Art of Process Chemistry

Nobuyoshi Yasuda received his bachelor from Tokyo Institute of Technology under the direction of Professor Teruaki Mukaiyama and Professor Hisashi Takei and his mater degree from the same university under the direction of Professor Hisashi Takei. After working at Fujisawa Pharmaceutical Company, Japan as a Medicinal Chemist, he received Ph. D. from Tokyo Institute of Technology in 1987. After spend one year as a postdoctoral fellow under Professor Robert M. Williams at Colorado State University from 1988 to 1989, he joined in Process Chemistry, Merck Research Laboratories in 1990. He has over 60 publications and over 50 patents.

• Preface xiList of Contributors xv1 Efavirenz ®, a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), and a Previous Structurally Related Development Candidate 1Nobuyoshi Yasuda and Lushi Tan1.1 First Drug Candidate 2 21.1.1 Project Development 21.1.1.1 Medicinal Route 21.1.1.2 Process Development 31.1.2 Chemistry Development 101.1.2.1 Sugasawa Reaction 101.1.2.2 Asymmetric Addition of 2-Pyridinylacetylene Anion to Ketimine 5 and 17 151.2 Efavirenz ® 191.2.1 Project Development 191.2.1.1 Medicinal Route 191.2.1.2 Process Development 201.2.2 Chemistry Development 341.2.2.1 Reaction Mechanism for the Lithium Acetylide Addition to pMB Protected Amino Ketone 41 351.2.2.2 Reaction Mechanism for the Zinc Acetylide Addition to Amino Ketone 36 401.3 Conclusion 41Acknowledgments 41References 422 CCR5 Receptor Antagonist 45Nobuyoshi Yasuda2.1 Project Development 452.1.1 Medicinal Route 452.1.2 Process Development 472.1.2.1 Route Selection for Cyclopentenone 2 472.1.2.2 Process Optimization for Preparation of 2 502.1.2.3 Optimization of the Preparation of Pyrazole 3 572.1.2.4 Optimization of the Preparation of Our Target 1 (End Game) 592.1.2.5 Overall Preparation Scheme 612.2 Chemistry Development 622.2.1 Kinetic Resolution 642.2.2 Modification of Ligands 672.2.3 NMR Studies Revealed the Reaction Mechanism 682.2.4 Additional Studies for Confirmation of the Retention–Retention Mechanism 722.3 Conclusion 74Acknowledgments 74References 743 5α-Reductase Inhibitors – The Finasteride Story 77J. Michael Williams3.1 Project Development 783.1.1 Finasteride 783.1.1.1 The Medicinal Chemistry Route 783.1.1.2 Process Development 803.1.2 The Second Generation Candidates 963.1.2.1 The Medicinal Chemistry Route 963.1.2.2 Process Development 973.2 Chemistry Development 1053.2.1 Mechanistic Studies – the DDQ Oxidation 1053.2.2 A New General Method for the Preparation of Weinreb Amides from Esters 1123.3 Conclusion 113Acknowledgments 113References 1134 Rizatriptan (Maxalt ®): A 5-HT 1D Receptor Agonist 117Cheng-yi Chen4.1 Project Development 1184.1.1 Medicinal Chemistry Route 1184.1.1.1 Problems of the Original Route 1194.1.1.2 Advantages of the Original Route 1194.1.2 Process Development 1194.1.2.1 Convergent Fisher Indole Synthesis 1194.1.2.2 Palladium-Catalyzed Indole Synthesis 1224.2 Chemistry Development 1314.2.2 New Indole Chemistry from Development of Pd Chemistry 1344.2.2.1 Discovery of New Indole Synthesis from Amines 1344.2.2.2 Direct Coupling of Iodoaniline with Ketone 1364.2.2.3 Application to Laropiprant Indole Synthesis 1394.3 Conclusion 141Acknowledgments 141References 1415 SERM: Selective Estrogen Receptor Modulator 143Zhiguo Jake Song5.1 Project Development 1445.1.1 Medicinal Route 1445.1.1.1 Problems of the Original Route 1455.1.2 Process Development 1455.1.2.1 Preparation of Intermediate 15 1475.1.2.2 Quinone Ketal Route to cis-Diaryl Dihydrobenzoxathiin 30 1475.1.2.3 Benzoxathiin Reduction Route to the cis-Diaryl Dihydrobenzoxathiin Intermediate 12 1505.1.2.4 Installation of Pyrrolidinyl Ethanol 1555.1.2.5 Final Deprotection and Isolation of Compound 1 1565.1.2.6 Overall Synthesis Summary 1575.2 Chemistry Development 1575.2.1 Mechanism of the Sulfoxide-Directed Olefin Reduction 1575.2.2 Application of the Sulfoxide-Directed Borane Reduction to Other Similar Compounds 1605.3 Conclusion 162Acknowledgments 162References 1636 HIV Integrase Inhibitor: Raltegravir 165Guy R. Humphrey and Yong-Li Zhong6.1 Project Development 1666.1.1 Medicinal Chemistry Route 1666.1.1.1 Advantages of the Medicinal Chemistry Route 1676.1.1.2 Problems with the Medicinal Chemistry Route 1676.1.2 Process Development 1686.1.2.1 First Generation Manufacturing Process for the Synthesis of 1 1686.1.2.2 Second Generation Manufacturing Process for the Synthesis of 1 1776.2 Further Chemistry Development 1836.2.1 Development of Microwave-Accelerated Thermal Rearrangement 1836.2.2 Mechanistic Studies on the Thermal Rearrangement 1856.3 Conclusion 189Acknowledgments 189References 1907 Cyclopentane-Based NK1 Receptor Antagonist 191Jeffrey T. Kuethe7.1 Project Development Compound 1 1927.1.1 Medicinal Route 1927.1.1.1 Problems of the Original Route 1937.1.2 Process Development 1947.1.2.1 Preparation of Cyclopentanone 27 1957.1.2.2 Conversion of Cyclopentenone 27 to Chiral Hydroxy Acid 26 1997.1.2.3 Etherification of 10 2027.1.2.4 Preparation of (R)-Nipecotate 76 and Completion of the Synthesis of 1 2097.2 Chemistry Development 2117.2.1 Reduction of the Allylic Alcohol 46 with Red-Al ® 2117.2.2 Oxonium Reduction Configuration Issue 2137.2.3 Ether Bond Formation with Chiral Imidate 67 214Acknowledgments 219References 2198 Glucokinase Activator 223Artis Klapars8.1 Project Development 2238.1.1 Medicinal Route 2238.1.1.1 Problems of the Original Route 2248.1.1.2 Advantages of the Original Route 2258.1.2 Process Development 2258.1.2.1 Preparation of Hydroxypyridine Fragment 9 2268.1.2.2 Enantioselective Preparation of the α-Arylpyrrolidine 12 2268.1.2.3 Elaboration of 12 to the Final Product 1 2308.1.2.4 Summary of Process Development 2328.2 Chemistry Development 2328.2.1 Development of Enantioselective α-Arylation of N-Boc Pyrrolidines 2328.2.2 Scope of Enantioselective α-Arylation of N-Boc Pyrrolidines 2348.2.3 Detailed Examination of the Coupling Reaction 2368.3 Conclusion 237Acknowledgments 238References 2389 CB1R Inverse Agonist – Taranabant 241Debra Wallace9.1 Project Development 2429.1.1 Introduction 2429.1.2 Medicinal Chemistry Route 2429.1.3 Initial Strategy – Amide Bond Formation as the Final Step 2439.1.3.1 Amide Bond Formation as the Final Step – Classical Resolution Approach 2449.1.3.2 Amide Bond Formation as the Final Step – Dynamic Kinetic Resolution 2509.2 Further Project Development 2539.2.1 Introduction 2539.2.2 New Synthetic Approach 2549.2.2.1 Enol Triflate Synthesis 2569.2.2.2 Synthesis of a Model Enamide 2589.2.2.3 Preliminary Hydrogenation Studies 2609.2.2.4 Formation of an Enol Tosylate 2619.2.2.5 Amidation of the Enol Tosylate 2629.2.2.6 Asymmetric Hydrogenation of Enamide 22 2659.2.2.7 Use of a Bromosubstituted-Enamide 2679.2.2.8 Use of a “Nitrile Protected” Enamide 2689.2.3 Evaluation and Route Selection 2719.3 Conclusion 273Acknowledgments 273References 273Index 275

"The book will be of great value to students looking to move into a career in process research; the enthusiasm and commitment of the authors comes over in the text, and the attention to detail and emphasis on mechanistic evaluation is a lesson to all. Academics will find much material that can be used in teaching . . . so in conclusion, this is an outstanding book which discusses the art of process research and developing process understanding." (Organic Process, Research & Development Journal, 17 December 2010)