Table of Contents

Preface xi

List of Contributors xv

1 Efavirenz ®, a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), and a Previous Structurally Related Development Candidate 1
Nobuyoshi Yasuda and Lushi Tan

1.1 First Drug Candidate 2 2

1.1.1 Project Development 2

1.1.1.1 Medicinal Route 2

1.1.1.2 Process Development 3

1.1.2 Chemistry Development 10

1.1.2.1 Sugasawa Reaction 10

1.1.2.2 Asymmetric Addition of 2-Pyridinylacetylene Anion to Ketimine 5 and 17 15

1.2 Efavirenz ® 19

1.2.1 Project Development 19

1.2.1.1 Medicinal Route 19

1.2.1.2 Process Development 20

1.2.2 Chemistry Development 34

1.2.2.1 Reaction Mechanism for the Lithium Acetylide Addition to pMB Protected Amino Ketone 41 35

1.2.2.2 Reaction Mechanism for the Zinc Acetylide Addition to Amino Ketone 36 40

1.3 Conclusion 41

Acknowledgments 41

References 42

2 CCR5 Receptor Antagonist 45
Nobuyoshi Yasuda

2.1 Project Development 45

2.1.1 Medicinal Route 45

2.1.2 Process Development 47

2.1.2.1 Route Selection for Cyclopentenone 2 47

2.1.2.2 Process Optimization for Preparation of 2 50

2.1.2.3 Optimization of the Preparation of Pyrazole 3 57

2.1.2.4 Optimization of the Preparation of Our Target 1 (End Game) 59

2.1.2.5 Overall Preparation Scheme 61

2.2 Chemistry Development 62

2.2.1 Kinetic Resolution 64

2.2.2 Modification of Ligands 67

2.2.3 NMR Studies Revealed the Reaction Mechanism 68

2.2.4 Additional Studies for Confirmation of the Retention–Retention Mechanism 72

2.3 Conclusion 74

Acknowledgments 74

References 74

3 5α-Reductase Inhibitors – The Finasteride Story 77
J. Michael Williams

3.1 Project Development 78

3.1.1 Finasteride 78

3.1.1.1 The Medicinal Chemistry Route 78

3.1.1.2 Process Development 80

3.1.2 The Second Generation Candidates 96

3.1.2.1 The Medicinal Chemistry Route 96

3.1.2.2 Process Development 97

3.2 Chemistry Development 105

3.2.1 Mechanistic Studies – the DDQ Oxidation 105

3.2.2 A New General Method for the Preparation of Weinreb Amides from Esters 112

3.3 Conclusion 113

Acknowledgments 113

References 113

4 Rizatriptan (Maxalt ®): A 5-HT 1D Receptor Agonist 117
Cheng-yi Chen

4.1 Project Development 118

4.1.1 Medicinal Chemistry Route 118

4.1.1.1 Problems of the Original Route 119

4.1.1.2 Advantages of the Original Route 119

4.1.2 Process Development 119

4.1.2.1 Convergent Fisher Indole Synthesis 119

4.1.2.2 Palladium-Catalyzed Indole Synthesis 122

4.2 Chemistry Development 131

4.2.2 New Indole Chemistry from Development of Pd Chemistry 134

4.2.2.1 Discovery of New Indole Synthesis from Amines 134

4.2.2.2 Direct Coupling of Iodoaniline with Ketone 136

4.2.2.3 Application to Laropiprant Indole Synthesis 139

4.3 Conclusion 141

Acknowledgments 141

References 141

5 SERM: Selective Estrogen Receptor Modulator 143
Zhiguo Jake Song

5.1 Project Development 144

5.1.1 Medicinal Route 144

5.1.1.1 Problems of the Original Route 145

5.1.2 Process Development 145

5.1.2.1 Preparation of Intermediate 15 147

5.1.2.2 Quinone Ketal Route to cis-Diaryl Dihydrobenzoxathiin 30 147

5.1.2.3 Benzoxathiin Reduction Route to the cis-Diaryl Dihydrobenzoxathiin Intermediate 12 150

5.1.2.4 Installation of Pyrrolidinyl Ethanol 155

5.1.2.5 Final Deprotection and Isolation of Compound 1 156

5.1.2.6 Overall Synthesis Summary 157

5.2 Chemistry Development 157

5.2.1 Mechanism of the Sulfoxide-Directed Olefin Reduction 157

5.2.2 Application of the Sulfoxide-Directed Borane Reduction to Other Similar Compounds 160

5.3 Conclusion 162

Acknowledgments 162

References 163

6 HIV Integrase Inhibitor: Raltegravir 165
Guy R. Humphrey and Yong-Li Zhong

6.1 Project Development 166

6.1.1 Medicinal Chemistry Route 166

6.1.1.1 Advantages of the Medicinal Chemistry Route 167

6.1.1.2 Problems with the Medicinal Chemistry Route 167

6.1.2 Process Development 168

6.1.2.1 First Generation Manufacturing Process for the Synthesis of 1 168

6.1.2.2 Second Generation Manufacturing Process for the Synthesis of 1 177

6.2 Further Chemistry Development 183

6.2.1 Development of Microwave-Accelerated Thermal Rearrangement 183

6.2.2 Mechanistic Studies on the Thermal Rearrangement 185

6.3 Conclusion 189

Acknowledgments 189

References 190

7 Cyclopentane-Based NK1 Receptor Antagonist 191
Jeffrey T. Kuethe

7.1 Project Development Compound 1 192

7.1.1 Medicinal Route 192

7.1.1.1 Problems of the Original Route 193

7.1.2 Process Development 194

7.1.2.1 Preparation of Cyclopentanone 27 195

7.1.2.2 Conversion of Cyclopentenone 27 to Chiral Hydroxy Acid 26 199

7.1.2.3 Etherification of 10 202

7.1.2.4 Preparation of (R)-Nipecotate 76 and Completion of the Synthesis of 1 209

7.2 Chemistry Development 211

7.2.1 Reduction of the Allylic Alcohol 46 with Red-Al ® 211

7.2.2 Oxonium Reduction Configuration Issue 213

7.2.3 Ether Bond Formation with Chiral Imidate 67 214

Acknowledgments 219

References 219

8 Glucokinase Activator 223
Artis Klapars

8.1 Project Development 223

8.1.1 Medicinal Route 223

8.1.1.1 Problems of the Original Route 224

8.1.1.2 Advantages of the Original Route 225

8.1.2 Process Development 225

8.1.2.1 Preparation of Hydroxypyridine Fragment 9 226

8.1.2.2 Enantioselective Preparation of the α-Arylpyrrolidine 12 226

8.1.2.3 Elaboration of 12 to the Final Product 1 230

8.1.2.4 Summary of Process Development 232

8.2 Chemistry Development 232

8.2.1 Development of Enantioselective α-Arylation of N-Boc Pyrrolidines 232

8.2.2 Scope of Enantioselective α-Arylation of N-Boc Pyrrolidines 234

8.2.3 Detailed Examination of the Coupling Reaction 236

8.3 Conclusion 237

Acknowledgments 238

References 238

9 CB1R Inverse Agonist – Taranabant 241
Debra Wallace

9.1 Project Development 242

9.1.1 Introduction 242

9.1.2 Medicinal Chemistry Route 242

9.1.3 Initial Strategy – Amide Bond Formation as the Final Step 243

9.1.3.1 Amide Bond Formation as the Final Step – Classical Resolution Approach 244

9.1.3.2 Amide Bond Formation as the Final Step – Dynamic Kinetic Resolution 250

9.2 Further Project Development 253

9.2.1 Introduction 253

9.2.2 New Synthetic Approach 254

9.2.2.1 Enol Triflate Synthesis 256

9.2.2.2 Synthesis of a Model Enamide 258

9.2.2.3 Preliminary Hydrogenation Studies 260

9.2.2.4 Formation of an Enol Tosylate 261

9.2.2.5 Amidation of the Enol Tosylate 262

9.2.2.6 Asymmetric Hydrogenation of Enamide 22 265

9.2.2.7 Use of a Bromosubstituted-Enamide 267

9.2.2.8 Use of a “Nitrile Protected” Enamide 268

9.2.3 Evaluation and Route Selection 271

9.3 Conclusion 273

Acknowledgments 273

References 273

Index 275