Flow and Microreactor Technology in Medicinal Chemistry (Methods & Principles in Medicinal Chemistry)

Learn to master a powerful technology to enable a faster drug discovery workflow The ultimate dream for medicinal chemists is the ability to synthesize new drug-like compounds with the push of a button. The key to synthesizing chemical compounds more quickly and accurately lies in computer-controlled technologies that can be optimized by machine learning. Recent developments in computer-controlled automated syntheses that rely on miniature flow reactors―with integrated analysis of the resulting products―provide a workable technology for synthesizing new chemical substances very quickly and with minimal effort. In Flow and Microreactor Technology in Medicinal Chemistry , early adopters of this ground-breaking technology describe its current and potential uses in medicinal chemistry. Based on successful examples of the use of flow and microreactor synthesis for drug-like compounds, the book introduces current as well as emerging uses for automated synthesis in a drug discovery context. Flow and Microreactor Technology in Medicinal Chemistry readers will also find: Numerous case studies that address the most common applications of this technology in the day-to-day work of medicinal chemists How to integrate flow synthesis with drug discovery How to perform enantioselective reactions under continuous flow conditions Flow and Microreactor Technology in Medicinal Chemistry is a valuable practical reference for medicinal chemists, organic chemists, and natural products chemists, whether they are working in academia or in the pharmaceutical industry. Cover 1 Title Page 5 Copyright 6 Contents 7 Series Editors Preface 13 Volume Editor's Preface 17 Chapter 1 Flow Chemistry at the Extremes: Turning Complex Reactions into Scalable Processes 21 1.1 Introduction 21 1.2 Temperature Extremes 22 1.2.1 Cryogenic Flow Chemistry 22 1.2.1.1 Organolithium Chemistry in Flow 23 1.2.1.2 Cyanation 30 1.2.2 High‐Temperature Flow Chemistry 30 1.3 In Situ Use of Hazardous Reagents 34 1.3.1 Vilsmeier Reagent 35 1.3.2 Phosgene 36 1.3.3 Diazomethane 37 1.4 Photochemistry on Scale 40 1.5 Conclusion and Outlook 45 References 46 Chapter 2 Automated Flow Chemistry Platforms 53 2.1 Introduction 53 2.2 Analytical Techniques 53 2.2.1 In‐line NMR Monitoring 54 2.2.2 In‐line Infrared Spectroscopy (IR) 55 2.2.3 Online HPLC and GC Sampling 55 2.2.4 UV/Vis Spectroscopy 57 2.2.5 Other Analytical Techniques 57 2.2.5.1 Online Mass Spectroscopy 57 2.2.5.2 In‐line Raman Spectroscopy 58 2.2.6 Future Opportunities 58 2.3 Automation 58 2.3.1 High‐Throughput Screening Platforms 58 2.3.2 Integrated Chemistry and Bioactivity Screening Platforms 59 2.3.3 Flexible and Modular Automated Platforms 63 2.3.3.1 Robotic Platform for Synthesis in Flow Informed by AI Planning 64 2.3.3.2 Reconfigurable System for Automated Optimization of Diverse Chemical Reactions 64 2.3.3.3 OpenFlowChem as a Flexible Software Platform 69 2.3.3.4 Internet‐Based Software Platform 70 2.3.3.5 Other Platforms 71 2.3.4 Self‐Optimization Algorithms 72 2.4 Summary and Future Perspective 80 References 80 Chapter 3 Flow Chemistry Opportunities for Drug Discovery 87 3.1 Introduction 87 3.1.1 Drug Discovery 87 3.1.2 Flow Chemistry 88 3.1.3 Merging Flow Chemistry and Drug Discovery 89 3.2 Current Drug Discovery Toolkit 90 3.2.1 Reactions for C‐Heteroatom Bond Formation 90 3.2.2 Reactions for CC Bond Formation 95 3.2.3 Heterocyclic Synthesis 96 3.3 Expanding Drug Discovery Toolkit Through Flow Chemistry 100 3.3.1 Handling Hazardous and Unstable Reagents 100 3.3.2 Combining Flow with Emerging Technologies 105 3.3.2.1 Photochemistry 105 3.3.2.2 Electrochemistry 108 3.4 Automated Flow Synthesis 110 3.5 Integrated Platforms 113 3.6 Conclusions and Outlook 115 References 115 Chapter 4 Flow Chemistry in Medicinal Chemistry: Applications to Bcr‐Abl Kinase Inhibitors 123 4.1 Introduction 123 4.2 Discovery of Imatinib 125 4.3 Ley Flow Synthesis of Imatinib 126 4.4 Buchwald Flow Synthesis of Imatinib 141 4.5 Jamison Flow Synthesis of Imatinib 148 4.6 “Hybrid Approach” to Imatinib 155 4.7 Closed‐Loop Discovery 160 4.8 Identification of Novel Bcr‐Abl Kinase Inhibitors Through Closed‐Loop Discovery 164 4.9 Conclusion 174 References 174 Chapter 5 Integrated Systems for Continuous Synthesis and Biological Screenings 179 5.1 Introduction: Continuous‐Flow Technology to Power Medicinal Chemistry 179 5.2 Equipment, Automated Systems, and Methods for Flow‐Based Medicinal Chemistry 181 5.2.1 Continuous‐Flow Synthesis Machines 182 5.2.2 Process Analytical Technology (PAT) for Effective Integration of Synthesis and Biological Screenings in Continuous Flow 184 5.2.3 Bioassays for In‐line Compound Screening 184 5.2.4 General Concepts for Automation, Remote Control, and Software Application to Integrated Systems 188 5.3 Flow Strategies for Building Bioactive Compound Libraries 189 5.3.1 Click Chemistry 189 5.3.2 Multicomponent Reactions (MCRs) 194 5.3.3 Linear and Multistep Synthesis 197 5.4 End‐to‐End Autonomous Discovery Platforms 201 5.5 Conclusions and Future Outlook 211 References 211 Chapter 6 Application of Continuous‐Flow Processing in Multistep API and Drug Syntheses 219 6.1 Introduction 219 6.2 Antibacterial Agents 220 6.2.1 Ciprofloxacin 220 6.2.2 Linezolid 221 6.2.3 Cefotaxime 222 6.2.4 Rifampicin 223 6.3 Anticancer Agents 225 6.3.1 Lomustine 225 6.3.2 Imatinib 225 6.4 Antifungal Agents 227 6.4.1 Fluconazole 227 6.4.2 Flucytosine 230 6.5 Anti‐HIV Agents 230 6.5.1 (R)‐Propylene Carbonate: An Intermediate Toward Anti‐HIV Drug, Tenofovir 230 6.5.2 Dolutegravir 231 6.5.3 Lamivudine 234 6.5.4 Efavirenz 235 6.6 Serotonin Modulators and Stimulators 236 6.6.1 Flibanserin 236 6.6.2 Vortioxetine 237 6.6.3 Melitracen HCl 238 6.7 Cholinesterase Inhibitor 239 6.7.1 Donepezil 239 6.8 Antimalarial Agent 240 6.8.1 Hydroxychloroquine 240 6.9 Non‐peptide Angiotensin II Receptor Blocker 241 6.9.1 Valsartan 241 6.10 Cystic Fibrosis Transmembrane Conductance Regulator 243 6.10.1 Ivacaftor 243 6.11 Non‐steroidal Anti‐inflammatory Agent 244 6.11.1 Ibuprofen 244 6.12 Conclusion 246 References 246 Chapter 7 Continuous‐Flow Multistep Synthesis of Active Pharmaceutical Ingredients 253 7.1 Introduction 253 7.2 Generators of Small Molecule Reagents 254 7.3 Two‐Step Flow Synthesis 257 7.3.1 Clausine C Derivatives 260 7.3.2 Amino Alcohol APIs from Glycerol 260 7.3.3 Oxymorphone 262 7.3.4 Hydroxychloroquine 263 7.4 Linear Multistep Flow Synthesis 263 7.4.1 Valsartan Precursor 266 7.4.2 Eflornithine 266 7.4.3 Ketamine 269 7.4.4 Lesinurad 271 7.5 Convergent Multistep Flow Synthesis 272 7.5.1 A Histone Deacetylase Inhibitor Precursor 272 7.5.2 Linezolid 272 7.6 Advanced Technologies for Multistep Flow Synthesis 275 7.6.1 Sensors and In‐line Analysis 275 7.6.2 Process Analytical Technology (PAT) 276 7.6.3 Self‐optimization 276 7.6.4 Modular Flow System 280 7.6.5 Toward Full Automation 281 7.7 Conclusion 283 References 283 Chapter 8 Enantioselective (Bio)Catalysis in Continuous‐flow as Efficient Tool for the Synthesis of Advanced Intermediates and Active Pharmaceutical Ingredients 289 8.1 Introduction 289 8.2 Homogeneous Enantioselective Catalysis in Continuous Flow 290 8.2.1 Homogeneous Enantioselective Organocatalysis 291 8.2.1.1 Enantioselective Michael Addition 291 8.2.1.2 Enantioselective Aldol Reaction 292 8.2.1.3 Enantioselective Photooxygenation 292 8.2.1.4 Enantioselective Imine Reduction 294 8.2.2 Organometallic Enantioselective Catalysis 295 8.2.2.1 Enantioselective Sulfoxidation 295 8.2.2.2 Enantioselective Epoxidation 296 8.2.2.3 Enantioselective Hydrogenation 297 8.2.2.4 Enantioselective Michael Addition 299 8.3 Heterogeneous Enantioselective Catalysis in Flow 300 8.3.1 Supported Organocatalysts 301 8.3.1.1 Enantioselective Allylation of Aldehydes 301 8.3.1.2 Enantioselective α‐Amination 302 8.3.1.3 Enantioselective Arylation of Aldehydes 302 8.3.1.4 Enantioselective Cyclopropanation 303 8.3.1.5 Enantioselective Michael Reaction 304 8.3.1.6 Enantioselective Tandem Michael Addition/Cyclization Reactions 306 8.3.1.7 Enantioselective Reduction of Imines 308 8.3.2 Supported Organometallic Catalysts 309 8.3.2.1 Enantioselective Hydrogenation 309 8.3.2.2 Enantioselective Hydroformylation 311 8.3.2.3 Enantioselective 1,4‐Addition to Enone 313 8.3.2.4 Enantioselective Nitroaldol Reaction 314 8.4 Enantioselective Biocatalysis in Flow 315 8.5 Asymmetric Total Synthesis in Continuous Flow 318 8.6 Conclusions 324 References 324 Chapter 9 Innovative Process Development of Pharmaceutical Intermediates Under Continuous‐Flow System 331 9.1 Introduction 331 9.2 Plug Flow Reactor System for Phosgenation Reaction 332 9.2.1 Introduction 332 9.2.2 Feasibility Study 333 9.2.3 Establishment and Development of Continuous‐Flow Process for API Synthesis 334 9.3 Simple and Practical Packed‐Bed Reactor System for Catalytic Reactions 337 9.3.1 Introduction 337 9.3.2 Deacylation Reaction with Anion‐Exchange Resin 338 9.3.2.1 Feasibility Study 338 9.3.2.2 Application for Pharmaceutical Intermediates and Scale‐up 339 9.3.3 Reductive Amination with Biocatalyst 342 9.4 Flow Reactor Facility for Large‐Scale Production 346 9.4.1 Concept of Our Flow Reactor System 346 9.4.2 Commercial Production 348 9.5 Conclusions 348 References 349 Index 353 EULA 365