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Book Details
Abstract
In recent years, a significant amount of progress has been made using green chemistry in the synthesis of synthetically useful compounds and molecules by replacing hazardous chemicals with greener alternatives. However, there is still room for improvement, especially in the pharmaceutical sector where new drugs are being formulated. This book examines green approaches to overcoming hazardous organic transformations. Summarizing recent developments, the book features a detailed description of some of the high impact active pharmaceutical ingredients that have been developed considering green chemistry approaches. It explores the design, engineering and process development and the calculations to account for waste. The book includes strategies to further advance green approaches in the development of generic pharmaceutical industries and features novel, innovative approaches that promote waste-free organic synthesis. This book is of interest to industrialists working in pharmaceuticals and researchers working in green chemistry.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Cover | Cover | ||
| Foreword | vii | ||
| Introduction | ix | ||
| Contents | xi | ||
| Chapter 1 Introduction to Hazardous Reagent Substitution in the Pharmaceutical Industry | 1 | ||
| 1.1 Role of Reagents in the Development of Organic Synthesis | 1 | ||
| 1.1.1 Inorganic Material in the Synthesis of APIs | 2 | ||
| 1.1.2 Organic Material in the Synthesis of APIs | 2 | ||
| 1.2 Process Mass Intensity (PMI) | 3 | ||
| 1.3 Stoichiometry of the Reagent | 4 | ||
| 1.4 Green Chemistry: Selection of Reagent | 5 | ||
| 1.5 Positive Impacts of Hazardous Reagent Substitution During Manufacturing | 6 | ||
| 1.6 Catalysts: Alternative Reaction Facilitators | 7 | ||
| 1.7 Nature of Reagents | 8 | ||
| 1.8 Rationale of Chapters Recommended for the Book | 11 | ||
| 1.9 Conclusions and Prospects | 13 | ||
| References | 15 | ||
| Chapter 2 Recyclability of Reagents | 18 | ||
| 2.1 Introduction | 18 | ||
| 2.2 Overview of Pharmaceutical Wastes | 19 | ||
| 2.2.1 Hazardous Pharmaceutical Wastes | 20 | ||
| 2.2.2 Non-hazardous Pharmaceutical Waste | 22 | ||
| 2.2.3 How do Pharmaceuticals Enter the Environment? | 22 | ||
| 2.3 Reagents Used in Process Development | 23 | ||
| 2.3.1 Solvent Utilization | 23 | ||
| 2.3.2 Role of Catalysts | 25 | ||
| 2.3.3 Pharma Packaging Materials | 27 | ||
| 2.4 Process Efficiency Metrics | 28 | ||
| 2.4.1 Atom Economy | 28 | ||
| 2.4.2 E factor | 29 | ||
| 2.4.3 Reaction Mass Efficiency | 30 | ||
| 2.4.4 Process Mass Intensity (PMI) | 30 | ||
| 2.4.5 Carbon efficiency | 31 | ||
| 2.5 Waste Management Practices Across the World | 31 | ||
| 2.5.1 Pharmaceutical Industry Wastewater and Its Treatment | 31 | ||
| 2.5.2 Case studies | 36 | ||
| 2.6 Conclusion | 49 | ||
| References | 49 | ||
| Chapter 3 Recoverable Polymer-supported DMAP Derivatives | 53 | ||
| 3.1 Introduction | 53 | ||
| 3.2 History | 54 | ||
| 3.3 Recovery Strategies of Soluble Polymer-supported Species | 54 | ||
| 3.4 DMAP | 57 | ||
| 3.4.1 DMAP Preparation | 57 | ||
| 3.4.2 Insoluble Polymer-supported DMAP | 58 | ||
| 3.4.3 Soluble Polymer-supported DMAP | 59 | ||
| 3.5 Polymer-supported DBU | 64 | ||
| 3.6 Polymer-supported TBD | 66 | ||
| 3.7 Conclusion | 68 | ||
| References | 69 | ||
| Chapter 4 Synthesis of Atorvastatin | 72 | ||
| 4.1 Introduction | 72 | ||
| 4.2 Medical Chemistry Route | 73 | ||
| 4.2.1 Synthetic Strategy | 73 | ||
| 4.2.2 Synthesis of Pyrrole Unit | 74 | ||
| 4.2.3 Elaboration of Aldehyde Intermediate 12 to Atorvastatin | 75 | ||
| 4.3 Process Development Route | 76 | ||
| 4.3.1 Synthetic Strategy | 76 | ||
| 4.3.2 Synthesis of 1,4-Diketone Component 18 | 77 | ||
| 4.3.3 Synthesis of Amine Side-chain Component 19 | 77 | ||
| 4.3.4 Paal-Knorr Reaction and Downstream Steps | 82 | ||
| 4.4 The Final Manufacturing Route Involving Non-hazardous Reagents | 83 | ||
| 4.4.1 Strategy | 83 | ||
| 4.4.2 1,4-Diketone Component 18 | 83 | ||
| 4.4.3 Side-chain Component 19 | 84 | ||
| 4.4.4 Endgame | 85 | ||
| 4.5 Conclusions | 86 | ||
| Acknowledgments | 87 | ||
| References | 87 | ||
| Chapter 5 Synthesis of Raloxifene | 90 | ||
| 5.1 Synthesis of Raloxifene | 90 | ||
| 5.2 Importance of Raloxifene | 91 | ||
| 5.3 First-generation Synthesis | 92 | ||
| 5.4 Second-generation Synthesis | 94 | ||
| 5.5 Third-generation Synthesis | 96 | ||
| 5.6 Transitioning from Hazardous to Non-hazardous Reagent Use | 98 | ||
| 5.7 Conclusion | 99 | ||
| Acknowledgments | 100 | ||
| References | 101 | ||
| Chapter 6 Synthesis of Montelukast | 102 | ||
| 6.1 Introduction | 102 | ||
| 6.2 Medicinal Chemistry Route | 103 | ||
| 6.2.1 Synthetic Strategy | 103 | ||
| 6.2.2 Synthesis of Diol Intermediate 13 | 103 | ||
| 6.2.3 Synthesis of Thiol Acid (20) | 105 | ||
| 6.2.4 Synthesis of Montelukast (free acid of 1) | 105 | ||
| 6.3 Process Development Route | 105 | ||
| 6.3.1 Synthetic Strategy | 105 | ||
| 6.3.2 Synthesis of Diol 13 and Thiol Acid 20 | 108 | ||
| 6.3.3 Synthesis of Montelukast Sodium 1 from 13 and 20 | 108 | ||
| 6.4 Final Manufacturing Route Involving Non-hazardous Reagents | 109 | ||
| 6.4.1 Synthetic Strategy | 109 | ||
| 6.4.2 Synthesis of Diol Intermediate | 109 | ||
| 6.4.3 Synthesis of Montelukast Sodium 1 | 113 | ||
| 6.5 Summary | 115 | ||
| Acknowledgments | 115 | ||
| References | 115 | ||
| Chapter 7 Development of a Safe, Scalable, Azide-free Synthesis of 1-Aryl-1H-tetrazoles Using Diformylhydrazine | 118 | ||
| 7.1 Introduction | 118 | ||
| 7.2 Results and Discussion | 121 | ||
| 7.3 Conclusion | 125 | ||
| 7.4 Representative Procedure | 127 | ||
| Acknowledgments | 127 | ||
| References | 127 | ||
| Chapter 8 New Directions from Academia | 130 | ||
| 8.1 Introduction | 130 | ||
| 8.2 Green Chemistry: A Functional Approach Winning Industrial Support | 133 | ||
| 8.3 Need for Academia-Industry Collaborations in the Current Scenario | 133 | ||
| 8.4 Impediments to Collaboration | 135 | ||
| 8.5 Keys to a Successful Collaboration | 136 | ||
| 8.6 Greening of Industries: Promoting Newer and Greener Methodologies from Academia | 137 | ||
| 8.7 Benefits of Greening Industries | 139 | ||
| 8.8 Innovations Stemming from Academia-Pharma Collaborations | 140 | ||
| 8.8.1 Academic Contribution to Drug Discovery | 140 | ||
| 8.8.2 Design and Development of Novel Pathways for Pharmaceutical Industries | 149 | ||
| 8.9 Redefining the Operational Methods of Global Industries Towards Sustainability | 157 | ||
| 8.9.1 Green Solvents | 157 | ||
| 8.9.2 Next-generation Catalyst Design | 158 | ||
| 8.9.3 Microwave-assisted Synthesis | 159 | ||
| 8.9.4 Flow Chemistry | 160 | ||
| 8.10 Conclusion | 161 | ||
| References | 162 | ||
| Subject Index | 168 |