
At a Glance
Hardcover
380 Pages
380 Pages
Dimensions(cm)
23.39 x 15.6 x 2.24
23.39 x 15.6 x 2.24
Hardcover
$413.75
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This book will provide a comprehensive, step-by-step approach to organic process research and development in the pharmaceutical, fine
chemical, and agricultural chemical industries. Process R&D describes the steps taken, following synthesis and evaluation, to bring key
compounds to market in a cost-effective manner. More people are being hired for work in this area as increasing numbers of drug candidates are
identified through combinatorial chemistry and high-throughput screening. The book is directed to industrial (primarily organic) chemists, and
academicians (particularly those involved in a growing number of start-up companies) and students who need insight into industrial process R&D. Current books do not describe hands-on, step-by-step, approaches to solving process development problems, including route, reagent,
and solvent selection; optimising catalytic reactions; chiral syntheses; and "green chemistry." "Practical Process Research and Development" will be a valuable resource for researchers, managers, and graduate students.
* Provides insights into generating rugged, practical, cost-effective processes for the chemical preparation of "small molecules"
* Breaks down process optimization into route, reagent and solvent selection, development of reaction conditions, workup, crystallizations and more
* Includes over 100 tips for rapid process development
* Presents guidelines for implementing and troubleshooting processes
chemical, and agricultural chemical industries. Process R&D describes the steps taken, following synthesis and evaluation, to bring key
compounds to market in a cost-effective manner. More people are being hired for work in this area as increasing numbers of drug candidates are
identified through combinatorial chemistry and high-throughput screening. The book is directed to industrial (primarily organic) chemists, and
academicians (particularly those involved in a growing number of start-up companies) and students who need insight into industrial process R&D. Current books do not describe hands-on, step-by-step, approaches to solving process development problems, including route, reagent,
and solvent selection; optimising catalytic reactions; chiral syntheses; and "green chemistry." "Practical Process Research and Development" will be a valuable resource for researchers, managers, and graduate students.
* Provides insights into generating rugged, practical, cost-effective processes for the chemical preparation of "small molecules"
* Breaks down process optimization into route, reagent and solvent selection, development of reaction conditions, workup, crystallizations and more
* Includes over 100 tips for rapid process development
* Presents guidelines for implementing and troubleshooting processes
Industry Reviews
"... A must reference on every process chemists (both the novice and the experienced practitioner) desk. This will be required reading by all new chemists, engineers and analysts in my department." --Sean T. Nugent, Searle Research & Development "Practical Process Research & Development is just that, practical... Especially enjoyable are author Neal G. Anderson's pithy 'tips'... Fun chemistry throughout." --CHEMICAL INNOVATION. June 2000 "The new volume by Dr. Anderson ranks with the very best on the subject covering almost all aspects of process research and development and scale up in an informative and readable manner. ...the many "Tips" given throughout the book are practical and informative and should be mandatory reading for all synthetic organic chemists, including those in research and discovery. ...could well become a standard text on the subject. Indeed, it is my recommendation that Process Chemistry departments throughout the industry buy two copies, one for themselves and one to help educate their colleagues in research/discovery. Many of the topics covered and the tips given in the book could also be of great use to anyone organizing organic chemistry practical courses for students. Perhaps the highest praise one can give this book is to say that Foreword by Barry Sharpless raises very high expectations and the book meets and at times exceed those expectations." --ORGANIC PROCESS RESEARCH & DEVELOPMENT, Vol.4, No.5, 2000 "Following enthusiastic Forwards by Barry Sharpless and Jerry Moniot, each chapter of the book addresses commonly encountered aspects of large-scale synthesis. Drawing extensively from literature case studies for illustration, Anderson also sprinkles useful tips throughout the text, while his use of lists, tables, and charts aids in reinforcing key concepts. The text readily succeeds as a highly practical tour throughout the considerations of chemical scale-up. Newly minted chemists will find this a valuable introductory text, while veteran researchers will also glean much from Anderson's extensive experience. The book can easily be recommended as a reading for a graduate organic synthesis course. Medicinal chemists may find this trove of practical synthetic know-how quite useful in their drug discovery programs. Certainly all readers will better appreciate the challenges faced by process chemists in bringing a compound through development and commercialization." --Christopher R. Schmid, Senior Research Scientist, Lilly Research Laboratories, Eli Lilly and Company, JOURNAL OF MEDICINAL CHEMISTRY, 2001, Vol. 44, No.7 "In summary, we believe that every newcomer to the exciting field of process research and development should read this book, but also experienced process chemists and even academics will find it very useful and stimulating. As the language of stock analysts and brokers is very popular today, we recommend Practical Process Research and Development, by Neal G. Anderson, as a "strong buy" because this investment will pay off very quickly." --ANGEWANDTE CHEMIE, 2001, 40, No. 7. "...Filled with valuable insights and personal experience... Dr. Anderson's book is indeed the best text on process development available to organic chemists. I have bought several for my group." --ADVANCED SYNTHESIS & CATALYSIS, 2001, Oljan Repic, Director of Process R&D, Novartis Institute for Biomedical Research
| Foreword | p. xv |
| Foreword | p. xix |
| Preface | p. xxi |
| About the Author | p. xxiii |
| Approaches to Process Development | |
| Introduction | p. 1 |
| The Importance of Simple Scale-up Operations | p. 5 |
| The Importance of Teamwork | p. 8 |
| Determining Operations That Can and Cannot Readily Be Used On Scale | p. 8 |
| Rotary Evaporation | p. 11 |
| Concentrating to Dryness | p. 11 |
| Triturating | p. 12 |
| Flammable Solvents | p. 13 |
| Decanting and Siphoning | p. 13 |
| Column Chromatography for Purification | p. 13 |
| Drying over Solid Desiccants | p. 14 |
| Drying Solutions by Azeotropic Distillation | p. 14 |
| Addition of Dangerous Reagents | p. 14 |
| Extended Additions | p. 15 |
| Maintaining Cryogenic Temperature | p. 15 |
| Fine Control of Heating and Cooling | p. 15 |
| Maintaining Constant pH | p. 16 |
| Efficient Mixing of Heterogeneous Systems | p. 16 |
| Tubular Flow Reactors | p. 16 |
| Rapid Quench and Transfers | p. 17 |
| Distillation | p. 17 |
| Solvent Displacement by Distillation (Solvent Chasing) | p. 17 |
| Reslurry | p. 17 |
| Charcoal Treatment | p. 17 |
| Filtration of Solid Particles | p. 18 |
| Drying Solids | p. 18 |
| Lyophilization | p. 18 |
| Safety Considerations | p. 19 |
| Taking Advantage of Serendipity and Good Observations | p. 20 |
| Define the Time Available for Process Optimization | p. 21 |
| References | p. 24 |
| Route Selection | |
| Introduction | p. 27 |
| Characteristics of Expedient Routes | p. 28 |
| Familiarity | p. 28 |
| Technical Feasibility | p. 28 |
| Availability of Suitable Equipment | p. 28 |
| Characteristics of Cost-Effective Routes | p. 30 |
| Technical Feasibility | p. 30 |
| Availability of Suitable Equipment | p. 30 |
| Long-Term Availability of Inexpensive Reagents and Starting Materials | p. 31 |
| Convergent Synthesis | p. 32 |
| Using Telescopic Work-ups | p. 34 |
| Minimizing Impact from Protecting Groups | p. 34 |
| Minimizing Number of Steps | p. 36 |
| Avoiding Adjusting Oxidation States | p. 38 |
| Enantiospecific and Stereospecific Reactions | p. 39 |
| Incorporating Unexpected Processing | p. 40 |
| Incorporating Rearrangements | p. 40 |
| Focusing on a Common Penultimate or Key Intermediate | p. 41 |
| Facile Rework for Final Product and Intermediates | p. 42 |
| Patent Protection for Manufacturing Route | p. 42 |
| Minimized Environmental Impact | p. 43 |
| Using Cost Estimates to Assess the Ultimate Route | p. 46 |
| Summary | p. 50 |
| References | p. 50 |
| Reagent Selection | |
| Introduction | p. 53 |
| The Ideal Reagent for Scale-up | p. 53 |
| Importance of Writing a Balanced Equation | p. 54 |
| Safety and Toxicity Considerations | p. 55 |
| Cost of Reagents | p. 56 |
| Atom Efficiency | p. 60 |
| Families of Reagents Useful for Scale-up | p. 61 |
| Reagents for Deprotonation | p. 61 |
| Alkoxide Bases | p. 62 |
| Amine Bases | p. 63 |
| Oxidations | p. 67 |
| Reductants | p. 71 |
| Hydroboration | p. 71 |
| Catalytic Reagents | p. 73 |
| Polymeric Reagents | p. 73 |
| Biocatalysts as Preparative Reagents | p. 76 |
| References | p. 78 |
| Solvent Selection | |
| Introduction | p. 81 |
| Solvation and Primary Solvent Characteristics | p. 81 |
| Primary Solvent Characteristics | p. 83 |
| Selecting Solvents Based on Physical Characteristics | p. 83 |
| Solvents Inappropriate for Scale-up | p. 84 |
| Solvents Useful for Scale-up | p. 85 |
| Selected Solvent Impurities | p. 89 |
| Applications of Solvents | p. 91 |
| Choosing Solvents for Homogeneous Reactions | p. 91 |
| Choosing Solvents to Increase the Desired Reaction Rate | p. 94 |
| Choosing Solvents to Provide Heterogeneous Reaction Conditions | p. 96 |
| Choosing Solvents to Increase the "Stir-ability" of Reactions | p. 97 |
| Choosing Solvents to Remove Impurities by Azeotropic Distillation | p. 98 |
| Choosing Solvents to Remove Impurities by Adding an Immisicible Solvent and Extraction | p. 99 |
| Choosing Solvents to Remove By-products by Crystallization or Precipitation | p. 100 |
| Choosing Solvents to Purify the Product by Crystallization or Recrystalization | p. 100 |
| Choosing Solvents to Increase the Safety of Operations | p. 100 |
| Choosing Solvents to Decrease Atmospheric Emissions and Losses to Process Streams | p. 101 |
| Choosing Readily Available Solvents | p. 101 |
| Choosing Solvents to Decrease Immediate Contributions to Overall Product Cost | p. 102 |
| Alternatives to Classical Solvents | p. 102 |
| Water | p. 102 |
| Neat Reactions | p. 106 |
| Possible Future Directions | p. 107 |
| References | p. 108 |
| Running the Reaction | |
| Introduction | p. 113 |
| Determining Reaction Safety | p. 113 |
| Assessing Safe Operating Conditions for the Laboratory | p. 115 |
| Selecting the Reaction Scale | p. 116 |
| Choose Equivalents of Reagents, Starting Materials, and Solvents | p. 117 |
| Employ Inert Conditions if Needed | p. 121 |
| Charge Starting Materials and Solvents | p. 122 |
| Select Reaction Temperature | p. 122 |
| Select the Duration and Temperature of an Addition | p. 124 |
| Select the Sequence of Additions | p. 128 |
| Select Reaction Pressure | p. 129 |
| Adjust Stirring | p. 131 |
| Monitor the Reaction Conditions | p. 132 |
| References | p. 133 |
| Effects of Water | |
| Introduction | p. 135 |
| Detecting and Quantitating Water | p. 136 |
| Removing Water from Routine Organic Processing | p. 137 |
| Entry of Water through Processing Air | p. 138 |
| Entry of Water through Solvents | p. 139 |
| Entry of Water through Reagents | p. 140 |
| Formation of Water as a By-product and Its Removal | p. 142 |
| Removing Water from Processing Equipment | p. 142 |
| References | p. 143 |
| In-Process Controls | |
| Introduction | p. 145 |
| The Importance of IPC for Processes Filed with the FDA | p. 147 |
| Choosing the Appropriate IPC | p. 148 |
| Generating Reproducible IPCs | p. 154 |
| Obtaining a Representative Sample of the Process Stream | p. 154 |
| Reproducible Sample Preparation | p. 156 |
| In-Line Assays | p. 159 |
| Generating Reproducible Assay Data | p. 161 |
| References | p. 163 |
| Optimizing the Reaction by Minimizing Impurities | |
| Introduction | p. 165 |
| Steps to Optimizing Reactions | p. 168 |
| Optimizing Reaction Temperature | p. 170 |
| Optimizing Number of Reagent Equivalents | p. 171 |
| Optimizing Addition of Reagents | p. 171 |
| Optimizing Use of Solvents and Cosolvents | p. 172 |
| Optimizing Reaction Concentration | p. 175 |
| Changing Reagents and Intermediates | p. 176 |
| Optimizing Catalysts and Ligands | p. 178 |
| Optimizing Stirring | p. 178 |
| Importance of Extending Reaction Times | p. 178 |
| Examine Other Operating Conditions | p. 178 |
| Minimizing Impurity Formation by Identifying Impurities First | p. 179 |
| Statistical Design of Experiments | p. 180 |
| Robotics and Automated Process Optimization | p. 182 |
| References | p. 183 |
| Optimizing Catalytic Reactions | |
| Introduction | p. 185 |
| Catalyst Selection/Ligand Selection | p. 187 |
| Optimizing Catalyst Concentration | p. 188 |
| Generating Active Catalysts | p. 191 |
| Importance of Extended Additions | p. 192 |
| Influence of Co-catalysts and Impurities | p. 193 |
| Catalyst Decomposition | p. 196 |
| Nonlinear Catalyst Effects | p. 196 |
| The Difficulty of Optimizing a Catalytic Reaction | p. 197 |
| References | p. 199 |
| Work-up | |
| Introduction | p. 203 |
| Aspects of Work-up | p. 204 |
| Quench | p. 205 |
| Extraction | p. 211 |
| Activating Carbon Treatment | p. 215 |
| Filtration | p. 216 |
| Concentrating Solutions and Solvent Displacement | p. 216 |
| Deionization and Removing Metals | p. 217 |
| Destruction of Process Streams | p. 217 |
| Derivatization | p. 219 |
| Solid-Supported Reagents | p. 219 |
| References | p. 220 |
| Tools for Purifying the Product: Column Chromatography, Crystallization, and Reslurrying | |
| Introduction | p. 223 |
| Purification by Column Chromatography | p. 224 |
| Crystallization | p. 226 |
| Crystallization Theory and Crystallization Pressures | p. 227 |
| Classification of Solids: Morphic States | p. 236 |
| Salt Selection | p. 238 |
| Predicting the Ability to Scale Up a Crystallization Process by Lab Examination | p. 241 |
| Washing and Drying Solid Products | p. 241 |
| Purification by Reslurrying | p. 243 |
| References | p. 245 |
| Final Product Form and Impurity Considerations | |
| Introduction | p. 249 |
| The Importance of Solid State Characteristics | p. 251 |
| Stability Testing | p. 253 |
| The Importance of Controlling Particle Size of a Drug Substance | p. 254 |
| Preparing and Selecting the Polymorph | p. 256 |
| Varying Crystallization Conditions in Order to Prepare Polymorphs | p. 258 |
| Purity and Impurity Considerations: Freezing the Final Process | p. 259 |
| Considerations for Preparing the Toxicology Batch and Subsequent Batches | p. 261 |
| Minimizing Impurities in the Drug Substance | p. 262 |
| References | p. 265 |
| Vessels and Mixing | |
| Introduction | p. 269 |
| Batch vs. Continuous Processing | p. 272 |
| Batch Processing | p. 274 |
| Continuous Operations | p. 274 |
| Semicontinuous Operations | p. 279 |
| Drawbacks of Continuous Processes | p. 281 |
| Use of Continuous Flow Reactors to Scale Up Processes | p. 281 |
| Static Mixers | p. 281 |
| Immobilized Catalysts | p. 283 |
| Photochemical Reactors | p. 284 |
| Microwave Reactors | p. 285 |
| Sonochemical Reactors | p. 285 |
| Plug Flow Reactors | p. 285 |
| Electrochemical Reactors | p. 286 |
| References | p. 288 |
| Preparing for and Implementing the Scale-up Run | |
| Introduction | p. 291 |
| Anticipating Scale-up Problems | p. 292 |
| Scale-up Considerations | p. 294 |
| Identify the Goals of Scale-up | p. 295 |
| Safety Considerations | p. 295 |
| Identify Critical Processing Steps | p. 297 |
| Define Equipment Limitations | p. 297 |
| Use a Rugged IPC for the Scale-up Operation | p. 298 |
| Develop Contingency Plans for Incomplete and Runaway Reactions | p. 299 |
| Know Effects of Extended and Interrupted Processing | p. 299 |
| Develop Methods to Qualify Components | p. 300 |
| Examine Process Tolerances for Scale-up | p. 301 |
| Ensure That Thorough Product Analyses Are in Place | p. 301 |
| Identify Cleaning Procedures and Waste Disposal Procedures | p. 302 |
| Guidelines for Documentation: Efficient Process Transfer | p. 302 |
| Implementing the Scale-up Run | p. 302 |
| Checklists to Prepare for the Scale-up Run | p. 307 |
| Guidelines for Executing the Run in a Pilot Plant or Manufacturing Operation | p. 309 |
| Guidelines for Executing the Run in a Kilo Lab Operation | p. 311 |
| References | p. 311 |
| Troubleshooting | |
| Introduction | p. 313 |
| Physical and Chemical Causes of Processing Problems | p. 314 |
| Steps for Troubleshooting a Process | p. 319 |
| Debottlenecking a Problem | p. 327 |
| References | p. 328 |
| Chiral Syntheses | |
| Introduction | p. 329 |
| Some Examples of Molecules Prepared by Asymmetric Synthesis | p. 330 |
| Products from Fermentation and the Chiral Pool | p. 330 |
| The Crystalline Nature of Enantiomeric Compounds and Approaches for Resolution | p. 332 |
| Compounds Prepared by Asymmetric Synthesis | p. 337 |
| Perspective on Asymmetric Synthesis | p. 341 |
| References | p. 342 |
| General Index | p. 345 |
| Reaction Type Index | p. 351 |
| Reagent Index | p. 353 |
| Table of Contents provided by Syndetics. All Rights Reserved. |
ISBN: 9780120594757
ISBN-10: 0120594757
Published: 20th March 2000
Format: Hardcover
Language: English
Number of Pages: 380
Audience: General Adult
Publisher: Elsevier Inc
Country of Publication: US
Dimensions (cm): 23.39 x 15.6 x 2.24
Weight (kg): 0.61
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