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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
| 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: 384
Audience: Professional and Scholarly
Publisher: ACADEMIC PR INC
Country of Publication: US
Dimensions (cm): 23.62 x 15.67 x 2.01
Weight (kg): 0.61
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