Handbook for Chemical Process Research and Development

Description

The Handbook for Chemical Process Research and Development focuses on developing processes for chemical and pharmaceutical industries. Forty years ago there were few process research and development activities in the pharmaceutical industry, partially due to the simplicity of the drug molecules. However, with the increasing structural complexity, especially the introduction of chiral centers into the drug molecules and strict regulations set by the EMA and FDA, process R&D has become one of the critical departments for pharmaceutical companies. This book assists with the key responsibility of process chemists to develop chemical processes for manufacturing pharmaceutical intermediates and final drug substances for clinical studies and commercial production Cover Half Title Handbook for Chemical Process Research and Development Copyright Dedication Contents Preface Acknowledgments Author List of Abbreviations 1. Modes of Reagent Addition: Control of Impurity Formation 1.1 Direct Addition 1.1.1 Sonogashira Reaction (I) Problematic “All-In” Conditions (II) Solutions–Semibatch Conditions (DA) 1.1.2 Michael Reaction (I) Problematic Reaction Conditions (RA Mode) (II) Chemistry Diagnosis (III) Solutions 1.1.3 Fischer Indole Synthesis (I) Reaction Problems (II) Solutions Procedure 1.1.4 Amide Formation 1.1.4.1 EEDQ-Promoted Amide Formation 1.1.4.2 CDI-Promoted Amide Formation 1.1.5 Thioamide Formation (I) Problems (II) Solutions Procedure 1.1.6 C–O Bond Formation 1.1.6.1 SRN1 Reaction 1.1.6.2 Mitsunobu Reaction 1.2 Reverse Addition 1.2.1 Grignard Reaction 1.2.1.1 Reaction with Alkyl Aryl Ketone 1.2.1.2 Grignard Reaction with Aldehydes 1.2.1.3 Reaction of Grignard Reagent with Ester 1.2.2 Copper-Catalyzed Epoxide Ring-Opening Solutions Procedure 1.2.3 Nitration Reaction (I) Problematic Addition Order (II) Chemistry Diagnosis (III) Solutions Procedure 1.2.4 Cyclization Reaction Procedure 1.2.5 Amide Formation 1.2.5.1 CDI-Promoted Amide Formation 1.2.5.2 Phenyl Chloroformate–Promoted Urea Formation 1.2.6 Reduction of Ketone to Hydrocarbon (I) Problematic Addition Order (II) Chemistry Diagnosis (III) Solutions Procedure 1.2.7 1,3-Dipole-Involved Reactions 1.2.7.1 Addition–Elimination/Cyclization 1.2.7.2 [3+2]-Cycloaddition 1.3 Other Addition Modes 1.3.1 Sequential Addition (I) Problematic Addition Sequence (II) Solutions (to Control the Concentration of CDMT) Procedure 1.3.2 Portionwise Addition 1.3.2.1 Cyclization 1.3.2.2 Dehydrochlorination 1.3.3 Slow Release of Starting Material/Reagent 1.3.3.1 Synthesis of Urea 1.3.3.2 Preparation of Alkylamine 1.3.4 Alternate Addition (I) Chemistry Diagnosis (II) Solutions 1.3.5 Concurrent Addition 1.3.5.1 Bromination Reaction 1.3.5.2 Difluoromethylation 1.3.5.3 Diels–Alder Reaction Notes 2. Process Optimization 2.1 Addition of Additives 2.1.1 Acid Additives 2.1.1.1 Hydrochloric Acid 2.1.1.2 Sulfuric Acid 2.1.1.3 Acetic Acid 2.1.1.4 Benzoic Acid as Amine Stabilizer 2.1.1.5 Trifluoroacetic Acid 2.1.1.6 Toluenesulfonic Acid 2.1.2 Base Additives 2.1.2.1 Potassium Carbonate 2.1.2.2 Sodium Hydrogen Carbonate 2.1.2.3 Diisopropylethylamine 2.1.2.4 1,4-Diazabicyclo[2.2.2]octane 2.1.2.5 Potassium tert-Butoxide 2.1.2.6 Sodium Methoxide 2.1.2.7 Sodium Acetate 2.1.2.8 Sodium Acrylate 2.1.3 Inorganic Salts 2.1.3.1 Lithium Salts 2.1.3.2 Sodium Bromide 2.1.3.3 Magnesium Salts 2.1.3.4 Calcium Chloride 2.1.3.5 Zinc Chloride 2.1.4 Assortment of Scavengers 2.1.4.1 Catechol as Methyl Cation Scavenger 2.1.4.2 Anisole as Quinone Methide Scavenger 2.1.4.3 Carboxylic Esters 2.1.4.4 Thionyl Chloride as Water Scavenger 2.1.4.5 1-Hexene as HCl Scavenger 2.1.4.6 Epoxyhexene as HBr Scavenger 2.1.4.7 Acetic Anhydride as Aniline Scavenger 2.1.4.8 Amberlite CG50 as Ammonia Scavenger 2.1.5 Other Additives 2.1.5.1 Imidazole 2.1.5.2 Triethylamine Hydrochloride 2.1.5.3 Methyl Trioctylammonium Chloride 2.1.5.4 TMSCl (or BF3 · Etherate) 2.1.5.5 Water 2.1.5.6 Hydroquinone 2.1.5.7 B(OMe)3 in Borane Reduction of Acid 2.1.5.8 Isobutanoic Anhydride 2.1.5.9 1,1-Dimethyl-2-Phenylethyl Acetate 2.1.5.10 Alcohols 2.1.5.11 1,4-Dioxane 2.1.5.12 Benzotriazole 2.1.5.13 1-Hydroxybenzotriazole 2.1.5.14 1,4-Dibromobutane 2.1.5.15 Diethanolamine 2.2 Approaches to Optimize Catalytic Reactions 2.2.1 Suzuki–Miyaura Reaction 2.2.1.1 Catalyst Poison 2.2.1.2 Precipitation of Palladium Catalyst 2.2.1.3 Instability of Arylboronic Acids 2.2.1.4 Problems Associated with Base 2.2.1.5 Dimer Impurity 2.2.2 Catalytic Deprotection 2.2.2.1 Debenzylation 2.2.2.2 Catalytic Removal of Cbz Group 2.2.3 Catalytic Hydrogenation 2.2.3.1 Reduction of Nitro Group 2.2.3.2 Reduction of Pyridine Ring 2.2.3.3 Reduction of Cyano Group 2.2.3.4 Reduction of Imine Intermediate 2.2.3.5 Catalytic Hydrogenation of Azide 2.2.4 Other Catalytic Reactions 2.2.4.1 Negishi Cross-Coupling Reaction 2.2.4.2 Cu(I)-Catalyzed Grignard Reaction 2.2.4.3 Decarboxylative Bromination 2.2.4.4 Sulfonylation Reaction 2.2.4.5 Preparation of Acid Chloride 2.2.4.6 Catalytic Dechlorination 2.3 Temperature and Pressure 2.3.1 Temperature Effect 2.3.1.1 Metal–Hydrogen/Halogen Exchange 2.3.1.2 Cyclization Reactions 2.3.1.3 Cross-Coupling Reaction 2.3.1.4 Vilsmeier Reaction 2.3.1.5 Oxidative Hydrolysis 2.3.1.6 Reduction of Ester 2.3.1.7 Michael Addition 2.3.1.8 Amide Formation 2.3.2 Pressure Effect 2.3.2.1 Nitrile Reduction 2.3.2.2 [3+2]-Cycloaddition 2.4 Other Approaches 2.4.1 Low Product Yield 2.4.1.1 Incomplete Reaction 2.4.1.2 Loss of Product during Isolation 2.4.1.3 Side Reactions of Starting Materials 2.4.1.4 Side Reactions of Intermediates 2.4.1.5 Side Reactions of Products 2.4.2 Problems Associated with Impurities 2.4.2.1 Residual Zn 2.4.2.2 Residual MTBE 2.4.2.3 Residual Water 2.4.2.4 Residual Oxygen 2.4.3 Reactions with Poor Selectivity 2.4.3.1 CIDR to Improve cis/trans Selectivity 2.4.3.2 Two-Step Process to Mitigate Racemization 2.4.3.3 Reduction of Carboxylic Acid 2.4.3.4 Sacrificial Reagent in Regioselective Acetylation 2.4.3.5 Protecting Group 2.4.3.6 Functional Group in SNAr Reaction 2.4.3.7 Enamine Exchange 2.4.3.8 Carryover Approach 2.4.4 Miscellaneous Reaction Problems 2.4.4.1 Friedel–Crafts Reaction 2.4.4.2 Reduction of C–C Double Bond 2.4.4.3 Reduction of Nitrile 2.4.4.4 Polymerization Issues 2.4.4.5 Activation of Functional Groups 2.4.4.6 Deactivation of Functional Groups 2.4.4.7 Side Reactions with Excess of Reagent 2.4.4.8 Optimization of Telescoped Process Notes 3. Hazardous Reactions 3.1 Oxidation Reactions 3.1.1 Oxidation of Olefins 3.1.1.1 Oxidation with mCPBA 3.1.1.2 Oxidation with Sodium Perborate 3.1.1.3 Oxidation with Ozone 3.1.1.4 Oxidation with KMnO4 3.1.2 Oxidation of Alcohols to Aldehydes or Ketones 3.1.2.1 SO3 · Py/DMSO System 3.1.2.2 Ac2O/DMSO System 3.1.2.3 TFAA/DMSO/TEA System 3.1.2.4 TEMPO/NaOCl System 3.1.2.5 RuCl3/NaOCl System 3.1.2.6 Sulfinimidoyl Chloride 3.1.3 Oxidation of Aldehydes to Acids Procedure 3.1.4 Oxidation of Sulfides to Sulfoxides 3.1.5 Oxidation of Sulfides to Sulfones 3.1.5.1 Oxidation with Oxone 3.1.5.2 Oxidation with Sodium Perborate 3.1.5.3 Oxidation with Sodium Periodate 3.1.5.4 Oxidation with NaOCl 3.1.5.5 Oxidation with H2O2/Na2WO4 3.1.5.6 Oxidation with TMSCl/KNO3 3.1.6 Other Oxidative Reactions 3.1.6.1 Dakin Oxidation 3.1.6.2 Hydroxylation 3.1.6.3 Oxidative Cyclization 3.1.6.4 Oxidation of Phosphite 3.2 Reduction Reactions 3.2.1 Boron-Based Reductive Reactions 3.2.1.1 Reduction with NaBH4 3.2.1.2 Reduction with Borane 3.2.2 Reduction with Lithium Aluminum Hydride Procedure 3.3 Nitrogen-Involved Hazardous Reactions 3.3.1 Diazonium Salts 3.3.1.1 Hydrolysis of Diazonium Salt 3.3.1.2 Diazonium Salt–Involved Cyclization 3.3.1.3 Nitroindazole Formation 3.3.1.4 Synthesis of Trifluoromethyl-Substituted Cyclopropanes 3.3.1.5 Sandmeyer Reaction 3.3.2 Azide Compounds 3.3.2.1 Nucleophilic Displacement 3.3.2.2 Nucleophilic Addition 3.3.3 Hydrazine 3.3.3.1 Wolff–Kishner Reduction 3.3.3.2 Synthesis of Indazole 3.3.3.3 Synthesis of Pyrazole 3.3.3.4 Synthesis of Triazole 3.3.3.5 Preparation of Dihydropyridazinone 3.3.3.6 Preparation of Phthalazin-1-ol 3.3.3.7 Preparation of Alkylamine 3.3.4 Preparation of Aryl (or Alkyl) Hydrazines and Related Reactions 3.3.4.1 Preparation of 5-Hydrazinoquinoline 3.3.4.2 Synthesis of Aminopyrazole 3.3.4.3 Fischer Indole Synthesis 3.3.4.4 Preparation of Alkylhydrazine 3.3.5 Hydroxylamine 3.3.6 Oxime Procedure 3.3.7 N-Oxide 3.3.8 Nitro Compounds 3.3.8.1 Preparation of Nitro Compounds by Nitration 3.3.8.2 Hazardous Reactions of Nitro Compounds 3.3.9 Ritter Reaction (I) Ritter Reaction Incident (II) Solutions 3.4 Other Hazardous Reactions and Reagents 3.4.1 Other Hazardous Reactions 3.4.1.1 Heck Reaction 3.4.1.2 Negishi Cross-Coupling Reaction 3.4.1.3 Blaise Reaction 3.4.1.4 Hydrogen/Metal Exchange 3.4.1.5 Halogenation Reactions 3.4.1.6 Dehydrochlorination 3.4.1.7 Thiocyanation 3.4.1.8 Gas-Involved Reactions 3.4.1.9 Darzens Reaction 3.4.2 Hazardous Reagents 3.4.2.1 Volatile Organic Compounds 3.4.2.2 High-Energy Compounds 3.4.2.3 Toxic Compounds Notes 4. Catalytic Reactions 4.1 Two-Phase Reactions 4.1.1 Nucleophilic Substitution Reactions 4.1.1.1 Enhancement of SN2 Reaction Rate 4.1.1.2 Replacement of DMSO in SNAr Reaction 4.1.1.3 Reduction of Amounts of Toxic Sodium Cyanide 4.1.1.4 Controls of Impurity Formation 4.1.2 Oxidation of Di-tert-Dutylphosphite 4.2 Dehydrobromination Procedure 4.3 Regioselective Chlorination Procedure 4.4 Regioselective Deprotonation Procedure 4.5 Amide Preparation 4.5.1 NaOMe as Catalyst Procedure 4.5.2 HOBt as Catalyst Procedure 4.6 Synthesis of Indole Procedure 4.7 N-Methylation Reaction Procedure 4.8 Baylis–Hillman Reaction Procedure 4.9 Catalytic Wittig Reaction 4.10 Negishi Cross-Coupling Reaction 4.11 Catalytic Hydrogenations 4.11.1 Chemoselective Hydrogenation 4.11.1.1 Using P(OPh)3 Additive 4.11.1.2 Nickel-Catalyzed Reduction 4.11.2 Catalytic Transfer Hydrogenation 4.11.2.1 Metal-Catalyzed Reductions 4.11.2.2 Organocatalytic Transfer Hydrogenation 4.12 Palladium-Catalyzed Rearrangement Procedure Notes 5. Grignard Reagent and Related Reactions 5.1 Preparation of Grignard Reagent 5.1.1 Use of Chlorotrimethylsilane 5.1.1.1 Preparation of 4-Fluoro-2-Methylphenylmagnesium Bromide 5.1.1.2 Preparation of (4-(2-(Pyrrolidin-1-yl)ethoxy)phenyl) magnesium Bromide 5.1.2 Use of Diisobutylaluminum Hydride Procedure 5.1.3 Use of Diisobutylaluminum Hydride/Iodine Procedure 5.1.4 Use of Grignard Reagent 5.1.4.1 Use of MeMgCl 5.1.4.2 Use of EtMgBr 5.1.4.3 Use of Heel 5.1.5 Use of Alkyl Halides 5.1.5.1 Iodomethane 5.1.5.2 1,2-Dibromoethane 5.1.6 Halogen–Magnesium Exchange 5.1.6.1 Preparation of Trifluoromethyl Substituted Aryl Grignard Reagents 5.1.6.2 Preparation of N-Methylpyrazole Grignard Reagent 5.1.6.3 Preparation of (4-Bromonaphthalen-1-yl)Magnesium Chloride 5.1.6.4 Magnesium-Ate Complex 5.2 Reactions of Grignard Reagents 5.2.1 Reactions with Ketones 5.2.1.1 Vinyl Grignard Reaction 5.2.1.2 Aryl Grignard Reaction 5.2.1.3 Grignard Reaction of Methylmagnesium Bromide 5.2.2 Reaction with Acid Chloride Procedure 5.2.3 Reaction with Amide 5.2.4 Michael Addition 5.2.5 Reaction with Epoxide (I) Chemistry Diagnosis (II) Solutions 5.2.6 Cross-Coupling Reactions 5.2.6.1 Suzuki Coupling Reaction 5.2.6.2 Iron-Catalyzed Coupling Reaction Notes 6. Challenging Reaction Intermediates 6.1 Effect of Intermediates 6.1.1 In Telescoping Steps 6.1.2 In Designing Synthetic Steps 6.2 Intermediate in the Product Isolation 6.2.1 Counter Ion Exchange (I) Problems (II) Solutions 6.2.2 Pictet–Spengler Condensation Procedure 6.2.3 Amide Reduction 6.3 Multiple Reaction Stages Procedure 6.4 Intermediate in the Process Development 6.4.1 Indirect Monitoring of the Intermediate 6.4.1.1 Derivatization of Acylimidazolide 6.4.1.2 Derivatization of N-Methylene Bridged Dimer 6.4.2 Direct Monitoring of the Intermediate Notes 7. Protecting Groups 7.1 Protection of Hydroxyl Group 7.1.1 Prevention of Side Reactions 7.1.1.1 Friedel–Crafts Alkylation 7.1.1.2 Removal of Trifluoromethanesulfonyl Group 7.1.2 Increasing Catalyst Activity 7.1.3 Selection of Protecting Group 7.1.3.1 Protection of Hydroxyphenylboronic Acid 7.1.3.2 Protection of Iodobutanol 7.1.3.3 Protection of 1-Hydroxypropan-2-yl Methanesulfonate 7.1.4 Protection of Diol for Separation of anti- and syn-Diols Procedure 7.2 Protection of Amino Group 7.2.1 Protection of Indole Nitrogen Procedure 7.2.2 Epoxide Ring Opening 7.2.3 Formation of Imines 7.2.3.1 Protection of Amine with Aryl Aldehyde 7.2.3.2 Protection of Amine with 4-Methyl-2-Pentanone 7.2.4 Indirect Protection Procedure 7.3 Protection of Carboxylic Acid 7.4 Protection of Aldehydes and Ketones 7.4.1 Protection of Ketone with Dimethyl Ketal 7.4.2 Dioxolane 7.4.3 Deprotection of Acetal 7.5 Protection of Acetylene 7.6 Unusual Protecting Groups 7.6.1 Boron-Containing Protecting Group 7.6.1.1 Borane Complex 7.6.1.2 Boronic Acid 7.6.2 N-Nitro Protecting Group 7.6.2.1 Regioselective Nitration 7.6.2.2 Activation of Aniline 7.6.3 Halogen as Protecting Group 7.6.3.1 Bromine Protecting Group 7.6.3.2 Chlorine as Protecting Group 7.7 Protecting Group Migration Notes 8. Reaction Solvents 8.1 Ethereal Solvents 8.1.1 Cyclopentyl Methyl Ether 8.1.1.1 Brook Rearrangement 8.1.1.2 N-Alkylation Reaction 8.1.2 Tetrahydrofuran 8.1.2.1 Grignard Reagent Formation 8.1.2.2 Bromination of Ketone 8.1.3 2-Methyl Tetrahydrofuran 8.1.3.1 Control of Impurity Formation 8.1.3.2 Improving Reaction Rate 8.1.3.3 Improving Layer Separation 8.1.4 Methyl tert-Butyl Ether 8.1.4.1 Chlorination Reaction 8.1.4.2 Darzens Reaction 8.1.5 Diethoxymethane and Dimethoxyethane 8.2 Protic Solvents 8.2.1 Reaction of Acyl Hydrazine with Trimethylsilyl Isocyanate 8.2.2 Amide Formation Procedure 8.2.3 Catalytic Reduction of Diaryl Methanol (I) Reaction Problems (II) Solutions 8.2.4 Catalytic Debenzylation (I) Reaction Problems (II) Solutions Procedure 8.2.5 Catalytic Reduction of Nitro Group 8.2.5.1 Leak of Palladium Catalyst 8.2.5.2 Side Product Formation 8.2.5.3 Classic Resolution of Acid 8.2.6 SN2 Reaction 8.3 Water as a Reaction Solvent 8.3.1 Iodination Reaction Procedure 8.3.2 Synthesis of Quinazoline-2,4-Dione Procedure (for Synthesis of 58a) 8.3.3 Synthesis of Pyrrolo Cyclohexanone Procedure 8.3.4 Synthesis of Thiourea (I) Reaction Problems (II) Solutions 8.4 Nonpolar Solvents 8.4.1 Condensation of Ketone with tert-Butyl Hydrazine-Carboxylate Procedure 8.4.2 Acid-Catalyzed Esterification 8.5 Polar Aprotic Solvents 8.5.1 Decarboxylative Blaise Reaction 8.5.2 Michael Addition Reaction 8.5.2.1 Acetone as a Solvent 8.5.2.2 Acetonitrile as a Solvent 8.5.3 SNAr Reaction 8.5.3.1 Preparation of Alkyl Aryl Ether 8.5.3.2 Preparation of Bisaryl Ether 8.6 Halogenated Solvents 8.6.1 Dichloromethane 8.6.1.1 Reaction with Pyridine 8.6.1.2 Synthesis of Benzo[d]isothiazolone 8.6.2 Trifluoroacetic Acid (I) Problems (II) Solutions Procedure 8.6.3 (Trifluoromethyl)benzene 8.6.4 Hexafluoroisopropanol 8.7 Carcinogen Solvent 8.8 Other Solvents 8.8.1 DW-Therm 8.8.2 Dowtherm A 8.8.2.1 Synthesis of 6-Chlorochromene 8.8.2.2 Conrad–Limpach Synthesis of Hydroxyl Naphthyridine 8.8.3 Polyethylene Glycol 8.8.4 Propylene Glycol Monomethyl Ether Procedure 8.8.5 Sulfolane 8.8.6 Ionic Liquid 8.9 Solvent-Free Reaction Procedure Notes 9. Base Reagent Selection 9.1 Inorganic Base 9.1.1 Sodium Bicarbonate 9.1.2 Potassium Carbonate 9.1.3 Sodium Hydride 9.1.4 Combination of LiOH with H2O2 9.1.4.1 Hydrolysis of Chiral Ester 9.1.4.2 Hydrolysis of Chiral Amide 9.2 Organic Base 9.2.1 Trialkylamine 9.2.1.1 Diisopropylethylamine 9.2.1.2 Triethylamine 9.2.2 Imidazole Procedure 9.2.3 2,6-Dimethylpiperidine 9.2.4 2-(N,N-Dimethylamino)pyridine 9.2.5 Metal Alkoxide Base 9.2.5.1 Potassium tert-Pentylate 9.2.5.2 Lithium tert-Butoxide 9.2.5.3 Potassium tert-Butoxide 9.2.5.4 Combination of Potassium tert-Butoxide with tert-Butyllithium 9.2.5.5 Sodium Methoxide Notes 10. Reagents for Amide Formation 10.1 CDI-Mediated Amide Preparation 10.1.1 Preparation of Amide Procedure 10.1.2 Preparation of Ureas 10.1.2.1 In the Absence of a Base 10.1.2.2 Activation via N-Methylation 10.2 Thionyl Chloride-Mediated Amide Preparation 10.2.1 Preparation of Acid Chloride Procedure 10.2.2 N-Sulfinylaniline-Involved Amide Preparation 10.3 Boc2O-Mediated Amide Preparation 10.4 Schotten–Baumann Reaction Procedure 10.5 Other Methods 10.5.1 Copper (II)-Catalyzed Transamidation 10.5.2 Cross-Coupling between Acyltrifluoroborates and Hydroxylamines Notes 11. Various Reagent Surrogates 11.1 Ammonia Surrogates 11.1.1 Ammonium Hydroxide Procedure 11.1.2 Ammonium Acetate 11.1.2.1 Condensation with Aldehyde 11.1.2.2 Condensation with Ketone 11.1.3 Ammonium Chloride 11.1.4 Hydroxylamine Hydrochloride 11.1.4.1 Reaction with Aldehyde 11.1.4.2 Reaction with Ketone 11.1.5 O-Benzylhydroxylamine 11.1.6 Hydroxylamine-O-Sulfonic Acid 11.1.6.1 SN2 Reaction of with Sulfinate 11.1.6.2 Reaction with Boronic Acid 11.1.7 4-Methylbenzenesulfonamide 11.1.8 Hexamethylenetetramine 11.1.9 Acetonitrile Procedure 11.1.10 Chloroacetonitrile 11.1.11 tert-Butyl Carbamate 11.1.12 Diphenylmethanimine Procedure 11.1.13 tert-Butylcarbamidine Procedure 11.1.14 Silylated Amines as Ammonia Equivalents Procedure (for the Preparation of 56) 11.1.15 Allylamines as Ammonia Equivalents Procedure 11.2 Carbon Monoxide Surrogates 11.2.1 N-Formylsaccharin 11.2.2 Paraformaldehyde 11.2.3 Molybdenum Carbonyl 11.3 Aldehyde Surrogates 11.3.1 Sodium Bisulfite 11.3.1.1 Oxidation of Aldehyde to Acid 11.3.1.2 Reductive Amination 11.3.1.3 Diels–Alder Reaction 11.3.1.4 Strecker Reaction 11.3.1.5 Transaminase DKR of Aldehyde 11.3.2 Sulfur Dioxide Solution Procedure 11.4 Sulfur Dioxide Surrogate 11.4.1 Synthesis of Alkyl Aryl Sulfones 11.4.2 Synthesis of Sulfonamides Notes 12. Telescope Approach 12.1 Hazardous Intermediates and Toxic Reagents 12.1.1 Chloroketone Intermediate Procedure 12.1.2 Lachrymatory Chloromethacrylate Intermediate 12.1.3 Chloromethyl Benzimidazole Procedure 12.1.4 Pyridine N-Oxide 12.1.5 Benzyl Bromide 12.2 Hygroscopic and Oily Intermediate 12.2.1 Oily Intermediates Procedure 12.2.2 Hygroscopic Solid 12.2.3 Amine Hydrochloride Salt Procedure 12.2.4 High Water-Soluble Intermediate 12.3 Filtration Problem 12.3.1 Preparation of Amide 12.3.2 Synthesis of ß-Nitrostyrene Procedure 12.4 Unstable Intermediates 12.4.1 Heteroaryl Chlorides Procedure 12.4.2 Toluenesulfonate Intermediate 12.4.3 Aldehyde Intermediates 12.4.3.1 Reduction/Grignard-Type Reaction 12.4.3.2 Oxidation/Wittig Reaction 12.4.4 Unstable Alkene Intermediates 12.4.4.1 Diels–Alder Reaction 12.4.4.2 Acrylate Formation/Heck Coupling 12.4.4.3 Protection/Heck Reaction/Deprotection 12.4.5 Unstable ß-Hydroxyketone Procedure 12.5 Expensive Catalyst 12.5.1 Imine Reduction/Debenzylation Procedure 12.5.2 Palladium-Catalyzed Debromination/Suzuki Cross-Coupling Reaction Procedure 12.6 Improvement of Overall Yields 12.6.1 Synthesis of Spirocyclic Hydantoin Procedure 12.6.2 Synthesis of Diaryl Compound 12.7 Reduction in Processing Solvents 12.7.1 Toluene as the Common Solvent 12.7.2 DMF as the Common Solvent Procedure 12.7.3 EtOAc as the Common Solvent 12.7.3.1 Acid Activation/Hydrazide Formation/Triazolone Formation 12.7.3.2 Reduction/Acid Activation/Acylation 12.7.4 THF as the Common Solvent Procedure 12.7.5 EtOH/THF as the Common Solvent Procedure 12.8 Solvent Exchange 12.9 Other Telescope Processes 12.9.1 Bromination/Isomerization Reactions 12.9.2 Fisher Indole Synthesis/Ring Rearrangement 12.9.3 Ylide Formation/Wittig Reaction/Cycloaddition Procedure 12.9.4 Overman Rearrangement Procedure 12.9.5 Nitro Reduction/Reductive Amination/Dehalogenation Procedure 12.9.6 Michael Addition/Elimination/Cycloaddition 12.9.7 Synthesis of Aryl Bromide 12.9.8 Synthesis of Lactam Procedure 12.9.9 Synthesis of (–)-Oseltamivir 12.10 Limitation of the Telescope Approach 12.10.1 Lack of Purity Control 12.10.2 Poor Product Yields 12.10.3 Lack of Compatibility Notes 13. Stereochemistry 13.1 Asymmetric Synthesis 13.1.1 Asymmetric Catalysis 13.1.1.1 Desymmetrization of Anhydride 13.1.1.2 Asymmetric Reduction of Enone 13.1.1.3 Sharpless Asymmetric Dihydroxylation 13.1.1.4 Enantioselective Alkylation 13.1.1.5 Asymmetric Cross-Benzoin Addition 13.1.1.6 CuH-Catalyzed Stereoselective Synthesis of 2,3-Disubstituted Indolines 13.1.2 Chiral Pool Synthesis 13.1.2.1 Generation of a New Chiral Center 13.1.2.2 Transfer of Chiral Center 13.1.3 Use of Chiral Auxiliaries 13.1.3.1 Diastereoselective Diels–Alder Reaction 13.1.3.2 Diastereoselective Synthesis of Boronic Acid 13.1.3.3 Synthesis of Chiral (S)-Pyridyl Amine 13.2 Kinetic Resolution 13.2.1 Classical Resolution 13.2.1.1 Resolution of Racemic Acid 13.2.1.2 Resolution of Racemic Base 13.2.1.3 Enantiomeric Enrichment 13.2.1.4 Diastereomer Salt Break 13.2.1.5 Examples of Diastereomeric Salts 13.2.2 Enzymatic Resolution 13.2.2.1 Resolution of Esters 13.2.2.2 Resolution of Amino Acids 13.2.2.3 Resolution Secondary Alcohols 13.2.3 Other Resolution Methods 13.2.3.1 Stereoselective Ligand Exchange 13.2.3.2 Diastereomer Salt Formation 13.2.3.3 Stereoselective Esterification of Racemic Diol 13.2.3.4 Chiral Chromatographic Separation 13.3 Dynamic Kinetic Resolution 13.3.1 Dynamic Kinetic Resolution via Imine Intermediate 13.3.1.1 Aldehyde-Catalyzed Dynamic Kinetic Resolution 13.3.1.2 Enantioselective Synthesis of Azabicyclic Rings 13.3.1.3 Asymmetric Synthesis of Chiral Amines 13.3.2 Dynamic Kinetic Resolution via Proton Transfer 13.3.2.1 Ketone Reduction 13.3.2.2 Racemization of Nitrile 13.3.2.3 Formation of Diastereomeric Salt 13.3.2.4 Epimerization of cis-Isomer to trans-Isomer 13.3.2.5 Isomerization of Cyclohexane Derivative 13.3.2.6 Fischer Indole Synthesis 13.3.3 Dynamic Kinetic Resolution via Reversible Bond Formation 13.3.3.1 Reversible C-C Bond Formation 13.3.3.2 Reversible C-N Bond Formation 13.3.3.3 Reversible C-O Bond Formation 13.3.3.4 Reversible C-S Bond Formation 13.3.4 Other Resolution Methods 13.3.4.1 Bromide-Catalyzed Dynamic Kinetic Resolution 13.3.4.2 Resolution of Sulfoxide 13.3.4.3 Resolution of Dihydropyrazole Carboxylate 13.3.4.4 Dynamic Kinetic Resolution via C–C σ-Bond Rotation 13.3.4.5 Dynamic Kinetic Isomerization via Ir-Catalyzed Internal Redox Transfer Hydrogenation 13.3.5 Various Dynamic Kinetic Resolution Examples Notes 14. Design of New Synthetic Route 14.1 Process Safety 14.1.1 Toxic Reagents and Products 14.1.1.1 Cyanogen Bromide 14.1.1.2 Hydrogen Cyanide (HCN) Evolution 14.1.1.3 Toxic Reagent–Hg(OAc)2 14.1.1.4 Toxic Reagent–PBr3 14.1.1.5 Toxic Reagent–Hydrogen Fluoride HF 14.1.1.6 Toxic Benzyl Halides 14.1.1.7 Lachrymatory 2-(Benzo[d])[1,3]dioxol-5-yl-2- Bromoacetic Acid 14.1.1.8 Phosphorus Oxychloride 14.1.1.9 Sulfonyl Chloride Intermediate 14.1.2 High-Energy Reagents 14.1.2.1 Azide-Involved Cycloaddition 14.1.2.2 Diazonium Salt-Involved Indazole Formation 14.1.2.3 Lithium Aluminum Hydride Reduction 14.1.3 Undesired Reaction Conditions 14.1.3.1 Acylation Reaction 14.1.3.2 SNAr Reaction 14.2 Process Costs 14.2.1 Expensive Starting Materials 14.2.1.1 Using Fluorine-Free Starting Material 14.2.1.2 Using Convergent Approach 14.2.2 Expensive Reagents 14.2.2.1 Kumada Coupling 14.2.2.2 Cross-Coupling Reaction 14.2.2.3 Chiral Acid in Amide Preparation 14.3 Low Product Yields 14.3.1 Cycloaddition Reaction 14.3.2 Resolution and Grignard Reaction 14.3.3 Resolution/Amide Formation/Cyclization 14.3.4 Chlorine Replacement Procedure 14.4 Convergent Approach 14.4.1 Decarboxylative Cross-Coupling Reaction 14.4.2 Synthesis of Chiral Amide 14.5 Multicomponent Reaction 14.5.1 Construction of Piperidinone Structure 14.5.2 Construction of Pyrimidinone Structure 14.6 Step-Economy Synthesis 14.6.1 Synthesis of Keto-Sulfone Intermediate 14.6.2 Synthesis of Bendamustine 14.7 Atom-Economic Synthesis 14.7.1 Synthesis of Carboxylic Acid 14.7.2 Stereoselective Synthesis of Diol 14.8 Problematic Intermediates 14.8.1 Unstable Alkyne 14.8.2 Oily Intermediates 14.8.2.1 Alkyl Alcohols 14.8.2.2 N-Acylpiperidine Derivatives 14.9 Reaction Selectivity 14.9.1 Iodination 14.9.2 N-Alkylation Reaction 14.9.3 Formation of Indole Derivative 14.9.4 Formation of Seven-Membered Ring 14.10 Residual Metals 14.10.1 C-N Bond Formation 14.10.2 C-C Bond Formation 14.10.3 Formation of C–C/C–N Bonds Reagents and Conditions 14.11 Minimum Oxidation Stage Change 14.11.1 Minimizing Nitrogen Oxidation Stage Adjustment 14.11.2 Minimizing Carbon Oxidation Stage Adjustment 14.11.2.1 Synthesis of Carboxylate Ester 14.11.2.2 Synthesis of Alkyl Chloride 14.12 Coupling Reagent–Free Amide Formation 14.13 Etching of Glass Reactors Procedure (Route II, Production of 312) Notes 15. Reaction Workup 15.1 Various Quenching Strategies 15.1.1 Acidic Quenching 15.1.1.1 Removal of Magnesium Salt 15.1.1.2 Removal of Zinc By-Products 15.1.2 Basic Quenching 15.1.2.1 Prevention of Thiadiazole Isomerization 15.1.2.2 Prevention of Etching Glass Reactor 15.1.3 Anhydrous Quenching 15.1.3.1 Removal of Zinc By-Products 15.1.3.2 Avoidance of Insoluble Organic Mass 15.1.3.3 Avoidance of Degradation of Product 15.1.3.4 Decomposition of Excess Reagent 15.1.4 Oxidative Quenching (I) Problematic Iodine (II) Solutions 15.1.5 Reductive Quenching 15.1.5.1 Triethylphosphite 15.1.5.2 Sodium Bisulfite 15.1.5.3 Ascorbic Acid 15.1.6 Disproportionation Quenching Procedure 15.1.7 Reverse Quenching 15.1.7.1 Control of Impurity Formation 15.1.7.2 Removal of Excess Reagent 15.1.7.3 Increase in Conversion 15.1.7.4 Prevention of Product Hydrolysis 15.1.7.5 Prevention of Product Decomposition 15.1.7.6 Prevention of Emulsion 15.1.7.7 Prevention of Exothermic Runaway 15.1.8 Concurrent Quenching (I) Problems (II) Solutions 15.1.9 Double Quenching 15.1.9.1 Acetone/HCl Combination 15.1.9.2 Acetone/Citric Acid Combination 15.1.9.3 Acetone/MeOH/H2O 15.1.9.4 Ethyl Acetate/Water Combination 15.1.9.5 Ethyl Acetate/Tartaric Acid 15.1.9.6 Ethyl Acetate/Aqueous Sodium Bicarbonate 15.1.9.7 Isopropanol/Citric Acid 15.1.9.8 Methyl Formate/Aqueous HCl 15.2 Direct Isolation 15.2.1 Cooling of Reaction Mixture 15.2.1.1 Direct Isolation from 2-Propanol 15.2.1.2 Direct Isolation from Isopropanol Acetate 15.2.1.3 Direct Isolation from Ethyl Acetate 15.2.1.4 Direct Isolation from Acetonitrile 15.2.2 Addition of Antisolvent 15.2.2.1 Adding Water to Acetic Acid 15.2.2.2 Addition of Water to DMF 15.2.2.3 Addition of Water to DMAc 15.2.2.4 Addition of Water to DMSO 15.2.2.5 Addition of Methanol to DMSO 15.2.3 Cooling/Addition of Antisolvent 15.2.3.1 Isolation of Sonogashira Product 15.2.3.2 Isolation of 6-Chlorophthalazin-1-ol 15.2.3.3 Isolation of 6-(pyridin-2-ylmethoxy)-1H-pyrazolo[3,4-b]pyrazine 15.2.4 Neutralization Procedure 15.2.5 Salt Formation Procedure 15.2.6 Miscellaneous Approaches 15.2.6.1 Direct Drop Process 15.2.6.2 Direct Removal Approach 15.3 Purification Strategies 15.3.1 Extraction 15.3.1.1 Methyl tert-Butyl Ether Extraction 15.3.1.2 Ethyl Acetate Extraction 15.3.1.3 Dodecane Extraction 15.3.1.4 n-Butanol Extraction 15.3.1.5 Anhydrous Extraction 15.3.1.6 Double Extraction 15.3.2 Salt Formation 15.3.2.1 Basic Organic Amines 15.3.2.2 Organic Acids 15.3.2.3 Quaternary Salt 15.3.3 Derivatization 15.3.3.1 Isolation/Purification of Aldehydes 15.3.3.2 Isolation/Purification of Diol 15.3.3.3 Isolation/Purification of Amino Diol 15.3.3.4 Isolation/Purification of Amine 15.3.4 Removal of Impurities 15.3.4.1 Removal of Ammonium Chloride 15.3.4.2 Removal of 9-BBN 15.3.4.3 Removal of Acetic Acid 15.3.4.4 Selective Hydrolysis Approach 15.4 Crystallization 15.4.1 Seed-Induced Crystallization 15.4.1.1 Avoiding Uncontrolled Crystallization 15.4.1.2 Avoiding Oiling Out 15.4.1.3 Control of Exothermic Crystallization 15.4.1.4 Polymorph Control 15.4.2 Various Other Crystallization Approaches 15.4.2.1 Reactive Crystallization 15.4.2.2 Addition of Water 15.4.2.3 Crystallization from Extraction Solvent 15.4.2.4 Three-Solvent System 15.4.2.5 Derivatization 15.4.2.6 Control of Crystal Size Distribution 15.4.2.7 Cocrystallization 15.5 Filtration Problems 15.5.1 Metal-Related Filtration Problems 15.5.1.1 Copper-Related Problems 15.5.1.2 TiCl4-Related Problems 15.5.1.3 Aluminum-Related Problems 15.5.2 Small Particle Size 15.5.2.1 Addition of Acetic Acid 15.5.2.2 Addition of 2-Propanol 15.5.2.3 Temperature Control 15.5.2.4 Polymorph Transformation 15.5.3 Low-Melting Solid Procedure 15.6 Removal of Residual Palladium 15.6.1 Crystallization 15.6.1.1 Crystallization of Suzuki Reaction Product 15.6.1.2 Crystallization in the Presence of Additives 15.6.2 Extraction 15.6.2.1 Liquid–Liquid Transportation 15.6.2.2 Extractive Precipitation 15.6.3 Adsorption 15.6.3.1 Activated Carbon 15.6.3.2 MP-TMT 15.6.3.3 Deloxan THP-II 15.6.3.4 Smopex 110 15.6.4 Distillation Procedure 15.6.5 Miscellaneous Methods 15.6.5.1 Adsorption–Crystallization 15.6.5.2 Adsorption and TMT Wash 15.6.5.3 Protecting Group 15.6.5.4 Salt Formation 15.6.6 Conclusion 15.7 Removal of Other Metals 15.7.1 Removal of Copper 15.7.1.1 Aqueous Ammonia 15.7.1.2 Thiourea 15.7.1.3 2,4,6-Trimercaptotriazine 15.7.2 Removal of Rhodium 15.7.2.1 Smopex-234 15.7.2.2 Ecosorb C-941 15.7.3 Removal of Ruthenium 15.7.3.1 Activated Carbon 15.7.3.2 Supercritical Carbon Dioxide 15.7.4 Removal of Zinc 15.7.4.1 Extraction with Trisodium Salt of EDTA 15.7.4.2 Use of Ethylenediamine 15.7.5 Removal of Magnesium Procedure 15.7.6 Removal of Aluminum 15.7.6.1 Use of Triethanolamine 15.7.6.2 Use of Crystallization 15.7.7 Removal of Iron and Nickel 15.7.7.1 Removal of Iron 15.7.7.2 Removal of Nickel 15.8 Removal of Impurities 15.8.1 Extractive Wash 15.8.1.1 Aqueous Wash 15.8.1.2 Organic Wash 15.8.2 Precipitation Approach 15.8.2.1 Precipitation of Product 15.8.2.2 Precipitation of By-Product 15.8.3 Use of Additives 15.8.3.1 Application of NaHSO3 15.8.3.2 Application of CaCl2 15.8.3.3 Application of CaCO3 15.8.3.4 Application of N-Methylpiperazine 15.8.3.5 Application of Dimethylamine 15.8.3.6 Application of Sodium Periodate 15.8.3.7 Application of Hydrogen Peroxide 15.8.3.8 Application of Phenylboronic Acid 15.8.3.9 Application of CO2 15.8.3.10 Application of Succinic Anhydride 15.8.3.11 Application of Pivaldehyde 15.8.3.12 Application of Benzyltributylammonium Chloride 15.8.3.13 Application of Sodium Dithionate 15.8.3.14 Application of Polymeric Resin 15.8.3.15 Application of Aqueous Ammonia 15.8.3.16 Application of DABCO 15.8.4 Transformation of Impurity to Starting Material or Product 15.8.4.1 Transformation to Starting Material 15.8.4.2 Transformation to Product Notes 16. Pharmaceutical Salts 16.1 Common Acids in the Salt Formation 16.2 Hydrochloride Salts Procedure 16.3 Various Pharmaceutical Salts 16.4 Salts of Acidic Drug Substances 16.4.1 Potassium Salts 16.4.1.1 Potassium Salt of 1,5-Naphthyridin-4(1H)-one 16.4.1.2 Potassium Salt of Amide 16.4.2 Calcium Salts 16.4.2.1 Salt Exchange from Sodium to Calcium Salt 16.4.2.2 Salt Exchange from Ammonium to Calcium Salt 16.4.3 Various Inorganic Salts 16.4.4 Salts with Organic Bases Notes 17. Solid Form 17.1 Polymorphism 17.1.1 Control of Polymorph by Seeding Procedure 17.1.2 Control of Polymorph by Temperature 17.1.2.1 Hydrolysis of Butyl Ester 17.1.2.2 Deprotection of Diol 17.1.3 Control of Polymorph via Slurrying Procedure 17.1.4 Control of Polymorph by Aging 17.2 Cocrystals 17.2.1 Cocrystal with l-Phenylalanine Procedure 17.2.2 Cocrystal with l-Pyroglutamic Acid Procedure 17.2.3 Cocrystal with Phosphoric Acid Procedure 17.3 Hydrates Procedure 17.4 API Particle Size Notes Index Cover back