Chirality in drug research / edited by Eric Francotte and Wolfgang Lindner.

Format:

Book

Contributor:

Francotte, Eric.

Lindner, W. (Wolfgang)

Rosengarten Family Fund.

Series:

Methods and principles in medicinal chemistry ; v. 33.

Methods and principles in medicinal chemistry ; v. 33

Language:

English

Subjects (All):

Chemistry, Pharmaceutical.

Drug Design.

Molecular Conformation.

Stereoisomerism.

Drugs--Research.

Drugs.

Drug development.

Chirality.

Medical Subjects:

Chemistry, Pharmaceutical.

Drug Design.

Molecular Conformation.

Stereoisomerism.

Physical Description:

xix, 351 pages : illustrations ; 25 cm.

Place of Publication:

Weinheim : Wiley-VCH, [2006]

Summary:

A fast growing number of pharmaceutically active compounds are chiral and their stereochemical molecular arrangement greatly influences their pharmacological properties. Since most pharmaceutical products nowadays are produced in chirally pure form, there is a strong focus on technology used for stereoselective drug synthesis, purification, analysis and testing. Here, the two editors from academia and a major pharmaceutical company have assembled an experienced, international team to provide first-hand practical advice on this increasingly important aspect of drug development.

This handbook is divided into the two main sections of synthesis and analysis. In the first section, the isolation of chiral drugs from natural sources, their production by chemical and enzymatic processes and the resolution of racemic mixtures in preparative chromatography are out-lined in separate chapters. For the section on qualitative and quantitative analysis, enantioselective chromatographic methods are presented as well as optical methods and CE-MS. With its unique industry-relevant aspects, this book is an invaluable aid to medicinal and pharmaceutical chemists involved in drug research in both industry and academia.

Contents:

1 Chiral Drugs from a Historical Point of View / Joseph Gal 3

1.2 A Word About Words 3

1.3 Old Chiral Drugs: Natural Remedies 3000BC-1900 4

1.4 Recognition of Chirality in Drugs 13

1.5 Enantioselectivity in Drug Action and Drug Metabolism: The Beginnings 16

1.6 Drug Chirality in the 20th Century 18

Synthesis

2 Stereoselective Synthesis of Drugs - An Industrial Perspective / Hons-Jurgen Federsel 29

2.1 Introduction: Historical Overview 29

2.2 Asymmetry from an Industrial Scale Perspective 32

2.3 Stereoselective Processes in Drug Manufacture - Drivers and Blockers 38

2.4 The Metal - Friend and Foe 41

2.5 Ligand Development - At the Core of Catalytic Chemistry 43

2.6 Asymmetric Reactions - A Rich Reservoir 45

2.6.1 Reductions 48

2.6.2 Oxidations 51

2.6.3 Carbon-Carbon Bond Formation 55

2.7 Retrospect and Prospect 59

3 Aspects of Chirality in Natural Products Drug Discovery / Philipp Krastel, Frank Petersen, Silvio Roggo, Esther Schmitt, Ansgar Schuffenhauer 67

3.2 Stereochemical Aspects of Natural Products 71

3.2.1 Chirality Analysis of Natural Products versus Drugs and Synthetics 71

3.2.2 Determination of the Relative and Absolute Stereochemistry of Natural Products 74

3.2.2.1 NMR Spectroscopy 74

3.2.2.2 Chiroptical Methods 75

3.2.2.3 X-ray Crystallography 75

3.2.2.4 Total Synthesis and Degradation Reactions 76

3.3 Mechanisms of Stereochemical Control in Natural Product Biosynthesis 77

3.3.1 Origin of D-Amino Acids in Non-ribosomal Peptides 77

3.3.2 Control of Chirality in Modular Polyketide Synthesis 79

3.3.3 Modes of Stereodifferentiating Cyclization 80

3.3.4 Terpene Biosynthesis in Plants 82

3.4 Biological Activity of Natural Products Related to Stereochemistry 83

3.4.1 Natural Products Active on the Nervous System 84

3.4.2 Gossypol, a Racemic Natural Product 86

3.4.3 Epimerization of Natural Products in vivo 87

3.4.4 Tubuline Stabilizing Agents 88

4 Biotransformation Methods for Preparing Chiral Drugs and Drug Intermediates / Michael Muller, Marcel Wubbolts 95

4.2 Examples of Established Applications of Biocatalysts in the Synthesis of Pharmaceuticals 96

4.2.1 Ephedrine Synthesis 96

4.2.2 Amino Acids 99

4.2.3 Amines 100

4.2.4 Penicillins/Cephalosporins 101

4.2.5 Racemic Resolution Using Hydrolytic Enzymes 103

4.2.6 Oxidoreductases 106

4.2.7 Oxynitrilases 108

4.2.8 Comparison of Nonenzymatic and Biocatalytic Transformations 108

4.3 Some Special Aspects of Biocatalysts, Recent Developments 111

4.3.1 Dynamic and Parallel Kinetic Resolution 111

4.3.2 Different Biocatalytic Approaches to One Building Block 112

4.3.3 Multipurpose Small Chiral Building Blocks 114

4.3.4 Optimization/New Access Using Molecular Biology Methods 116

4.3.5 Metabolic Engineering 116

4.3.6 Reaction Engineering 118

4.4 Conclusions and Outlook 119

Separations

5 Resolution of Chiral Drugs and Drug Intermediates by Crystallisation / Kazuhiko Saigo 127

5.2 Physical Enantioseparation - Preferential Crystallization 127

5.3 Chemical Enantioseparation - Diastereomeric Salt Formation 133

5.4 The Bridge Between Preferential Crystallization and Diastereomeric Salt Formation 141

5.5 Process Research on the Enantioseparation of Racemates by Diastereomeric Salt Formation 143

5.5.1 The Role of Water in the Stabilization of Less-soluble Diastereomeric Salts - A Key Intermediate for the Synthesis of Duloxetine, 3-(Methyl-amino)-1-(2-thienyl)propan-1-ol 143

5.5.2 Reciprocal Enantioseparation - A Key Intermediate for ACE Inhibitors, 2-Hydroxy-4-phenylbutyric Acid, and 1-(4-Methyl-phenyl)ethylamine 146

5.5.3 Solvent Switch - A Key Intermediate for Lysine Production, [alpha]-Amino-[epsilon]-caprolactam 147

5.6 Examples of Enantioseparations in the Pharmaceutical Industry 149

6 Isolation and Production of Optically Pure Drugs by Enantioselective Chromatography / Eric Francotte 155

6.2 General Considerations Regarding the Preparation of Single Stereoisomers of Chiral Drugs 156

6.2.1 The Different Approaches 156

6.2.2 Enantioselective Chromatography 157

6.3 Preparative Chiral Stationary Phases 158

6.3.1 Classification of Chiral Stationary Phases 158

6.3.2 Polymeric Phases 161

6.3.2.1 Polysaccharide-based CSPs 161

6.3.2.2 Polyacrylamide CSPs 164

6.3.2.3 Polymeric CSPs Derived from Tartaric Acid 164

6.3.3 Brush-type CSPs 165

6.3.3.1 [pi]-Acidic and [pi]-Basic Phases 165

6.3.3.2 Cyclodextrin-based CSPs 166

6.3.3.3 Chirobiotic CSPs 166

6.3.3.4 Chiral Ion-exchange Stationary Phases 167

6.4 Strategies for Performing Enantioselective Separations 168

6.4.1 Selecting the Right CSP 168

6.4.2 Selecting the Racemic Solute 170

6.4.3 Selecting the Right Synthetic Step 170

6.5 Preparative Enantioselective Resolution of Chiral Drugs 172

6.5.1 Laboratory-scale Separations 172

6.5.2 Pilot-scale Separations 176

6.5.3 Process-scale Separations 177

6.5.4 Production-scale Separations 178

6.5 Other Enantioselective Chromatographic Techniques 179

6.5.1 Gas Chromatography 179

6.5.2 Membranes 180

6.5.3 Centrifugal Partition Chromatography 180

6.5.4 Electrophoretic Methods 181

7 Stereoselective Chromatographic Methods for Drug Analysis / Norbert M. Maier, Wolfgang Lindner 189

7.2 The Role of Enantioselective Analysis in Drug Development 191

7.3 Separation Techniques in Enantiomer Analysis 192

7.4 Principle of Enantiomer Separation 194

7.4.1 Indirect Enantiomer Separation 195

7.4.2 Direct Enantiomer Separation 196

7.4.2.1 Chiral Mobile Phase Additives (CMPA) 196

7.4.2.2 Chiral Stationary Phases 197

7.5 Molecular Requirements for Chiral Recognition 198

7.6 Thermodynamic Principles of Enantiomer Separation 199

7.7 Role of Mobile Phase in Enantiomer Separation 202

7.8 Chiral Selectors and Chiral Stationary Phases Employed in Liquid Chromatographic Enantiomer Separation 205

7.8.1 CSPs Derived from Polymers 207

7.8.1.1 CSPs Derived from Natural Polymers 207

7.8.1.1.1 Polysaccharide-type CSPs 207

7.8.1.1.2 Protein-type CSPs 215

7.8.1.2 CSPs Derived from Synthetic Polymers 218

7.8.1.2.1 Helical Poly(methacrylates) 218

7.8.1.2.2 Chiral Poly(methacrylamides) 218

7.8.1.2.3 Tartardiamide-network Polymers 219

7.8.1.2.4 Poly(diaminocyclohexane-N,N-diacrylamide) 219

7.8.1.2.5 Molecularly Imprinted Polymers 221

7.8.2 Macrocyclic CSPs 224

7.8.2.1 Cyclodextrin-type CSPs 224

7.8.2.2 Glycopeptide-type CSPs 226

7.8.2.3 Crown Ether-type CSP 231

7.8.3 CSPs Based on Low-Molecular-Weight Molecules 233

7.8.3.1 Donor-Acceptor-type CSPs 233

7.8.3.2 Ion-exchange-type CSPs 237

7.8.3.2 Ligand-exchange-type CSPs 240

7.8.4 CSPs Based on Target-specific Bioaffinity Systems 240

7.8.4.1 Antibody-type CSPs 241

7.8.4.2 Aptamer-type CSPs 242

8 Capillary Electrophoresis Coupled to Mass Spectrometry for Chiral Drugs Analysis / Serge Rudaz, Jean-Luc Veuthey 261

8.2 Capillary Electrophoresis (CE) 262

8.3 CE-MS Coupling 263

8.3.1 CE-ESI-MS 263

8.3.2 Other CE-MS Coupling 265

8.4 Chiral Separation Strategies 265

8.5 Partial Filling 268

8.5.1 Partial Filling with Crown Ethers 268

8.5.2 Partial Filling with Neutral Derivatized CD 268

8.6 Partial Filling - Counter Current Technique 270

8.6.1 Anionic Analytes - Positively Charged Chiral Selectors 271

8.6.2 Cationic Analytes - Negatively Charged Chiral Selectors 271

8.7 Chiral Micellar Electrokinetic Chromatography 274

8.8 Quantitative Aspects in CE-MS and Parameters for CE-ESI-MS Coupling 276

8.9 Capillary Electrochromatography Coupled to Mass Spectrometry 277

9 Powerful Chiral Molecular Tools for Preparation of Enantiopure Alcohols and Simultaneous Determination of Their Absolute Configurations by X-Ray Crystallography and/or [superscript 1]H NMR Anisotropy Methods / Nobuyuki Harada 283

9.2 Methodologies for Determining Absolute Configuration 284

9.2.1 Nonempirical Methods for Determining Absolute Configurations of Chiral Compounds 284

9.2.2 Relative and/or Empirical Methods for Determining Absolute Configuration Using an Internal Reference of Absolute Configuration 285

9.3 CSDP Acid, Camphorsultam Dichlorophthalic Acid (-)-1, Useful for the Enantioresolution of Alcohols by HPLC and Simultaneous Determination of Their Absolute Configurations by X-ray Crystallography 287

9.4 A Novel Chiral Molecular Tool, 2-Methoxy-2-(1-naphthyl)propionic Acid (M[alpha]NP Acid (S)-(+)-3), Useful for Enantioresolution of Alcohols and Simultaneous Determination of Their Absolute Configurations by the [superscript 1]H NMR Anisotropy Method 295

9.4.1 Facile Synthesis of M[alpha]NP Acid (3) and Its Enantioresolution with Natural (-)-Menthol 298

9.4.2 The [superscript 1]H NMR Anisotropy Method for Determining the Absolute Configuration of Secondary Alcohols: the Sector Rule and Applications 399

9.4.3 Enantioresolution of Various Alcohols Using M[alpha]NP Acid and Simultaneous Determination of Their Absolute Configurations 304

9.4.4 Recent Applications of the M[alpha]NP Acid Method to Various Alcohols 307

9.4.5 Application of the M[alpha]NP Acid Method to Chiral meta-Substituted Diphenylmethanols 313

9.5 Absolute Configuration of the Thyroid Hormone Analog KAT-2003 as Determined by the [superscript 1]H NMR Anisotropy Method with M[alpha]NP Acid 314

10 Keywords in Chirality Modeling Molecular Modeling of Chirality - Software and Literature Research on Chirality in Modeling, Chirality in Docking, Chiral Ligand-Receptor Interaction and Symmetry / Gerd Folkers, Mine Yarim, Pavel Pospisil 323

10.2 Chirality in QSAR 324

10.3 Molecular Modeling in Chiral Chromatography 325

10.4 Chirality of Protein Residues, Homology Modeling 326

10.5 Chiral Selective Binding, MDS methods 327

10.5.1 DNA 327

10.5.2 Topoisomerase II-DNA Crossover Recognition 328

10.5.3 Chiral Catalysis 328

10.5.4 Chiral Ligand-Receptor Interactions - Proteins 329

10.6 Docking of Chiral Compounds 331

10.7 Molecular Modeling Software Dealing with Chirality and Some References to Its Successful Application 332

10.7.1 ChemDraw 6.0 (CambridgeSoft) - an Example of the Classical Program 333

10.7.2 Chirano - Chirality of Nucleic Acid Chains 333

10.7.3 Corina - Chirality in 3D Structure Generator 334

10.7.4 Omicron from OpenEye Software - Chirality from 1D Formulas 334

10.7.5 Cache Software BioMedCache - Chirality Convention in Semiempirical Calculations 335

10.7.6 Accelrys 335

10.7.7 Schrodinger-Generation of Stereoisomers 335

10.7.8 Tripos - Stereochemistry Module StereoPlex 336

10.7.9 MOE - DAPPER 337.

Notes:

Includes bibliographical references and index.

Local Notes:

Acquired for the Penn Libraries with assistance from the Rosengarten Family Fund.

ISBN:

3527310762

9783527310760

OCLC:

67873889