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Chirality in drug research / edited by Eric Francotte, Wolfgang Lindner. — KGaA, Weinheim, DE : Wiley-VCH, c2006.—(63.326/C611) |
Contents
Contents
Introduction
1 Chiral Drugs from a Historical Point of View 3
Joseph Cal
1.1 Introduction 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
References 24
Synthesis
2 Stereoselective Synthesis of Drugs-An Industrial Perspective 29
Hans-Jurgen Federsel
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
2.7 Retrospect and Prospect 59
References 62
3 Aspects of Chirality in Natural Products Drug Discovery 67
Philipp Krastel， Frank Petersen， Silvio Roggo， Esther Schrnitt， and Ansgar Schuffenhauer
3.1 Introduction 67
3.2 Stereochemical Aspects of Natural Products 71
3.3 Mechanisms of Stereochemical Control in Natural Product Biosynthesis 77
3.4 Biological Activity of Natural Products Related to Stereochemistry 83
References 90
4 Biotransformation Methods for Preparing Chiral Drugs and Drug Intermediates 95
Michael Muller and Marcel Wubbolts
4.1 Introduction 95
4.2 Examples of Established Applications of Biocatalysts in the Synthesis of Pharmaceuticals 96
4.3 Some Special Aspects of Biocatalysts， Recent Developments 111
4.4 Conclusions and Outlook 119
References 120
Separations
5 Resolution of Chiral Drugs and Drug Intermediates by Crystallization 127
Kazuhiko Saigo
5.1 Introduction 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
5.6 Examples of Enantioseparations in the Pharmaceutical Industry 149
References 152
6 Isolation and Production of Optically Pure Drugs by Enantioselective Chromatography 155
Eric Francotte
6.1 Introduction 155
6.2 General Considerations Regarding the Preparation of Single Stereoisomers of Chiral Drugs 156
6.3 Preparative Chiral Stationary Phases 158
6.4 Strategies for Performing Enantioselective Separations 168
6.5 Preparative Enantioselective Resolution of Chiral Drugs 172
6.5 Other Enantioselective Chromatographic Techniques 179
6.6 Conclusion 181
References 182
7 Stereoselective Chromatographic Methods for Drug Analysis 189
Norber M. Maier and Wolfgang Lindner 189
7.1 Introduction 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
7.5 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
7.9 Conclusions 244
References 245
8 Capillary Electrophoresis Coupled to Mass Spectrometry for Chira Drugs Analysis 261
Serge Rudaz andJean-Luc Veuthey
8.1 Introduction 261
8.2 Capillary Electrophoresis (CE) 262
8.3 CE-MS Coupling 263
8.4 Chiral Separation Strategies 265
8.5 Partial Filling 268
8.6 Partial Filling - Counter Current Technique 270
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
8.10 Discussion and Conclusion 278
References 280
9 Powerful Chiral Molecular Tools for Preparation of Enantiopure Alcohols and Simultaneous Determination of Their Absolute Configurations by X-Ray Crystallography and/or 1H NMR Anisotropy Methods 283
Nobuyuki Harada
9.1 Introduction 283
9.2 Methodologies for Determining Absolute Configuration 284
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)propior Acid (MαNP Acid (S)-(+)-3)， Useful for Enantioresolution of Alcohols and Simultaneous Determination of Their Absolute Configurations by the 1H NMR Anisotropy Method 295
9.5 Absolute Configuration of the Thyroid Hormone Analog ICAT-2 as Determined by the 1H NMR Anisotropy Method with MαNP Acid 314
9.6 Conclusion 319
References 319
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 323
Gerd Folkers， Mine Yarim， and Pavel Pospisil
10.1 Introduction 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
10.6 Docking of Chiral Compounds 331
10.7 Molecular Modeling Software Dealing with Chirality and Some References to Its Successful Application 332
References 338
Subject Index 341
