From Bench to Pilot Plant: Process Research in the Pharmaceutical Industry (ACS Symposium Series, No. 817)

The ACS Symposium Series was first published in 1974 to provide a mechanism for publishing symposia quickly in book form. The purpose of the series is to publish timely, comprehensive books developed from ACS sponsored symposia based on current scientific research. Occasion-ally, books are developed from symposia sponsored by other organizations when the topic is of keen interest to the chemistry audience. Before agreeing to publish a book, the proposed table of contents is reviewed for appropriate and comprehensive coverage and for interest to the audience. Some papers may be excluded to better focus the book; others may be added to provide comprehensiveness. When appropriate, overview or introductory chapters are added. Drafts of chapters are peer-reviewed prior to final acceptance or rejection, and manuscripts are prepared in camera-ready format. As a rule, only original research papers and original review papers are included in the volumes. Verbatim reproductions of previously published papers are not accepted. ACS SYMPOSIUM SERIES 817 fw001 1 Title Page 1 Half Title Page 3 Copyright 4 Foreword 5 pr001 6 Preface 6 1 9 Chapter 1 Anatomy of Process Research and Development 9 I. Introduction 9 II. The Drug Development Cycle 10 III. Scale-up of Chemical Processes 12 IV. The Role of Chemical Development 13 V. Optimization in Chemical Development 14 VI. Process Safety 17 VII. Environmental Safety 18 VIII. Conclusion 21 References 22 2 23 Chapter 2 Design and Development of Practical Syntheses of MRSA Carbapenems 23 References 36 3 38 Chapter 3 Synthesis of Steroid 'Antedrugs' for Evaluation as Safe Treatments for Asthma: Practical Synthesis of the Inhaled Steroid GR250495X 38 Synthesis of GR250495X 41 Route 1 41 Route 1a 43 Route 2 45 Route 3 48 Summary 50 Acknowledgements 50 References 50 4 52 Chapter 4 Development of a Catalytic, Asymmetric Michael Addition in the Synthesis of Endothelin Antagonist ABT-546 52 Early Synthetic Work 53 Development of the Michael Addition 56 Optimization 56 Synthesis of ABT-546 59 Nitroketone synthesis 59 Pyrrolidine synthesis 61 End game 62 Scope of the Michael Addition 62 Summary 65 References 65 5 67 Chapter 5 Process Chemistry: Creativity in Large Scale: Lessons from Scale-Up 67 Fully Developed Process 70 A Validated/Developed Process 71 Process Freeze Points 91 Acknowledgments 91 References 92 6 94 Chapter 6 Synthesis of RO 113-0830, a Matrix Metalloproteinase Inhibitor: From Research Scheme to Pilot-Plant Production 94 Process Chemistry 95 Medicinal Chemistry Synthesis 95 Final API Production Step 95 Final Intermediate Issues 97 Critical Bond Forming Reaction 99 Supply of Advanced Intermediates 101 Synthesis of p-chloro-p'-thiophenyl ether 101 Synthesis of Pyran Esters 103 Current Plant Synthesis 104 References 104 7 106 Chapter 7 Four Generations of Pyrrolopyrimidines 106 References 117 8 118 Chapter 8 Synthesis, Discovery, and Separation of the Atropisomers of CP-465,022 118 References 137 9 138 Chapter 9 Practical Convergent Synthesis of SERM 2 138 Experimental 143 References 145 ix001 146 Author Index 146 ix002 147 Subject Index 147 A 147 B 147 C 147 D 148 E 148 F 149 G 149 H 149 L 149 M 149 N 150 O 150 P 150 R 151 S 151 T 152 V 152 W 153 The ACS Symposium Series was first published in 1974 to provide a mechanism for publishing symposia quickly in book form. The purpose of the series is to publish timely,comprehensive books developed from ACS sponsored symposia based on current scientific research. Occasion-ally,books are developed from symposia sponsored by other organizations when the topic is of keen interest to the chemistry audience. Provides examples of successful process development in the pharmaceutical industry. The nine chapters share considerations for selecting reagents, solvent, concentrations, temperatures, pH, and stir rates during the scale-up stage. Topics include the synthesis of steroid antedrugs for evaluation as safe treatments for asthma, the development of a catalytic assymmetric Michael addition in the synthesis of endothelin antagonist ABT-546, four generations of pyrrolopyimidines, and the separation of two rotational isomers of CP- 465,022. The volume examines the bridges between research, product development and manufacturing, examines the transfer of small scale research results to a marketable product through stages of scale up, and discusses how to alleviate the problems of high cost, environmental concerns, and safety
From Bench to Pilot Plant: Process Research in the Pharmaceutical Industry examines the bridges between research, product development and manufacturing. The volume examines the transfer of small scale research results to a marketable product through stages of scale up and discusses how to alleviate the problems of high cost, environmental concerns, and safety. Chapters include advances in technology of product development, and transferring modern research methodologies to scale up and manufacturing. Annotation ^IFrom Bench to Pilot Plant: Process Research in the Pharmaceutical Industry^R examines the bridges between research, product development and manufacturing. The volume examines the transfer of small scale research results to a marketable product through stages of scale up and discusses how to alleviate the problems of high cost, environmental concerns, and safety. Chapters include advances in technology of product development, and transferring modern research methodologies to scale up and manufacturing This volume explains the process development for chemists working in the pharmaceutical industry, from the design of the molecule and its synthesis to scale-up chemical modification which meets operational and cost-effective needs to organic revision of the synthetic pathway for safety and extended manufacturing In this report we would like to discuss the importance of process development in the pharmaceutical industry.