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Abstract
Building on key reactions presented in Volume 1, Synthetic Methods in Drug Discovery Volume 2 covers a range of important reaction types including organometallic chemistry, fluorination approaches and asymmetric methods as well as new and exciting areas such as Csp2-Csp3 couplings, catalytic amide bond forming reactions, hydrogen borrowing chemistry and methods to access novel motifs and monomers. This book provides both academic and industrial perspectives on key reactions giving the reader an excellent overview of the techniques used in modern synthesis. Reaction types are conveniently framed in the context of their value to industry and the challenges and limitations of methodologies are discussed with relevant illustrative examples. Moreover, key opportunities in expanding chemical space are presented, including the increasingly important syntheses that introduce three-dimensional molecular shape. Edited and authored by leading scientists from both academia and industry, this book will be a valuable reference for all chemists involved in drug discovery as well as postgraduate students in medicinal chemistry.
Contains contributions from many distinguished synthetic chemists andprovides both academic and industrial perspectiveson key reactions giving the readeranexcel-lent overview of the techniques used in modernsynthesis.
Prof. Gianluca Sbardella
This book is a must-have handbook and a highly valuable reference for all chemists involved in drug discovery as well as postgraduate students in medicinal chemistry.
Prof. Gianluca Sbardella
David Blakemore has spent his entire career in the pharmaceutical industry. Following his post-docs in Cambridge and Paris, he joined Warner-Lambert as a Group Leader in the Discovery Chemistry group. In 2001, he joined Pfizer in Sandwich and is currently the Synthesis Lead for the World-Wide Medicinal Chemistry Group at Pfizer Neusentis. Part of David’s role is in liaising with academics to highlight key areas of chemistry that could be of real value to the pharmaceutical industry and to develop interactions in those areas.
Paul Doyle has spent his entire career at the interface of chemistry and biology in the service of drug discovery. After his first degree in chemistry at Oxford, Paul completed his D.Phil. at the University of Sussex studying bio-organic synthetic chemistry. He spent a 15-year early career in a wide variety of therapeutic discovery programmes at the Wellcome Foundation before establishing one of the first UK discovery CROs, Biofocus. In 2008, Paul joined Peakdale as CEO.
Yvette Fobian has spent the majority of her career in the pharmaceutical industry. After completing her PhD and spending a year in Monsanto’s Corporate Research, she joined the Medicinal Chemistry Group in Searle/Monsanto in 1997 and ultimately Pfizer in 2003 following a series of mergers and acquisitions. In her most current role, Yvette is in an excellent position to see first-hand the needs and impact of synthetic enablement for both small and large scale delivery within the discovery team.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Cover | Cover | ||
| Preface | vii | ||
| Contents | ix | ||
| Chapter 11 Lithium, Magnesium, and Copper: Contemporary Applications of Organometallic Chemistry in the Pharmaceutical Industry | 1 | ||
| 11.1 Introduction | 1 | ||
| 11.2 Applications of Directed Metalation in the Pharmaceutical Industry | 2 | ||
| 11.2.1 ortho-Lithiation of Aromatic Systems | 2 | ||
| 11.2.2 Union of DoM and Cross-coupling Reactions | 5 | ||
| 11.2.3 Examples of ortho-Lithiation Chemistry in Drug Synthesis | 7 | ||
| 11.2.4 Magnesiation of Pyridines and Pyrimidines: New Generation of Multimetallic Reagents | 9 | ||
| 11.2.5 α-Lithiation of Saturated Azaheterocycles\r | 16 | ||
| 11.2.6 Conclusion | 29 | ||
| 11.3 Applications of i-PrMgCl LiCl | 29 | ||
| 11.3.1 Magnesium–Halogen Exchange | 32 | ||
| 11.3.2 1,2-Addition | 35 | ||
| 11.3.3 Electrophilic Cyanation | 37 | ||
| 11.3.4 Synthesis of Boronic Esters/Acids | 40 | ||
| 11.4 Conjugate Addition and Substitution Reactions of Organometallic Reagents | 41 | ||
| 11.4.1 Overview of Organocuprate Chemistry | 43 | ||
| 11.4.2 Conjugate Addition | 45 | ||
| 11.4.3 Substitution | 54 | ||
| 11.4.4 Removal of Cu | 62 | ||
| 11.4.5 Conclusion | 64 | ||
| References | 65 | ||
| Chapter 12 C–N Bond Formation via Hydrogen Transfer | 75 | ||
| 12.1 Introduction | 75 | ||
| 12.2 N-Alkylation via Hydrogen Borrowing | 77 | ||
| 12.2.1 Synthesis of Primary, Secondary, and Tertiary Amines | 77 | ||
| 12.2.2 Alkylation of Weak Nitrogen Nucleophiles | 82 | ||
| 12.2.3 Limitations and Advances | 84 | ||
| 12.2.4 Hydrogen Transfer with Amines or Carboxylic Acids | 84 | ||
| 12.3 Dehydrogenative Amide Synthesis | 88 | ||
| 12.3.1 Lactamisation of Amino Alcohols | 88 | ||
| 12.3.2 Intermolecular Dehydrogenative Amide Couplings | 90 | ||
| 12.3.3 Dehydrogenative Couplings of Alcohol or Amine Surrogates | 99 | ||
| 12.4 Heterocycle Synthesis | 103 | ||
| 12.4.1 Dehydrogenative Synthesis of Heteroaromatics: Pyridines, Pyrazines, and Pyrroles | 104 | ||
| 12.4.2 Dehydrogenative Synthesis of Bicyclic Heteroaromatics | 106 | ||
| 12.4.3 Synthesis of Non-aromatic Heterocycles | 109 | ||
| 12.5 Summary | 118 | ||
| References | 119 | ||
| Chapter 13 Synthesis of Sulfonamides | 123 | ||
| 13.1 Introduction | 123 | ||
| 13.2 Synthesis from Arenes | 123 | ||
| 13.3 Synthesis from Thiols and Aryl Amines | 127 | ||
| 13.4 Organometallic Intermediates in the Synthesis of Sulfonamides | 130 | ||
| 13.4.1 Organolithium and Grignard Additions | 130 | ||
| 13.4.2 Palladium-catalysed Synthesis of Aryl Sulfonamides | 133 | ||
| 13.5 Conclusion | 136 | ||
| References | 136 | ||
| Chapter 14 Asymmetric Methods and Their Use in the Pharmaceutical Industry | 139 | ||
| 14.1 Introduction | 139 | ||
| 14.2 Asymmetric Hydrogenation | 140 | ||
| 14.2.1 Introduction | 140 | ||
| 14.2.2 Alkenes | 142 | ||
| 14.2.3 Ketones | 153 | ||
| 14.2.4 Chiral Amine Synthesis via Asymmetric Hydrogenation | 162 | ||
| 14.2.5 Heterocycles | 169 | ||
| 14.2.6 Future Directions | 176 | ||
| 14.3 Chiral Reduction of Ketones | 182 | ||
| 14.3.1 Introduction | 182 | ||
| 14.3.2 CBS Reagent as Reducing Agent for Ketones | 182 | ||
| 14.3.3 DIP-Cl Reagent as a Reducing Agent for Ketones | 194 | ||
| 14.4 Enantioselective Oxidation of Olefins: Enantioselective Epoxidation and Enantioselective Dihydroxylation | 205 | ||
| 14.4.1 Enantioselective Epoxidation | 205 | ||
| 14.4.2 Enantioselective Dihydroxylation | 213 | ||
| 14.4.3 Enantioselective Epoxidation and Dihydroxylation – Conclusions | 220 | ||
| 14.5 Chiral Auxiliaries and Organocatalysis in Drug Discovery | 222 | ||
| 14.5.1 Introduction | 222 | ||
| 14.5.2 Chiral Auxiliaries | 222 | ||
| 14.5.3 Organocatalysis | 238 | ||
| 14.6 Chapter Conclusion | 250 | ||
| References | 250 | ||
| Chapter 15 Fluorination Approaches | 263 | ||
| 15.1 Introduction | 263 | ||
| 15.2 Nucleophilic Reagents for Fluorination | 265 | ||
| 15.3 Electrophilic Reagents for Fluorination | 266 | ||
| 15.4 Synthesis of Alkyl Fluorides | 267 | ||
| 15.4.1 Nucleophilic Substitution | 267 | ||
| 15.4.2 Deoxyfluorination of Alcohols | 272 | ||
| 15.4.3 Decarboxylative Fluorination of Carboxylic Acids | 286 | ||
| 15.4.4 Direct Fluorination of Hydrocarbons | 290 | ||
| 15.4.5 α-Fluorination of Carbonyl Compounds and their Derivatives\r | 293 | ||
| 15.5 Synthesis of Aryl Fluorides | 301 | ||
| 15.5.1 Classical Approaches | 301 | ||
| 15.5.2 Pd-catalysed Fluorination of Aryl Halides and Derivatives | 308 | ||
| 15.5.3 Fluorination of Organolithiums/Grignard Reagents | 313 | ||
| 15.5.4 Fluorination of Aryl Stannanes | 317 | ||
| 15.5.5 Fluorination of Boronic Acids | 318 | ||
| 15.5.6 Fluorination of Aryl Silanes | 323 | ||
| 15.5.7 Pd-mediated Directed Fluorination | 324 | ||
| 15.6 Difluoromethylation | 327 | ||
| 15.7 Trifluoromethylation | 337 | ||
| References | 357 | ||
| Chapter 16 The Development of Csp3–Csp2 Coupling Methodology | 371 | ||
| 16.1 Introduction | 371 | ||
| 16.2 Catalytic Process | 372 | ||
| 16.3 Oxidative Addition | 375 | ||
| 16.4 Transmetallation and Reductive Elimination | 376 | ||
| 16.5 Enhancing Reductive Elimination with Palladium Dialkylbiarylphosphines | 377 | ||
| 16.6 Transmetallation and Coupling of Organoboron Species | 389 | ||
| 16.7 Transmetallation and Coupling of Alkoxy-Substituted Borates | 397 | ||
| 16.8 Nickel Catalysed Processes for Csp3-Csp2 Coupling | 402 | ||
| 16.9 Summary and Conclusion | 408 | ||
| Acknowledgments | 409 | ||
| References | 409 | ||
| Chapter 17 Catalytic Amide Bond Forming Methods | 413 | ||
| 17.1 Amidation of Carboxylic Acids | 413 | ||
| 17.1.1 Homogeneous Metal Catalysed Amidation of Carboxylic Acids | 414 | ||
| 17.1.2 Heterogeneous Catalysts for the Amidation of Carboxylic Acids | 415 | ||
| 17.1.3 Non-metal Catalysts for the Amidation of Carboxylic Acids | 416 | ||
| 17.2 Transamidation | 417 | ||
| 17.2.1 Metal Catalysed Transamidation | 418 | ||
| 17.2.2 Non-metal Catalysed Transamidation | 420 | ||
| 17.3 Amidation of Esters | 423 | ||
| 17.3.1 Metal Catalysed Amidation of Esters | 423 | ||
| 17.3.2 Non-metal Catalysed Amidation of Esters | 424 | ||
| 17.4 Amidation of Aldehydes (without Oxime Intermediates) | 426 | ||
| 17.4.1 Metal Catalysed Amidation of Aldehydes | 426 | ||
| 17.5 Amidation of Alcohols | 430 | ||
| 17.5.1 Homogeneous Metal Catalysed Amidation of Alcohols | 430 | ||
| 17.5.2 Heterogeneous Metal Catalysed Amidation of Alcohols | 432 | ||
| 17.6 Amidation of Nitriles | 433 | ||
| 17.6.1 Hydration of Nitriles to Primary Amides | 433 | ||
| 17.6.2 Amine Addition to Nitriles | 434 | ||
| 17.6.3 Catalysed Ritter and Ritter-type Reactions | 435 | ||
| 17.7 Oxime/oxime Intermediates to Amides | 436 | ||
| 17.7.1 Catalytic Aldoxime Rearrangement and Coupling into Primary, Secondary and Tertiary Amides | 437 | ||
| 17.7.2 Catalytic Beckmann Rearrangements | 439 | ||
| 17.8 Aminocarbonylations | 440 | ||
| 17.8.1 Aminocarbonylation of C–X Bonds | 440 | ||
| 17.8.2 Aminocarbonylation of C–H Bonds | 443 | ||
| 17.9 Miscellaneous Amidations | 446 | ||
| 17.10 Conclusion | 448 | ||
| References | 448 | ||
| Chapter 18 Accessing Novel Molecular Motifs and Monomers | 454 | ||
| 18.1 Introduction | 454 | ||
| 18.2 The Value of a Medicinal Chemistry Friendly Building Block (Monomer) Collection | 455 | ||
| 18.3 Development of the Pfizer Monomer Collection | 459 | ||
| 18.3.1 Expanding the Reagent Collection Scope | 460 | ||
| 18.3.2 Creation of a Tier 1 Monomer Collection at Pfizer | 460 | ||
| 18.3.3 Building a Tier 1 Monomer Set | 461 | ||
| 18.3.4 Creation of Enabled Monomer Set for Parallel (Library) Synthesis | 463 | ||
| 18.4 Expanding Monomer Diversity | 465 | ||
| 18.4.1 In situ Monomer Strategy | 465 | ||
| 18.4.2 Expanding Diversity of Other Limited-availability Monomer Sets | 477 | ||
| 18.5 Utility and Accessibility of Fluorinated Monomers | 489 | ||
| 18.5.1 The Utility of Fluorine in Medicinal Chemistry | 489 | ||
| 18.5.2 Fluorine Addition to Monomer Sets | 490 | ||
| 18.6 Multi-step Library Synthesis | 492 | ||
| 18.7 Future Directions | 497 | ||
| 18.8 Final Thoughts | 497 | ||
| References | 499 | ||
| Subject Index | 505 |