This book reviews the challenges and opportunities posed by flow chemistry in drug discovery, and offers a handy reference tool for medicinal chemists interested in the synthesis of biologically active compounds.
Prepared by expert contributors, the respective chapters cover not only fundamental methodologies and reactions, such as the application of catalysis, especially biocatalysis and organocatalysis; and non-conventional activation techniques, from photochemistry to electrochemistry; but also the development of new process windows, processes and reactions in drug synthesis. Particular attention is given to automatization and library synthesis, which are of great importance in the pharmaceutical industry. Readers will also find coverage on selected topics of general interest, such as how flow chemistry is contributing to drug discovery R&D in developing countries, and the green character of this enabling technology, for example in the production of raw materials for the pharmaceutical industry from waste.
Given its scope, the book appeals to medicinal chemistry researchers working in academia and industry alike, as well as professionals involved in scale-up and drug development.
Author(s): Jesus Alcazar, Antonio de la Hoz, Angel Díaz-Ortiz
Series: Topics in Medicinal Chemistry, 38
Publisher: Springer
Year: 2021
Language: English
Pages: 506
City: Cham
Preface
Contents
List of Abbreviations
Flow Chemistry in Drug Discovery: Challenges and Opportunities
1 Introduction
1.1 Introduction to Flow Chemistry
1.2 Flow Chemistry Setup
1.3 Types of Transformations
2 The Drug Discovery Process in Pharma
3 Flow Chemistry as a Tool to Improve Drug Discovery
3.1 Green Components of Flow Chemistry
3.2 Diversity Oriented Synthesis (DOS) in Flow
3.3 Catalysis in Flow
3.3.1 Hetero- and Homogeneous Catalysis
3.3.2 Biocatalysis
3.3.3 Photocatalysis
3.4 Electrochemistry in Flow
3.5 Library Synthesis and Automation Using Flow
3.6 Artificial Intelligence (AI) and Flow Chemistry
4 Conclusions and Outlook
References
Green Aspects of Flow Chemistry for Drug Discovery
1 Introduction
2 Solvents
2.1 Supercritical Fluids and Ionic Liquids
2.2 Deep Eutectic Solvents
2.3 Biomass-Derived Solvents
2.4 Miscellaneous
3 Enabling Technologies
3.1 Photochemistry
3.2 Electrochemistry
3.3 Biocatalysis
3.4 Microwaves
4 Hazardous Reagents
4.1 Azides
4.2 Diazomethane
4.3 Hydrogenation
4.4 Carbonylation
4.5 Miscellaneous
5 Monitoring, Optimization, and Scale-Up in the Pharmaceutical Industry
5.1 Monitoring
5.2 Automatization
5.3 3D Printing
5.4 Optimization
5.5 Process Intensification and Scale-Up
6 Quantification of Sustainability (LCA)
7 Conclusions
References
Photochemistry in Flow for Drug Discovery
1 Introduction
2 Carbon-Carbon and Carbon-Heteroatom Bond Formation
2.1 Diazonium Salts and Diazo Compounds for C-C and C-X Bond Formation
2.2 Photoinduced Metal- and Dye-Catalysed C-C and C-X Bond Formation
2.3 C-C Bond Formation via Photodecarboxylation
3 Photochemical Cyclization Reactions
4 Photochemical Rearrangement Reactions
5 Incorporation of Fluorine and Fluorine-Containing Groups
6 Trend to Photochemical-Assisted Biocatalysis
7 Summary
References
Electrochemistry in Flow for Drug Discovery
1 Introduction
1.1 General Introduction
1.2 Introduction to Electrochemistry
1.3 Fundamentals of Organic Electrochemistry
1.4 Methods for Organic Electrosynthesis
1.4.1 Controlled Potential Electrolysis (Potentiostatic)
1.4.2 Constant Current Electrolysis (Galvanostatic)
1.5 Cyclic Voltammetry
1.6 Direct vs Indirect Electrolysis
1.7 Types of Cells
1.7.1 Batch Cells
1.7.2 Flow Electrochemical Reactors
Parallel Plate Flow Cells
Thin-Layer Flow Cells
Porous Flow Cells
Automated Flow Electrolysis Platforms
2 Flow Electrochemistry for Drug Discovery
2.1 Flow Electrosynthesis of Pharmaceutically Relevant Scaffolds/Fragments
2.1.1 Electrochemical Synthesis of Nitrile-Containing Scaffolds
2.1.2 Electrochemical Synthesis of Benzoxazoles and Benzothiazoles
2.1.3 Electrosynthesis of N-Containing Heterocycles by Nitrogen-Centred Radicals
2.1.4 Electrochemical Anodic Aryl-Aryl Cross-Coupling in Flow Cells
2.1.5 Electrosynthesis of N-Containing Heterocycles by Shono Oxidations
2.1.6 Flow Electrochemical Synthesis for Chiral Selectivity
2.2 Electrochemistry `On-Route´ to Small Molecule Drugs
2.3 Flow Electrochemistry for Late-Stage Functionalisation
2.4 Flow Electrochemistry for Metabolic Studies
2.5 Automated Flow Electrosynthesis
2.6 Conclusions
References
Recent Advances of Asymmetric Catalysis in Flow for Drug Discovery
1 Introduction
2 Homogeneous Catalysis
2.1 Hydrogenation and Hydroacylation
2.2 Oxidation Reactions
2.3 Other Types of Reactions with Transition-Metal Catalysts
2.4 Other Types of Reactions with Organocatalysts
3 Heterogeneous Catalysis
3.1 Hydrogenation and Hydroformylation
3.2 Organocatalysis
3.2.1 Enamine-Iminium Catalysis
3.2.2 Chiral Phosphoric Acid
3.2.3 Other Types of Organocatalysis
3.3 Transition-Metal Catalysis
3.4 Lewis Acid Catalysis
3.5 Biocatalysis
4 Application for Multistep Synthesis of a Complex Molecule
5 Perspective
References
Multiple Organolithium Reactions for Drug Discovery Using Flash Chemistry
1 Introduction
2 Flash Chemistry
2.1 Reactions Mediated by Decomposable Intermediates
2.2 Reactions Mediated by Isomerizable Intermediates
2.3 Reactions Mediated by Racemizable Intermediates
3 Reaction Integration
3.1 Linear Integration
3.2 Convergent Integration
3.3 Three-Component Coupling Based on Convergent and Linear Integration
4 Conclusion
References
Organocatalysis in Continuous Flow for Drug Discovery
1 Introduction
2 Achiral Organocatalysts in Continuous Flow
2.1 Carbene Catalyzed Reactions
2.2 Lewis Base Catalyzed Reactions
2.3 Lewis Acid Catalyzed Reactions
2.4 Photocatalytic Reactions
2.5 Phosphine Catalyzed Reactions
3 Chiral Organocatalysis in Continuous Flow
3.1 Pyrrolidine-Derived Catalysts
3.2 TRIP-Derived Catalysts
3.3 Thiourea-Derived Catalysts
3.4 Cinchona-Derived Catalysts
3.5 Squaramide-Derived Catalysts
3.6 Diamine-Derived Catalysts
3.7 Imidazolidinone-Derived Catalysts
3.8 Chiral Carbene-Derived Catalyst
4 Direct Application of Organocatalysis in Continuous Flow for Drug Synthesis
5 Conclusions
References
Biocatalysis in Flow for Drug Discovery
1 Introduction
1.1 Biocatalysis in Drug Development
1.2 Enzymes in Early-Stage Drug Discovery Approaches
1.3 Flow Chemistry as an Enabling Tool for Enzymes
1.4 To Immobilise or Not to Immobilise?
2 Transaminase
2.1 Transaminase in Continuous Flow
2.2 Outlook for Transaminase in Continuous Flow
3 Oxidoreductases
3.1 Ketoreductase and Alcohol Dehydrogenase
3.2 Application of KRED/ADH in Continuous Flow
3.3 Outlook for KRED/ADH in Drug Discovery
3.4 Other Oxidoreductases in Continuous Flow
3.4.1 Imine Reductase in Continuous Flow
3.4.2 Amine/Amino Acid Dehydrogenase
3.4.3 Hydrogenase
3.4.4 Oxidases in Continuous Flow
Carbohydrate Oxidases
Alcohol Oxidases
3.5 Outlook for Oxidoreductases in Continuous Flow
4 Chemoenzymatic Catalysis in Flow for Drug Discovery
4.1 Chemoenzymatic Systems in Continuous Flow
4.2 Outlook for Continuous Chemoenzymatic Processes for Drug Discovery
5 Microreactors and Biocatalysis for Library Compounds Generation
5.1 The Future of Microreactor Technology in Biocatalysis
6 Miscellaneous Reactions
6.1 Pickering Emulsion
6.2 Esterifications
6.3 Carboligation
6.4 Lyases for Drug Synthesis
6.5 Cyanation
6.6 Protein Modification
6.7 Cofactor Regeneration
7 The Future of Flow Biocatalysis for Early-Stage Drug Discovery
References
Improved Synthesis of Bioactive Molecules Through Flow Chemistry
1 Introduction
2 Synthesis of Bioactive Natural Products Under Continuous Flow Conditions
3 Good Manufacturing Practice (GMP) and Continuous Good Manufacturing Practice (cGMP)
3.1 API Manufacturing Under Continuous Flow Conditions
4 Conclusion and Perspectives
References
New Biomass Reagents for the Synthesis of Bioactive Compounds
1 Introduction
2 D-mannose as a Biomass Reagent for the Synthesis of Bioactive Compounds
3 Furfural as a Biomass Reagent for the Synthesis of Bioactive Compounds
4 Cashew Nutshell Liquid (CNSL) as a Biomass Reagent for the Synthesis of Bioactive Compounds
5 Penicillium antarcticum as a Biomass Reagent for the Synthesis of Bioactive Compounds
6 Conclusions
References
Flow Chemistry Supporting Access to Drugs in Developing Countries
1 Introduction
1.1 Disease Burden and Pharmaceutical Landscape in Developing Countries
1.2 Flow Chemistry in the Pharmaceutical Industry
2 Continuous Flow Synthesis of APIs in Developing Countries
2.1 Lamivudine
2.2 Tenofovir
2.3 Efavirenz
2.4 Darunavir
2.5 Isoniazid
2.6 Ethambutol
2.7 Levetiracetam and Brivaracetam
2.8 Capecitabine
2.9 Daclatasvir
2.10 Clozapine
2.11 Dimethyl Fumarate
2.12 Mepivacaine and Its Analogues
2.13 Oseltamivir Phosphate
2.14 Nevirapine
2.15 Dolutegravir
3 Conclusion and Outlook
References
Drug Discovery Automation and Library Synthesis in Flow
1 Introduction
2 Nanomole Reaction-Screening and Micromole-Scale Synthesis in Flow
2.1 Introduction
2.2 Nanomole-HTE in Batch
2.3 Nanomole HTE in Flow: Instrument Development
2.4 HTE in Flow: Instrument Validation
2.5 HTE in Flow: Suzuki-Miyaura Coupling
3 HTE in Flow for Photochemical Reaction Discovery
3.1 Introduction
3.2 System Setup and Validation
3.3 In Droplet HTE Reaction Discovery
4 Automated Radial Synthesis and Parallel Functionalization of Rufinamide in Flow
4.1 Introduction
4.2 Instrument Design
4.3 Synthesis of Rufinamide and Derivatives in Flow
5 Integrated Design-Make-Test Cycle Platform
5.1 Introduction
5.2 Abl Kinase Inhibitors
5.3 DPP4 Inhibitors
6 Conclusions and Outlook
References
