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
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