

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      A convenient, mild and green synthesis of NH-sulfoximines in flow reactors

      • Leonardo Degennaro1
      • Arianna Tota1
      • Sonia De Angelis1
      • Michael Andresini1
      • Cosimo Cardellicchio2
      • Maria Annunziata Capozzi1
      • Giuseppe Romanazzi3
      • Renzo Luisi1
      • 1 University of Bari, Department of Pharmacy - Drug Sciences, Bari, Italy
      • 2 CNR ICCOM, Department of Chemistry, Bari, Italy
      • 3 Politecnico di Bari, DICATECh, Bari, Italy

      NH-Sulfoximines are emerging as useful and important targets in drug discovery and synthetic organic chemistry. We report herein the development of an efficient, convenient, and sustainable continuous flow strategy, for the direct straightforward preparation of NH-sulfoximines using sulfides or sulfoxides as suitable starting material. The flow process uses PhI(OAc)2 as the oxidant and aqueous solutions of ammonia as the N-source. The scope of the reaction has been demonstrated by using several substituted sulfides and sulfoxides including enantioenriched and biologically relevant starting materials. The flow strategy was found more convenient with respect to conventional batch processing.

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      A continuous flow method for the desulfurization of substituted thioimidazoles applied to the synthesis of new etomidate derivatives

      • Marcus Baumann, Ian R Baxendale
      • Durham University, Department of Chemistry, Durham, UK

      A simple yet robust flow set-up for the efficient desulfurization of a series of thioimidazoles is presented generating the corresponding imidazole derivatives in high yields. The strategic choice of peristaltic over piston pumps allowed reliable delivery of the heterogeneous stream of thioimidazole substrate into a T-piece where it reacted with NaNO2 in the presence of acetic acid. This approach enabled the controlled and safe formation of the reactive nitrosonium species without uncontrolled exposure to hazardous nitrous oxide by-products as observed in related batch protocols. The value of the resulting imidazole products was further demonstrated by their conversion into various esters representing new derivatives of the known analgesic etomidate via an efficient one pot Corey-Gilman-Ganem oxidation procedure.

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      High throughput photo-oxidations in a packed bed reactor system

      • Caleb J. Kong, Daniel Fisher, Bimbisar K. Desai,. Yuan Yang, Saeed Ahmad, Katherine Belecki, B. Frank Gupton
      • Department of Chemistry and Department of Chemical and Life Science Engineering, Virginia Commonwealth University, 601 W. Main St. Richmond, VA 23220, USA

      The efficiency gains produced by continuous-flow systems in conducting photochemical transformations have been extensively demonstrated. Recently, these systems have been used in developing safe and efficient methods for photo-oxidations using singlet oxygen generated by photosensitizers. Much of the previous work has focused on the use of homogeneous photocatalysts. The development of a unique, packed-bed photoreactor system using immobilized rose bengal expands these capabilities as this robust photocatalyst allows access to and elaboration from these highly useful building blocks without the need for further purification. With this platform we were able to demonstrate a wide scope of singlet oxygen ene, [4+2] cycloadditions and heteroatom oxidations. Furthermore, we applied this method as a strategic element in the synthesis of the high-volume antimalarial artemisinin.

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      Phase separation macrocyclization in a complex pharmaceutical setting: application toward the synthesis of vaniprevir

      Eric Godin, Anne-Catherine Bédard, Michael Raymond, Shawn K. Collins*

      • Département de Chimie, Centre for Green Chemistry and Catalysis, Université de Montréal, CP 6128 Station Downtown, Montréal, Québec, H3C 3J7 Canada

      A phase separation/continuous flow strategy employing an oxidative Glaser–Hay coupling of alkynes has been applied toward the synthesis of the macrocyclic core of complex pharmaceutical vaniprevir. The phase separation/continuous flow strategy afforded similar yields at 100–500 times the concentration and at shorter reaction times than common slow addition/high dilution techniques. In addition, dendritic PEG cosolvents were employed in the phase separation strategy for the first time and shown to allow productive macrocyclization at concentrations up to 200 mM.

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      Method for the synthesis of N-(phosphonomethyl)glycine

      Inventors: Sebastian Burck, Frederic Bruyneel, Patrick Notte

      • Assignee: Monsanto Technology LLC

      A method for the synthesis of N-(phosphonomethyl)glycine or one of its derivatives selected from the group consisting of its salts, its phosphonate esters, or its phosphonate ester salts, which includes the steps of: a) forming, in the presence an acid catalyst, a reaction mixture having 2,5-diketopiperazine, formaldehyde and a compound including one or more P-0-P anhydride moieties, the moieties having one P atom at the oxidation state (+III) and the other P atom at the oxidation state (+III) or (+V), to form N,N′-bisphosphonomethyl-2,5-diketopiperazine, its mono- to tetra phosphonate esters, the dehydrated forms of N,N′-bisphosphonomethyl-2,5-diketopiperazine and the phosphonate esters of its dehydrated forms; and b) hydrolyzing the N,N′-bisphosphonomethyl-2,5-diketopiperazine, its dehydrated forms or their phosphonate esters to obtain N-(phosphonomethyl)glycine or one of its derivatives selected from the group consisting of its salts, its phosphonate esters and its phosphonate ester salts.

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      Isoquinoline derivatives

      Inventors: Simona M. Ceccarelli, Ravi Jagasia, Roland Jakob-Roetne, Rainer E. Martin, Juergen Wichmann

      • Assignee: Hoffmann La Roche Inc

      The present invention relates to the use of compounds of general formula

      wherein
      R1 is phenyl or pyridinyl, which are optionally substituted by halogen, cyano or lower alkyl substituted by halogen, or is dihydro-pyran-4-yl;
      R2 is hydrogen or lower alkyl;
      R3 is —(CHR)n-phenyl, optionally substituted by lower alkoxy or S(O)2-lower alkyl,or is heterocycloalkyl, optionally substituted by ═O and lower alkyl,
      or is —(CH2)n-five or six membered heteroaryl, optionally substituted by lower alkyl,
      or is hydrogen, lower alkyl, lower alkyl substituted by halogen, lower alkyl substituted by hydroxy, —NR—S(O)2-lower alkyl, —(CH2)n-cycloalkyl or —(CH2)n—S(O)2-lower alkyl; or
      R2 and R3 form together with the N-atom to which they are attached a heterocycloalkyl ring, selected from the group consisting of 1,1-dioxo-thiomorpholinyl, morpholinyl, or pyrrolidinyl, optionally substituted by hydroxyl;
      R is hydrogen or lower alkyl;
      n is 0, 1 or 2;
      or to a pharmaceutically acceptable acid addition salt, to a racemic mixture or to its corresponding enantiomer and/or optical isomers thereof,
      for the treatment of schizophrenia, obsessive-compulsive personality disorder, depression, bipolar disorders, anxiety disorders, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson’s disease, dementia, Alzheimer’s disease, mild cognitive impairment, chemotherapy-induced cognitive dysfunction (“chemobrain”), Down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington’s disease, stroke, and disturbances due to radiation therapy, chronic stress, optic neuropathy or macular degeneration, or abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine or cocaine.

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      Removal of nitrogen-containing impurities form alcohol compositions

      Inventors:, Thomas Mark Douglas, Nakul Thakar

      • Assignee: Technip E&C Ltd

      Process for the treatment of an alcohol composition containing nitrogen-containing contaminants by contacting the alcohol composition in the vapor phase with an adsorbent in an adsorption zone.

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      Substituted 1,6-naphthyridines

      Inventors:, Simona M. Ceccarelli, Ravi Jagasia, Roland Jakob-Roetne, Rainer E. Martin, Jens-Uwe Peters, Juergen Wichmann

      • Assignee: Hoffmann La Roche Inc

      The present invention relates to the use of compounds of general formula I wherein R′, R1, R2 and R3 are as

      defined herein, or to a pharmaceutically acceptable acid addition salt, to a racemic mixture or to its corresponding enantiomer and/or optical isomers thereof, and for methods to treat a variety of neurodegenerative and neuropsychiatric diseases.

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      Process for the preparation of efavirenz and devices suitable therefore

      Inventors, Camille A. Correia, Kerry Gilmore, David Tyler McQuade, Peter H. Seeberger

      • Assignee: Max-Planck-Gesellschaft zur Forderung der Wissenschaften

      The invention relates to a process for the preparation of Efavirenz via an efficient transition metal catalyzed cyclization, to a device suitable to perform such process as well as to novel intermediates.

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      RAFT polymers

      Inventors:, John Chiefari, Christian Hornung, Almar Postma, Simon Saubern

      • Assignee: Commonwealth Scientific and Industrial Research Organization CSIRO

      The invention provides for a process for removing thiocarbonylthio groups from polymer prepared by RAFT polymerization, the process comprising:
      introducing into a flow reactor a solution comprising the RAFT polymer in solvent; and promoting a reaction within the flow reactor that removes the thiocarbonylthio groups so as to form a solution that flows out of the reactor comprising the RAFT polymer absent the thiocarbonylthio groups.

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      Method for preparing caprolactam by using a microreactor under lewis acid catalysis

      Inventors:, Kai Guo, Xin Li, Zheng Fang, Kai Zhang, Qi Yu, Pingkai Ouyang

      • Assignee: Nanjing Tech University

      A method for preparing caprolactam by using a microreactor under Lewis acid catalysis, wherein a hydroxyl group in a cyclohexanone oxime is activated to obtain a cyclohexanone oxime sulfonates intermediate, then rearranged under Lewis acid catalysis to prepare the caprolactam. The method of this invention has a simple process and a high operation safety and selectivity, the reaction condition is mild, an efficient reaction can take place even at room temperature, the reaction time is short, the conversion of the cyclohexanone oxime can reach 100% within a short time, the selectivity of the caprolactam can reach 99%, the energy consumption is greatly reduced in the premise of maintaining a high yield, and the production cost is reduced, being an efficient and green and environmentally friendly method of for synthesizing the caprolactam.

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      Grignard reagents on a tab: direct magnesium insertion under flow conditions

      • Lena Huck†,‡
      • Antonio de la Hoz
      • Angel Díaz-Ortiz
      • Jesus Alcázar
      • Janssen Research and Development, Janssen-Cilag, S.A., C/Jarama 75, 45007 Toledo, Spain
      • Facultad de Ciencias Químicas, Universidad de Castilla-La Mancha, 13071 Ciudad Real, Spain

      An on-demand preparation of organomagnesium reagents is presented using a new flow protocol. The risks associated with the activation of magnesium are circumvented by a new on-column initiation procedure. Required amounts of solutions with a precise titration were obtained. Telescoped flow or batch reactions allow access to a diverse set of functional groups.

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      Co-production of HMF and gluconic acid from sucrose by chemo-enzymatic method

      • Hongli Wu, Ting Huang, Fei Cao, Qiaogen Zou, Ping Wei, Pingkai Ouyang
      • College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, 30 South Puzhu Road, Nanjing 211816 PR China

      Co-production of multi-products is one of the core principles of chemical industry, and it is also an important way to improve the atom economy. Herein, we proposed an approach to co-producing two valuable platform compounds, gluconic acid (GA) and 5-hydroxymethyl furfural (HMF), from sucrose by successive hydrolysis, oxidation and dehydration. In the enzymatic oxidation step, only glucose was oxidized to GA, meanwhile fructose was 100% retained. In the further biphasic dehydration system, only fructose was converted into HMF, whereas GA was maintained with over 95% recovery. After three reactions, the yields of HMF and GA were respectively 42.5% and 48% when the initial feedstock of sucrose was 200 g/L. Two products were easily separated because GA was completely existed in aqueous phase, and HMF was mainly in organic phase. In the whole process, only commercial enzymes and mineral acid were used instead of self-made catalysts.

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      The Application of a Continuous Grignard Reaction in the Preparation of Fluconazole

      • Sudha Korwar
      • Somi Amir
      • Perrer N. Tosso
      • Bimbisar K. Desai
      • Caleb J. Kong
      • Swara Fadnis
      • Nakul S. Telang
      • Saeed Ahmad
      • Thomas D. Roper
      • B. Frank Gupton*
      • Department of Chemistry and Department of Chemical and Life Science, Engineering, Virginia Commonwealth University, 601 W. Main St., R ichmond, VA 23220, USA

      The application of continuous methods in the synthesis of active pharmaceutical ingredients continues to receive significant attention in the academic as well as the industrial research communities. One of the major advantages of continuous methods is the ability to safely access kinetic synthons as well as highly reactive reagents that are typically unavailable through traditional batch methods. In this work, we report the high‐yielding, clean formation of an aryl‐turbo Grignard and its selective addition to a highly‐enolizable 1,3‐dichloroacetone, for the continuous synthesis of a key intermediate for fluconazole, a widely‐prescribed anti‐fungal agent. In addition, process optimization of the final API was also carried out to arrive at a semi‐continuous method to this essential medicine.

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      Efficient synthesis of 5-(chloromethyl) furfural (CMF) from high fructose corn syrup (HFCS) using continuous flow processing

      T. M. Kohla, B. Bizeta, P. Kevana, C. Sellwooda, J. Tsanaktsidisa, C. H. Hornunga

      • a CSIRO Manufacturing Flagship, Bag 10, Clayton South, Australia

      Using continuous flow processing the synthesis of 5-(chloromethyl) furfural (CMF) from both solid sugars and high fructose corn syrup (HFCS) was achieved. The use of HFCS allows for a convenient liquid sugar feedstock, which in turn through our improved three pump system, allows for production of CMF with no additional handling of stock solutions. Extensive reaction optimisation was also carried out with large increases in reaction efficiency achieved over existing batch processes.

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      Barbier continuous flow preparation and reactions of carbamoyllithiums for nucleophilic amidation

      Maximilian Andreas Ganiek, Matthias Richard Becker, Guillaume Berionni, Hendrik Zipse, Paul Knochel

      • LMU München, Department of Chemistry, München, Germany

      An ambient temperature continuous flow method for nucleophilic amidation and thioamidation is described. Deprotonation of formamides by lithium diisopropylamine (LDA) affords carbamoyllithium intermediates that are quenched in situ with various electrophiles such as ketones, allyl bromides, Weinreb and morpholino amides. The nature of the reactive lithium intermediates and the thermodynamics of the metalation were further investigated by ab initio calculations and kinetic experiments.

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      Polymer-supported photosensitizers for oxidative organic transformations in flow and under visible light irradiation

      • John M. Tobin
      • Timothy J. D. McCabe
      • Andrew W. Prentice
      • Sarah Holzer
      • Gareth O. Lloyd
      • Martin J. Paterson
      • Valeria Arrighi
      • Peter A. G. Cormack
      • Filipe Vilela
      • School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS Scotland, United Kingdom
      • WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow, G1 1XL Scotland, United Kingdom

      A 2,1,3-benzothiadiazole (BTZ)-based vinyl cross-linker was synthesized and copolymerized with large excesses of styrene using free radical polymerization to deliver heterogeneous triplet photosensitizers in three distinct physical formats: gels, beads, and monoliths. These photosensitizers were employed for the production of singlet oxygen (1O2) and for the aerobic hydroxylation of arylboronic acids via superoxide radical anion (O2•–), whereby the materials demonstrated good chemical and light stability. BTZ-containing beads and monoliths were exploited as photosensitizers in a commercial flow reactor, and 1O2 production was also demonstrated using direct sunlight irradiation, with a conversion rate comparable to the rates achieved when a 420 nm LED module is used as the source of photons.

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      Direct valorisation of waste cocoa butter triglycerides via catalytic epoxidation, ring-opening and polymerisation

      Dorota D Plazaa, Vinzent Strobelb, Parminder Kaur KS Heerb, Andrew B Sellarsd, Seng-Soi Hoongd, Andrew J Clarkd, Alexei A Lapkinb

      • a School of Engineering, University of Warwick, Coventry, UK
      • b Department of Chemical Engineering and Biotechnology, University of Cambridge, UK
      • c Aachener Verfahrenstechnik – Process Systems Engineering, RWTH Aachen University, Aachen, Germany
      • d Department of Chemistry, University of Warwick, Coventry, UK

      Development of circular economy requires significant advances in the technologies for valorisation of waste, as waste becomes new feedstock. Food waste is a particularly important feedstock, containing large variation of complex chemical functionality. Although most food waste sources are complex mixtures, waste from food processing, no longer suitable for the human food chain, may also represent relatively clean materials. One such material requiring valorisation is cocoa butter.

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      Hydrogen sulfide chemistry in continuous flow: Efficient synthesis of 2-oxopropanethioamide

      David Cantillo1,2, Phillip A. Inglesby3, Alistair Boyd3, Oliver Kappe1,2

      • 1 Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria
      • 2 Research Center Pharmaceutical Engineering (RCPE), Inffeldgasse 13, 8010 Graz, Austria
      • 3 AstraZeneca, Silk Road Business Park, Macclesfield, SK10 2NA, United Kingdom

      A safe and scalable procedure for the synthesis of 2-oxopropanethioamide, an intermediate in the synthesis of a potent β-secretase (BACE-1) inhibitor, from the reaction of acetyl cyanide with hydrogen sulfide gas under continuous-flow conditions has been developed. The toxic gas could be accurately dosed using a mass-flow controller or a peristaltic pump. The reaction proceeded smoothly at room temperature in the presence of a small amount of triethylamine as basic catalyst. After a residence time of 15 min, excellent yield (96%) and purity (>99%) were obtained for the target compound. The high reaction selectivity permitted a simple workup procedure consisting of evaporation of all volatiles.

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      Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

      Chinmay A. Shukla1,2, Amol A. Kulkarni1,2

      • 1 Academy of Scientific and Innovative Research (AcSIR), CSIR-National Chemical Laboratory (NCL) Campus, Pune 411008, India
      • 2 Chem. Eng. & Proc. Dev. Div., CSIR-National Chemical Laboratory, Dr. Homi Bhaba Road, Pashan, Pune 411008, India

      The implementation of automation in the multistep flow synthesis is essential for transforming laboratory-scale chemistry into a reliable industrial process. In this review, we briefly introduce the role of automation based on its application in synthesis viz. Auto sampling and inline monitoring, optimization and process control. Subsequently, we have critically reviewed a few multistep flow synthesis and suggested a possible control strategy to be implemented so that it helps to reliably transfer the laboratory-scale synthesis strategy to a pilot scale at its optimum conditions. Due to the vast literature in multistep synthesis, we have classified the literature and have identified the case studies based on few criteria viz. Type of reaction, heating methods, processes involving in-line separation units, telescopic synthesis, processes involving in-line quenching and process with the smallest time scale of operation. This classification will cover the broader range in the multistep synthesis literature.

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      Utilizing on‐and off‐line monitoring tools to follow a kinetic resolution step during flow synthesis

      Kathleen A. Farley, Usa Reilly, Dennis P. Anderson, Brian P. Boscoe, Mark W. Bundesmann, David A. Foley, Manjinder S. Lall, Chao Li, Matthew R. Reese, Jiangli Yan

      • Medicinal Sciences, Pfizer Worldwide Research and Development, Groton, CT, United States

      In situ reaction monitoring tools offer the ability to track the progress of a synthetic reaction in real time to facilitate reaction optimization and provide kinetic/mechanistic insight. Herein, we report the utilization of flow NMR, flow IR, and other off-line spectroscopy tools to monitor the progress of a flow chemistry reaction. The on-line and off-line tools were selected to facilitate the stereoselective kinetic resolution of a key racemic monomer, which lacked a chromophore, making conventional reaction monitoring difficult.

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      Flow Synthesis of Cyclobutanones via [2+2] Cycloaddition of Keteneiminium Salts and Ethylene Gas

      Claudio Battilocchioa, Grazia Iannuccia, Shiyi Wanga, Edouard Godineaub, Amandine Kriegerb, Alain De Mesmaekerb, Steven V Ley*a

      • a Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, UK
      • b Syngenta Crop Protection AG, Crop Protection Research, Schaffhauserstrasse 101, CH-4332, Switzerland

      A flow chemistry process for the synthesis of 2-substituted cyclobutanones, via [2+2] cycloaddition of keteneiminium salts and ethylene gas, is reported. Our approach uses rapid and mild reaction conditions to access a diverse array of products with good to excellent yield, alongside a good level of functional group compatibility.

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      Continuous Flow α-Arylation of N,N-Dialkylhydrazones under Visible-Light Photoredox Catalysis

      • Juan A. Vega
      • José Manuel Alonso
      • Gabriela Méndez
      • Myriam Ciordia
      • Francisca Delgado
      • Andrés A. Trabanco
      • Neuroscience Medicinal Chemistry, Janssen Research & Development, Jarama 75A, 45007 Toledo, Spain

      The first direct α-arylation of aldehyde-derived N,N-dialkylhydrazones with electron deficient aryl and heteroaryl cyanides under visible-light photoredox catalysis has been developed. Structurally complex α,α′-diaryl-N,N-cycloalkylhydrazones were obtained in moderate yields by repetition of the direct arylation protocol. A continuous-flow procedure for the preparation of α-aryl-N,N-dialkylhydrazones on a multigram scale has also been established.

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      Utilization of flow chemistry in catalysis: New avenues for the selective synthesis of Bis(indolyl)methanes

      • Swapna S. Mohapatraa,b
      • Zoe E. Wilsona
      • Sujit Royb
      • Steven V. Leya
      • a Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
      • b Organometallics & Catalysis Laboratory, School of Basic Sciences, Indian Institute of Technology, Bhubaneswar 751013, India

      Flow chemistry enables the preparation of bis(indolyl)methanes from various indoles and structurally divergent aldehydes using Sc(OTf)3 catalysis. The reaction is regioselective for C-3 functionalization of the indoles, occurring over short reaction times allowing for rapid investigation of scope with straightforward work up facilitating product isolation.

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      Continuous-flow synthesis of highly functionalized imidazo-oxadiazoles facilitated by microfluidic extraction

      Ananda Herath, Nicholas D. P. Cosford

      • Cancer Metabolism & Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA

      A versatile continuous-flow synthesis of highly functionalized 1,2,4-oxadiazoles starting from carboxylic acids is reported. This process was applied to the multistep synthesis of imidazo[1,2-a]pyridin-2-yl-1,2,4-oxadiazoles, using a three reactor, multistep continuous-flow system without isolation of intermediates. This continuous-flow method was successfully combined with a single-step liquid–liquid microextraction unit to remove high boiling point polar solvents and impurities and provides the target compounds in high purity with excellent overall yields.

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      Preparation of Forced Gradient Copolymers Using Tube-in-Tube Continuous Flow Reactors

      Simon Saubern, Xuan Nguyen, Van Nguyen, James Gardiner, John Tsanaktsidis, John Chiefari

      • CSIRO Manufacturing, Clayton, VIC, Australia

      The preparation of forced gradient polymers has received considerable attention using batch reactors, while the preparation of usable quantities of forced gradient copolymers using continuous flow reactors has been hampered by the need to vary the composition of the monomer feedstock continuously during the reaction. A reactor that allows for addition of a monomer feedstock continuously at all points along the length of the reactor tubing allows for the preparation of forced gradient copolymers in continuous flow reactors, allowing for the scale-up and bulk preparation of these polymers. This study reports here the initial investigation of preparing forced gradient copolymers using the reversible addition–fragmentation chain transfer methodology in tube-in-tube continuous flow reactors.

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      A Continuous Flow Synthesis and Derivatization of 1,2,4-Thiadiazoles

      • Marcus Baumann
      • Ian R. Baxendale
      • Department of Chemistry, University of Durham, South Road, DH1 3LE Durham, United Kingdom.

      A continuous flow process is presented that enables the efficient synthesis and derivatization of 1,2,4-thiadiazole heterocycles. Special attention was given to the safe handling of the versatile yet hazardous trichloromethane sulfenylchloride reagent including its in-line quenching in order to eliminate malodourous and corrosive by-products. Based on this flow method gram quantities of 5-chloro-3-phenyl-1,2,4-thiadiazole were safely prepared allowing for further elaboration of this valuable building block by reaction with different nitrogen-, sulfur- and oxygen-based nucleophiles. This synthetic approach was subsequently applied to generate a series of bromophenyl-5-chloro-1,2,4-thiadiazoles providing a valuable entry towards further structural diversification on this important heterocyclic scaffold.

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      Self-Optimisation and Model-Based Design of Experiments for Developing a C–H Activation Flow Process

      Alexander Echtermeyer1,2, Yehia Amar2, Jacek Zakrzewski2, Alexei Lapkin2

      • 1 Aachener Verfahrenstechnik – Process Systems Engineering, RWTH Aachen University, Aachen, Germany
      • 2 Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, United Kingdom

      A recently described C(sp3)–H activation reaction to synthesise aziridines was used as a model reaction to demonstrate the methodology of developing a process model using model-based design of experiments (MBDoE) and self-optimisation approaches in flow. The two approaches are compared in terms of experimental efficiency. The self-optimisation approach required the least number of experiments to reach the specified objectives of cost and product yield, whereas the MBDoE approach enabled a rapid generation of a process model.

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      Diels–Alder reactions of myrcene using intensified continuous-flow reactors

      Christian H. Hornung, Miguel Á. Álvarez-Diéguez, Thomas M. Kohl and John Tsanaktsidis

      • CSIRO Manufacturing, Bag 10, Clayton South, Victoria 3169, Australia

      This work describes the Diels–Alder reaction of the naturally occurring substituted butadiene, myrcene, with a range of different naturally occurring and synthetic dienophiles. The synthesis of the Diels–Alder adduct from myrcene and acrylic acid, containing surfactant properties, was scaled-up in a plate-type continuous-flow reactor with a volume of 105 mL to a throughput of 2.79 kg of the final product per day. This continuous-flow approach provides a facile alternative scale-up route to conventional batch processing, and it helps to intensify the synthesis protocol by applying higher reaction temperatures and shorter reaction times.

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      Active Site-Mapping of Xylan-Deconstructing Enzymes with Arabinoxylan Oligosaccharides Produced by Automated Glycan Assembly

      Deborah Senf, Colin Ruprecht, Goswinus de Kruijff, Sebastian Simonetti, Frank Schuhmacher, Peter Seeberger, Fabian Pfrengle

      • Max-Planck-Institute of Colloids and Interfaces, Biomolecular Systems, Potsdam, Germany

      Xylan-degrading enzymes are crucial for the deconstruction of hemicellulosic biomass, making the hydrolysis products available for various industrial applications such as biofuel production. To determine the substrate specificities of these enzymes, we prepared a collection of complex xylan oligosaccharides by automated glycan assembly. Seven differentially protected building blocks provided the basis for the modular assembly of 2-substituted, 3-substituted, and 2-/3-substituted arabino- and glucuronoxylan oligosaccharides. Elongation of the xylan backbone relied on iterative additions of C4-fluorenylmethoxylcarbonyl (Fmoc) protected xylose building blocks to a linker-functionalized resin. Arabinofuranose and glucuronic acid residues have been selectively attached to the backbone using fully orthogonal 2-(methyl)naphthyl (Nap) and 2-(azidomethyl)benzoyl (Azmb) protecting groups at the C2- and C3-hydroxyls of the xylose building blocks. The arabinoxylan oligosaccharides are excellent tools to map the active site of glycosyl hydrolases involved in xylan deconstruction. The substrate specificities of several xylanases and arabinofuranosidases were determined by analyzing the digestion products after incubation of the oligosaccharides with glycosyl hydrolases.

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      Mixed-Linkage Glucan Oligosaccharides Produced by Automated Glycan Assembly Serve as Tools to Determine the Substrate Specificity of Lichenase

      Pietro Dallabernardina, Frank Schuhmacher, Peter H Seeberger, Fabian Pfrengle

      • Max-Planck-Institute of Colloids and Interfaces, Biomolecular Systems, Potsdam, Germany

      The mixed-linkage (1→3),(1→4)-D-glucan (MLG) specific glycosyl hydrolase lichenase is an important biochemical tool for the structural characterization of MLGs. It holds potential for application in the brewery, animal feed, and biofuel industries. Several defined MLG oligosaccharides obtained by automated glycan assembly are used to analyze the substrate specificities of Bacillus subtilis lichenase. Two glucose building blocks (BBs), equipped with a temporary Fmoc protecting group in the C-3 or C-4 position, served to assemble different oligosaccharides using an automated oligosaccharide synthesizer. Light-induced cleavage of the glycan products from the solid support followed by global deprotection provided seven MLG oligosaccharides of different length and connectivity. After incubation of the MLG oligosaccharides with lichenase, the digestion products were analyzed by HPLC-MS. These digestion experiments provided insights into the enzyme’s active site that is in line with other recent evidence suggesting that the substrate specificity of lichenases has to be reconsidered. These results demonstrate that synthetic MLG oligosaccharides are useful tools to analyse mixed-linkage β-glucanases.

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      Improving the throughput of batch photochemical reactions using flow: Dual photoredox and nickel catalysis in flow for C(sp2) C(sp3) cross-coupling

      • Irini Abdiaj, Jesús Alcázar
      • Janssen Research and Development, Janssen-Cilag, S.A., C/Jarama 75, 45007 Toledo, Spain

      We report herein the transfer of dual photoredox and nickel catalysis for C(sp2)single bondC(sp3) cross coupling form batch to flow. This new procedure clearly improves the scalability of the previous batch reaction by the reactor’s size and operating time reduction, and allows the preparation of interesting compounds for drug discovery in multigram amounts.

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      Synthesis of Cycloalkyl Substituted 7-Azaindoles via Photoredox Nickel Dual Catalytic Cross-Coupling in Batch and Continuous Flow

      • Natalie Palaychuk, Travis J. DeLano, Michael J. Boyd, Jeremy Green, and Upul K. Bandarage
      • Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, Massachusetts 02210, United States

      An efficient photoredox/Ni dual catalytic Csp2–Csp3 cross-coupling protocol in a continuous-flow regime to synthesize a variety of regioisomeric cycloalkyl substituted 7-azaindoles has been developed. These transformations proceed efficiently under mild conditions (blue LED light irradiation at 30 °C over 40 min residence time in mixed solvent systems). Reactions are easy to perform and afford most of the desired 2-, 3-, 4-, 5-, and 6-cycloalkyl substituted 7-azaindoles in moderate-to-good yield.

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      Acridinium-Based Photocatalysts: A Sustainable Option in Photoredox Catalysis

      • Amruta Joshi-Pangu
      • François Lévesque
      • Hudson G. Roth
      • Steven F. Oliver
      • Louis-Charles Campeau
      • David Nicewicz
      • Daniel A. DiRocco
      • Process Research & Development, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States
      • Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States

      The emergence of visible light photoredox catalysis has enabled the productive use of lower energy radiation, leading to highly selective reaction platforms. Polypyridyl complexes of iridium and ruthenium have served as popular photocatalysts in recent years due to their long excited state lifetimes and useful redox windows, leading to the development of diverse photoredox-catalyzed transformations. The low abundances of Ir and Ru in the earth’s crust and, hence, cost make these catalysts nonsustainable and have limited their application in industrial-scale manufacturing. Herein, we report a series of novel acridinium salts as alternatives to iridium photoredox catalysts and show their comparability to the ubiquitous [Ir(dF-CF3-ppy)2(dtbpy)](PF6).

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      Halogenation of organic compounds using continuous flow and microreactor technology

      • David Cantilloab
      • C. Oliver Kappe*ab
      • a Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, Graz, Austria
      • b Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria

      The halogenation of organic substrates is one the most important transformations in organic synthesis. The most straightforward, inexpensive and atom economic halogenations involve the use of elemental halogens (X2) or hydrogen halides (HX). However, X2 and HX reagents are highly reactive, toxic and corrosive materials. Halogenations using these reagents are usually very fast and exothermic reactions, in which selectivity issues occur. Using continuous flow chemistry halogenations involving X2 and HX can be performed in a safe and controllable manner. Reagents can be accurately dosed even for gas/liquid reactions, and exotherms are easily controlled. Hazardous chemicals can be readily quenched in line avoiding any undesired exposures and significantly enhancing the process safety.

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      Application of the Photoredox Coupling of Trifluoroborates and Aryl Bromides to Analog Generation Using Continuous Flow

      • Travis J. DeLano, Upul K. Bandarage, Natalie Palaychuk, Jeremy Green, and Michael J. Boyd
      • Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, Massachusetts 02210, United States

      A method for the coupling of aryl bromides with potassium alkyl trifluoroborates, via nickel/photoredox dual catalysis, has been developed for use in continuous flow. This operationally simple protocol is able to form Csp3–Csp2 bonds with significantly reduced reaction times and a broader substrate scope than when conducted in batch. The utility of this method for rapid analog synthesis has been demonstrated by the synthesis of a small library of alkyl-substituted quinazolines.

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      Design and Development of Pd-catalyzed Aerobic N-Demethylation Strategies for the Synthesis of Noroxymorphone in Continuous Flow Mode

      Bernhard Gutmanna,b, David Cantilloa,b, Ulrich Weiglc, D Phillip Coxd, C. Oliver Kappea,b

      • a,b Institute of Chemistry, University of Graz, Nawi Graz, Heinrichstrasse 28, 8010 Graz, Austria and Research Center Pharmaceutical Engineering (RCPE), Inffeldgasse 13, 8010 Graz, Austria
      • c Cilag AG, Hochstrasse 201, 8200 Schaffhausen, Switzerland
      • d Noramco Inc., 503 Carr Road, Suite 200, Wilmington, DE 19809, USA

      Strategies for the generation of noroxymorphone from 14-hydroxymorphinone are presented. Noroxymorphone is the key intermediate in the synthesis of various opioid antagonists, including naloxone, naltrexone and nalmefene, as well as mixed agonists-antagonists like nalbuphine. The transformation requires removal of the N-methyl group from the naturally occurring opiates and a double bond hydrogenation. The pivotal reaction step thereby is a N-methyl oxidation with colloidal palladium(0) as catalyst and pure oxygen as terminal oxidant. The reaction produces a 1,3-oxazolidine intermediate, which can be readily hydrolyzed to the corresponding secondary amine. Different reaction sequences and various phenol protection groups were explored. The most direct route consumes only H2, O2 and H2O as stoichiometric reagents and produces only H2O as by-product. Challenges inherent in gas-liquid reactions with oxygen as oxidant were addressed by developing a continuous flow process.

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      γ-Glutamyl-dipeptides: Easy tools to rapidly probe the stereoelectronic properties of the ionotropic glutamate receptor binding pocket

      • Lucia Tamborinia
      • Veronica Nicosiaa
      • Paola Contia
      • Federica Dall'Oglioa
      • Carlo De Michelia
      • Birgitte Nielsenb
      • Anders A. Jensenb
      • Darryl S. Pickeringb
      • Andrea Pintoa
      • a Department of Pharmaceutical Sciences (DISFARM), University of Milan, Via Mangiagalli 25, 20133 Milan, Italy
      • b Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen OE, Denmark

      γ-Glutamyl-dipeptides, built by condensing the distal carboxylate of l-Glu (or d-Glu) onto a series of differently functionalized amino acids, were prepared and used as tools for rapidly probing the stereo-electronic properties of iGluRs, searching for subtype-selective ligands.

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      Expedited access to thieno[3,2-c]quinolin-4(5H)-ones and benzo[h]-1,6-naphthyridin-5(6H)-ones via a continuous flow photocyclization method

      • Y. Fanga
      • G. K. Tranmer*ab
      • * Corresponding author
      • a College of Pharmacy, Faculty of Health Science, University of Manitoba, Winnipeg, Canada
      • b Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, Canada

      A single-step continuous flow method has been developed that gives expedited access to complex heterocycles via an intramolecular photochemical cyclization. Herein we report the first examples of the photochemically-induced generation of thieno[3,2-c]quinolin-4(5H)-ones, 16 examples, and benzo[h]-1,6-naphthyridin-5(6H)-ones, 6 examples. Overall, the continuous flow method provides access to complex heterocycles in two steps from commercially available starting materials in good yields and with greater atom efficiency than traditional batch reactions.

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      A benchtop NMR spectrometer as a tool for monitoring mesoscale continuous-flow organic synthesis: equipment interface and assessment in four organic transformations

      • Cynthia M. Archambaulta
      • Nicholas E. Leadbeater*a
      • * Corresponding author
      • a Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, USA

      An approach is reported for monitoring continuous-flow reactions by means of a low-field benchtop NMR spectrometer. The spectrometer is interfaced with a mesofluidic reactor and used as a tool for optimising four organic transformations, namely an acid-catalysed esterification, a Knoevenagel condensation, a Diels–Alder reaction, and an alkylation. Reactions need to be performed either solvent-free or at relatively high concentration in order to monitor them effectively using the NMR spectrometer, but this allows for the leveraging of one of the key advantages of flow processing, namely process intensification.

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      BODIPY-based conjugated microporous polymers as reusable heterogeneous photosensitisers in a photochemical flow reactor

      • J. M. Tobina
      • J. Liub
      • H. Hayesa
      • M. Demleitnera
      • D. Ellisa
      • V. Arrighia
      • Z. Xu*b
      • F. Vilela*a
      • * Corresponding author
      • a School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, UK
      • b Department of Biology and Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, China

      BODIPY-based conjugated microporous polymers (BDP_CMP and PHTT_BDP) have been synthesised via two distinct methods of assembly: high-yielding Suzuki–Miyaura cross-coupling of BODIPY-containing building blocks, and post-synthetic conversion of an aldehyde-equipped CMP host that was synthesised in the absence of metal-based catalysts. Both approaches yielded BODIPY-based materials featuring a high BET surface area (484–769 m2 g−1) and a bathochromic shift in the maximum light absorbance (520–550 nm). Singlet oxygen production employing the BODIPY-based materials at 530 nm was carried out heterogeneously in a commercial photochemical flow reactor.

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      Reformatsky and Blaise reactions in flow as a tool for drug discovery. One pot diversity oriented synthesis of valuable intermediates and heterocycles

      • L. Hucka,b
      • M. Bertona
      • A. de la Hozb
      • A. Díaz-Ortizb
      • J. Alcázar*a
      • * Corresponding author
      • a Janssen Research and Development, Janssen-Cilag, S.A., C/ Jarama 75, Toledo, Spain
      • b Facultad de Ciencias Químicas, Universidad de Castilla-La Mancha, Ciudad Real, Spain

      The application of Reformatsky and Blaise reactions for the preparation of a diverse set of valuable intermediates and heterocycles in a one-pot protocol is described. To achieve this goal, a greener activation protocol for zinc in flow conditions has been developed to introduce this metal efficiently into α-bromoacetates. The organozinc compounds were added to a diverse set of ketones and nitriles to obtain a wide range of functional groups and heterocyclic systems.

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      Visible light activation of Boronic Esters enables efficient photoredox C(sp2)–C(sp3) cross-couplings in flow

      Fabio Limaa, Dr. Mikhail A. Kabeshova, Dr. Duc N. Trana, Dr. Claudio Battilocchioa, Dr. Joerg Sedelmeierb, Dr. Gottfried Sedelmeierb, Dr. Berthold Schenkelb, S. V. Ley*a

      • * Corresponding author
      • a Department of Chemistry, University of Cambridge, Cambridge, UK
      • b Novartis Pharma AG, Basel, Switzerland

      We report herein a new method for the photoredox activation of boronic esters. Using these reagents, an efficient and high-throughput continuous flow process was developed to perform a dual iridium- and nickel-catalyzed C(sp2)–C(sp3) coupling by circumventing solubility issues associated with potassium trifluoroborate salts. Formation of an adduct with a pyridine-derived Lewis base was found to be essential for the photoredox activation of the boronic esters. Based on these results we were able to develop a further simplified visible light mediated C(sp2)–C(sp3) coupling method using boronic esters and cyano heteroarenes under flow conditions.

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      Engineering chemistry: integrating batch and flow reactions on a single, automated reactor platform

      • D. E. Fitzpatricka
      • S. V. Ley*a
      • * Corresponding author
      • a Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK

      Synthesis chemistry need not be limited to either only batch or only flow; rather, in the future we expect that it will consist of an amalgamation of the best and most appropriate methods. We have therefore devised a single reactor platform to conduct both batch and flow reactions, either singly or in concert, using open source technologies to automate, control and monitor individual processes. We illustrate this concept with the multistep synthesis of 5-methyl-4-propylthiophene-2-carboxylic acid to showcase the utility of this approach in a telescoped manner. Automated downstream processing techniques, consisting of continuous extraction and solvent switching steps, were also included, further freeing the chemist from routine laboratory tasks.

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      Triphenylphosphine-grafted, RAFT-synthesised, porous monoliths as catalysts for Michael addition in flow synthesis

      Kristine J. Barlowa, Victor Bernabeua, Xiaojuan Haoa, Timothy C. Hughesa, Oliver E. Hutta, Anastasios Polyzosa,b, Kathleen A. Turnera, Graeme Moada

      • a CSIRO Manufacturing Flagship, Bag 10, Clayton South, Victoria 3169, Australia
      • b University of Melbourne, School of Chemistry, Parkville, Victoria 3010, Australia

      We describe the preparation and application of triphenylphosphine functional polystyrene-based porous monolithic catalysts for use as flow reactors. RAFT (reversible addition-fragmentation chain transfer)-crosslinking polymerisation of styrene and divinylbenzene provided monoliths which were then functionalized by RAFT “grafting from” polymerisation of 4-styryldiphenylphosphine mediated by the retained thiocarbonylthio functionality. Under the chosen conditions, the retention of the RAFT functionality was proved by chain extension experiments in which the monoliths were five times re-subjected to the grafting conditions. Importantly, the bound triphenylphosphine-functionality was demonstrated to be catalytically active when the monoliths were used as flow reactors in performing Michael addition of 1-hexanethiol to tert-butyl acrylate and of acetyl acetone to diethyl azodicarboxylate. Conversions from reagent to product of up to 77% were achieved. The monoliths were susceptible to oxidation of the phosphine groups most likely caused by adventitious oxygen in the non-degassed reaction medium, but were successfully regenerated by trichlorosilane reduction and reused.

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      Ethyl Lithiodiazoacetate: Extremely unstable intermediate handled efficiently in flow

      Simon T. R. Müllera, Tobias Hokampa, Svenja Ehrmanna, Paul Hellierb, Thomas Wirtha

      • a Cardiff University School of Chemistry Cardiff UK
      • b Parc Industriel de la Chartreuse Pierre Fabre Médicament Castres CEDEX France

      Ethyl diazoacetate(EDA) is one of the most prominent diazo reagents. It is frequently used in metal–carbene-type reactions. However, EDA can also be used as a nucleophile under base catalysis. Whilst the addition of EDA to aldehydes can be performed using organic bases, the addition of EDA to other carbonyl electrophiles requires the use of organometallics such as lithium diisopro-pylamide (LDA). The generated ethyl lithiodiazoacetate is highly reactive and decomposes rapidly, even at low temperatures. Herein, we report a continuous flow protocol that overcomes the problems associated with the instantaneous decomposition of ethyl lithiodiazoacetate. The addition of ethyl lithiodiazoacetate to ketones provides direct access to tertiary diazoalcohols in good yields.

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      A facile hybrid ‘flow and batch’ access to substituted 3,4-dihydro-2H-benzo[b][1,4]oxazinones

      • Andrew J. S. Lina
      • Cecilia C. Russella
      • Jennifer R. Bakera
      • Shelby L. Fraileyab
      • Jennette A. Sakoffc
      • Adam McCluskey*a
      • * Corresponding authors
      • a Chemistry, Centre for Chemical Biology, School of Environmental & Life Sciences, University of Newcastle, University Drive, Callaghan, Australia
      • b Chemical Engineering, Trine University, Angola, 46703 USA
      • c Department of Medical Oncology, Calvary Mater Newcastle Hospital, Waratah, Australia

      We describe a simple flow chemistry approach to libraries of ethyl 3-oxo-2-(substituted-phenylamino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylates (12a–l) and N-ethyl-3-oxo-2-(substituted-phenylamino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamides (13a–l) in 38–87% yields. This scaffold is poorly described in the chemical literature. Screening against a panel of 11 cancer and one normal cell line showed that the amide linked library 13a–l was devoid of toxicity. Whereas the ester linked analogues 12b, 12c, 12g, 12j and 12l were highly cytotoxic with growth inhibition (GI50) values from 0.34 to >50 μM across all cell lines, with the 2-OH-Ph substituted 12l analogue presenting with sub-micromolar potency against the A2780 (ovarian; 0.34 ± 0.04 μM), BEC-2 (glioblastoma; 0.35 ± 0.06 μM), MIA (pancreas; 0.91 ± 0.054 μM) and SMA (murine glioblastoma; 0.77 ± 0.029 μM) carcinoma cell lines. Interestingly, the U87 glioblastoma cell line showed inherent resistance to growth inhibition by all analogues (GI50 32 to >50 μM) while the A2780 cells were highly sensitive (GI50 3.8–0.34 μM), suggesting that the analogues developed herein may be valuable lead compounds for the development of ovarian carcinoma specific cytotoxic agents. The differences in amide versus ester cytotoxicity was consitent with esterase cleaveage to release the cytotoxic warhead.

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      Continuous flow biocatalysis: production and in-line purification of amines by immobilised transaminase from Halomonas elongata

      • Matteo Planchestainera
      • Martina Letizia Contenteab
      • Jennifer Cassidya
      • Francesco Molinarib
      • Lucia Tamborini*c
      • Francesca Paradisi*ad
      • * Corresponding authors
      • a UCD School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland
      • b Department of Food, Environmental and Nutritional Sciences (DeFENS), Università degli studi di Milano, Via Mangiagalli 25, Milan, Italy
      • c Department of Pharmaceutical Sciences (DISFARM), Università degli studi di Milano, Via Mangiagalli 25, Milan, Italy
      • d School of Chemistry, University of Nottingham, University Park, Nottingham, UK

      The continuous flow synthesis of a series of amines was successfully achieved by exploiting the enhanced stability and broad substrate scope of an immobilised transaminase from Halomonas elongata (HEWT). A series of substrates were tested in flow reactors and transformed into the corresponding amines in good to excellent yields. The process was implemented with an integrated in-line purification step for the recovery of the pure amines.

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      Method and device for the synthesis of artemisinin

      Inventors:, Peter H. Seeberger, Daniel Kopetzki, Francois Lévesque

      • Assignee:
      • Max-Planck-Gesellschaft zur Forderung der Wissenschaften

      The present invention is directed to a method for producing artemisinin having the formula

      from dihydroartemisinic acid in a continuous flow reactor using singlet oxygen as well as to the continuous flow reactor for producing artemisinin.

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      A laboratory-scale continuous flow chlorine generator for organic synthesis

      • Franz J. Straussa
      • David Cantillo*ab
      • Javier Guerrac
      • C. Oliver Kappe*ab
      • * Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, Graz, Austria
      • a Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
      • b Crystal Pharma, Gadea Pharmaceutical Group, A Division of AMRI, Parque Tecnológico de Boecillo, Valladolid, Spain

      A simple continuous flow setup for the generation and use of elemental chlorine for organic synthesis has been developed. The chlorine generator is based on the reaction of HCl with NaOCl, generating NaCl and H2O as the only side products. As a proof-of-concept, the reactor has been applied for a variety of chlorinations and oxidations of organic compounds.

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      Continuous processing and efficient in situ reaction monitoring of a hypervalent iodine (III) mediated cyclopropanation using benchtop NMR spectroscopy

      • Batool Ahmed-Omera
      • Eric Sliwinskia
      • John Paul Cerrotib
      • Steven V Leya
      • aDepartment of chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
      • bMagritek GmbH, Gebäude VO