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

✍ Scribed by Esther Alza (editor)

• Publisher: Wiley-VCH
• Tongue: English
• Leaves: 365
• Category: Library

✦ Synopsis

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 isa valuable practical reference for medicinal chemists, organic chemists, and natural products chemists, whether they are working in academia or in the pharmaceutical industry.

✦ Table of Contents

Cover
Title Page
Copyright
Contents
Series Editors Preface
Volume Editor's Preface
Chapter 1 Flow Chemistry at the Extremes: Turning Complex Reactions into Scalable Processes
1.1 Introduction
1.2 Temperature Extremes
1.2.1 Cryogenic Flow Chemistry
1.2.1.1 Organolithium Chemistry in Flow
1.2.1.2 Cyanation
1.2.2 High‐Temperature Flow Chemistry
1.3 In Situ Use of Hazardous Reagents
1.3.1 Vilsmeier Reagent
1.3.2 Phosgene
1.3.3 Diazomethane
1.4 Photochemistry on Scale
1.5 Conclusion and Outlook
References
Chapter 2 Automated Flow Chemistry Platforms
2.1 Introduction
2.2 Analytical Techniques
2.2.1 In‐line NMR Monitoring
2.2.2 In‐line Infrared Spectroscopy (IR)
2.2.3 Online HPLC and GC Sampling
2.2.4 UV/Vis Spectroscopy
2.2.5 Other Analytical Techniques
2.2.5.1 Online Mass Spectroscopy
2.2.5.2 In‐line Raman Spectroscopy
2.2.6 Future Opportunities
2.3 Automation
2.3.1 High‐Throughput Screening Platforms
2.3.2 Integrated Chemistry and Bioactivity Screening Platforms
2.3.3 Flexible and Modular Automated Platforms
2.3.3.1 Robotic Platform for Synthesis in Flow Informed by AI Planning
2.3.3.2 Reconfigurable System for Automated Optimization of Diverse Chemical Reactions
2.3.3.3 OpenFlowChem as a Flexible Software Platform
2.3.3.4 Internet‐Based Software Platform
2.3.3.5 Other Platforms
2.3.4 Self‐Optimization Algorithms
2.4 Summary and Future Perspective
References
Chapter 3 Flow Chemistry Opportunities for Drug Discovery
3.1 Introduction
3.1.1 Drug Discovery
3.1.2 Flow Chemistry
3.1.3 Merging Flow Chemistry and Drug Discovery
3.2 Current Drug Discovery Toolkit
3.2.1 Reactions for C‐Heteroatom Bond Formation
3.2.2 Reactions for CC Bond Formation
3.2.3 Heterocyclic Synthesis
3.3 Expanding Drug Discovery Toolkit Through Flow Chemistry
3.3.1 Handling Hazardous and Unstable Reagents
3.3.2 Combining Flow with Emerging Technologies
3.3.2.1 Photochemistry
3.3.2.2 Electrochemistry
3.4 Automated Flow Synthesis
3.5 Integrated Platforms
3.6 Conclusions and Outlook
References
Chapter 4 Flow Chemistry in Medicinal Chemistry: Applications to Bcr‐Abl Kinase Inhibitors
4.1 Introduction
4.2 Discovery of Imatinib
4.3 Ley Flow Synthesis of Imatinib
4.4 Buchwald Flow Synthesis of Imatinib
4.5 Jamison Flow Synthesis of Imatinib
4.6 “Hybrid Approach” to Imatinib
4.7 Closed‐Loop Discovery
4.8 Identification of Novel Bcr‐Abl Kinase Inhibitors Through Closed‐Loop Discovery
4.9 Conclusion
References
Chapter 5 Integrated Systems for Continuous Synthesis and Biological Screenings
5.1 Introduction: Continuous‐Flow Technology to Power Medicinal Chemistry
5.2 Equipment, Automated Systems, and Methods for Flow‐Based Medicinal Chemistry
5.2.1 Continuous‐Flow Synthesis Machines
5.2.2 Process Analytical Technology (PAT) for Effective Integration of Synthesis and Biological Screenings in Continuous Flow
5.2.3 Bioassays for In‐line Compound Screening
5.2.4 General Concepts for Automation, Remote Control, and Software Application to Integrated Systems
5.3 Flow Strategies for Building Bioactive Compound Libraries
5.3.1 Click Chemistry
5.3.2 Multicomponent Reactions (MCRs)
5.3.3 Linear and Multistep Synthesis
5.4 End‐to‐End Autonomous Discovery Platforms
5.5 Conclusions and Future Outlook
References
Chapter 6 Application of Continuous‐Flow Processing in Multistep API and Drug Syntheses
6.1 Introduction
6.2 Antibacterial Agents
6.2.1 Ciprofloxacin
6.2.2 Linezolid
6.2.3 Cefotaxime
6.2.4 Rifampicin
6.3 Anticancer Agents
6.3.1 Lomustine
6.3.2 Imatinib
6.4 Antifungal Agents
6.4.1 Fluconazole
6.4.2 Flucytosine
6.5 Anti‐HIV Agents
6.5.1 (R)‐Propylene Carbonate: An Intermediate Toward Anti‐HIV Drug, Tenofovir
6.5.2 Dolutegravir
6.5.3 Lamivudine
6.5.4 Efavirenz
6.6 Serotonin Modulators and Stimulators
6.6.1 Flibanserin
6.6.2 Vortioxetine
6.6.3 Melitracen HCl
6.7 Cholinesterase Inhibitor
6.7.1 Donepezil
6.8 Antimalarial Agent
6.8.1 Hydroxychloroquine
6.9 Non‐peptide Angiotensin II Receptor Blocker
6.9.1 Valsartan
6.10 Cystic Fibrosis Transmembrane Conductance Regulator
6.10.1 Ivacaftor
6.11 Non‐steroidal Anti‐inflammatory Agent
6.11.1 Ibuprofen
6.12 Conclusion
References
Chapter 7 Continuous‐Flow Multistep Synthesis of Active Pharmaceutical Ingredients
7.1 Introduction
7.2 Generators of Small Molecule Reagents
7.3 Two‐Step Flow Synthesis
7.3.1 Clausine C Derivatives
7.3.2 Amino Alcohol APIs from Glycerol
7.3.3 Oxymorphone
7.3.4 Hydroxychloroquine
7.4 Linear Multistep Flow Synthesis
7.4.1 Valsartan Precursor
7.4.2 Eflornithine
7.4.3 Ketamine
7.4.4 Lesinurad
7.5 Convergent Multistep Flow Synthesis
7.5.1 A Histone Deacetylase Inhibitor Precursor
7.5.2 Linezolid
7.6 Advanced Technologies for Multistep Flow Synthesis
7.6.1 Sensors and In‐line Analysis
7.6.2 Process Analytical Technology (PAT)
7.6.3 Self‐optimization
7.6.4 Modular Flow System
7.6.5 Toward Full Automation
7.7 Conclusion
References
Chapter 8 Enantioselective (Bio)Catalysis in Continuous‐flow as Efficient Tool for the Synthesis of Advanced Intermediates and Active Pharmaceutical Ingredients
8.1 Introduction
8.2 Homogeneous Enantioselective Catalysis in Continuous Flow
8.2.1 Homogeneous Enantioselective Organocatalysis
8.2.1.1 Enantioselective Michael Addition
8.2.1.2 Enantioselective Aldol Reaction
8.2.1.3 Enantioselective Photooxygenation
8.2.1.4 Enantioselective Imine Reduction
8.2.2 Organometallic Enantioselective Catalysis
8.2.2.1 Enantioselective Sulfoxidation
8.2.2.2 Enantioselective Epoxidation
8.2.2.3 Enantioselective Hydrogenation
8.2.2.4 Enantioselective Michael Addition
8.3 Heterogeneous Enantioselective Catalysis in Flow
8.3.1 Supported Organocatalysts
8.3.1.1 Enantioselective Allylation of Aldehydes
8.3.1.2 Enantioselective α‐Amination
8.3.1.3 Enantioselective Arylation of Aldehydes
8.3.1.4 Enantioselective Cyclopropanation
8.3.1.5 Enantioselective Michael Reaction
8.3.1.6 Enantioselective Tandem Michael Addition/Cyclization Reactions
8.3.1.7 Enantioselective Reduction of Imines
8.3.2 Supported Organometallic Catalysts
8.3.2.1 Enantioselective Hydrogenation
8.3.2.2 Enantioselective Hydroformylation
8.3.2.3 Enantioselective 1,4‐Addition to Enone
8.3.2.4 Enantioselective Nitroaldol Reaction
8.4 Enantioselective Biocatalysis in Flow
8.5 Asymmetric Total Synthesis in Continuous Flow
8.6 Conclusions
References
Chapter 9 Innovative Process Development of Pharmaceutical Intermediates Under Continuous‐Flow System
9.1 Introduction
9.2 Plug Flow Reactor System for Phosgenation Reaction
9.2.1 Introduction
9.2.2 Feasibility Study
9.2.3 Establishment and Development of Continuous‐Flow Process for API Synthesis
9.3 Simple and Practical Packed‐Bed Reactor System for Catalytic Reactions
9.3.1 Introduction
9.3.2 Deacylation Reaction with Anion‐Exchange Resin
9.3.2.1 Feasibility Study
9.3.2.2 Application for Pharmaceutical Intermediates and Scale‐up
9.3.3 Reductive Amination with Biocatalyst
9.4 Flow Reactor Facility for Large‐Scale Production
9.4.1 Concept of Our Flow Reactor System
9.4.2 Commercial Production
9.5 Conclusions
References
Index
EULA