Multistep synthesis

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

Nopphon Weeranoppanant^{1, 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

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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.

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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-Rentsch^1,2, 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

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Definitive screening designs for multistep kinetic models in flow

Christopher A. Hone^a, Alistair Boyd^b, Anne O’Kearney-McMullan^b, Richard A. Bourne^a*, Frans L. Muller^a*

• ^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

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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

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

N. Perrer Tosso, Bimbisar K. Desai, Eliseu De Oliveira, Juekun Wen, John Tomlin, and B. Frank Gupton*

• Department of Chemistry and Department of Chemical and Life Science Engineering, Virginia Commonwealth University, 601 West Main Street, Richmond, Virginia 23220, United States

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A Continuous Flow Strategy for the Facile Synthesis and Elaboration of Semi‐Saturated Heterobicyclic Fragments

Nicola Luise, Eleanor Wyatt, Gary Tarver, Paul Graham Wyatt

• University of Dundee, School of Life Sciences, DD1 5EH Dundee, UNITED KINGDOM

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Using Carbon Dioxide as a Building Block in Continuous Flow Synthesis

Hyowon Seo, Long V. Nguyen, Timothy F. Jamison

• Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts

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A Convergent Continuous Multistep Process for the Preparation of C4-Oxime-Substituted Thiazoles

Edouard Godineau ^*†, Claudio Battilocchio ^†‡, Matthias Lehmann ^†, Steven V. Ley ^†, Ricardo Labes ^‡, Letitia Birnoschi ^‡, Srinivas Subramanian ^§, C.S Prasanna ^§ , Amol Gorde ^§, Mahesh Kalbagh ^§, Vivek Khade ^§, Anton Scherrer ^†, Anthony C. O’Sullivan ^†

• ^† Syngenta Crop Protection, Process Research, Schaffhauserstrasse 101, CH-4332, Switzerland
• ^‡ Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, UK
• ^§ Syngenta Research and Technology Centre, Santa Monica Works, Corlim, Goa India, 403110

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Multistep Continuous-Flow Processes for the Preparation of Heterocyclic Active Pharmaceutical Ingredients

Romaric Gérardy, Jean-Christophe M. Monbaliu

• Center for Integrated Technology and Organic Synthesis, Department of Chemistry, University of Liège, Liège, Belgium

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A combination of flow and batch mode processes for the efficient preparation of mGlu2/3 receptor negative allosteric modulators (NAMs)

Raveendra Panickar Dhanya, Ananda Herath, Douglas J. Sheffler, Nicholas D.P. Cosford

• Cancer Metabolism and Signaling Networks Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA

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A concise flow synthesis of indole-3-carboxylic ester and its derivatisation to an auxin mimic

Marcus Baumann, Ian R. Baxendale and Fabien Deplante

• Department of Chemistry, University of Durham, South Road, Durham, Durham, DH1 3LE, UK

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Sustainable flow synthesis of a versatile cyclopentenone building block

Marcus Baumann^†, Ian R. Baxendale^†, Paolo Filipponi^‡, Te Hu^†

• ^† Department of Chemistry, University of Durham, South Road, DH1 3LE Durham, U.K
• ^‡ Novartis Pharma AG, Fabrikstrasse 14, 4002 Basel, Switzerland

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Telescoped continuous flow generation of a library of highly substituted 3-thio-1,2,4-triazoles.

Mariana C. F. C. B. Damião^a, Renan Galaverna^a, Alan P. Kozikowski^b, James Eubanks^c, Julio C. Pastre^a

• ^a Institute of Chemistry, University of Campinas - UNICAMP, PO Box 6154 - Zip Code 13083-970, Campinas, SP, Brazil
• ^b StarWise Therapeutics LLC - University Research Park – Zip Code 53719-1235, Madison, Wisconsin, USA
• ^c Division of Genetics and Development - Krembil Research Institute – Zip Code M5T 2S8, Toronto, Ontario, Canada

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Continuous preparation and use of dibromoformaldoxime as a reactive intermediate for the synthesis of 3- bromoisoxazolines

Claudio Battilocchio^a*, Francesco Bosica^a, Sam M. Rowe^a, Bruna L. Abreu^a, Edouard Godineau^b*, Matthias Lehmann^b, Steven V. Ley^a

• ^a Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
• ^b Syngenta Crop Protection AG, Crop Protection Research, Schaffhauserstrasse 101, CH-4332 Stein, Switzerland

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Flow assisted synthesis: a key fragment of SR 142948A

Matthew Oliver Kitching, Olivia E Dixon, Marcus Baumann, Ian Richard Baxendale

• University of Durham, Chemistry, Durham, UK

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Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

Chinmay A. Shukla^1,2, Amol A. Kulkarni^1,2

• ¹ Academy of Scientific and Innovative Research (AcSIR), CSIR-National Chemical Laboratory (NCL) Campus, Pune 411008, India
• ² Chem. Eng. & Proc. Dev. Div., CSIR-National Chemical Laboratory, Dr. Homi Bhaba Road, Pashan, Pune 411008, India

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Continuous-flow synthesis of highly functionalized imidazo-oxadiazoles facilitated by microfluidic extraction

Ananda Herath, Nicholas D. P. Cosford

• Cancer Metabolism & Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA

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Photodecarboxylations in an advanced meso-scale continuous flow photoreactor

Sam Josland¹, Saira Mumtaz², Michael Oelgemöller^{2 *}

• ¹ University of Southampton, Department of Chemistry, University Road, Southampton, SO17 1BJ, United Kingdom
• ² James Cook University, College of Science, Technology and Engineering, Townsville, QLD 4811, Australia

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A Short Multi-step Flow Synthesis of a Potential Spirocyclic Fragrance Component

Ian R. Baxendale*

• Department of Chemistry, University of Durham, South Road, Durham, DH1 3LE, UK

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The development of a short route to the API ropinirole hydrochloride

Zeshan Yousuf^a, Andrew K. Richards^b, Andrew N. Dwyer^c, Bruno Linclau^a, David C. Harrowven^{* a}

• ^a Chemistry, University of Southampton, Highfield, Southampton, UK
• ^b GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, UK
• ^c Formally at GlaxoSmithKline Innovation and Sustainable Manufacturing COE, Worthing, UK

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Chemical Assembly Systems: Layered Control for Divergent, Continuous, Multistep Syntheses of Active Pharmaceutical Ingredients

Dr. Diego Ghislieri, Dr. Kerry Gilmore, Prof. Dr. Peter H. Seeberger^*

• Department of Biomolecular Systems, Max-Planck Institute for Colloids and Interfaces, Universität Berlin, Germany

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A Concise Flow Synthesis of Efavirenz

Dr. Camille A. Correia¹, Dr. Kerry Gilmore¹, Prof. Dr. D. Tyler McQuade³, Prof. Dr. Peter H. Seeberger^{1 2 *}

• ¹ Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam (Germany)
• ² Institute for Chemistry and Biochemistry, Freie Universität Berlin, Arnimallee 22, 14195 Berlin (Germany)
• ³ Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306 (USA)

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Flow synthesis of organic azides and the multistep synthesis of imines and amines using a new monolithic triphenylphosphine reagent

Catherine J. Smith, Christopher D. Smith, Nikzad Nikbin, Steven V. Ley, Ian R. Baxendale

• Innovative Technology Centre, Cambridge, UK

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Multistep Flow Synthesis of 5-Amino-2-aryl-2H-[1,2,3]-triazole-4-carbonitriles

YDr. Jérôme Jacq, Dr. Patrick Pasau^*

• UCB Biopharma, Avenue de l'Industrie, 1420 Braine l'Alleud (Belgium)

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Continuous Flow Synthesis of Thieno[2,3-c]isoquinolin-5(4H)-one Scaffold: A Valuable Source of PARP-1 Inhibitors

Paolo Filipponi^†, Carmine Ostacolo^‡, Ettore Novellino^‡, Roberto Pellicciari^†§, Antimo Gioiello^*†

• ^†Dipartimento di Scienze Farmaceutiche, Università di Perugia, Via del Liceo 1, I-06123 Perugia, Italy
• ^‡Dipartimento di Farmacia, Università degli Studi di Napoli Federico II, Napoli, Italy §TES Pharma S.r.l., Corciano (Perugia), Italy

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Integration of enabling methods for the automated flow preparation of piperazine-2-carboxamide

Richard J. Ingham¹, Claudio Battilocchio¹, Joel M. Hawkins², Steven V. Ley¹

• ¹ Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK
• ² Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA

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Applying Flow Chemistry: Methods, Materials, and Multistep Synthesis

D. Tyler McQuade^{1 3}, Peter H. Seeberger^{1 2}

• ¹ Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces
• ² Institute for Chemistry and Biochemistry, Freie Universität Berlin,
• ³ Department of Chemistry and Biochemistry, Florida State University

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Synthesis of RAFT Block Copolymers in a Multi-Stage Continuous Flow Process Inside a Tubular Reactor

Christian H. Hornung, Xuan Nguyen, Stella Kyi, John Chiefari, Simon Saubern

• CSIRO Materials Science & Engineering, Victoria, Australia.

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An expeditious synthesis of imatinib and analogues utilising flow chemistry methods

Mark D Hopkin, Ian Baxendale, Steven.V.Ley

• Dept of Chemistry, University of Cambridge, UK

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A Multi-Step Continuous Flow Process for the N-Demethylation of Alkaloids

Yuji Nakano¹, G. Paul Savage¹, Simon Saubern¹, Peter J. Scammells², Anastasios Polyzos¹

• ¹ CSIRO Materials Science and Engineering, Victoria, Australia.
• ² Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia.

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A Two-Stage Continuous-Flow Synthesis of Spirooxazine Photochromic Dyes

Mark York¹²³, Adriana Edenharter¹

• ¹CSIRO Materials Science and Engineering, Clayton, Vic. 3169, Australia.
• ²Cooperative Research Centre for Polymers, Notting Hill, Vic. 3168, Australia.
• ³Advanced Polymerik Pty Ltd, Notting Hill, Vic. 3168, Australia.

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Synthesis of an H3 Antagonist via Sequential One-Pot Additions of a Magnesium Ate Complex and an Amine to a 1,4-Ketoester followed by Carbonyl-Directed Fluoride Addition

Joel M. Hawkins, Pascal Dubé, Mark T. Maloney, Lulin Wei. Marcus Ewing, Stephen M. Chesnut, Joshua R. Denette, Brett M. Lillie, Rajappa Vaidyanathan

• Pharmaceutical Sciences, Pfizer Inc., Groton, USA

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Scale-Up of Flow-Assisted Synthesis of C2-Symmetric Chiral PyBox Ligands

Claudio Battilocchio^1,3, Marcus Baumann¹, Ian R. Baxendale¹, Mariangela Biava³, Matthew O. Kitching¹, Steven V. Ley¹, Rainer E. Martin^*2, Stephan A. Ohnmacht², Nicholas D. C. Tappin¹

• ¹Department of Chemistry, University of Cambridge, UK
• ²F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Basel, Switzerland
• ³Department of Pharmaceutical Chemistry and Technology, Sapienza University of Rome, Italy

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Synthesis of a Drug-Like Focused Library of Trisubstituted Pyrrolidines Using Integrated Flow Chemistry and Batch Methods

Marcus Baumann¹, Ian R. Baxendale¹, Steven V. Ley¹, Christoph Kuratli², Rainer E. Martin², Josef Schneider²

• ¹Innovative Technology Centre, University of Cambridge, U.K.
• ²F. Hoffmann-La Roche Ltd., Basel, Switzerland

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Synthesis of (+)-Dumetorine and Congeners by Using Flow Chemistry Technologies

Elena Riva², Anna Rencurosi¹, Stefania Gagliardi¹, Daniele Passarella², Marisa Martinelli^1*

• ¹NiKem Research S.r.l., Milan, Italy
• ²Università degli Studi di Milano,Milan, Italy

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Preparation of fluoxetine by multiple flow processing steps

Batoul Ahmed-Omer, Adam J. Sanderson

• Eli Lilly and Co. Ltd.
• Lilly Research Centre, UK.

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Diastereoselective Chain-Elongation Reactions Using Microreactors for Applications in Complex Molecule Assembly

Catherine F. Carter¹, Heiko Lange¹, Daiki Sakai², Ian R. Baxendale¹, Steven V. Ley¹

• ¹Innovative Technology Centre, University of Cambridge, UK, CB2 1EW, UK
• ²Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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A fully automated, multistep flow synthesis of 5-amino-4-cyano-1,2,3-triazoles

Catherine J. Smith, Nikzad Nikbin, Steven V. Ley, Heiko Lange, Ian R. Baxendale

• Innovative Technology Centre, Cambridge, UK

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A breakthrough method for the accurate addition of reagents in multi-step segmented flow processing

Heiko Lange¹, Catherine F. Carter¹, Mark D. Hopkin¹, Adrian Burke², Jon G. Goode², Ian R. Baxendale¹, Steven V. Ley¹

• ¹Innovative Technology Centre, University of Cambridge, UK
• ²Mettler-Toledo AutoChem UK

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One-Flow, Multistep Synthesis of Nucleosides by Brønsted Acid-Catalyzed Glycosylation

Adam Sniady, Matthew W. Bedore, Timothy F. Jamison

• Novartis Institutes for Biomedical Research Inc., Cambridge, USA MIT, Cambridge, USA

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Safe and Reliable Synthesis of Diazoketones and Quinoxalines in a Continuous Flow Reactor

Laetitia J. Martin¹, Andreas L. Marzinzik¹, Steven V. Ley², Ian R. Baxendale²

• ¹Novartis Institute for BioMedical Research, Basel, Switzerland
• ²Innovative Technology Centre, Department of Chemistry, University of Cambridge

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Preparation of arylsulfonyl chlorides by chlorosulfonylation of in situ generated diazonium salts using a continuous flow reactor

Laia Malet-Sanz, Julia Madrzak, Steven V.Ley, Ian R.Baxendale

• Innovative Technology Centre, University of Cambridge

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Synthesis of Highly Substituted Nitropyrrolidines, Nitropyrrolizines and Nitropyrroles via Multicomponent-Multistep Sequences within a Flow Reactor

Marcus Baumann, Ian R. Baxendale, Andreas Kirschning, Steven V. Ley^*, Jens Wegner

• Department of Chemistry, University of Cambridge

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Flow synthesis of tricyclic spiropiperidines as building blocks for the histrionicotoxin family of alkaloids

Malte Brasholz¹, Brian A. Johnson², James M. Macdonald¹, Anastasios Polyzos¹, John Tsanaktsidis¹, Simon Saubern¹, Andrew B. Holmes^1,2, John H. Ryan¹

• ¹CSIRO Molecular and Health Technologies, Victoria, Australia
• ²School of Chemistry, Bio 21 Institute, University of Melbourne, Victoria, Australia

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The application of flow microreactors to the preparation of a family of casein kinase I inhibitors

Francesco Venturoni, Nikzad Nikbin, Steven V. Ley, Ian R. Baxendale

• Innovative Technology Centre, Department of Chemistry, University of Cambridge

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A highly efficient flow reactor process for the synthesis of N-Boc-3,4-dehydro-l-proline methyl ester

Lucia Tamborini, Paola Conti, Andrea Pinto, Carlo De Micheli

• Dipartimento di Scienze Farmaceutiche ‘Pietro Pratesi’,
• Università degli Studi di Milano, Italy

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Multi-Step Synthesis by Using Modular Flow Reactors: The Preparation of YneOnes and Their Use in Heterocycle Synthesis

Ian R. Baxendale¹, Søren C. Schou², Jörg Sedelmeier¹, Steven V. Ley¹

• ¹ITC, Department of Chemistry, University of Cambridge
• ²LEO Pharma, Medicinal Chemistry Research, Denmark

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Multistep Synthesis Using Modular Flow Reactors: Bestmann-Ohira Reagent for the Formation of Alkynes and Triazoles

Ian R. Baxendale¹, Steven V. Ley¹, Andrew C. Mansfield², Christopher D. Smith¹

• ¹ITC, Department of Chemistry, University of Cambridge,
• ²Pfizer Global R&D Research Centre, Sandwich, (UK)

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Efficient Continuous Flow Synthesis of Hydroxamic Acids and Suberoylanilide Hydroxamic Acid Preparation

E. Riva¹, S. Gagliardi², Caterina Mazzoni², M. Martinelli², D. Passarella¹, D. Vigo², A. Rencurosi²

• ¹Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, Italy
• ²NiKem Research S.r.l., Milan, Italy

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Tagged phosphine reagents to assist reaction work-up by phase-switched scavenging using a modular flow reactor

Christopher D. Smith, Ian Baxendale, Geoffrey Tranmer, Marcus Baumann, Stephen Smith, Russell Lewthwaite, Steven V. Ley

• Department of Chemistry, University of Cambridge, UK

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A flow process for the multi-step synthesis of the alkaloid natural product oxomaritidine: a new paradigm for molecular assembly

Ian R. Baxendale, Jon Deeley, Charlotte M. Griffiths-Jones, Steven V. Ley, Steen Saaby, Geoffrey K. Tranmer

• Innovative Technology Centre, University of Cambridge

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