Publications abstracts

    To date, the Vapourtec R-Series system has featured in 1003 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.

    The Photochemical Mediated Ring Contraction of 4H-1,2,6-Thiadiazines To Afford 1,2,5-Thiadiazol-3(2H)-one 1-Oxides

    • Emmanouil Broumidisa, Christopher G. Thomsona, Brendan Gallaghera, Lia Sotorríosa, Kenneth G. McKendricka, Stuart A. Macgregor*a, Martin J. Patersona, Janet E. Lovettb, Gareth O. Lloydc, Georgina M. Rosaira, Andreas S. Kalogiroud,e, Panayiotis A. Koutentis*e, and Filipe Vilela*a,f
    • aInstitute of Chemical Sciences, School of Engineering & Physical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS, United Kingdom
    • bSUPA School of Physics and Astronomy and BSRC, University of St Andrews, St. Andrews, KY16 9SS, United Kingdom
    • cJoseph Banks Laboratories, School of Chemistry, University of Lincoln, Brayford Pool, Lincoln LN6 7TS, United Kingdom
    • dDepartment of Life Sciences, School of Sciences, European University Cyprus, 6 Diogenes Str., Engomi, P.O. Box 22006, 1516 Nicosia, Cyprus
    • eDepartment of Chemistry, University of Cyprus, P.O. Box 20537, 1678 Nicosia Cyprus
    • fContinuum Flow Lab, School of Engineering & Physical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS, United Kingdom

    1,2,6-Thiadiazines treated with visible light and 3O2 under ambient conditions are converted into difficult-to-access 1,2,5-thiadiazole 1-oxides (35 examples, yields of 39–100%). Experimental and theoretical studies reveal that 1,2,6-thiadiazines act as triplet photosensitizers that produce 1O2 and then undergo a chemoselective [3 + 2] cycloaddition to give an endoperoxide that ring contracts with selective carbon atom excision and complete atom economy. The reaction was optimized under both batch and continuous-flow conditions and is also efficient in green solvents.

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    Development of a Continuous Flow Baldwin Rearrangement Process and Its Comparison to Traditional Batch Mode

    • Arlene Bonnera
    • Marcus Baumanna
    • aSchool of Chemistry, University College Dublin, Science Centre South, Belfield, Dublin 4, Ireland D04 N2E2

    A new and highly efficient continuous flow process is presented for the synthesis of aziridines via the thermal Baldwin rearrangement. The process was initially explored using traditional batch synthesis techniques but suffered from moderate yields, long reaction times, and moderate diastereoselectivities. Here we demonstrate that the process can be greatly improved upon its transfer to continuous flow, which afforded the aziridine targets in high yields, short reaction times, and consistently high diastereoselectivities, with the high-throughput process rendering multigram quantities of product in short periods of time. In addition, flow processing extended the substrate scope including several examples that had failed in batch mode, thus demonstrating the value of this overlooked entry into valuable aziridine species.

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    Continuous Flow Oxidation of Alcohols Using TEMPO/NaOCl for the Selective and Scalable Synthesis of Aldehydes

    • Parth Naika, Jorge García-Lacunaa, Patrick O’Neillb, and Marcus Baumanna
    • aSchool of Chemistry, University College Dublin, Science Centre South, Belfield D04 N2E5, Ireland
    • bPfizer Ireland, Ringaskiddy P43 X336, Ireland

    A simple and benign continuous flow oxidation protocol for the selective conversion of primary and secondary alcohols into their respective aldehyde and ketone products is reported. This approach makes use of catalytic amounts of TEMPO in combination with sodium bromide and sodium hypochlorite in a biphasic solvent system. A variety of substrates are tolerated including those containing heterocycles based on potentially sensitive nitrogen and sulfur moieties. The flow approach can be coupled with inline reactive extraction by formation of the carbonyl-bisulfite adduct which aids in separation of remaining substrate or other impurities. Process robustness is evaluated for the preparation of phenylpropanal at decagram scale, a trifluoromethylated oxazole building block as well as a late-stage intermediate for the anti-HIV drug maraviroc which demonstrates the potential value of this continuous oxidation method.

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    Development of Continuous Flow Processes to Access Pyrrolo[2,1-f][1,2,4]triazin-4-amine: An RSM for the Synthesis of Antiviral Drugs

    • Maksim Vasileva, Aravind S. Gangua, Praveen Gajulaa, Nathaniel D. Kaetzela, Vasudevan Natarajana, Bimbisar Desaia, Gopal Sirasania, Bo Qua, and Chris H. Senanayakea
    • aTCG GreenChem, Inc., 701 Charles Ewing Boulevard, Ewing, New Jersey 08628, United States

    Pyrrolo[2,1-f][1,2,4]triazines are important scaffolds in a number of active pharmaceutical ingredients with a broad range of biological activities to treat broad-spectrum viral infections. We recently reported the synthesis at the kilogram scale in batch mode with extensive process safety studies, where NaH was applied as the base to deprotonate 2-cyanopyrrole, and then in situ prepared monochloramine solution was utilized for the N-amination, followed by cyclization with formamidine acetate to produce the required pyrrolo[2,1-f][1,2,4]triazine (1) as the regulatory starting material for the antiviral drug Remdesivir. To meet the market demand of Remdesivir for the treatment of the recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a high-throughput process is required to supply this key starting material on a large scale in a timely manner. In this Article, we report the second-generation synthesis of pyrrolo[2,1-f][1,2,4]triazine 1 by employing continuous flow chemistry tools. The amination step was adapted to continuous flow by applying in situ monochloramine synthesis and utilizing a process-friendly soluble base KOt-Bu. The new multistage continuous flow approaches, including both chemical steps, extractions and separations, afford a viable process to access this widely employed key starting material 1 for the synthesis of Remdesivir.

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    Late-Stage C(sp2)–C(sp3) Diversification via Nickel Oxidative Addition Complexes

    Carlota Odena1,3, María Lourdes Linares4, Nahury Castellanos-Blanco1, Ryan T. McGuire1, Jose Manuel Alonso4, Alejandro Diéguez5, Eric Tan5, Jesús Alcázar4, Peter Buijnsters5 Santiago Cañellas4 and Ruben Martin1,2

    • 1Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països Catalans 16, 43007 Tarragona, Spain
    • 2ICREA, Passeig Lluïs Companys 23, 08010 Barcelona, Spain
    • 3Department de Química Analítica i Química Orgànica, Universitat Rovira i Virgili, c/ Marcel·lí Domingo 1, 43007 Tarragona, Spain
    • 4Janssen Research and Development, Janssen-Cilag, S. A. c/ Rio Jarama 75, 45007 Toledo, Spain
    • 5Medicinal Chemistry, Janssen Pharmaceutica, N. V. B-2340 Beerse, Belgium

    Nickel catalysis has emerged as a powerful technique for streamlining the access to exceedingly complex organic molecules from simple precursors. However, nickel-catalyzed cross-couplings with advanced synthetic intermediates still remain a considerable challenge. Herein, we describe a technique based on the utilization of nickel oxidative addition complexes (Ni-OAC) of drug-like molecules as a platform to rapidly and reliably generate lead candidates with enhanced C(sp3) fraction. The potential of Ni-OACs to access new chemical space has been assessed in three different C(sp2)–C(sp3) bond-forming events without recourse to specialized ligand backbones. Reactions with Ni-OACs proceed under exceptionally mild conditions and with improved generality when compared to nickel-catalyzed reactions. The development of an automated process for forging C(sp2)–C(sp3) architectures further illustrates the robustness and generality of Ni-OACs, thus offering a new gateway to expedite the design-make-test-analyze (DMTA) cycle in drug discovery

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    Recent advances in photoredox catalytic transformations by using continuous-flow technology

    • Xin Yuana
    • Hai-Bin Fana
    • Jie Liua
    • Long-Zhou Qina
    • Jian Wanga
    • Xiu Duana
    • Jiang-Kai Qiua,b
    • Kai Guoa,b
    • aCollege of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, Jiangsu, China
    • bState Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing 211800, Jiangsu, China

    Photoredox catalysis is regarded as an economically appealing method for highly efficient and sustainable chemical syntheses. Nevertheless, numerous recent studies have revealed several unresolved disadvantages; for example, based on the Bouguer-Lambert-Beer law, the short propagation distance of photons in traditional batch reactors hampers the scalability of photocatalytic reactions. The introduction of continuous-flow technology for photochemical synthesis has resolved several of these problems. The use of photochemistry in microreactors has resulted in various transformations. Superior mixing ability, more effective heat transfer, and the easier magnification of continuous-flow chemical reactions are key to its success. Continuous-flow technology has allowed the optimization of several different types of conversion. Photoredox catalysts are effective under various reaction conditions because of their single-electron transfer properties. Common photocatalysts include transition metal complexes containing ruthenium, iridium, copper, iron, or manganese; organic photocatalysts; and heterogeneous photocatalysts. This review covers the types of photocatalysts that have recently been used in continuous-flow photochemistry.

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    Metal-Free Addition of Alkyl Bromides to Access 3,3-Disubstituted Quinoxalinones Enabled by Visible-Light Photoredox Catalysis

    • Jennie Liaoa, David N. Hunterb, Ugochinyere Nancy Oloyedeb, Joseph W. McLaughlinb, Cheng Wangb, and Abdellatif El Marrounib
    • aProcess Research & Development, MRL, Merck & Co., Inc., West Point, Pennsylvania 19486, United States
    • bDiscovery Chemistry, MRL, Merck & Co., Inc., West Point, Pennsylvania 19486, United States

    A metal-free addition of unactivated alkyl bromides to quinoxalin-2(1H)-ones is described. This method enables the construction of valuable 3,3-disubstituted dihydroquinoxalin-2(1H)-ones bearing quaternary carbon centers under mild, visible-light photoredox catalysis. High functional group tolerance is observed in both the quinoxalinone and alkyl bromide partners. The ability to scale up this method was demonstrated under photo-flow conditions to enable gram-scale synthesis.

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    Direct Arylation of Thiophenes in Continuous Flow

    • Alessandro Petronillia, Prof. Tommaso Carofiglioa and Dr. Paolo Zardia,b
    • aDepartment of Chemical Sciences, University of Padova, Via Francesco Marzolo 1, 35131 Padova, Italy
    • bDepartment of Chemical and Geological Sciences, University of Modena and Reggio Emilia, Via Giuseppe Campi 103, 41125 Modena, Italy

    Synthetic methodologies involving direct C−H functionalization are promising to improve sustainability in organic synthesis. However, these newly developed strategies may have a scarce appeal for larger scale applications due to the high catalyst loading, harsh conditions or their typically long reaction times that affect severely the process productivity. Flow chemistry technology is a recognized tool to improve both the efficiency and scalability in organic synthesis that can overcome these issues. In the present paper we studied an “in flow” method for the direct arylation of thiophene derivatives with aromatic bromides to promptly afford heteroaromatic biaryls, which are recurrent motifs both in biologically active molecules and in functional materials. By using a packed-bed reactor containing potassium carbonate as the solid base and an automated system, we could develop a reliable methodology for thiophene arylation in flow with yields up to 90 % within a residence time of 30–60 minutes. This strategy is suitable for a wide variety of substrates and allowed the reaction to be carried out at gram-scale reaching a productivity value of 1.1 g h−1.

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    Metal-free synthesis of selenoesters directly from carboxylic acids using bifunctional selenoureas under batch and continuous-flow conditions

    • Mouzma Mhatea, Chandra Sekhara Mahantaa, Devendra K. Dhakedb, Velyutham Ravichandirana and Sharada Prasanna Swaina
    • aDepartment of Medicinal Chemistry and Centre for Marine Therapeutics (CMT), National Institute of Pharmaceutical Education and Research-Kolkata, 168, Maniktala Main Road, Kolkata 700054, India
    • bDepartment of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research-Kolkata, 168, Maniktala Main Road, Kolkata 700054, India

    A new metal-free method for the synthesis of selenoesters directly from carboxylic acids in a flow reactor is reported. The carboxylic acids, Michael acceptors, and bifunctional selenoureas (source of selenium and nucleophile, activator of carbonyl group) were reacted to obtain selenoesters (up to 70% yield). An evidence-backed plausible mechanism is also presented.

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    Continuous Flow Synthesis of Cycloparaphenylene Building‐Blocks on a Large Scale

    Jan H. Griwatza,b, Mika L. Kesslera, Hermann A. Wegnera,b

    • aInstitute of Organic Chemistry, Justus Liebig University Giessen, Heinrich-Buff-Ring 17, 35392 Giessen, Germany
    • bCenter for Materials Research, Justus Liebig University Giessen, Heinrich-Buff-Ring 16, 35392 Giessen, Germany

    The synthesis of [n]cycloparaphenylenes ([n]CPPs) and similar nanohoops is usually based on the combination of building blocks to a macrocyclic precursor, which is then aromatized in the final step. Access to those building blocks in large amounts will simplify the synthesis and studies of CPPs as novel functional materials in applications. Herein, we report a continuous flow synthesis of key CPP building blocks using versatile synthesis techniques such as electrochemical oxidation, lithiations and Suzuki cross couplings in self-built reactors on up-to kilogram scale.

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    Continuous Flow Chemistry: A Novel Technology for the Synthesis of Marine Drugs

    • Laura F. Peñaa, Paula González-Andrésa, Lucía G. Partea, Raúl Escribanoa, Javier Guerraa, Asunción Barberoa and Enol Lópeza
    • aDepartment of Organic Chemistry, Campus Miguel Delibes, University of Valladolid, 47011 Valladolid, Spain

    In this perspective, we showcase the benefits of continuous flow chemistry and photochemistry and how these valuable tools have contributed to the synthesis of organic scaffolds from the marine environment. These technologies have not only facilitated previously described synthetic pathways, but also opened new opportunities in the preparation of novel organic molecules with remarkable pharmacological properties which can be used in drug discovery programs.

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    Visible-Light-Mediated TiO2-Catalyzed Aerobic Dehydrogenation of N-Heterocycles in Batch and Flow

    • Junghoon Noha, Jun-Young Choa, Mincheol Parkb, and Boyoung Y. Parka
    • aDepartment of Fundamental Pharmaceutical Science, Kyung Hee University, Seoul 02447, South Korea
    • bDepartment of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul 02447, South Korea

    We report a simple and environmentally friendly method for synthesizing N-containing heterocycles via a visible-light-mediated aerobic dehydrogenation reaction. Using a nontoxic, stable, and inexpensive titanium dioxide catalyst, a variety of substituted quinoline, indole, quinoxaline, and 3,4-dihydroisoquinoline derivatives could be synthesized using the green oxidant molecular oxygen. Improved reactivity and scalability of this reaction were demonstrated by adapting the photochemical multiphasic reaction to a continuous flow system. To gain insight into the mechanism, we also conducted several mechanistic studies, including absorption analysis, light on–off testing, and NMR analysis. Especially, oxygen is reduced to hydrogen peroxide, and dimethyl sulfoxide is a critical scavenger of the oxidant byproduct for ensuring high yields.

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    Continuous flow synthesis of pyridinium salts accelerated by multi-objective Bayesian optimization with active learning

    John H. Dunlapab, Jeffrey G. Ethierab, Amelia A. Putnam-Neeb ac, Sanjay Iyerd, Shao-Xiong Lennon Luoe, Haosheng Fenge, Jose Antonio Garrido Torresf, Abigail G. Doyleg, Timothy M. Swagere, Richard A. Vaiaa, Peter Miraua, Christopher A. Crousea and Luke A. Baldwina

    • aMaterials and Manufacturing Directorate, Air Force Research Laboratory, Wright-Patterson AFB, OH 45433, USA.
    • bUES, Inc., Dayton, OH 45431, USA
    • cNational Research Council Research Associate, Air Force Research Laboratory, Wright-Patterson AFB, OH 45433, USA
    • dDepartment of Chemistry, Purdue University, West Lafayette, IN 47907, USA
    • eDepartment of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
    • fDepartment of Chemistry, Princeton University, Princeton, NJ 08544, USA
    • gDepartment of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA

    We report a human-in-the-loop implementation of the multi-objective experimental design via a Bayesian optimization platform (EDBO+) towards the optimization of butylpyridinium bromide synthesis under continuous flow conditions. The algorithm simultaneously optimized reaction yield and production rate (or space-time yield) and generated a well defined Pareto front. The versatility of EDBO+ was demonstrated by expanding the reaction space mid-campaign by increasing the upper temperature limit. Incorporation of continuous flow techniques enabled improved control over reaction parameters compared to common batch chemistry processes, while providing a route towards future automated syntheses and improved scalability. To that end, we applied the open-source Python module, nmrglue, for semi-automated nuclear magnetic resonance (NMR) spectroscopy analysis, and compared the acquired outputs against those obtained through manual processing methods from spectra collected on both low-field (60 MHz) and high-field (400 MHz) NMR spectrometers. The EDBO+ based model was retrained with these four different datasets and the resulting Pareto front predictions provided insight into the effect of data analysis on model predictions. Finally, quaternization of poly(4-vinylpyridine) with bromobutane illustrated the extension of continuous flow chemistry to synthesize functional materials.

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    Liquid/liquid heterogeneous reaction monitoring: Insights into biphasic Suzuki-Miyaura cross-coupling

    • Yusuke Sato1, Junliang Liu1, Ikenna Edward Ndukwe2, Maria Victoria Silva Elipe2, Daniel J. Griffin3, James I. Murray4,5, Jason E. Hein1,5,6,7
    • 1Department of Chemistry, The University of British Columbia, Vancouver, BC V6T 1Z1, Canada
    • 2Pivotal Attribute Sciences, Drug Substance Technologies, Amgen, Inc., Thousand Oaks, CA 91320, USA
    • 3Pivotal and Commercial Synthetics, Drug Substance Technologies, Amgen, Inc., Cambridge, MA 02142, USA
    • 4Pivotal and Commercial Synthetics, Drug Substance Technologies, Amgen, Inc., Thousand Oaks, CA 91320, USA
    • 5Acceleration Consortium, University of Toronto, Toronto, ON, Canada
    • 6Department of Chemistry, University of Bergen, Bergen, Norway

    Monitoring the reaction progress of biphasic reaction mixtures has long presented a significant challenge to modern analytical techniques. While a multitude of widely utilized chemical transformations have been performed under such conditions, in-line separation and analysis of each phase have not been possible, inhibiting detailed kinetic and mechanistic studies of these important processes. Herein, we disclose a novel sampling technology capable of accurately monitoring reaction progress in biphasic mixtures using online high-performance liquid chromatography (HPLC) and multinuclear flow nuclear magnetic resonance (NMR) spectroscopy. A biphasic sampling platform was developed to circulate a single phase of a biphasic reaction mixture for analysis using these techniques. The utility of this methodology was demonstrated through analysis of boronic acid distribution and speciation under basic conditions as well as for monitoring the reaction progress of a biphasic Suzuki-Miyaura cross-coupling.

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    Shining a Light on the Advances, Challenges and Realisation of Utilising Photoredox Catalysis in Pharmaceutical Development

    • Dr. Emily E. Callard-Langdona
    • Dr. Alan Stevena
    • Dr. Rachel J. Kahana
    • aCatSci Ltd, CBTC2, Capital Business Park, Wentloog, Cardiff, CF3 2PX UK

    Photoredox catalysis has advanced significantly over the last fifteen years, with improvements in technology facilitating implementation in both academic and industrial settings. Despite these advances, the uptake of photoredox catalysis in pharmaceutical development and manufacture has been slow, in part due to the challenge of developing a robust, transferable process. This perspective provides insight on the successes and difficulties encountered when applying photoredox catalysis to pharmaceutical development. It is hoped greater understanding of the challenges faced by the pharmaceutical industry will inform future research and encourage collaboration.

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    Modular Photochemical Flow Synthesis of Structurally Diverse Benzyne and Triazine Precursors

    • Jorge García-Lacunaa
    • Marcus Baumanna
    • aSchool of Chemistry, University College Dublin, Science Centre South, Belfield, Dublin 4, Dublin, Ireland

    Benzyne and related arynes are classical high-energy species with a rich history of widespread applications in synthesis. However, despite several synthetic routes being available to generate arynes and their precursors, none represents an ideal entry to benzyne chemistry in view of safety, scalability, and sustainability. Here we report a new photochemical flow process allowing for the generation of benzyne precursors in high yields, and throughput, with easy isolation of multigram quantities of products. This process leverages a catalyst-free photochemical rearrangement via a photoexcited nitro arene which involves a cyclic hydroxylamine intermediate that has been fully characterized. The resulting precursors were converted to benzynes via a second photochemical flow process generating heterocyclic targets upon trapping with azide and sydnone partners. Remarkably, when reacting the benzyne precursors with secondary amines, a wide range of aryl triazines is obtained in good yields via a third photo-flow transformation. This represents a modular approach to synthesize these species, that avoids the use of potentially explosive diazonium salts. Ultimately, three photochemical flow processes using a single high-power LED light source (365 nm, adjustable in-put power) are presented with manifest benefits compared to batch processing. Moreover, the functionalization of a pendent carboxyl group to form sets of biologically relevant aryl triazine-based amides highlights further applications of these unique and industrially relevant triazine entities.

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    Research Activities at Faculty of Chemical Technology, Hanoi University of Industry – 20 Years of Growth and Development

    Tuan Anh Nguyena, The Huu Nguyena, Van Dong Phama, Minh Tan Vua, Thi Mai Huong Phama

    • aHanoi University of Industry, 298 Cau Dien Street, Bac Tu Liem District, Hanoi, 10000 Viet Nam

    Hanoi University of Industry, with a 125-year history of construction and development, is the leading institution for training and applied scientific research in Vietnam. It offers a wide range of disciplines, types, and levels of education to produce high-quality human resources for the country’s industrialization, national modernization, and international integration efforts. The university currently boasts over 1,500 staff and lecturers, three campuses covering nearly 50 hectares, and a student population of more than 30,000. Hanoi University of Industry provides multidisciplinary training, providing high-quality human resources for society. In which, the Faculty of Chemical Technology was established on March 1, 2003, in 20 years of construction and development, the faculty has constantly grown, annually providing the society with many high-quality human resources, with many fields of study diverse, learning, training: Chemical engineering technology, Environmental engineering technology, Food technology and Pharmaceutical chemistry. Besides, the faculty, students and students of the faculty have made great efforts in training, studying and doing scientific research, achieving many excellent achievements.

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    Metabolite Changes of Perna canaliculus Following a Laboratory Marine Heatwave Exposure: Insights from Metabolomic Analyses

    • Awanis Azizan1, Leonie Venter1, Peet J. Jansen van Rensburg2, Jessica A. Ericson3, Norman L. C. Ragg3 and Andrea C. Alfaro1
    • 1Aquaculture Biotechnology Research Group, School of Science, Auckland University of Technology, Private Bag 92006, Auckland 1142, New Zealand
    • 2Human Metabolomics, North-West University, Potchefstroom 2520, South Africa
    • 1Cawthron Institute, Private Bag 2, Nelson 7042, New Zealand

    Temperature is considered to be a major abiotic factor influencing aquatic life. Marine heatwaves are emerging as threats to sustainable shellfish aquaculture, affecting the farming of New Zealand’s green-lipped mussel [Perna canaliculus (Gmelin, 1791)]. In this study, P. canaliculus were gradually exposed to high-temperature stress, mimicking a five-day marine heatwave event, to better understand the effects of heat stress on the metabolome of mussels. Following liquid chromatography-tandem mass spectrometry analyses of haemolymph samples, key sugar-based metabolites supported energy production via the glycolysis pathway and TCA cycle by 24 h and 48 h of heat stress. Anaerobic metabolism also fulfilled the role of energy production. Antioxidant molecules acted within thermally stressed mussels to mitigate oxidative stress. Purine metabolism supported tissue protection and energy replenishment. Pyrimidine metabolism supported the protection of nucleic acids and protein synthesis. Amino acids ensured balanced intracellular osmolality at 24 h and ammonia detoxification at 48 h. Altogether, this work provides evidence that P. canaliculus has the potential to adapt to heat stress up to 24 °C by regulating its energy metabolism, balancing nucleotide production, and implementing oxidative stress mechanisms over time. The data reported herein can also be used to evaluate the risks of heatwaves and improve mitigation strategies for aquaculture.

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    Combining Tailored Ionic Liquids with Ti3C2Tx MXenes for an Enhanced Load-Carrying Capacity Under Boundary Lubrication

    Philipp G. Grützmachera, Roman Neuhausera, Kristof Stagelb, Katharina Bica-Schröderb, Guido Boidic, Carsten Gachota, Andreas Rosenkranzd

    • aInstitute for Engineering Design and Product Development Research Unit Tribology E307-05, TU Wien, 1060 Vienna, Austria
    • bInstitut für Angewandte Synthesechemie (IAS), Sustainable Organic Synthesis and Catalysis research group, TU Wien, 1060 Vienna, Austria
    • cAC2T research GmbHViktor-Kaplan-Straße 2/C, 2700 Wiener Neustadt, Austria
    • dDepartment of Chemical Engineering, Biotechnology and Materials (FCFM), Universidad de Chile, Santiago 8370448, Chile

    To improve the efficiency and lifetime of mechanical components, new lubrication systems are needed. Two complementary material classes, which have demonstrated a promising tribological performance, are ionic liquids and MXenes (2D transition metal carbides and nitrides). Herein, Ti3C2Tx MXenes are used as additives in ionic liquids (ILs) to improve their load-carrying capacity under boundary lubrication. The specifically synthesized ILs share the same cation (trioctyl(methyl)phosphonium) but different anions (dimethyl phosphate and dibutyl phosphate for IL1 and IL2, respectively) to assess the effect of the anion’s alkyl chain length. The wear reduction performance is tested with a cylinder-on-ring contact in a standardized Brugger tester, which is suitable to study boundary lubrication and to assess the antiwear ability of the IL/MXene lubricant blends. MXenes indicate an excellent dispersibility in both ILs over 24 h. It is found that, irrespective of the used IL, the addition of MXenes always increases the load-carrying capacity. Particularly, significantly reduced wear and thus a high load-carrying capacity are observed for the combination IL2/MXenes, which also outperform fully formulated commercially available lubricants such as turbine oils.

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    An all-in-one multipurpose robotic platform for the self-optimization, intensification and scale-up of photocatalysis in flow

    Aidan Slatterya,Zhenghui Wena, Pauline Tenblada, Diego Pintossia, Jesus Sanjose-Ordunaa, Tim den Hartoga, b, c, Timothy Noela

    • aFlow Chemistry Group, van ’t Hoff Institute for Molecular Sciences (HIMS), University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands
    • bZuyd University of Applied Sciences, Nieuw Eyckholt 300, 6419 DJ Heerlen, The Netherlands
    • cThe Netherlands Organisation for Applied Scientific Research (TNO), High Tech Campus 25, 5656AE Eindhoven, The Netherlands

    The optimization, intensification, and scaling up of chemical processes are essential and time-consuming aspects of contemporary chemical manufacturing, necessitating expertise and precision due to their intricate and sensitive nature. However, these process development problems are often carried out independently and consecutively, which can exacerbate the already significant consumption of time and resources involved in the process. In this work, we present a versatile, all-in-one robotic platform for the autonomous optimization, intensification, and scaling up of photocatalytic reactions in flow. This platform overcomes associated challenges through the integration of readily available hardware and custom software, offering a hands-off solution. Our open source platform combines a liquid-handler, syringe pumps, a tunable high-powered photoreactor, cheap IoT devices and an in-line NMR to enable automated, data-rich optimization using a Closed-Loop Bayesian Optimization strategy. The use of a high-power continuous-flow capillary photoreactor enables highly reproducible data to be obtained, as it mitigates issues related to mass, heat, and photon transport that are often the main sources of irreproducibility in photocatalytic transformations. A user-friendly graphical interface allows chemists without programming or machine learning expertise to easily optimize, monitor, and analyze photocatalytic reactions for chemical spaces of both continuous and discrete variables. The system’s effectiveness was demonstrated by testing it on challenging photocatalytic transformations, which resulted in increased overall reaction yields and an impressive up to 550-fold improvement in space-time yields compared to batch processes. Additional tests on literature-reported reactions previously optimized in flow yielded substantial increases in both yield and space-time yield. Overall, our studies demonstrate that combining flow-based reactor technology with Bayesian optimization yields superior and unbiased results compared to human effort and intuition in terms of pace, precision, and outcomes for the optimization of photocatalytic reactions. Finally, due to its ability to autonomously generate datasets that include both optimal and suboptimal conditions, our RoboChem platform also contributes to advancing the field towards a digitally-driven era in synthetic chemistry.

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    Multi-platform synthesis of ondansetron featuring process intensification in flow

    • Yoshio Hatoa,b
    • Timothy F. Jamisona
    • aDepartment of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
    • bShionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., Toyonaka, Osaka 561-0825, Japan

    Efficient and robust synthetic processes of active pharmaceutical ingredients (APIs) are highly desirable, and continuous flow chemistry is a critical component of this endeavor. The clinical importance of ondansetron, a World Health Organization essential medicine, prompted us to investigate continuous synthetic approaches to this API. Our efforts to improve the synthetic processes led to a continuous condensation step and a continuous Mannich reaction. A continuous work-up and purification process was also established for the former. A batch process was employed for an elimination and Michael addition step, as it not only accommodated the physical properties of the reaction mixtures, but also provided a high productivity of the desired product. Taken together, these findings demonstrate the complementary advantages of flow and batch chemistry in API synthesis.

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    Resurgence and advancement of photochemical hydrogen atom transfer processes in selective alkane functionalizations

    Liang Changa, Shun Wangb, Qing Anb, Linxuan Liub, Hexiang Wangb, Yubo Lib, Kaixuan Fengb and Zhiwei Zuob

    • aSchool of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
    • bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China

    The selective functionalization of alkanes has long been recognized as a prominent challenge and an arduous task in organic synthesis. Hydrogen atom transfer (HAT) processes enable the direct generation of reactive alkyl radicals from feedstock alkanes and have been successfully employed in industrial applications such as the methane chlorination process, etc. Nevertheless, challenges in the regulation of radical generation and reaction pathways have created substantial obstacles in the development of diversified alkane functionalizations. In recent years, the application of photoredox catalysis has provided exciting opportunities for alkane C–H functionalization under extremely mild conditions to trigger HAT processes and achieve radical-mediated functionalizations in a more selective manner. Considerable efforts have been devoted to building more efficient and cost-effective photocatalytic systems for sustainable transformations. In this perspective, we highlight the recent development of photocatalytic systems and provide our views on current challenges and future opportunities in this field.

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    Photo- and Electrochemical Cobalt Catalysed Hydrogen Atom Transfer for the Hydrofunctionalisation of Alkenes

    • Samikshan Jana1
    • Victor Jose Mayerhofer1
    • Christopher Teskey2
    • 1RWTH: Rheinisch-Westfalische Technische Hochschule Aachen, Institute of Organic Chemistry, GERMANY
    • 2RWTH Aachen: Rheinisch-Westfalische Technische Hochschule Aachen, Institute of Organic Chemistry, Landoltweg 1, 52074, Aachen, GERMANY

    Catalytic hydrogen atom transfer from metal-hydrides to alkenes allows feedstock olefins to be used as alkyl radical precursors. The chemoselectivity of this process makes it an attractive synthetic tool and as such it has been regularly used in synthesis of complex molecules. However, onwards reactivity is limited by compatibility with the conditions which form the key metal-hydride species. Now, through the merger with photocatalysis or electrochemistry, milder methods are emerging which can unlock entirely new reactivity and offer perspectives on expanding these methods in unprecedented directions. This review outlines the most recent developments in electro- and photochemical cobalt catalysed methods and offers suggestions on the future outlook.

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    The α-alkylation of ketones in flow

    • Ella Coopera
    • Emma Alcocka
    • Mark Powera
    • Gerard McGlackena
    • aSchool of Chemistry and Analytical and Biological Chemistry Research Facility, University College Cork, T12 YN60 Cork, Ireland

    The α-deprotonation and alkylation of ketones is a fundamental transformation in organic chemistry. However, the apparent simplicity of this process belies its complexity. Oftentimes experimental conditions are non-ideal, and yields are low. Herein, we directly target these issues, and provide a continuous flow methodology which leads to excellent yields, reduces reaction time, avoids cryogenic temperatures, minimises exposure to alkyllithiums/alkylhalides, and can be scaled-out.

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    Continuous Flow Synthesis of Cyclobutenes Using LED Technology

    • Megan Smytha
    • Thomas S Moodya,b
    • Scott Wharrya
    • Marcus Baumannc
    • aBiocatalysis group, Almac Sciences Ltd, Craigavon, United Kingdom of Great Britain and Northern Ireland
    • bManufacturing, Arran Chemical Company, Athlone, Ireland
    • bChemistry, University of Durham, Durham, United Kingdom of Great Britain and Northern Ireland

    Cyclobutenes are highly strained ring systems of considerable synthetic interest that can be accessed via cycloaddition reactions between alkenes and alkynes. However, their traditional preparation relies on photochemical [2+2]-cycloadditions that exploit low wavelength UV radiation emitted from inefficient medium-pressure Hg-lamps. This paper reports on the development of a modern approach using a high-power LED set-up emitting at the boundary of UV-A and visible light in conjunction with a continuous flow reactor. The resulting flow process renders a series of cyclobutenes from maleimides and various commercial alkynes. This provides a more energy-efficient approach that is readily scalable to access multigram quantities of cyclobutenes in high chemical yields and short residence times. The value of these products is exemplified by flow-based hydrogenations yielding highly substituted cyclobutanes which represent sought after building blocks in modern medicinal chemistry programs.

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    Accelerated Chemical Reaction Optimization Using Multi-Task Learning

    • Connor J. Taylor*a,b, Kobi C. Feltonc, Daniel Wighb,c, Mohammed I. Jeraald, Rachel Graingera, Gianni Chessaria, Christopher N. Johnsona, and Alexei A. Lapkin*b,c,d
    • aAstex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom
    • bInnovation Centre in Digital Molecular Technologies, Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, United Kingdom
    • cDepartment of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge CB3 0AS, United Kingdom
    • dCambridge Centre for Advanced Research and Education in Singapore Ltd., 1 Create Way, CREATE Tower #05-05, 138602, Singapore

    Functionalization of C–H bonds is a key challenge in medicinal chemistry, particularly for fragment-based drug discovery (FBDD) where such transformations require execution in the presence of polar functionality necessary for protein binding. Recent work has shown the effectiveness of Bayesian optimization (BO) for the self-optimization of chemical reactions; however, in all previous cases these algorithmic procedures have started with no prior information about the reaction of interest. In this work, we explore the use of multitask Bayesian optimization (MTBO) in several in silico case studies by leveraging reaction data collected from historical optimization campaigns to accelerate the optimization of new reactions. This methodology was then translated to real-world, medicinal chemistry applications in the yield optimization of several pharmaceutical intermediates using an autonomous flow-based reactor platform. The use of the MTBO algorithm was shown to be successful in determining optimal conditions of unseen experimental C–H activation reactions with differing substrates, demonstrating an efficient optimization strategy with large potential cost reductions when compared to industry-standard process optimization techniques. Our findings highlight the effectiveness of the methodology as an enabling tool in medicinal chemistry workflows, representing a step-change in the utilization of data and machine learning with the goal of accelerated reaction optimization.

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    Efficient degassing and ppm-level oxygen monitoring flow chemistry system

    • Paulius Baronasa
    • Jacob Lynge Elholma
    • Kasper Moth-Poulsena,b,c,d
    • aThe Institute of Materials Science of Barcelona, ICMAB-CSIC, Bellaterra, 08193, Barcelona, Spain
    • bCatalan Institution for Research & Advanced Studies, ICREA, Pg. Lluís Companys 23, 08010 Barcelona, Spain
    • cDepartment of Chemical Engineering, Universitat Politècnica de Catalunya, EEBE, Eduard Maristany 10–14, 08019 Barcelona, Spain
    • dChalmers University of Technology, Department of Chemistry and Chemical Engineering. SE-412 96 Gothenburg, Sweden

    Low oxygen levels are critical for a long range of chemical transformations carried out in both flow and batch chemistry. Here, we present an inline continuous flow degassing system based on gas permeable membrane inside vacuum chamber for achieving and monitoring ppm-level oxygen concentrations in solutions. Oxygen presence was monitored with a molecular oxygen probe and a continuously running UV-Vis spectrometer. An automated setup for discovering optimal reaction conditions for minimal oxygen presence was devised. The parameters tested were; flow rate, vacuum pressure, solvent back-pressure, tube material, tube length and solvent oxygen solubility. The inline degassing system was proved to be effective to remove up to 99.9% of ambient oxygen from solvents at a flow rate of 300 μl/min and 4 mbar vacuum pressure inside the degassing chamber. Reaching lower oxygen concentrations was limited by gas permeation in the tubing following the degassing unit, which could be addressed by purging large volume flow reactors with an inert gas after degassing. Among all factors, oxygen solubility in solvent was found to play a significant role for achieving efficient degassing of solvents. Data presented here can be used to choose optimal experimental parameters for oxygen sensitive reactions in flow chemistry reaction setups. The data was also fitted to an analytically derived model from simple differential equations in physical context of the experiment.

    Photo-Flow Technology for Chemical Rearrangements: A Powerful Tool to Generate Pharmaceutically Relevant Compounds

    • Antonella Ilenia Alfanoa, Sveva Pellicciaa, Giacomo Rossinob, Orazio Chianesec, Vincenzo Summaa, Simona Collinab, and Margherita Brindisia
    • aDepartment of Pharmacy (DoE 2023-2027), University of Naples Federico II, via D. Montesano 49, 80131 Naples, Italy
    • bDepartment of Drug Sciences, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy
    • cGenetic S.p.A., Via Canfora, 64, 84084 Fisciano (Salerno), Italy

    In recent years, photochemistry has increasingly emerged as an enabling methodology in both academia and the pharmaceutical industry. Long photolysis times and the gradual reduction of light penetration remained for many years unsolved issues for photochemical rearrangements, triggering the generation of highly reactive species in an uncontrolled fashion and causing the formation of multiple side products. The emergence of continuous-flow chemistry significantly helped to overcome these issues, thus prompting the implementation of photo-flow-based approaches for the generation of pharmaceutically relevant substructures. This Technology Note highlights the benefits of flow chemistry for photochemical rearrangements, including Wolff, Favorskii, Beckmann, Fries, and Claisen rearrangements. We showcase recent advances for photo-rearrangements in continuous flow applied to the synthesis of privileged scaffolds and active pharmaceutical ingredients.

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    Boronic Acids and Their Derivatives as Continuous-Flow-Friendly Alkyl Radical Precursors

    • Monica Olivaa, Viktoriia V. Chernobrovkinab, Erik V. Van der Eyckena,b, Upendra Kumar Sharmaa
    • aLaboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven (KU Leuven), Celestijnenlaan 200F, 3001 Leuven, Belgium
    • bPeoples’ Friendship University of Russia (RUDN University), Miklukho-Maklaya street 6, 117198 Moscow, Russia

    Since its recognition as an enabling tool to form challenging C–C and C–heteroatom bonds under mild and sustainable conditions, photoredox catalysis has been in the spotlight within the synthetic community. As a consequence, the interest in developing novel synthetic strategies has spiked together with the need to define suitable technologies to overcome scale-up issues dictated by the Bouguer–Beer–Lambert law. In this context, continuous-flow reactors play a major role in increasing the efficiency of a given photocatalyzed reaction, thus rendering scale-up processes more accessible. In the alkyl radical precursor landscape, boron-based species have begun to play a predominant role. Though the reactivity of trifluoroborates has been deeply investigated, the interest in using other boron species as radical precursors in photocatalyzed reactions has recently arisen. This late exploration lies in the fact that the high oxidation potential of boronic acids (BAs) hinders their possible applications. Nevertheless, to circumvent this issue, a diverse array of activation modes has been developed, exploiting in most cases the inherent Lewis acidity of the boronic acid. The aim of this Account is to highlight our recent contribution to this vibrant field with a focus on broad applicability, selectivity, and scalability via continuous-flow methodology. For the sake of clarity, the Account is discussed under the following sections.

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    Advances in continuous polymer analysis in flow with application towards biopolymers

    • Samuel B. H. Pattersona, Raymond Wongb, Graeme Barkera & Filipe Vilelaa
    • aSchool of Engineering and Physical Sciences, Institute of Chemical Sciences, Heriot Watt University, Edinburgh, EH14 4AS, UK
    • bShimadzu Centre of Excellence, Milton Keynes, UK

    Biopolymers, polymers derived from renewable biomass sources, have gained increasing attention in recent years due to their potential to replace traditional petroleum-based polymers in a range of applications. Among the many advantages of biopolymers can be included their biocompatibility, excellent mechanical properties, and availability from renewable feedstock. However, the development of biopolymers has been limited by a lack of understanding of their properties and processing behaviours. Continuous analysis techniques have the potential to hasten progress in this area by providing real-time insights into the properties and processing of biopolymers. Significant research in polymer chemistry has focused on petroleum-derived polymers and has thus provided a wealth of synthetic and analytical methodologies which may be applied to the biopolymer field. Of particular note is the application of flow technology in polymer science and its implications for accelerating progress towards more sustainable and environmentally friendly alternatives to traditional petroleum-based polymers. In this mini review we have outlined several of the most prominent use cases for biopolymers along with the current state-of-the art in continuous analysis of polymers in flow, including defining and differentiating atline, inline, online and offline analysis. We have found several examples for continuous flow analysis which have direct application to the biopolymer field, and we demonstrate an atline continuous polymer analysis method using size exclusion chromatography.

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    Continuous Flow-Facilitated CB2 Agonist Synthesis, Part 1: Azidation and [3 + 2] Cycloaddition

    • Peter Sagmeistera,b, Michael Prieschla,b, Dainis Kaldrec, Chethana Gadiyard, Christian Moessnerc, Joerg Sedelmeierc, Jason D. Williamsa,b, and C. Oliver Kappea,b
    • aCenter for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, AustriaM/li> bInstitute of Chemistry, NAWI Graz, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
    • cDepartment of Process Chemistry & Catalysis, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland
    • dDepartment of Solid State Sciences, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland

    We report the use of continuous flow processing to enable the first two steps of a new route toward a cannabinoid receptor type 2 agonist, RG7774. First, an alkyl azide is formed using sodium azide at an elevated temperature. Flow processing allows this to be done in a safe and rapid manner, providing a quantitative yield in 1 min residence time. The subsequent [3 + 2] cycloaddition with 2-cyanoacetamide requires basicity within a fairly narrow range to facilitate the reaction while preventing the decomposition of starting materials. A kinetic model was proposed for the cycloaddition step, with validation in both batch and flow. Three different flow reactor setups were then examined to emulate combinations of plug flow reactors (PFRs) and continuous stirred tank reactors (CSTRs). The use of CSTRs enables operation above the solubility limit of the product, improving the mass intensity and productivity. The desired triazole product can consistently be isolated in ∼80% yield with >99% purity and ∼9.5 g/h productivity. This serves to lay the foundation for the remaining route development to RG7774. Furthermore, the developed kinetic models are used as a basis for the proposed scale-up setup of a combined PFR (1 L) + CSTR cascade (3 × 5 L) for a pilot scale, which would produce up to 8.9 kg/h of the triazole product.

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    Continuous Flow-Facilitated CB2 Agonist Synthesis, Part 2: Cyclization, Chlorination, and Amination

    • Michael Prieschla,b, Peter Sagmeistera,b, Christian Moessnerc, Joerg Sedelmeierc, Jason D. Williamsa,b, and C. Oliver Kappea,b
    • aCenter for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
    • bInstitute of Chemistry, NAWI Graz, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
    • cDepartment of Process Chemistry & Catalysis, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland

    A new route to the cannabinoid receptor type 2 agonist, RG7774, has been developed circumventing an alkylation with poor regioselectivity as the final step. In the new synthetic route, this side chain is incorporated from the beginning. In this article, the development of the final four transformations is detailed, using a combination of batch and flow processing. Due to poor solubility, an N-pivaloylation was performed in batch, followed by cyclization at up to 200 °C, enabled by flow processing. The following chlorination and SNAr steps were examined in both batch and flow for improved handling of hazardous reagents and intermediates, as well as enhanced heat transfer. A workup between these two steps was found to be vital in preventing side product formation from residual dimethylamine. To achieve this on a laboratory scale, a continuous solid phase treatment was developed, whereby two cation exchange columns (containing SCX-2 silica) were cycled, with monitoring by UV/vis analysis. These four steps were demonstrated with a combined yield of 72%, which serves as a significant positive contribution to the new route’s high overall yield of 53%.

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    Flow Electrochemistry for the N-Nitrosation of Secondary Amines

    • Rojan Alia, Dr. Rasool Babaahmadia, Dr. Matthew Didsburyb, Dr. Rebecca Stephensb, Prof. Rebecca L. Melena, Prof. Thomas Wirtha
    • aSchool of Chemistry, Cardiff University, Park Place, Main Building, Cardiff, CF10 3AT UK
    • bBAE Systems, Glascoed, Usk, Monmouthshire, NP15 1XL UK

    A flow electrochemical method towards the synthesis of N-nitroso compounds from secondary amines using cheap and readily available sodium nitrite has been developed. Sodium nitrite dissolved in aqueous acetonitrile made additional electrolytes unnecessary. This mild and straightforward approach made the use of acids or other harsh and toxic chemicals redundant. This procedure was applied to an assortment of cyclic and acyclic secondary amines (27 examples) resulting in yields of N-nitrosamines as high as 99 %. To demonstrate the practicality of the process, scaled-up reactions were performed. Finally, selected products could be purified by using an in-line acidic extraction.

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    Alkene reactions with superoxide radical anions in flow electrochemistry

    Rojan Alia, Tuhin Patraa and Thomas Wirtha

    • aSchool of Chemistry, Cardiff University, Park Place, Main Building, Cardiff CF10 3AT (UK)

    Alkenes were cleaved to ketones by using dioxygen in a flow electrochemical set-up. The pressurised system allowed efficient gas-liquid mixing with a stabilised flow. This mild and straightforward approach avoids the use of transition metals and harsh oxidants.

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    Antimicrobial Evaluation of New Pyrazoles, Indazoles and Pyrazolines Prepared in Continuous Flow Mode

    Adam Burke1, Mara Di Filippo1, Silvia Spiccio1, Anna Maria Schito2, Debora Caviglia2,3, Chiara Brullo3, Marcus Baumann1

    • 1Science Centre South, School of Chemistry, University College Dublin, Dublin 4, Ireland
    • 2Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa, 16132 Genoa, Italy
    • 3Section of Medicinal Chemistry, Department of Pharmacy (DIFAR), University of Genoa, 16132 Genoa, Italy

    Multi-drug resistant bacterial strains (MDR) have become an increasing challenge to our health system, resulting in multiple classical antibiotics being clinically inactive today. As the de-novo development of effective antibiotics is a very costly and time-consuming process, alternative strategies such as the screening of natural and synthetic compound libraries is a simple approach towards finding new lead compounds. We thus report on the antimicrobial evaluation of a small collection of fourteen drug-like compounds featuring indazoles, pyrazoles and pyrazolines as key heterocyclic moieties whose synthesis was achieved in continuous flow mode. It was found that several compounds possessed significant antibacterial potency against clinical and MDR strains of the Staphylococcus and Enterococcus genera, with the lead compound (9) reaching MIC values of 4 µg/mL on those species. In addition, time killing experiments performed on compound 9 on Staphylococcus aureus MDR strains highlight its activity as bacteriostatic. Additional evaluations regarding the physiochemical and pharmacokinetic properties of the most active compounds are reported and showcased, promising drug-likeness, which warrants further explorations of the newly identified antimicrobial lead compound.

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    Photochemical Synthesis of Pyrazolines from Tetrazoles in Flow

    • Adam Burkea
    • Silvia Spiccioa
    • Mara Di Filippoa
    • Marcus Baumanna
    • aSchool of Chemistry, University College Dublin, Science Centre South, D04 N2E2, Dublin, Ireland

    Pyrazolines and their pyrazole congeners are important heterocyclic building blocks with numerous applications in the fine chemical industries. However, traditional routes towards these entities are based on multistep syntheses generating substantial amounts of chemical waste. Here we report an alternative approach using UV-light to convert tetrazoles into pyrazolines via a reagent-free photo-click strategy. This route generates nitrile imine dipoles in situ that are trapped with different dipolarophiles rendering a selection of these heterocyclic targets in high chemical yields. A continuous flow method is ultimately realized that generates multigram quantities of product in a safe and readily scalable manner thus demonstrating the value of this photochemical approach for future exploitations in industry.

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    Continuous Flow Inter- and Intramolecular Macrolactonization under High Dilution Conditions

    • Dashrat Vishambar Sutara
    • Neha Uttamrao Saranga
    • Akash Bandu Jamdadea
    • Boopathy Gnanaprakasama
    • aDepartment of Chemistry, Indian Institute of Science Education and Research, Dr. Homi Bhabha Road, Pashan, Pune 411008, India

    An efficient continuous flow process for the macrolactonization of seco acids and diacids using diols in the presence of Mukaiyama reagent (N-methyl-2-chloropyridinium iodide) has been developed for medium to large sized macrocyclic lactones. In comparison with other methods, the continuous flow process provided good to high yield in a short reaction time. By using this methodology, a wide range of macrocyclic lactones (11 compounds), dilactones (15 compounds), and tetralactone derivatives (2 compounds) with various ring sizes (12–26 atoms in the core) were synthesized in just 35 min of residence time. Advantageously, macrolactonization under the flow process is very elegant to handle the high dilution of reactants with a defined perfluoroalkoxy alkanes (PFA) tube reactor volume (7 mL).

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    Visible-Light Photoredox-Catalyzed Giese Reaction of α-Silyl Ethers with Various Michael Acceptors

    • Young Woo Kanga
    • Ran Hui Kima
    • Shafrizal Rasyid Atriardia
    • Sang Kook Wooa
    • aDepartment of Chemistry, University of Ulsan, 93 Daehak-Ro, Nam-Gu, Ulsan 44610, Korea

    We developed a photocatalyzed Giese reaction of various weakly activated Michael acceptors with a neutral silicon-based radical precursor and applied it at large-scale using a continuous flow reactor. The developed method successfully overcomes the substrate scope limitations of previous studies, shows good functional groups tolerance, and affords good to excellent yields. On the basis of mechanistic studies, we propose a reaction mechanism that involves an in situ generated alkoxymethyl radical via single-electron oxidation of α-trimethylsilyl-substituted ethers.

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    Skeletal Editing Approach to Bridge-Functionalized Bicyclo[1.1.1]pentanes from Aza-Bicyclo[2.1.1]hexanes

    Brandon A. Wright1, Anastassia Matviitsuk2, Michael J. Black1, Pablo García-Reynaga2, Luke E. Hanna2, Aaron T. Herrmann2, Michael K. Ameriks2, Richmond Sarpong1, Terry P. Lebold2

    • 1Department of Chemistry, University of California, Berkeley, California 94720, United States
    • 2Janssen Research and Development, San Diego, California 92121, United States

    The ability to rapidly navigate a wide diversity of chemical space from simple building blocks is a cornerstone of medicinal chemistry campaigns. Aza-bicyclo[2.1.1]hexane (aza-BCH) and bicyclo[1.1.1]pentane (BCP) scaffolds have recently emerged as attractive classes of sp3-rich cores for replacing flat, aromatic scaffolds with metabolically resistant, three-dimensional frameworks. Over the last decade, these pharmaceutically desirable properties and increased synthetic accessibility have led to a marked increase in the adoption of aza-BCHs and BCPs into drug scaffolds. While multiple, independent methods have been developed for the preparation of these structural motifs, strategies to directly convert, or scaffold hop, between these bioisosteric subclasses through single-atom skeletal editing would enable efficient interpolation within this valuable chemical space. Herein, we describe a strategy to scaffold hop between aza-BCH and BCP cores through a nitrogen-deleting skeletal edit. Photochemical [2+2] cycloadditions, used to prepare multifunctionalized aza-BCH frameworks, are coupled with a subsequent deamination step to afford bridge-functionalized BCPs, for which few synthetic solutions currently exist. The modular sequence provides access to various privileged bridged bicycles of pharmaceutical relevance bearing substituents that can be further derivatized.

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    Visible-Light Photocatalysis Academic–Industrial Collaboration Retrospective: Shared Learning and Impact Analysis

    • Kevin P. Colea
    • James J. Douglasa,b
    • Travis Hammerstadb
    • Corey R. J. Stephensonb
    • aSynthetic Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States
    • bDepartment of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States

    The 4.5 year academic–industrial collaboration between the process chemistry group at Lilly and the Stephenson group (Boston University and University of Michigan) is summarized. From the industrial perspective, the relationship benefitted Lilly by enabling the development of visible-light photoredox catalysis processes with an expert partner as well as the establishment of internal technology platforms to support such processes. In addition to the funding element, the academic side benefited from the ability to access pharmaceutically relevant problems and tap into continuous processing capabilities at Lilly. Another positive outcome of the collaboration was the inspiration of spinoff projects, which themselves generated substantial value in the academic setting. The postdoctoral researchers involved benefitted from the unique mentorship opportunity provided by the collaboration and access to resources from both academia and industry. We will analyze the impact of the collaboration in terms of personal development, publications, and new technologies that resulted, which we feel were highly beneficial for both sides of the collaboration.

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    Catalytic multi-step continuous-flow processes for scalable transformation of eugenol into potential fragrances

    • Fábio M.S. Rodriguesa
    • Vitaliy Masliya
    • Madalena F.C. Silvaa
    • Alexandre P. Felgueirasa
    • Rui M.B. Carrilhoa
    • Mariette M. Pereiraa
    • aUniversity of Coimbra, Coimbra Chemistry Centre, Department of Chemistry, Rua Larga, 3004-535 Coimbra, Portugal

    Catalytic multi-step processes were optimized and developed under continuous-flow conditions, to transform eugenol into potential new fragrances. One approach consisted in the direct catalytic conversion of eugenyl acetate into the corresponding cyclic carbonate, through a two-step protocol that utilizes two different tubular flow reactors for Mn(V)-catalysed epoxidation, using imidazole as co-catalyst and hydrogen peroxide as the oxidant, followed by the epoxide carboxylation with carbon dioxide, catalysed by a binary ZnBr2/TBAB catalytic system. With this methodology, a productivity of 7.68 g product per day was obtained. The other approach is an efficient hydroformylation/acetalization sequential process, which operates through a multi-stage flow system consisting of a tubular reactor for the Rh(I)/xantphos-catalysed hydroformylation, coupled in series with a K10 packed bed reactor for the aldehyde acetalization step. This pioneering strategy allowed obtaining 94 % chemoselectivity for acetal formation and 96 % regioselectivity for the linear product, resulting in a process productivity of 10.02 g product per day.

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    Development and optimization of a continuous flow ester reduction with LiAlH4 in the synthesis of a key intermediate for a PI3Kδ inhibitor (CPL302415)

    • Stanisław Michałeka,b
    • Anna M. Maja
    • Lidia Gurba-Bryśkiewicza
    • Wioleta Maruszaka
    • Marcin Zagozdaa
    • Zbigniew Ochalb
    • Krzysztof Dubiela
    • Maciej Wieczoreka
    • aCelon Pharma S.A., ul. Marymoncka 15, 05-152 Kazuń Nowy, Poland
    • bFaculty of Chemistry, Warsaw University of Technology, ul. Noakowskiego 3, 00-664 Warsaw, Poland

    Herein we present the development of highly productive and chemoselective ester reduction in a continuous flow system with lithium aluminum hydride (LAH) at mild temperature. The reaction was utilized for the reduction of an important precursor in the synthesis of a new PI3Kδ inhibitor (CPL302415), which is now under evaluation for the treatment of systemic lupus erythematosus. The productivity and the selectivity of the flow LAH reduction were compared with those of batch reaction, as well those of Ru-catalyzed ester reduction. The reaction has a high space–time yield (1130 kg h−1 m−3). The process was optimized using a design of experiments (DoE) approach.

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    Lipase-Mediated Synthesis of Oleoyl Ethanolamide Starting from High-Oleic Sunflower Oil Soapstock

    • Elisabetta Brennaa
    • Valeria De Fabritiisa
    • Fabio Parmeggiania
    • Francesca Tentoria
    • Davide Tessaroa
    • aDipartimento di Chimica, Materiali ed Ingegneria Chimica “Giulio Natta”, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133, Milano, Italy

    This work describes the lipase-mediated synthesis of oleoyl ethanolamide, a dietary supplement for body weight loss recently approved by FDA. The target compound is prepared by conversion of the oleic acid contained in a mixture of fatty acids recovered by enzymatic hydrolysis of soapstock, a side-product of high oleic sunflower oil refinement. The use of a packed-bed reactor (a glass column loaded with the commercial lipase Lipozyme 435) in continuous flow mode improves the space-time yield of the reaction and the catalyst productivity. The nontoxic, bioderived, and renewable solvent limonene is used in the reaction medium. The process has been run for more than 157 h of continuous operation, demonstrating the stability and efficiency of the biocatalyst. Additionally, at the end of the reaction, only oleoyl ethanolamide crystallizes from the reaction mixture, thus, it is collected by simple filtration of the outlet solution in 53% isolation yield, showing 99% chemical purity, while all the byproducts of the reaction are left behind in the mother liquors.

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    Continuous-Flow Technology for Chemical Rearrangements: A Powerful Tool to Generate Pharmaceutically Relevant Compounds

    • Antonella Ilenia Alfanoa, Sveva Pellicciaa, Giacomo Rossinob, Orazio Chianesec, Vincenzo Summaa, Simona Collinab, and Margherita Brindisia
    • aDepartment of Pharmacy (DoE 2023-2027), University of Naples Federico II, via D. Montesano 49, 80131, Naples, Italy
    • bDepartment of Drug Sciences, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy
    • cGenetic S.p.A., Via Canfora, 64, 84084 Fisciano (Salerno), Italy

    The efficacy, safety, and scale-up of several chemical rearrangements remain unsolved problems due to the associated handling of hazardous, toxic, and pollutant chemicals and high-risk intermediates. For many years batch processes have been considered the only possibility to drive these reactions, but continuous-flow technology has emerged, for both academic laboratories and pharmaceutical companies, as a powerful tool for easy, controlled, and safer chemistry protocols, helping to minimize the formation of side products and increase reaction yields. This Technology Note summarizes recently reported chemical rearrangements using continuous-flow approaches, with a focus on Curtius, Hofmann, and Schmidt reactions. Flow protocols, general advantages and safety aspects, and reaction scope for the generation of both privileged scaffolds and active pharmaceutical ingredients will be showcased.

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    Continuous Flow Synthesis of Substituted 3, 4-Propylenedioxythiophene Derivatives

    • Dattatray L. Tarangea
    • Nagaraj Nayaka
    • Anil Kumara
    • aDepartment of Chemistry, Indian Institute of Technology-Bombay (IITB), Powai, Mumbai 400076, India

    We report a continuous flow method for the process intensification of commercially important propylenedioxythiophene (ProDOT) monomers. A new four-step synthetic route was designed to make the whole process more economical and continuous flow amenable. Apart from being safe and having a higher throughput via continuous flow, we could optimize each of the synthetic steps to quantitative conversion. GC–MS analysis was used to monitor each of the processes during optimization. The overall process could be completed in around 65 min, starting from the commercially available materials, as compared to the few days via the reported batch processes. Furthermore, we have shown that the most critical step of the Williamson etherification could be intensified via continuous flow to the space–time yield (STY) of 63 g/h/L as compared to 0.16 g/h/L via the traditional batch process. As all the synthetic steps in our continuous flow process were optimized to quantitative conversions, it opens up the possibility of telescoping of the whole process. We believe that our findings will be able to fill the existing gap in the process intensification for the synthesis of commercially important ProDOT-based monomers.

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    Flow photochemistry — from microreactors to large-scale processing

    • Mengxue Zhanga
    • Philippe Rotha
    • aCorning SAS, 7 bis avenue de Valvins, CS 70156 Samois sur Seine, 77215 Avon Cedex, France

    Miniaturized continuous photoreactors have been recently receiving an increasing amount of attention from researchers both in academia and in industry. The upscaling of flow photoreactors without compromising the reactor performances, however, remains a major challenge for large-scale processes. This review provides an overview of existing commercial flow photoreactors, and the scaling-up strategies of photochemical processes using commercial flow reactors or in-house-fabricated reactors with recent illustrated examples. The strategies to upscale flow photoreactors will be discussed as well as the design principles. In addition, the topic of reactor characterization will be mentioned alongside the selection of the most relevant parameter to lead to a pertinent comparison across scales.

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    Continuous-flow photochemistry as an automated platform integrated with closed-loop AI/ML approaches

    Brenda Pijper1, Jesus Alcázar1, Gabriela Oksdath-Mansilla2, Fabricio Román Bisogno2

    • 1Discovery Chemistry, Janssen, Pharmaceutical Companies of Johnson and Johnson, Janssen-Cilag, S.A., Calle Río Jarama 75A, 45007 Toledo, Spain
    • 2INFIQC-CONICET-UNC, Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, X5000HUA Córdoba, Argentina

    In this Activity article, Brenda Pijper (Horizon 2020 PhotoReAct early-stage researcher in the Chemical Technologies group at Janssen, the Pharmaceutical Companies of Johnson & Johnson) and Jesus Alcázar (head of the Chemical Technologies group at Janssen) and Gabriela Oksdath-Mansilla and Fabricio R. Bisogno (both professors at the Universidad Nacional de Córdoba and researchers at the National Scientific and Technical Research Council of Argentina [CONICET]) discuss the current state of continuous-flow photochemistry in drug discovery and its future as an automated platform integrated with closed-loop artificial intelligence and machine learning (AI/ML) approaches.

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    Laboratory Scale Continuous Flow Systems for the Enantioselective Phase Transfer Catalytic Synthesis of Quaternary Amino Acids

    • Milena Krstić1, Sergio Rossi1, Miguel Sanz2, Alessandra Puglisi1
    • 1Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 19, 20133 Milano, Italy
    • 2Taros Chemicals, GmbH & Co. KG Emil-Figge-Str 76a, 44227 Dortmund, Germany

    The use of stereoselective phase-transfer catalysis as a reliable method for the enantioselective synthesis of optically active α-amino acid derivatives using achiral Schiff base esters has been well-developed in batch in the last 40 years. Recently, continuous flow technology has become of great interest in the academy and industry, since it offers safer process operating conditions and higher efficiency compared to a traditional batch processing. Herein, we wish to report the first example of enantioselective phase transfer benzylation of alanine Schiff base ester, under continuous flow conditions. Two different methodologies were investigated: a liquid-solid phase transfer catalytic benzylation using a packed-bed reactor and a liquid-liquid phase transfer catalytic benzylation in continuous stirred-tank reactors. Liquid-liquid phase transfer process in flow showed slightly better productivity than the batch process, while solid-liquid phase transfer benzylation proved much more advantageous in terms of productivity and space-time yield. Furthermore, continuous flow system allowed the isolation of benzylated product without any work up, with a significant simplification of the process. In both cases, phase transfer asymmetric benzylation promoted by Maruoka catalyst demonstrated high enantioselectivity of target quaternary amino ester in flow, up to 93% ee.

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    Continuous Flow Synthesis of Non-Symmetrical Ureas from CO2

    • Alexandre Labichea, Maylis Norlöffa, Dr. Sophie Feuillastrea, Dr. Frederic Tarana, Dr. Davide Audisioa
    • aUniversité Paris Saclay, CEA, Département Médicaments et Technologies pour la Santé, SCBM, 91191 Gif-sur-Yvette, France

    We report on a continuous flow synthetic process of non-symmetrical ureas, based on the implementation of a Staudinger/aza-Wittig reaction sequence. This flow technology allows obtaining the key urea functional group directly from the fundamental C1 building block CO2. A library of 26 derivatives, including alkyl/alkyl, alkyl/aryl and aryl/aryl ureas could be synthesised. In addition, the method was also suitable for the synthesis of S-thiocarbamates. The potential for large-scale reaction implementation and a first application to continuous flow 13C-isotope labeling are shown.

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    Flow photochemical Giese reaction via silane-mediated activation of alkyl bromides

    • Fabiola Faniniab, Alberto Luridianaa, Daniele Mazzarellaac, Antonella Ilenia Alfanoad, Perryvan der Heidea, Juan A. Rincóne, Pablo García-Losadae, Carlos Mateose, Michael O. Frederickf, Manuel Nuñog, Timothy Noëla
    • aFlow Chemistry Group, Van ’t Hoff Institute for Molecular Sciences (HIMS), University of Amsterdam Science Park 904, 1098 XH Amsterdam, The Netherlands
    • bDepartment of Biomolecular Sciences, University of Urbino “Carlo Bo”, Piazza Rinascimento 6, I-61029 Urbino, Italy
    • cDepartment of Chemical Sciences, University of Padova Institution, Via Francesco Marzolo, 1, 35131 Padova, Italy
    • dDepartment of Pharmacy, Department of Excellence 2018-2022, School of Medicine and Surgery, University of Naples “Federico II”, Via D. Montesano 49, I-80131 Naples, Italy
    • eCentro de Investigación Lilly S.A., Avda. de la Industria 30, Alcobendas-Madrid 28108, Spain
    • fSmall Molecule Design and Development, Eli Lilly and Company, Indianapolis, IN 46285, United States
    • gVapourtec Ltd. Park Farm Business Centre, Fornham St Genevieve, Bury St Edmunds, Suffolk IP28 6TS, United Kingdom

    Organic halides play a key role as building blocks in synthesis because of their low cost and wide availability. In recent years, halogen-atom transfer (XAT) has emerged as a reliable approach to exploit these substrates in radical processes. Herein, we report a hydroalkylation of electron-poor olefins using alkyl bromides based on a UVA-induced silane-mediated XAT reaction. Our protocol is operationally simple, displays a broad scope and does not require a photocatalyst. Flow technology was used to reduce the reaction times and scale the process. Notably, a two-step protocol, combining the XAT protocol with a subsequent Horner-Wadsworth-Emmons reaction, has been developed to enable the allylation of C(sp3)–Br bonds.

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    Generation of 1,2-Difluorobenzene via a Photochemical Fluorodediazoniation Step in a Continuous Flow Mode

    • Kevin Simonab, Desiree Znidarab, Julien Boutetc, Gérard Guillamotc, Jean-Yves Lenoirc, Doris Dallingerab, and C. Oliver Kappeab
    • aCenter for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, Graz 8010, Austria
    • bInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, Graz 8010, Austria
    • cSeqens SAS, 21 Chemin de la Sauvegarde, 21 Ecully Parc, Ecully 69130, France

    A proof-of-concept study for the synthesis of 1,2-difluorobenzene from 2-fluoroaniline via the Balz–Schiemann reaction using HF/pyridine as the fluorinating reagent is reported. Key to success for a fast reaction, a clean reaction profile─and thus high product selectivity─was a photochemically induced fluorodediazoniation of the in situ-generated diazonium salt performed in a continuous flow mode. A high-power 365 nm light-emitting diode provided a more robust and efficient irradiation system compared to a medium-pressure Hg lamp with respect to the reaction performance on scale-out runs and reaction time, allowing the generation of 1,2-difluorobenzene within a 10 min residence time and a product selectivity of ≥95% at full conversion.

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    Continuous flow synthesis of phenyl glucosazone and its conversion to 2H-1,2,3-Triazole building blocks

    Maria Molnara, Marcus Baumanna

    • aSchool of Chemistry, Science Centre South, University College Dublin, Dublin, D04 N2E2, Ireland

    A continuous flow approach for the generation of phenyl glucosazone from glucose and phenyl hydrazine is reported giving the pure target in 53% isolated yield. This thermal process generates the target product as an insoluble material that causes reactor fouling via adhering to the reactor walls. To overcome this issue a segmented flow approach was realised whereby streams of air and the reaction solution were combined in a T-piece and directed through the heated reactor coil. The resulting micro-mixing prevented reactor fouling and blocking and allowed for multi-hour reactions to generate the desired target in high yield. The value of the phenyl glucosazone product was demonstrated via its oxidative cyclisation into 2H-phenyl-1,2,3-triazoles which represent important heterocyclic scaffolds.

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    Continuous Flow Epoxidation of Alkenes Using a Homogeneous Manganese Catalyst with Peracetic Acid

    • Ailbhe A. Ryanabc, Seán D. Dempseyabc, Megan Smytha, Karen Faheyb, Thomas S. Moodyab, Scott Wharrya, Paul Dingwallc, David W. Rooneyc, Jillian M. Thompsonc, Peter C. Knipec, and Mark J. Muldoonc
    • aAlmac Group, Craigavon BT63 5QD, United Kingdom
    • bArran Chemical Company, Roscommon N37 DN24, Ireland
    • cQueen’s University Belfast, Belfast BT9 5AG, United Kingdom

    Epoxidation of alkenes is a valuable transformation in the synthesis of fine chemicals. Described herein are the design and development of a continuous flow process for carrying out the epoxidation of alkenes with a homogeneous manganese catalyst at metal loadings as low as 0.05 mol%. In this process, peracetic acid is generated in situ and telescoped directly into the epoxidation reaction, thus reducing the risks associated with its handling and storage, which often limit its use at scale. This flow process lessens the safety hazards associated with both the exothermicity of this epoxidation reaction and the use of the highly reactive peracetic acid. Controlling the speciation of manganese/2-picolinic acid mixtures by varying the ligand:manganese ratio was key to the success of the reaction. This continuous flow process offers an inexpensive, sustainable, and scalable route to epoxides.

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    The applications of organozinc reagents in continuous flow chemistry: Negishi coupling

    Roop Varghese Ruberta, Rony Rajan Paula

    • aDepartment of Chemistry, CMS College Kottayam, Kottayam, Kerala, 686001, India

    The design and implementation of flow technique helps organic chemists to resolve numerous challenges that are encountered during various catalytic reactions. Flow technologies, which offer solutions for technical and/or chemical issues, have gained popularity over the last two decades in the field of organic chemistry. The selectivity, efficiency, and safety of the entire process has been accelerated by flow reactors as they improve mass and heat transfer, speeds up the mixing of the reaction, and they offer exact control of the reaction parameters. This review mainly describes the utilization of flow chemistry in reactions involving organiozinc reagent, particularly Negishi coupling. The Negishi coupling of organozinc reagent is a valuable tool for the formation of C-C bond with functional group tolerance and are used extensively in total synthesis. This review also portrays a comparative study of organozinc reagents prepared using different procedures. A study of the effect of different catalysts over the same reaction is also carried out. An overview of different flow techniques that are employed has also been incorporated.

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    Alternate end-game strategies towards Nirmatrelvir synthesis: Defining a continuous flow process for the preparation of an anti-COVID drug

    • Karuna Veeramania, Manish Shindea, Vishnuvardhana Vema Reddy Edab, Bala Chennaiah Darapanenib, Rama Mohan Hindupurc, Srinivasa Rao Madarapuc, Saikat Senb, Srinivas Orugantib
    • a10X Chemical Process Automation Laboratory, Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, Telangana, India
    • bCentre for Process Research and Innovation, Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, Telangana, India
    • cAurigene Pharmaceutical Services Limited, JP Nagar Road, Miyapur, Hyderabad 500 049, Telangana, India

    Scalable alternate end-game strategies for the synthesis of the anti-COVID drug molecule Nirmatrelvir (1, PF-07321332) have been described. The first involves a direct synthesis of 1 via amidation of the carboxylic acid 7 (suitably activated as a mixed anhydride with either pivaloyl chloride or T3P) with the amino-nitrile 10·HCl. T3P was found to be a more practical choice since the reagent promoted efficient and concomitant dehydration of the amide impurity 9 (derived from the amino-amide contaminant 8·HCl invariably present in 10·HCl) to 1. This observation allowed for the development of the second strategy, namely a continuous flow synthesis of 1 from 9 mediated by T3P. Under optimized conditions, this conversion could be achieved within 30 min in flow as opposed to 12–16 h in a traditional batch process. The final API had quality attributes comparable to those obtained in conventional flask processes.

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    Iron-catalyzed [4 + 2] annulation of amidines with α,β-unsaturated ketoxime acetates toward 2,4,6-trisubstituted pyrimidines

    • Qinghuan Wua, Luchao Lia, Binyan Xua, Jie Suna, Dong Jib, Yuguang Lib, Lei Shenb, Zheng Fanga, Jindian Duana, Beining Chenc, Kai Guoa
    • aCollege of Biotechnology and Pharmaceutical Engineering, State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, 211816, China
    • bInstitute of Nanjing Advanced Biomaterials & Processing Equipment, Nanjing, 211299, China
    • cDepartment of Chemistry, University of Sheffield, Sheffield, S3 7HF, UK

    An iron-catalyzed [4 + 2] annulation of amidines with α,β-unsaturated ketoxime acetates is described. This strategy employs amidines as CN units and provides a new protocol for the construction of 2,4,6-trisubstituted pyrimidines under batch and continuous flow conditions in moderate to good yields, exhibiting good functional group tolerance, scalability and operational simplicity.

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    Visible-Light Photoredox Catalysis for the Synthesis of Fluorinated Aromatic Compounds

    • Tomasz Kliśa
    • aFaculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland

    Fluorine-containing functional groups are important motifs influencing physical and biological properties of organic compounds. Visible-light photoredox catalysis as a powerful strategy for the activation of small molecules contributed significantly to the rapid progress of new synthetic procedures allowing introduction of fluorine atoms into organic substrates. In this review, we highlight the distinct strategies for transition metal- and organic-photocatalytic fluorination of arenes and heteroarenes by a broad range of fluorinating compounds. The presented procedures are divided into two groups. The first group involves the reactions enabling a direct attachment of CF3-, CnFm-, F-, CF3O-, CF3S-, and SO2F- substituents to various aromatic compounds. The second group presents the tandem reactions where the formation of the aromatic system occurs after installation of the fluorine-containing group on the non-aromatic fragment of the molecule.

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    Process intensification of dendritic fibrous nanospheres of silica (DFNS) via continuous flow: a scalable and sustainable alternative to the conventional batch synthesis

    • Karuna Veeramaniabc
    • Nagaraj Nayaka
    • Neil R. Cameronc
    • Anil Kumar*a
    • aDepartment of Chemistry, Indian Institute of Technology-Bombay (IITB), Powai, Mumbai-400076, India
    • bIITB-Monash Research Academy, Indian Institute of Technology-Bombay (IITB), Powai, Mumbai-400076, India
    • cIITB-Monash Research Academy, Indian Institute of Technology-Bombay (IITB), Powai, Mumbai-400076, India

    In this manuscript, we report the scalable continuous flow synthesis of dendritic fibrous nanospheres of silica (DFNS) which have been speedily making a significant mark in the world of heterogeneous nanocatalysis for over a decade by virtue of their unique morphology. Further, this work also demonstrates the telescoping of the complete process intensification of this material through combination of scalable reactors like the spinning disk reactor and the dynamically agitated tubular reactor. This intensified synthetic protocol performed through continuous flow chemistry is a scalable, efficient, feasible, quicker, and sustainable route of synthesis. Interestingly, this protocol is generic and may be easily extrapolated to the process intensification of a wide range of similar hydrothermal biphasic nanoparticle systems, thus widening the horizons of controlled, intensified, and sustainable production of nanomaterials.

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    Continuous-flow Fe-zeolite-catalyzed temperature-directed synthesis of bioactive tetraketones and xanthenes using epoxides and cyclic-1,3-diketones via a Meinwald rearrangement

    • Shankhajit Mondala
    • Akanksha M. Pandeya
    • Boopathy Gnanaprakasama
    • aDepartment of Chemistry, Indian Institute of Science Education and Research (IISER) Pune, Dr. Homi Bhabha Road, Pune 411008, Maharashtra, India

    An environmentally benign approach for bioactive tetraketones using epoxides and cyclic-1,3-diketones in the presence of Fe-zeolite as a catalyst via a Meinwald rearrangement was developed under batch and continuous flow modes. Further increasing the temperature to 180 °C, these tetraketones underwent a cyclization reaction in the presence of catalytic Fe-zeolite to afford xanthene derivatives. Moreover, this Fe-zeolite catalyst was also used for the reaction of aldehyde and cyclic 1,3-diketone, affording the tetraketone in a high yield. Advantageously, the present approach enables gram-scale synthesis in batches as well as in continuous flow. This approach can sustainably generate many bioactive tetraketones and xanthenes as it does not produce any waste. The Fe-zeolite used in this process is easy to synthesize in the multigram scale, inexpensive, easy to recover, and recyclable.

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    Development of an automated platform for C(sp3)-C(sp3) bond formation via XAT chemistry

    • Brenda Pijpera
    • Irini Abdiaja
    • Daniele Leonorib
    • Jesus Alcázara
    • aJanssen Cilag SA, Discovery Chemistry, Jarama 75A, 45007 Toledo, SPAIN
    • bRWTH Aachen, Institute of Organic Chemistry, GERMANY

    Increasing Fsp3 in drug molecules is of high importance in the pharmaceutical industry to escape the flatland. However, there is a lack of diverse methods to introduce C(sp3) into a molecule in library synthesis. In this work, we report the combination of continuous flow chemistry with photochemistry to create an automated platform for library synthesis using halogen atom transfer (XAT) reaction to increase Fsp3 in drug molecules. The chemistry has a broad scope of alkyl halides and electron deficient alkenes. We report a library synthesis of 84 compounds with a productivity of 1.5 reactions per hour, a scope of 51 isolated compounds and the reproducibility and scalability of the chemistry. Providing an efficient automated tool to synthesize drug-like molecules with increased Fsp3 in drug discovery and development.

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    Photochemical Synthesis of Pyrazolines from Tetrazoles in Flow

    Adam Burkea, Silvia Spiccioa, Mara Di Filippoa, Marcus Baumannb

    • aChemistry, University College Dublin, Dublin, Ireland
    • bChemistry, University of Durham, Durham, United Kingdom of Great Britain and Northern Ireland

    Pyrazolines and their pyrazole congeners are important heterocyclic building blocks with numerous applications in the fine chemical industries. However, traditional routes towards these entities are based on multistep syntheses generating substantial amounts of chemical waste. Here we report an alternative approach using UV-light to convert tetrazoles to pyrazolines via a reagent-free photo-click strategy. This route generates nitrile imine dipoles in situ that are trapped with different dipolarophiles rendering a selection of these heterocyclic targets in high chemical yields. A continuous flow method is ultimately realized that generates multi-gram quantities of product in a safe and readily scalable manner thus demonstrating the value of this photochemical approach for future exploitations in industry.

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    Continuous Process to Safely Manufacture an Aryldiazoacetate and Its Direct Use in a Dirhodium-Catalyzed Enantioselective Cyclopropanation

    • Stephen P. Lathropa, Laurie B. Mlinara, Onkar N. Manjrekara, Yong Zhoua, Kaid C. Harpera, Eric R. Saciaa, Molly Higginsa, Andrew R. Bogdanb, Zhe Wanga, Steven M. Richtera, Wei Gongc, Eric A. Voightc, Jeremy Henlea, Moiz Diwana, Jeffrey M. Kallemeyna, Jack C. Sharlandd, Bo Weid, and Huw M. L. Daviesd
    • aProcess Research and Development, AbbVie Inc., North Chicago, Illinois 60064, United States
    • bAdvanced Chemistry Technologies, AbbVie Inc., North Chicago, Illinois 60064, United States
    • cDrug Discovery Science & Technology, AbbVie Inc., North Chicago, Illinois 60064, United States
    • dDepartment of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States

    We report the development and demonstration of a continuous-flow process for the safe formation, extraction, and drying of aryldiazoacetate 2, which enables direct use in a fed-batch dirhodium-catalyzed enantioselective cyclopropanation reaction to provide cyclopropane 4. Designing this process with safety as a primary objective, we identified the appropriate arylsulfonyl hydrazone starting material and organic soluble base to facilitate a Bamford–Stevens diazo-generating flow process at 30 °C, well below the thermal onset temperature (Tonset = 57 °C), while also minimizing accumulation of the highly energetic diazo intermediate (ΔHD = −729 J/g). The Bamford–Stevens reaction byproducts are efficiently removed via a continuous aqueous extraction utilizing a liquid–liquid hydrophobic membrane separator. Continuous molecular sieve drying of the organic layer was demonstrated to maintain water levels <100 ppm in the final aryldiazoacetate solution, thereby ensuring acceptable reactivity, selectivity, and purity in the water sensitive cyclopropanation reaction. The full process was successfully executed on a 100 g scale, setting the foundation for the wider application of this and related chemistries on a kilogram scale.

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    Multicompartment polymeric colloids from functional precursor Microgel: Synthesis in continuous process

      • aDWI – Leibniz-Institute for Interactive Materials e.V, Forckenbeckstraße 50, 52074 Aachen, Germany
      • bInstitute of Technical and Macromolecular Chemistry, RWTH Aachen University, Worringerweg 2, 52074 Aachen, Germany
      • cAachen-Maastricht Institute for Biobased Materials (AMIBM), Maastricht University, Urmonderbaan 22, 6167 RD Geleen, The Netherlands
      • dZuyd University of Applied Sciences, Nieuw Eyckholt 300, 6419 DJ Heerlen, The Netherlands
      • eJülich Centre for Neutron Science (JCNS-1), Forschungszentrum Jülich GmbH, Wilhelm-Johnen-Straβe, 52428 Jülich, Germany
      • fCNRS, UMR 8232 – IPCM – Institut Parisien de Chimie Moléculaire – Polymer Chemistry Team, Sorbonne Université, 4 Pl. Jussieu, 75005 Paris, France

      Raspberry-like poly(oligoethylene methacrylate-b-N-vinylcaprolactam)/polystyrene (POEGMA-b-PVCL/PS) patchy particles (PPs) and complex colloidal particle clusters (CCPCs) were fabricated in two-, and one-step (cascade) flow process. Surfactant-free, photo-initiated reversible addition-fragmentation transfer (RAFT) precipitation polymerization (Photo-RPP) was used to develop internally cross-linked POEGMA-b-PVCL microgels with narrow size distribution. Resulting microgel particles were then used to stabilize styrene seed droplets in water, producing raspberry-like PPs. In the cascade process, different hydrophobicity between microgel and PS induced the self-assembly of the first formed raspberry particles that then polymerized continuously in a Pickering emulsion to form the CCPCs. The internal structure as well as the surface morphology of PPs and CCPCs were studied as a function of polymerization conditions such as flow rate/retention time (Rt), temperature and the amount of used cross-linker. By performing Photo-RPP in tubular flow reactor we were able to gained advantages over heat dissipation and homogeneous light distribution in relation to thermally-, and photo-initiated bulk polymerizations. Tubular reactor also enabled detailed studies over morphological evolution of formed particles as a function of flow rate/Rt.

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      TBADT-Mediated C-C Bond Formation Exploiting Aryl Aldehydes in a Photochemical Flow Reactor

      • Adam Cruisea
      • Marcus Baumanna
      • aUniversity College Dublin, School Of Chemistry, Science Centre - South, Dublin 4 Belfield, IRELAND

      A robust and general photochemical process is reported converting various aryl aldehydes into β-ketonitriles and related species. Tetrabutylammonium decatungstate (TBADT) is used as photocatalyst in combination with a high-power LED emitting at 365 nm. Standardization and scalability are enabled by using a flow reactor platform integrating the LED light source placed within an encased reactor coil. Under optimized conditions a variety of aromatic and heteroaromatic aldehydes is reacted with acrylonitrile, methyl methacrylate and phenyl vinyl sulfone to give the desired products in high yields, short residence times of 5-30 minutes and a throughput of up to 41 mmol/h. This continuous process overcomes limitations previously encountered for aromatic substrates and represents an effective means to generate a variety of difunctionalized building blocks for further elaborations with an ideal atom economy.

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      Synthesis of picramide using nitration and ammonolysis in continuous flow

      • Ankit Kumar Mittala
      • Gaurav Prakasha
      • Pramod Pathaka
      • Debabrata Maitia
      • aIndian Institute of Technology Bombay, Chemistry, INDIA

      This paper describes a safer, scalable and continuous process for synthesis of picramide. The process consists of two steps: step-1. nitration of p-nitroanisole (PNAN) to 2,4,6-trinitrianisole (TNAN); step-2. ammonolysis of TNAN to picramide. Both the steps were optimized in flow, with yield of 90% and 98% in step-1 and step-2 respectively. Picramide with HPLC purity greater than 99% was obtained. When compared with batch, in step-1, flow process provided significant advantage in selectivity and yield. The optimized flow process was scaled to 25 g/hr production rate in a laboratory flow reactor. The method can be considered fit for the safe production of picramide at commercial scale.

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      End-to-End Automated Synthesis of C(sp3)-Enriched Drug-like Molecules via Negishi Coupling and Novel, Automated Liquid–Liquid Extraction

      • Irini Abdiaja
      • Santiago Cañellasa
      • Alejandro Diegueza
      • Maria Lourdes Linaresa
      • Brenda Pijpera
      • Alberto Fontanaa
      • Raquel Rodrigueza
      • Andres Trabancoa
      • Eduardo Palaoa
      • Jesus Alcázar*a
      • aDiscovery Chemistry, Janssen Research and Development, Janssen-Cilag, S.A., C/ Jarama 75, E-45007Toledo, Spain

      Herein, we report an end-to-end process including synthesis, work-up, purification, and post-purification with minimal human intervention using Negishi coupling as a key transformation to increase Fsp3 in bioactive molecules. The main advantages of this protocol are twofold. First, the automated sequential generation of organozinc reagents from readily available alkyl halides offers a large diversity of alkyl groups to functionalize (hetero)aryl halide scaffolds via Pd-catalyzed Negishi coupling in continuous flow. Second, a fully automated liquid–liquid extraction has been developed and successfully applied for unattended operations. The workflow was completed with mass-triggered preparative high-performance liquid chromatography HPLC, providing an efficient production line of compounds with enriched sp3 character and better drug-like properties. The modular nature allows a smooth adaptation to a wide variety of synthetic methods and protocols and makes it applicable to any medchem laboratory.

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      Flow platform for the synthesis of benzodiazepines

      • Maria Ivanovaa
      • Thomas Poissona
      • Philippe Jubaulta
      • Julien Legrosa
      • aNormandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA, 76000, Rouen, France

      Benzodiazepines possess a wide spectrum of valuable pharmacological effects and are among the leading drugs, commonly prescribed ones for various pathologies. Herein we describe the continuous flow synthesis of six benzodiazepines from aminobenzophenones: diazepam, fludiazepam, nordazepam, nitrazepam, clonazepam, oxazepam.

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      Mimicking natural metabolisms: cell‐free flow preparation of dopamine

      • Silvia Donzellaa
      • Agostina Colaciccoa
      • Luca Nespolia
      • Dr. Martina L. Contentea
      • aDepartment of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, via Celoria, 2, 20133 Milan, Italy

      The biosynthesis of dopamine (DA) from L-tyrosine as starting material is an excellent yet challenging strategy. Here we developed a versatile, multi-enzymatic platform for the biocatalytic preparation of DA in a continuous mode with excellent conversion (90 %) and reaction time (45 min). The system exploits the immobilization of a decarboxylase from Bacillus pumilis (Fdc) and a tyrosinase from Agaricus bisporus (Tyr), which were combined to mimic the in-vivo synthesis of DA (both primary and secondary metabolisms) giving rise to an efficient strategy with a considerable reduction of process associated costs and environmental impact. To enhance the system automation, an in-line purification via catch-and-release procedure was added.

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      Improving the Sustainability and Safety of Ursodeoxycholic Acid Synthesis in Continuous Flow Process with Water

      • Hahyeon Kima
      • Jonghyun Leeb
      • Seung Jae Leec
      • Jeong Eun Oha
      • Soo Dong Kima
      • Yashwardhan R. Malpanic
      • Ye-Jin Hwangd
      • aDepartment of Biomedical and Pharmaceutical Science, Kyung Hee University, 26 Kyughee-daero, Dongdaemun-gu, Seoul 02447, Republic of Korea
      • bDepartment of Basic Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyughee-daero, Dongdaemun-gu, Seoul 02447, Republic of Korea
      • cAPI Synthesis Team, Daewoong-Bio, 29-Jeyakdanji-ro, Hyangnam-eup, Hwaseung-si, Hyeonggi-do 18608, Republic of Korea
      • dDepartment of Chemistry and Chemical Engineering, Education and Research Center for Smart energy and Materials, Inha University 100 Inha-ro, Michugol-gu, Incheon, Republic of Korea

      A clog-free sustainable method for the synthesis of ursodeoxycholic acid through selective hydrogenation was developed using Raney nickel in a continuous flow process. To increase the sustainability and safety of the continuous flow system, water as a green solvent was used to remove the salt compound causing serious clogging problems and to generate hydrogen gas by electrolysis. Furthermore, a real-time monitoring system was installed in the flow system to check the system pressure and collective volume of the reaction solution, allowing immediate confirmation of blockages. Eventually, the continuous flow system was successfully developed with a short residence time of 4 minutes, almost full conversion, and high selectivity of 94.0% dr. This continuous flow system lasts 10 consecutive days with lower catalyst loading (the ratio of Raney nickel to 7-oxo-LCA = 4.44 w/w) without clogging problems.

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      The design of experiments (DoE) in optimization of an aerobic flow Pd-catalyzed oxidation of alcohol towards an important aldehyde precursor in the synthesis of phosphatidylinositide 3-kinase inhibitor (CPL302415)

      • Stanisław Michałeka,b
      • Lidia Gurba-Bryśkiewicza
      • Wioleta Maruszaka
      • Marcin Zagozdaa
      • Anna M. Maja
      • Zbigniew Ochalb
      • Krzysztof Dubiela
      • Maciej Wieczoreka
      • aCelon Pharma S.A., Ul. Marymoncka 15, 05-152 Kazuń Nowy, Poland
      • bFaculty of Chemistry, Warsaw University of Technology, Ul. Noakowskiego 3, 00-664 Warsaw, Poland

      Herein, we describe the development of a green, scalable flow Pd-catalyzed aerobic oxidation for the key step in the synthesis of CPL302415, which is a new PI3Kδ inhibitor. Applying this environmental-friendly, sustainable catalytic oxidation we significantly increased product yield (up to 84%) and by eliminating of workup step, we improved the waste index and E factor (up to 0.13) in comparison with the stoichiometric synthesis. The process was optimized by using the DoE approach.

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      Exploring Visible Light for Carbon–Nitrogen and Carbon–Oxygen Bond Formation via Nickel Catalysis

      • Shengqing Zhua
      • Huan Lia
      • Yingying LIa
      • Zhonghou HUANGa
      • Lingling Chua
      • aState Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Center for Advanced Low-Dimension Materials, College of Chemistry and Chemical Engineering, Donghua University, Shanghai 201620, China

      Heteroatom-containing motifs are one of the most privileged scaffolds for pharmaceuticals, agrochemical, and functional materials. Transition-metal-catalyzed carbon-heteroatom bond-forming reactions have emerged as an indispensable synthetic tool for the rapid assembly of these valuable skeletons. Although impressive progress, the development of general and efficient methods for the catalytic construction of carbon-heteroatom bonds with earth-abundant catalysts under mild conditions is still highly desirable. Utilizing the new and unique reactivity uncovered by photo excitation, recently, exciting progress has been made in the area of visible light-driven nickel-catalyzed carbon-heteroatom bond-forming reactions, enabling facile access the diverse carbon-heteroatom bonds under exceptionally mild conditions. In this review, we highlight recent synthetic methodology development for the formation of C-N and C-O bonds via visible-light-driven high-valent nickel complexes or photoexcited nickel complexes, with in-depth discussions with reaction designs and mechanistic scenarios.

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      Consecutive photochemical reactions enabled by a dual flow reactor coil strategy

      • Ruairi Crawforda
      • Mara Di Filippoa
      • Duncan Guthrieb
      • Marcus Baumanna
      • aSchool of Chemistry, Science Centre South, University College Dublin, D04 N2E2, Dublin, Ireland
      • bVapourtec, Fornham St Genevieve, Bury St Edmunds, Suffolk, IP28 6TS, UKM

      The application of a dual reactor coil for consecutive photochemical reactions is presented in continuous flow mode. This strategy enables for the first time the use of a single LED-based light source to perform two distinct photochemical reactions in an uninterrupted fashion. This approach is demonstrated for the telescoped synthesis and functionalisation of drug-like quinolines and compared to alternatives exploiting two photochemical reactor set-ups operated in sequence. The presented strategy enables the intensified exploitation of photochemical reactions in modern synthesis.

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      Spheroplasts preparation boosts the catalytic potential of a squalene-hopene cyclase

      • Ana I. Benítez-Mateosa
      • Andreas Schneider
      • Eimear Hegartya
      • Bernhard Hauer
      • Francesca Paradisia
      • aDepartment of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Freiestrasse 3, 3012, Bern, Switzerland
      • bInstitute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569, Stuttgart-Vaihingen, Germany

      Squalene-hopene cyclases 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 squalene-hopene-cyclase spheroplasts. By removing the outer cell membrane, we produce stable and substrate-accessible biocatalysts. These spheroplasts exhibit 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 is also higher than the purified enzyme for all high molecular weight terpenes. In addition, we introduce a concept for the carrier-free immobilization of spheroplasts via crosslinking, crosslinked spheroplasts. The crosslinked spheroplasts maintain 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 squalene-hopene cyclases, but also to make biocatalytic processes even greener and more cost-efficient.

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      Membrane-based TBADT recovery as a strategy to increase the sustainability of continuous-flow photocatalytic HAT transformations

      • Zhenghui Wena
      • Diego Pintossia
      • Manuel Nuñob
      • Timothy Noëla
      • aFlow Chemistry Group, Van ‘t Hoff Institute for Molecular Sciences, Faculty of Science, University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands
      • bVapourtec Ltd., Park Farm Business Centre, Fornham St Genevieve, Bury St Edmunds, Suffolk, IP28 6TS, UK

      Photocatalytic hydrogen atom transfer (HAT) processes have been the object of numerous studies showcasing the potential of the homogeneous photocatalyst tetrabutylammonium decatungstate (TBADT) for the functionalization of C(sp3)–H bonds. However, to translate these studies into large-scale industrial processes, careful considerations of catalyst loading, cost, and removal are required. This work presents organic solvent nanofiltration (OSN) as an answer to reduce TBADT consumption, increase its turnover number and lower its concentration in the product solution, thus enabling large-scale photocatalytic HAT-based transformations. The operating parameters for a suitable membrane for TBADT recovery in acetonitrile were optimized. Continuous photocatalytic C(sp3)-H alkylation and amination reactions were carried out with in-line TBADT recovery via two OSN steps. Promisingly, the observed product yields for the reactions with in-line catalyst recycling are comparable to those of reactions performed with pristine TBADT, therefore highlighting that not only catalyst recovery (>99%, TON > 8400) is a possibility, but also that it does not happen at the expense of reaction performance.

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      Two-Step Continuous-Flow Synthesis of 6-Membered Cyclic Iodonium Salts via Anodic Oxidation

      • Julian Spils1
      • Thomas Wirth2
      • Boris J. Nachtsheim1
      • 1Institute for Organic and Analytical Chemistry, University of Bremen, Leobener Straße 7, 28359 Bremen 2School of Chemistry, Cardiff University, Park Place, Main Building, Cardiff CF10 3AT (UK)

      A multi-step continuous-flow procedure for the generation of six-membered diaryliodonium salts was developed. This is a significant improvement of existing batch methods with regard to scalability and atom economy. The method uses easily accessible benzyl acetates in Friedel-Crafts-like alkylations while a subsequent anodic oxidative cyclization directly generates the corresponding cyclic iodonium salts.

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      Development of a flow process for an easy and fast access to 2-pyrone derivatives

      • Grazia Isa C. Righettia
      • Francesca Tentoria
      • Elisabetta Brennaa
      • Cristian Gambarottia
      • aDepartment of Chemistry, Materials and Chemical Engineering “Giulio Natta”, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milano, Italy

      2-Pyrones are compounds widely present in nature and they represent interesting building blocks both in medicinal and synthetic chemistry. Due to their peculiar pharmacological activity and structure, they have attracted much attention during the last decades and several protocols for their synthesis have been developed. In this work we propose the synthesis of bio-sourced 2-pyrones, exploiting continuous-flow conditions for an easy, sustainable and fast access to these important molecules.

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      Intraligand Charge Transfer Enables Visible-Light-Mediated Nickel-Catalyzed Cross-Coupling Reactions

      • Cristian Cavedona,b, Sebastian Gisbertza,b,Susanne Reischauera,b, Sarah Voglc, Eric Sperlichd, John H. Burkee, Rachel F. Wallicke, Stefanie Schrottkef, Wei-Hsin Hsua, Lucia Anghileria,b, Yannik Pfeiferd, Noah Richtera, Christian Teutlofff, Henrike Müller-Werkmeisterd, Dario Cambiéa, Peter H. Seebergera,b, Josh Vura-Weise, Renske M. van der Veene,g, Arne Thomasc, Bartholomäus Piebera
      • 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
      • cDepartment of Chemistry, Functional Materials, Technische Universität Berlin, Hardenbergstraße 40, 10623 Berlin, Germany
      • dInstitute of Chemistry, University of Potsdam, Karl-Liebknecht-Strasse 24–25, 14476 Potsdam, Germany
      • eDepartment of Chemistry, University of Illinois Urbana-Champaign, Urbana, Illinois, 61801 USA
      • fDepartment of Physics, Freie Universität Berlin, Arnimallee 22, 14195 Berlin, Germany
      • gHelmholtz Zentrum Berlin für Materialien und Energie GmbH, Hahn-Meitner-Platz 1, 14109 Berlin, Germany

      We demonstrate that several visible-light-mediated carbon−heteroatom cross-coupling reactions can be carried out using a photoactive NiII precatalyst that forms in situ from a nickel salt and a bipyridine ligand decorated with two carbazole groups (Ni(Czbpy)Cl2). The activation of this precatalyst towards cross-coupling reactions follows a hitherto undisclosed mechanism that is different from previously reported light-responsive nickel complexes that undergo metal-to-ligand charge transfer. Theoretical and spectroscopic investigations revealed that irradiation of Ni(Czbpy)Cl2 with visible light causes an initial intraligand charge transfer event that triggers productive catalysis. Ligand polymerization affords a porous, recyclable organic polymer for heterogeneous nickel catalysis of cross-coupling reactions. The heterogeneous catalyst shows stable performance in a packed-bed flow reactor during a week of continuous operation.

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      A practical flow synthesis of 1,2,3-triazoles

      • Dawid Drelinkiewicza
      • Richard J. Whitbya
      • aSchool of Chemistry, Faculty of Engineering and Physical Sciences, The University of Southampton, Southampton, UK

      A robust and versatile protocol for synthesis of 1-monosubstituted and 1,4-disubstituted 1H-1,2,3-triazoles was established under continuous flow conditions using copper-on-charcoal as a heterogeneous catalyst. This methodology allowed for the synthesis of a diverse set of substituted 1,2,3-triazoles with good functional group tolerance and high yields. 2-Ynoic acids were also used as small-chain alkyne donors in a decarboxylation/cycloaddition cascade, allowing gaseous reagents to be bypassed, delivering desired triazoles in high yields. The developed methodology was used to synthesize an antiepileptic agent, rufinamide, which was obtained in 96% isolated yield.

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      A simple one-pot oxidation protocol for the synthesis of dehydrohedione from Hedione

      • James S. Sharleya, Guido Gambacortaa, Ana María Collado Pérezb, Estela Espinos Ferrib, Amadeo Fernandez Mirandab, Isabelle Fernández Fernándezb, Jorge Sanchez Quesadab, Ian R.Baxendalea
      • aDepartment of Chemistry, University of Durham, South Road, Durham, DH1 3LE, United Kingdom
      • bInternational Flavours & Fragrances Inc., Avda Felipe Klein 2, 12580, Benicarló, Castellón, Spain

      A new method for the oxidiation of Hedione 1 to dehydrohedione 2, a high value intermediate in the flavour and fragrance industry, has developed based upon one pot α-chlorination-elimination sequence which can be readily scaled. The spontaneous elimination of the α-chloro in methanol was unprecedented and has allowed for the oxidation, typically performed in multiple steps/reactions, to be carried out as a one-pot protocol. A continuous flow process for performing the reaction utilising sulfuryl chloride has also demonstrated allowing for steady, safe evolution of SO2 gas during the reaction.

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      Self-healing and polymer welding of soft and stiff epoxy thermosets via silanolates

      • Amelia A. Putnam-Neeba
      • Jordan M. Kaisera,b
      • Amber M. Hubbarda
      • Dayton P. Streeta
      • Matthew B. Dickersona
      • Dhriti Nepala
      • Luke A. Baldwina
      • aAir Force Research Laboratory, Wright Patterson Air Force Base, Dayton, OH, 45433, USA
      • bUES, Inc, Dayton, OH, 45432, USA

      Incorporating dynamic bonds into polymers enables static thermosets to be transformed into active materials, possessing the reprocessability of thermoplastics while maintaining the bulk properties of fully crosslinked networks. This new class of materials, termed covalent adaptable networks (CANs), has helped bridge the gap between traditional thermosets and thermoplastics. Here, epoxy-based adaptable networks were synthesized by combining a diepoxide monomer with an oligosiloxane prepolymer containing aminopropyl groups, which crosslink irreversibly, and silanolate end-groups, which participate in dynamic bonding. Two separate diepoxide crosslinkers were used to give a range of soft to stiff materials with a Young’s modulus varying from 12 MPa to 2.2 GPa. This study documents how the thermal and mechanical properties (e.g., glass transition temperature and modulus) are affected by compositional changes in these silanolate networks. Dynamic bonding also results in self-healing properties, offering the ability to repair structural polymers and composites. When combined with tunable mechanical properties, self-healing capabilities make these materials well-suited to be sustainable alternatives for many traditional thermosets. For example, we demonstrated the ability to weld a stiff epoxy thermoset to a dissimilar soft material, a feature traditional epoxies do not permit.

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      Multicomponent Direct Assembly of N-Heterospirocycles Facilitated by Visible-Light-Driven Photocatalysis

      • Oliver M. Griffithsa
      • Steven V. Leya
      • aYusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.

      N-heterospirocycles are interesting structural units found in both natural products and medicinal compounds but have relatively few reliable methods for their synthesis. Here, we enlist the photocatalytic generation of N-centered radicals to construct β-spirocyclic pyrrolidines from N-allylsulfonamides and alkenes. A variety of β-spirocyclic pyrrolidines have been constructed, including drug derivatives, in moderate to very good yields. Further derivatization of the products has also been demonstrated as has a viable scale-up procedure, making use of flow chemistry techniques.

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      Scalable synthesis of favipiravir via conventional and continuous flow chemistry

      • Thanat Tiyasakulchaia
      • Netnapa Charoensetakula
      • Thitiphong Khamkhenshorngphanuchb
      • Chawanee Thongpanchangaa
      • Onsiri Srikunc
      • Yongyuth Yuthavonga
      • Nitipol Srimongkolpithaka
      • aNational Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani, Thailand
      • bDepartment of General Education, Faculty of Science and Health Technology, Navamindradhiraj University, Bangkok, Thailand
      • cGovernment Pharmaceutical Organization (GPO), Bangkok, Thailand

      Decagram scale synthesis of favipiravir was performed in 9 steps using diethyl malonate as cheap starting material. Hydrogenation and bromination steps were achieved by employing a continuous flow reactor. The synthetic process provided a total of 16% yield and it is suitable for larger-scale synthesis and production.

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      Merging dual photoredox/cobalt catalysis and boronic acid (derivatives) activation for the Minisci reaction

      Serena Pillitteria, Prabhat Ranjanb, Gerardo M. Ojeda-Carraleroa,c, Laura Y. Vázquez Amayaa, Javier E. Alfonso-Ramosd, Erik V. Van der Eyckena,e, Upendra K. Sharmaa

      • aLaboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven (KU Leuven), Celestijnenlaan 200F, B-3001 Leuven, Belgium
      • bAachen Maastricht Institute for Biobased Materials (AMIBM), Maastricht University, Urmonderbaan 22, 6167 RD Geleen, The Netherlands
      • cDepartment of General and Inorganic Chemistry, Faculty of Chemistry, University of Havana, Zapata y G, Havana 10400, Cuba
      • dLaboratory of Computational and Theoretical Chemistry, Faculty of Chemistry, University of Havana, Zapata y G, Havana 10400, Cuba
      • ePeoples’ Friendship University of Russia (RUDN University), Miklukho-Maklaya street 6, 117198 Moscow, Russia

      The merger of open-shell and closed-shell organometallic chemistry steps has enabled multiple effective cross-coupling pathways. Here we report a visible-light promoted photoredox-cobalt catalyzed Minisci reaction of N-heteroarenes under mild and sustainable conditions, employing various boronic acids and derivatives as alkyl radical precursors. This study demonstrates the prominent ability of the Co co-catalyst to promote the oxidation step of the photocatalytic cycle following a reductive quenching pathway, thus avoiding the use of stoichiometric (inorganic) oxidants. This feature enables the straightforward application of photo-flow conditions, particularly attractive for an easy scale-up and to enhance the efficiency of the reaction (throughput: 0.78 mmol/h in flow vs 0.02 mmol/h in batch) Furthermore, the process is predominantly selective towards the C2-alkylation of quinolines, and a mechanistic rationale has been provided with both experimental and DFT calculation support. The developed protocol demonstrates broad applicability for the alkylation of different N-heteroarenes under suitable homogeneous conditions for a flow-compatible Minisci reaction.

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      The Merger of Benzophenone HAT Photocatalysis and Silyl Radical-Induced XAT Enables Both Nickel-Catalyzed Cross-Electrophile Coupling and 1,2-Dicarbofunctionalization of Olefins

      • Alberto Luridianaa, Daniele Mazzarellaa, Luca Capaldoa, Juan A. Rincónb, Pablo García-Losadab, Carlos Mateosb, Michael O. Frederickc, Manuel Nuñod, Wybren Jan Bumae and Timothy Noëla
      • aFlow Chemistry Group, Van’t Hoff Institute for Molecular Sciences (HIMS), University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands
      • bCentro de Investigación Lilly S.A., Avda. de la Industria 30, Alcobendas-Madrid 28108, Spain
      • cSmall Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, United States
      • dVapourtec Ltd. Park Farm Business Centre, Fornham St Genevieve, Bury St Edmunds, Suffolk IP28 6TS, U.K.
      • eMolecular Photonics, Van’t Hoff Institute for Molecular Sciences (HIMS), University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands

      A strategy for both cross-electrophile coupling and 1,2-dicarbofunctionalization of olefins has been developed. Carbon-centered radicals are generated from alkyl bromides by merging benzophenone hydrogen atom transfer (HAT) photocatalysis and silyl radical-induced halogen atom transfer (XAT) and are subsequently intercepted by a nickel catalyst to forge the targeted C(sp3)–C(sp2) and C(sp3)–C(sp3) bonds. The mild protocol is fast and scalable using flow technology, displays broad functional group tolerance, and is amenable to a wide variety of medicinally relevant moieties. Mechanistic investigations reveal that the ketone catalyst, upon photoexcitation, is responsible for the direct activation of the silicon-based XAT reagent (HAT-mediated XAT) that furnishes the targeted alkyl radical and is ultimately involved in the turnover of the nickel catalytic cycle.

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      Taming photocatalysis in flow: easy and speedy preparation of α-aminoamide derivatives

      • Ricardo I. Rodrígueza
      • Marina Sicignanoa
      • Montaña J. Garcíaa
      • Rodrigo G. Enríqueza
      • Silvia Cabrerab,c
      • José Alemána,c,d
      • aOrganic Chemistry Department, Science Faculty, Universidad Autónoma de Madrid, Madrid-28049, Spain
      • bInorganic Chemistry Department, Science Faculty, Universidad Autónoma de Madrid, Madrid-28049, Spain
      • cInstitute for Advanced Research in Chemical Sciences (IAdChem), Universidad Autónoma de Madrid, 28049 Madrid, Spain
      • dCenter for Innovation in Advanced Chemistry (ORFEO-CINQA), Universidad Autónoma de Madrid, Spain

      α-Aminoamides are reiterative molecular subunits in transcendental molecules, which bear attractive functionalities for (bio)synthetic purposes. Herein, their preparation by harnessing flow photocatalysis is described, which provides significant improvements over other catalytic methods in terms of efficiency while outperforming an analogous batch setup. A reaction time of five minutes, operational simplicity and absence of purification steps for the isolation of final products evidence an enhanced performance.

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      Synthesis of CTA and DNAN using flow chemistry

      • Ankit Kumar Mittala
      • Gaurav Prakasha
      • Pramod Pathaka
      • Debabrata Maitia
      • aIndian Institute of Technology Bombay, Department of Chemistry, Mumbai, INDIA

      This paper describes a flow chemistry approach for synthesising two high-energy molecules, cyanuric triazide (CTA) and 2,4-dinitroanisole (DNAN), and scaling them up to multi-gram scale using an automated flow reactor system. The flow chemistry approach offers high degree of safety and easy to scale compared to conventional syntheses. The development of two processes: a. CTA via azidation of cyanuric chloride; b. DNAN via methoxylation of 2,4-dinitrichlorobenzene (2,4-DNCB) on an automated commercially available flow reactor system is described. High yield (> 95%) was achieved in both the processes. Very short reaction times (30 seconds) were applied. The process parameters were optimized using the automated flow chemistry system. The optimized process was scaled to multi gram scale (> 30 g/hr). The method can be considered fit for the safe production of CTA and DNAN at multi gram scale in laboratory.

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      Flow synthesis of photocatalytic semiconductor–metal hybrid nanocrystals

      • Tal Cohena,b
      • Nir Waiskopfa,b
      • Adar Levia,b
      • David Stonea,b
      • Sergei Remennikb
      • Uri Banina,b
      • aThe Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
      • bThe Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Jerusalem 91904, Israel

      Semiconductor–metal hybrid nanostructures are promising materials for photocatalytic applications, providing high efficiencies compared to their composing counterparts. So far, the synthesis of such hybrid nanoparticles was limited to batch reactors, achieving tunability while demonstrating how each of the nanocrystals’ characteristics affects photocatalytic performances. Yet, new methodologies should be established to increase the synthetic yield while maintaining high control over the resulting structures. Herein, scalable advanced flow techniques are introduced, yielding ZnSe–metal hybrid nanoparticles either in a thermal growth or photo-induced growth regime. Firstly, thermal gold growth in the flow reactor is achieved with good control over the metal tip size and the nanoparticle morphology. We address the dependence of the reaction on temperature, the precursor to nanorod molar ratios, and additional parameters. Additionally, light-induced growth by the flow reactor is demonstrated for platinum clusters. The quality of the resulting hybrids is directly demonstrated by their functionality in photocatalytic hydrogen generation by water reduction, displaying enhanced activity compared to bare ZnSe nanorods. The fairly straightforward adaptation of such powerful flow-reaction techniques to scale-up photocatalytic hybrid nanoparticle syntheses takes them one step forwards towards the realization of their potential in real-life application scenarios.

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      Taylor-vortex membrane reactor for continuous gas-liquid reactions

      • Baldassarre Veneziaa
      • David C. Morrisb
      • Asterios Gavriilidisa
      • aDepartment of Chemical Engineering, University College London, Torrington Place, London, UK
      • bAutichem Ltd, Unit 4, Gatewarth Industrial Estate Barnard Street Warrington WA5 1DD

      A unique Taylor-vortex membrane reactor (TVMR) design for continuous gas-liquid reactions is presented in this work. The reactor consists of a cylindrical rotor inside a stationary concentric cylindrical vessel, and a flexible system of equispaced baffle rings surrounding the rotor. This restricts the annular cross section to a small gap between the baffles and the rotor, and divides the annulus into 18 mixing zones. The baffles support a 6 m long PFA tubular membrane that is woven around the rotor. At 4 mL/min inlet flowrate, the TVMR showed a plug-flow behaviour and outperformed the unbaffled reactor, having 5 – 12 times lower axial dispersion. The continuous aerobic oxidation of benzyl alcohol was performed for 7 h using the Pd(OAc)2/pyridine catalyst in toluene at 100 °C and 1.1 MPa oxygen pressure. A stable conversion of 30% was achieved with 85% benzaldehyde selectivity, and no pervaporation of organics into the gas phase.

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      Statistical optimization modeling of organic dye photodegradation process using slag nanocomposite

      • Kingsley Safoa
      • Hussien Nobya,b
      • Mitsuhara Matatoshic
      • Hiroshi Naraginoc
      • Ahmed H. El-Shazlya,d
      • aDepartment of Chemical and Petrochemicals Engineering, Egypt-Japan University of Science and Technology, New Borg Al-Arab City, Alexandria, Egypt
      • bMaterials Engineering and Design, Faculty of Energy Engineering, Aswan University, Aswan, Egypt
      • cInterdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1 Kasuga Kouen, Kasuga, Fukuoka, 816-8580, Japan
      • dDepartment of Chemical Engineering, Faculty of Engineering, Alexandria University, Alexandria, Egypt

      The photocatalytic activity of three solvothermal prepared steel slag nanocomposites, SSNP-10, SSNP-20, and SSNP-30, was tested in this work for methylene blue (MB) dye degradation. Using SSNP for the first time, the photocatalytic degradation of MB dye was optimized using Box–Behnken design (BBD) in a response surface approach. The influence of essential operating parameters was experimentally examined, modeled, and optimized. The analysis of variance (ANOVA) results revealed that the suggested quadratic models significantly agreed with the experimental investigation, with p-values less than 0.0001 and an R2 value of 0.9914. Accordingly, the optimized conditions were 32.83 mg catalyst dose, 11.42 pH, 41.34 min irradiation times, and 10.63 mg/L MB dye concentration. The optimized degradation efficiency of the MB dye was 89.43% under these conditions. The result was experimentally validated with the optimal operating parameters for SSNP-10, SSNP-20, and SSNP-30, and the photodegradation efficiencies were 90.07%, 88.94%, and 87.28%, respectively. A pseudo-first-order reaction kinetics of 0.0293, 0.0291, and 0.0267 was achieved for SSNP-10, SSNP-20, and SSNP-30 with a regression coefficient of 0.9514, 0.9312, and 0.9042, respectively. According to Pareto analysis, the operational factors that had the greatest effect on dye degradation efficiency were catalyst dosage (F-value 585.32) > MB concentration (F-value 423.89) > irradiation period (F-value 368.01) > pH (F-value 362.34). The results showed that the SSNP catalyst was the key parameter for the generation of hydroxyl radicals responsible for the photodegradation of MB dye and may be useful for other contaminants’ degradation.

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      4,7-Diarylbenzo[c][1,2,5]thiadiazoles as fluorophores and visible light organophotocatalysts

      • Dominic Taylora
      • Thomas Malcomsonb
      • Adilet Zhakeyevc
      • Shengxian Chengd
      • Georgina M. Rosaira
      • Jose Marques-Huesoc
      • Zhengtao Xue
      • Martin J. Patersona
      • Scott J. Dalgarnoa
      • Filipe Vilelaa
      • aInstitute of Chemical Sciences, School of Engineering and Physical Science, Heriot-Watt University, Riccarton, Edinburgh EH14 4AS, UK.
      • bDepartment of Chemistry, Lancaster University, Lancaster, LA1 4YB, UK
      • cInstitute of Sensors, Signals and Systems, School of Engineering and Physical Science, Heriot-Watt University, Riccarton, Edinburgh EH14 4AS, UK
      • dDepartment of Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong
      • eInstitute of Materials Research and Engineering (IMRE), Agency of Science, Technology and Research (A*STAR), 2 Fusionopolis Way, Innovis, Singapore 138634

      Electron donor–acceptor (D–A) systems based on the benzo[c][1,2,5]thiadiazole (BTZ) motif have been extensively researched for use in photovoltaics or as fluorescent sensors. However, their use as potential visible-light organophotocatalysts has not received any in-depth study. Here we report the synthesis, characterisation, and application of a library of 26 D–A compounds based on the BTZ group. By varying the donor groups whilst keeping the BTZ acceptor group the same, we have been able to systematically modify the photocatalyst’s optoelectronic and photophysical properties. These photocatalysts were then validated using a Minisci-type decarboxylative alkylation of electron deficient heteroarenes as a test reaction under both batch and continuous flow conditions.

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      Recent advances in chemical fixation of CO2 based on flow chemistry

      • Hui Luoa
      • Jing Rena
      • Ying Suna
      • Yunlin Liub
      • Feng Zhoua,c
      • Guoyue Shia
      • Jian Zhoua,d
      • aSchool of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China
      • bSchool of Chemistry and Chemical Engineering, Guangzhou University, Guangzhou, 510006, China
      • cInstitute of Eco-Chongming, Shanghai 202162, China
      • dState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. China

      Carbon dioxide (CO2) is an attractive C1 building block in chemical synthesis due to its abundance, availability and sustainability. However, the low reactivity and high stability generally limits its transformations under mild conditions to value added chemicals. Recent advances in flow chemistry provide effective means for the chemical transformation of CO2, and many new methods and techniques that fully utilized the advantages of continuous flow platforms for the chemical fixation of CO2 have been realized. In view of the rapid development and the urgent need for continuous transformation of CO2, herein we wish to present an update of the recent advances in this research area.

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      Kinetics and hydrodynamics of Candida antartica lipase-catalyzed synthesis of glycerol dioleate (GDO) in a continuous flow packed-bed millireactor

      • Nurul Nadiah Abd Razaka,b
      • Patrick Cognetb
      • Yolande Pérèsb
      • Lai Ti Gewa,e
      • aDepartment of Biological Sciences, School of Medical and Life Sciences, Sunway University, Petaling Jaya, Selangor, 47500, Malaysia
      • bLaboratoire de Génie Chimique, Université de Toulouse, CNRS, INPT, UPS, Toulouse, 31423, France
      • cCentre for Carbon Dioxide Capture and Utilization (CCDCU), School of Engineering and Technology, Sunway University, Petaling Jaya, Selangor, 47500, Malaysia
      • dDepartment of Engineering, Lancaster University, Lancaster, LA1 4YW, United Kingdom
      • eSunway Materials Smart Science & Engineering (SMS2E) Cluster, Sunway University, Petaling Jaya, Selangor, 47500, Malaysia

      Diacylglycerols (DAG) have been widely used in many industries due to their remarkable capabilities as emulsifiers and stabilisers. However, developing a sustainable and an effective synthesis method for DAG remains a challenge. Continuous flow bio-reactor is recognized to be more productive, controllable, and reliable instrument for developing green and intensified processes. In this work, a continuous flow packed bed millireactor was employed for the synthesis of glycerol dioelate (GDO) catalyzed by immobilized lipase namely Candida antartica. Experiments were carried out to evaluate the kinetic parameters as well as to assess the internal and external mass transfer limitations. Using one-factor-at-a-time variables method, maximum oleic acid conversion and GDO selectivity were achieved at 85% and 74% respectively, at 0.15 g of lipase, 77 min of residence time with 1.6:1 molar ratio of oleic acid/glycerol. Hydrodynamic studies showed that the esterification reaction is kinetically controlled and unaffected by external and internal mass transfer. Employing Lilly–Hornby model for kinetic evaluation, Km values increased with increasing flow rates, whereas, Vmax appeared to be flow rate independent. Reusability tests revealed that the activity of immobilized lipase remained the same after 9 successive reaction cycles. At 11 days of operation, the stability of the lipase in the continuous packed bed millireactor decreased only 5–7%, indicating satisfying operational results and recyclability. This work may promote the enzymatic engineering synthesis of DAG, facilitating the creation of a cleaner and safer process. It has the potential to broaden the application of enzymes in continuous flow micro or millireactors.

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      Microfluidic Asymmetrical Synthesis and Chiral Analysis

      • Konstantin A.Kochetkova
      • Nataliya A.Bystrovaa
      • Pavel A.Pavlovb
      • Maxim S.Oshchepkovb
      • Aleksandr S.Oshchepkovc
      • aNesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, ul. Vavilova 28, Moscow 119991, Russia
      • bMendeleev University of Chemical Technology of Russia, Miusskaya pl. 9, Moscow 125047, Russia
      • cMax Planck Institute for the Science of Light, Department of Physics, D-91058 Erlangen, Germany
      Graphical Abstract

      In recent years, more attention has been paid to efficient, cost-effective and energy-saving technologies. In particular, there is a lot of recent information on the advantages of microfluidic technologies, combining economy, safety and environmental friendliness with reproducibility, high yields and high stereoselectivity of chemical reactions. Therefore, an important task is to generalize the available material on microfluidic technologies in order to identify new horizons of application in the field of a chiral synthesis. The difficulties of implementation microfluidic a chiral synthesis, its capabilities and prospects for further development are discussed in detail in this review. Various types of microfluidic reactors, synthetic schemes for carrying out chemical reactions are considered, and their comparison with traditional methods of synthesis is also given. Finally, a description is given of enantioselective analysis using microfluidic technologies and the possibilities for further improvement of microfluidics are discussed.

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      Evaluation of unexpected protecting group removal in solid-phase peptide synthesis: Quantified using continuous flow methods

      • Victoire Laudea
      • Manuel Nuñoa
      • Roger C. Mosesa
      • Duncan Guthriea
      • aVapourtec Ltd, Bury Saint Edmunds, UK

      As peptides gained interest as new drugs in the past years, their synthetic routes had been the subject of review and improvement. Fmoc/tBu-based solid-phase peptide synthesis (SPPS) is the most convenient technique, and the implementation in continuous flow has allowed for single-pass coupling and deprotection reactions. The focus of this research is to evaluate the relationship between undesired solvent-promoted reactions and final crude purity, by studying volume changes of a variable bed flow reactor through the synthesis. Based on the temperature, typical solvents for SPPS such as dimethylformamide (DMF) or N-methyl-2-pyrrolidone (NMP) can cause unwanted Fmoc removal during wash steps. It was found that for every millilitre of DMF used at 80°C, up to 1 μmol of Fmoc-protected peptide is deprotected, leading to additional impurities. This effect can, however, be minimised by adding additives such as HOBt, which reduces such unwanted deprotection to just 0.1 μmol/ml.

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      Synthesis of Benzothiazinones from Benzoyl Thiocarbamates: Application to Clinical Candidates for Tuberculosis Treatment

      • William Connorsa
      • Ryan DeKortea
      • Simon C. C. Lucasb
      • Ariamala Gopalsamyb
      • Robert E Zieglera
      • aAstraZeneca Pharmaceuticals LP, Medicinal Chemistry, United States
      • bAstraZeneca Pharmaceuticals LP, Hit Discovery, United Kingdom

      Benzothiazinones are a structural motif found in biologically active compounds, such as the clinical candidates BTZ-043 and Macozinone for the treatment of tuberculosis. We describe a robust, two-step method to synthesize 2-amino-substituted benzothiazinones from benzoyl thiocarbamates, which were prepared in a one-pot procedure from benzoyl chlorides. The intramolecular cyclization and ethoxy displacement steps were also amenable to adoption in continuous flow as exemplified by select substrates.

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      Synthesis of new heterocyclic resveratrol analogues in milli- and microreactors: intensification of the Wittig reaction

      • Milena Mlakića, Lucija Rajiča,b, Anabela Ljubićb, Vitomir Vušakb, Bruno Zelićc,d, Martin Gojunc, Ilijana Odake, Ivona Čulee, Ivana Šagudb, Anita Šalićc, Irena Škorića
      • aDepartment of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10 000, Zagreb, Croatia
      • bPliva R&D, Teva Pharmaceutical Industries Ltd, Prilaz baruna Filipovića 29, HR-10 000, Zagreb, Croatia
      • cDepartment of Reaction Engineering and Catalysis, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10 000, Zagreb, Croatia
      • dDepartment of Packaging, Recycling and Environmental Protection, University North, Trg dr. Žarka Dolinara 1, HR-48 000, Koprivnica, Croatia
      • eDepartment of Chemistry, Faculty of Science and Education, University of Mostar, Matice hrvatske bb, 88 000, Mostar, Bosnia and Herzegovina

      Resveratrol is a natural bioactive non-flavonoid polyphenol that protects from cardiovascular disease, neurodegenerative diseases and various cancers. Unfortunately, the amounts of resveratrol in plants are low and therefore, chemical synthesis is still the main way to obtain this valuable structure. In this work, Wittig reaction was chosen as the synthetic route for the study on technology influence in batch vs. micro- or milliflow reactors during the production of new resveratrol-like compounds. A series of reactions was carried out by batch synthesis, and intensified in a milli- and a microreactor, changing the reaction conditions to increase the efficiency and productivity of the process. Results were compared based on conversion, yield, productivity and trans/cis ratio. Similar yields and conversions were obtained in all reaction systems, but in much shorter time in the milli- and microscale compared to the batch reactor. On the other hand, higher productivities were obtained in the millireactor and microreactor, making them better systems for the proposed reactions of new heterocyclic resveratrol analogues synthesis.

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      Multistep Continuous Flow Synthesis of Isolable NH2‐Sulfinamidines via Nucleophilic Addition to Transient Sulfurdiimide

      • Michael Andresinia
      • Sebastien Carretb
      • Leonardo Degennaroa
      • Fulvio Ciriacoa
      • Jean-François Poissonb
      • Renzo Luisia
      • aUniversity of Bari: Universita degli Studi di Bari Aldo Moro, Pharmacy - Drug Sciences, Via E. Orabona,4, 70125 Bari, ITALY
      • bUniversite Grenoble Alpes, Chemistry, rue de la chimie, 38000 Grenoble, FRANCE

      The growing interest in novel sulfur pharmacophores led to recent advances in the synthesis of some S(IV) and S(VI) motifs. However, preparation and isolation of uncommon primary sulfinamidines, the aza-analogues of sulfinamides, is highly desirable. Here we report a multistep continuous flow synthesis of poorly explored NH 2 -sulfinamidines by nucleophilic attack of organometallic reagents to in situ prepared N -(trimethylsilyl)- N -trityl-λ 4 -sulfanediimine (Tr-N=S=N-TMS). The transformation can additionally be realized under mild conditions, at room temperature, via a highly chemoselective halogen-lithium exchange of aryl bromides and iodides with n -butyllithium. Moreover, the synthetic potential of the methodology was assessed exploring further manipulations of the products and accessing novel S(IV) analogues of celecoxib, tasisulam, and relevant sulfinimidoylureas.

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      A multi-step continuous flow synthesis of pomalidomide

      • Maria Ivanovaa
      • Julien Legrosa
      • Thomas Poissona,b
      • Philippe Jubaulta
      • aNormandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA, 76000, Rouen, France
      • bInstitut Universitaire de France, Paris, France

      The immunomodulatory drugs (IMiDs) thalidomide, pomalidomide, and lenalidomide are widely used to treat multiple myeloma. The permanent need of IMiDs analogues in clinical screening and practice has created the demand to find a reliable and robust method for their preparation. To reach this goal, the use of flow chemistry is quite appealing, allowing a safe operation, an excellent reproducibility and an efficient process. Herein, we describe a continuous 3–4 step flow approach for the synthesis of the pomalidomide (38–47% overall yield) and a few analogues.

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      Continuous Flow Preparation of Benzylic Sodium Organometallics

      • Johannes H. Harenberga
      • Dr. Rajasekar Reddy Annapureddya
      • Prof. Dr. Konstantin Karaghiosoffa
      • Prof. Dr. Paul Knochela
      • aDepartment Chemie, Ludwig-Maximilians-Universität München, Butenandtstraße 5–13, Haus F, 81377 München, Germany

      We report a lateral sodiation of alkyl(hetero)arenes using on-demand generated hexane-soluble (2-ethylhexyl)sodium (1) in the presence of TMEDA. (2-Ethylhexyl)sodium (1) is prepared via a sodium packed-bed reactor and used for metalations at ambient temperature in batch as well as in continuous flow. The resulting benzylic sodium species are subsequently trapped with various electrophiles including carbonyl compounds, epoxides, oxetane, allyl/benzyl chlorides, alkyl halides and alkyl tosylates. Wurtz-type couplings with secondary alkyl halides and tosylates proceed under complete inversion of stereochemistry. Furthermore, the utility of this lateral sodiation is demonstrated in the synthesis of pharmaceutical relevant compounds. Thus, fingolimod is prepared from p-xylene applying the lateral sodiation twice. In addition, 7-fold isotopically labeled salmeterol-d7 and fenpiprane as well as precursors to super linear alkylbenzene (SLAB) surfactants are prepared.

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      Flow Chemistry Opportunities for Drug Discovery

      • María Lourdes Linaresa
      • Enol Lópezb
      • Eduardo Palaoa
      • Jesús Alcázara
      • aJanssen Research and Development, Janssen-Cilag, S.A., Discovery Chemistry, C/ Jarama, 75, 45007 Toledo Spain
      • bUniversidad de Castilla-La Mancha, Facultad de Ciencias y Tecnologías Químicas, Av. Camilo José Cela, 14, 13005 Ciudad Real Spain

      This chapter provides an overview on how flow chemistry can be integrated in the drug discovery process, going beyond traditional transformations applied in the Pharma sector and accessing novel chemical space. Its combination with photochemistry and electrochemistry is allowing the development of new reactivities to access complex molecules in a more efficient way. Integration of flow chemistry in automated platforms will enhance its productivity and reduce cycle times in drug discovery.

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      Innovative Process Development of Pharmaceutical Intermediates Under Continuous-Flow System

      • Koji Machidaa
      • Hiroaki Yasukouchia
      • aPharma & Supplemental Nutrition Solutions Vehicle, Kaneka Corporation, Pharma Business Division Research Group, 1-8 Miyamae-cho, Takasago-cho, Takasago, Hyogo, 676-8688 Japan

      Continuous-flow processing has many advantages over conventional batch processing, including high process safety, productivity, and scalability. This emerging technology expands the possibility of synthetic chemistry into new areas. Recently, many researchers in pharmaceutical companies have increasingly tried to apply continuous-flow methodologies to their manufacturing process. Here, we introduce a safe and efficient plug flow reactor system for hazardous reactions and a simple and practical packed-bed reactor system for catalytic reactions by taking advantage of flow technology. Our flow systems showed that they apply to the synthesis of various pharmaceutical intermediates in good to excellent yields and are readily scaled up while increasing the process safety and efficiency. Furthermore, we designed and installed commercial flow reactors and successfully implemented large-scale productions using the facilities under GMP condition.

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      Flow Chemistry in Medicinal Chemistry: Applications to Bcr – Abl Kinase Inhibitors

      • Paul Richardsona
      • aPfizer-La Jolla, Medicine Design, 10770 Science Center Drive, La Jolla, CA, 92121 USA

      There continues to be an exponential growth in continuous/flow chemistry throughout the pharmaceutical industry with the advantages of this technology being well appreciated. While the ability to utilize such an approach to seamlessly scale a compound through development is often highlighted, the need to move rapidly in the discovery phase can be a barrier to investment in flow in medicinal chemistry laboratories. In addition, challenges exist most notably with heterogeneous reactions (insolubility of products) as well as with executing reactions prevalent in drug discovery most notably Pd-mediated cross-couplings. The current review highlights several case studies focusing on the application of flow chemistry technologies to the synthesis/discovery of inhibitors of Bcr-Abl kinase (such as imatinib, nilotinib, and ponatinib) and, through these, showcases a number of solutions/strategies to how these problems can be overcome.

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      Flow Chemistry at the Extremes: Turning Complex Reactions into Scalable Processes

      • Andrew R. Bogdana
      • aAbbVie, Inc., Drug Discovery Science and Technology, 1 North Waukegan Rd, North Chicago, IL, 60064 USA

      The field of flow chemistry has expanded over the past number of years and is now being routinely used by the pharmaceutical industry in the manufacturing of active pharmaceutical ingredients (APIs). Specifically, flow chemistry is being used to convert precarious batch processes into high-throughput flow processes. A few common themes emerge when analyzing the literature, specifically the use of temperature extremes as well as the generation/use of hazardous reagents. Advances in photochemistry have also permitted ultraviolet and visible light-mediated processes to be reproducibly run on scale. Applications of the aforementioned processes are discussed herein, with specific attention being paid to scalability.

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      Application of Continuous-Flow Processing in Multistep API and Drug Syntheses

      • Faith M. Akwia
      • Paul Wattsa
      • aNelson Mandela University, Faculty of Science, Department of Chemistry, University Way, Port Elizabeth, 6031 South Africa

      The use of flexible and cost-effective manufacturing technologies for the production of active pharmaceutical intermediates (APIs) is one major pathway toward solving drug shortage and inaccessibility, which is a multifaceted global issue. With the introduction of enabling technologies such as continuous-flow processing to the pharmaceutical industry, some of the bottlenecks attributed to API manufacturing that are contributing toward drug shortage and access can easily be mitigated. To demonstrate, most recent routes toward the continuous-flow synthesis of 20 APIs, of which more than 50% are on the World Health Organization’s 2018 list of essential medicines, are discussed herein. This chapter aims at highlighting the potential of continuous-flow processing as a viable technology for the efficient and sustainable manufacture of APIs to counteract drug shortage and inaccessibility in order to promote the engagement of relevant stakeholders to facilitate capacity building for local production of essential medicines in affected populations mostly situated in developing economies.

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      Heterogeneous metallaphotoredox catalysis in a continuous-flow packed bed reactor

      • Wei-Hsin Hsua,b
      • Susanne Reischauera,b
      • Peter H Seebergera,b
      • Bartholomäus Piebera
      • Dario Cambiéa
      • aMax Planck Institute of Colloids and Interfaces, Biomolecular Systems Department, Am Mühlenberg 1, 14476 Potsdam, Germany
      • bFreie Universität Berlin, Institute for Chemistry and Biochemistry, Arnimallee 22, 14195 Berlin, Germany

      Metallaphotoredox catalysis is a powerful and versatile synthetic platform that enables cross-couplings under mild conditions without the need for noble metals. Its growing adoption in drug discovery has translated into an increased interest in sustainable and scalable reaction conditions. Here, we report a continuous flow approach to metallaphotoredox catalysis using a heterogeneous catalyst that combines the function of a photo- and a nickel catalyst in a single material. The catalyst is embedded in a packed bed reactor to combine reaction and (catalyst) separation in one step. The use of a packed bed simplifies the translation of optimized batch reaction conditions to continuous flow, as the only components presents in the reaction mixture are the substrate and a base. Using the cross-coupling of sulfinates with aryl halides as a model system, a productivity of 4 mmol/h was achieved. The catalyst was shown to be stable, with a very low decrease of the yield (~1% per day) during a continuous experiment over seven days, and to be effective for C–O arylations when carboxylic acids are used as nucleophile instead of sulfinates.

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      An Overview on the Production of Biodiesel Enabled by Continuous Flow Methodologies

      • Claudia Carluccia
      • aCNR-Institute of Nanotechnology (CNR-NANOTEC), c/o Campus Ecotekne, Via Monteroni, 73100 Lecce, Italy

      Biodiesel was produced via transesterification reaction catalyzed by acids, bases, enzymes or supercritical fluids. The catalysis was homogeneous or heterogeneous and the process could be carried out in batch or using a continuous flow process. Microreactors allowed us to obtain better control of the experimental variables, such as temperature, pressure and flow rate, carrying out the reactions in safe conditions, avoiding exothermic and dangerous processes. The synthetic methodologies in continuous flow, combined with other technologies as microwave irradiation or ultrasounds, led to complete automation of the process with an increase in efficiency, also applicable on an industrial scale.

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      Continuous flow synthesis of azobenzenes via Baeyer–Mills reaction

      • Jan H. Griwatza,b
      • Anne Kunza,b
      • Hermann A. Wegnera,b
      • aInstitute of Organic Chemistry, Justus Liebig University, Heinrich-Buff-Ring 17, 35392 Giessen, Germany
      • bCenter for Material Research (ZfM/LaMa), Justus Liebig University, Heinrich-Buff-Ring 16, 35392 Giessen, Germany

      Azobenzene, as one of the most prominent molecular switches, is featured in many applications ranging from photopharmacology to information or energy storage. In order to easily and reproducibly synthesize non-symmetric substituted azobenzenes in an efficient way, especially on a large scale, the commonly used Baeyer–Mills coupling reaction was adopted to a continuous flow setup. The versatility was demonstrated with a scope of 20 substances and the scalability of this method exemplified by the synthesis of >70 g of an azobenzene derivative applied in molecular solar thermal storage (MOST) systems.

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      Synthesis of 2,4,6-Trisubstituted Pyrimidines via Iron-Catalyzed Homocoupling of α,β-Unsaturated Ketoximes

      • Kai Guoa
      • Gaochen Xua
      • Xuemei Wanga
      • Chenglong Jiaa
      • Huan Yana
      • Sai Zhanga
      • Qinghuan Wua
      • Ning Zhua
      • Zheng Fanga
      • Jindian Duana
      • aCollege of Biotechnology and Pharmaceutical Engineering, State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University,30 Puzhu Rd S., Nanjing 211816, China

      A FeCl2-catalyzed homocoupling of α,β-unsaturated ketoximes in batch and flow is reported. This protocol demonstrates broad substrate scope and functional group tolerance, providing an alternate route toward the synthesis of 2,4,6-trisubstituted pyrimidines under mild conditions. Also a gram-scale reaction has been performed to evaluate the applicability of this method.

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      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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      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 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, and efficient 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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      Photocatalytic Approach to α,α-Difluoroalkyl Alcohols

      • Georgii Kachkovskyia
      • Marcin Cieślaka
      • Piotr Graczyka
      • Przemysław Zawadzkia
      • Justyna Kalinowska-Tłuścikb
      • Mateusz Werłosa,b
      • aSelvita SA., Bobrzyńskiego 14, 30-348 Kraków, Poland
      • bFaculty of Chemistry Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland

      A convenient approach to previously poorly accessible α,α-difluoroalkyl alcohols by visible light-mediated photocatalysis was developed. Broad scope of the transformation together with experimental simplicity and scalability using flow techniques open good prospects for further studies of properties (including biological) of these novel products.

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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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      An electrochemical γ-C–H arylation of amines in continuous flow

      • José A.Fornia
      • Milena L.Czyza
      • David W.Luptonb
      • Anastasios Polyzosa,c
      • aSchool of Chemistry, The University of Melbourne, Parkville 3010, Victoria, Australia
      • bSchool of Chemistry, Monash University, Clayton 3800, Victoria, Australia
      • cCSIRO Manufacturing, Research Way, Clayton VIC 3168, Australia

      Reported here is a regioselective C(sp3)–C(sp2) cross coupling reaction between inert γ-C(sp3)–H bonds in aliphatic amines and cyanoarenes under electrochemical conditions in flow. The developed methodology takes advantage of a removable redox active auxiliary, which triggers selective 1,7-hydrogen atom transfer to functionalise an aliphatic C–H bond at the γ-position of an alkyl amine. In this reaction, a cyanoarene radical anion functions as both a selective arylating reagent and a redox active mediator, enabling the controlled one electron reduction of the redox active auxiliary. This strategy offers a new approach towards γ-C(sp3)–H bond functionalisation allowing generation of, amongst others, sterically crowded carbon centres under mild reaction conditions and in the absence of additional catalysts or radical initiators.

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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. Soutoa
      • aDepartamento 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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      Optimizing the Performance of the Meso-Scale Continuous-Flow Photoreactor for Efficient Photocatalytic CO2 Reduction with Water Over Pt/TiO2/RGO Composites

      • Samar Nabila
      • Elsayed A. Shalabya
      • Marwa F. Elkadyb,c
      • Yoshihisa Matsushitad
      • Ahmed H. El-Shazlyb,e
      • aDepartment of Environmental Studies, Institute of Graduate Studies and Research, Alexandria University, Alexandria, 21526, Egypt
      • bChemical and Petrochemicals Engineering Department, Egypt-Japan University of Science and Technology, Alexandria, 21934, Egypt
      • cFabrication Technology Department, Advanced Technology and New Materials Research Institute (ATNMRI), City of Scientific Research and Technological Applications, Alexandria, Egypt
      • dEgypt-Japan University of Science and Technology, 179 New Borg El‐Arab, Alexandria, 21934, Egypt
      • eChemical Engineering Department, Faculty of Engineering, Alexandria University, Alexandria, 21544, Egypt

      Tuning the reaction parameters to maximize products yield is one of the major needs for any process. The goal of this research is to increase the reduction of CO2 with water by examining the operating parameters of a meso-scale continuous-flow type photochemical reactor over hydrothermally synthesized photocatalysts such as Pt/TiO2 and Pt/TiO2/RGO. Effects of catalyst type, weight of catalyst utilized, photochemical reactor temperature, retention time by variating the liquid water flow rate, and cocatalyst loading were investigated to increase the concentration of total organic carbon compounds including HCHO and CH3OH. The effect of titanium dioxide phase ratio (anatase: rutile) presence at the Pt/TiO2/RGO photocatalysts was also studied. The results revealed that the 0.3 wt.% Pt/TiO2/RGO5% photocatalyst which includes a phase ratio of 81:19 for anatase: rutile respectively has the superior photocatalytic activity to other studied photocatalysts. The physciochemical properties of different prepared photocatalytic samples were determined using various characterization techniques. Analyzing the liquid products on gas chromatography, it was found that CH3OH represents the major product whereas HCHO was the minor one. This reactor exhibits a great performance towards CO2 photocatalytic reduction under the optimized conditions.

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      From Platform to Knowledge Graph: Evolution of Laboratory Automation

      • Jiaru Baia
      • Liwei Caoa
      • Sebastian Mosbacha,b
      • Jethro Akroyda,b
      • aDepartment of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge CB3 0AS, United Kingdom
      • bCambridge Centre for Advanced Research and Education in Singapore (CARES), CREATE Tower #05-05, 1 Create Way, 138602 Singapore
      • cCambridge Centre for Advanced Research and Education in Singapore (CARES), CREATE Tower #05-05, 1 Create Way, 138602 Singapore
      • dThe 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 toward 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 standardized communication protocols are indispensable. In this perspective, we recategorize 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 hypothesize 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 the laboratory.

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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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      Automated Synthesis of Chondroitin Sulfate Oligosaccharides

      • Chien-Fu Lianga
      • Heung Sik Hahma,b
      • Narayana Murthy Sabbavarapu
      • Peter H. Seeberger
      • aDepartment of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany
      • bDepartment of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany

      Glycosaminoglycans (GAGs) are important sulfated carbohydrates prevalently found in the extracellular matrix that serve many biological functions. The synthesis of structurally diverse but defined GAGs is extremely challenging as one has to account for the various sulfation patterns. Described is the automated synthesis of chondroitin sulfate hexasaccharides on a solid support equipped with a photolabile linker. The linker cleavage from the resin is performed in a continuous-flow photoreactor under chemically mild conditions. This approach serves as a general scheme to access oligosaccharides of all GAG families.

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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 Duffya
      • Mara Di Filippoa
      • Marcus Baumanna
      • aUniversity 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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      Lithium aluminum hydride in flow: overcoming exotherms, solids, and gas evolution en route to chemoselective reductions

      Aliakbar Mohammadzadeha, Sepideh Sharifa, Volodymyr Semeniuchenkoa, Norman Townsendb, Andrew D. Corbettb, Michael G. Organa

      • aFlow Chemistry Core Facility, Centre for Catalysis Research and Innovation (CCRI)Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON, K1N 6N5, Canada
      • bToronto Research Chemicals, a Subsidiary of LGC, 20 Martin Ross Avenue, Toronto, ON, M3J 2K8, Canada

      A reactor has been designed specifically to conduct lithium aluminum hydride reductions in flow. The reactor readily accommodates strong hydrogen gas evolution and allows strict control over the combination of starting material and reductant, the reaction itself, and quenching, all of which are conducted within the confines of the reactor leading to a safe process.

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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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      Modular allylation of C(sp3)−H bonds by combining decatungstate photocatalysis and HWE olefination in flow

      • Luca Capaldo1
      • Stefano Bonciolini1
      • Antonio Pulcinella1
      • Manuel Nuño2
      • Timothy Noël1
      • 1 Flow Chemistry Group, van ’t Hoff Institute for Molecular Sciences (HIMS), University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands
      • 2Vapourtec Ltd., Park Farm Business Centre, Fornham St Genevieve, Bury St Edmunds, Suffolk IP28 6TS, United Kingdom

      The late-stage introduction of allyl groups provides an opportunity to synthetic organic chemists for subsequent diversification, providing rapid access to new chemical space. Here, we report the development of a modular synthetic sequence for the allylation of strong aliphatic C(sp3)–H bonds. Our sequence features the merger of two distinct steps to accomplish this goal, including a photocatalytic Hydrogen Atom Transfer and an ensuing Horner-Wadsworth-Emmons reaction. This practical protocol enables the modular and scalable allylation of valuable building blocks and medicinally relevant molecules.

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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: [email protected]
      • 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: [email protected]
      • *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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