Handbook for Chemical Process Research and Development 9781498767996

Table of contents :
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

Citation preview

Handbook for Chemical Process Research and Development

Handbook for Chemical Process Research and Development Wenyi Zhao

CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2017 by Wenyi Zhao CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Printed on acid-free paper Version Date: 20160819 International Standard Book Number-13: 978-1-4987-6799-6 (Hardback) This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http:// www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Names: Zhao, Wenyi (Chemist) Title: Handbook for chemical process research and development / Wenyi Zhao. Description: Boca Raton : CRC Press, 2017. | Includes bibliographical references and index. Identifiers: LCCN 2016032433 | ISBN 9781498767996 (hardcover : alk. paper) Subjects: LCSH: Drugs--Research. | Drugs--Research--Methodology. | Pharmaceutical industry. Classification: LCC RM301.25 .Z44 2017 | DDC 615.1/9--dc23 LC record available at https://lccn.loc.gov/2016032433 Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com

is dedicated to my parents.

Contents Preface...........................................................................................................................................xxix Acknowledgments .......................................................................................................................xxxix Author ..............................................................................................................................................xli List of Abbreviations..................................................................................................................... xliii Chapter 1

Modes of Reagent Addition: Control of Impurity Formation ......................................1 1.1

1.2

Direct Addition ..................................................................................................2 1.1.1 Sonogashira Reaction ........................................................................... 2 (I) Problematic “All-In” Conditions .....................................................2 (II) Solutions–Semibatch Conditions (DA) ..........................................2 1.1.2 Michael Reaction .................................................................................. 3 (I) Problematic Reaction Conditions (RA Mode) ................................3 (II) Chemistry Diagnosis ......................................................................3 (III) Solutions .......................................................................................3 1.1.3 Fischer Indole Synthesis .......................................................................3 (I) Reaction Problems...........................................................................4 (II) Solutions ........................................................................................ 4 Procedure ..............................................................................................4 1.1.4 Amide Formation ................................................................................. 5 1.1.4.1 EEDQ-Promoted Amide Formation .....................................5 1.1.4.2 CDI-Promoted Amide Formation .........................................6 1.1.5 Thioamide Formation...........................................................................6 (I) Problems .......................................................................................... 7 (II) Solutions ........................................................................................ 7 Procedure .............................................................................................. 7 1.1.6 C–O Bond Formation ...........................................................................8 1.1.6.1 SRN1 Reaction ....................................................................... 8 1.1.6.2 Mitsunobu Reaction ..............................................................9 Reverse Addition ............................................................................................. 10 1.2.1 Grignard Reaction .............................................................................. 11 1.2.1.1 Reaction with Alkyl Aryl Ketone ....................................... 11 1.2.1.2 Grignard Reaction with Aldehydes .................................... 12 1.2.1.3 Reaction of Grignard Reagent with Ester ........................... 12 1.2.2 Copper-Catalyzed Epoxide Ring-Opening ........................................ 13 Solutions .............................................................................................14 Procedure ............................................................................................ 14 1.2.3 Nitration Reaction .............................................................................. 14 (I) Problematic Addition Order .......................................................... 14 (II) Chemistry Diagnosis .................................................................... 15 (III) Solutions ..................................................................................... 15 Procedure ............................................................................................ 15 1.2.4 Cyclization Reaction .......................................................................... 15 Procedure ............................................................................................ 16 1.2.5 Amide Formation ............................................................................... 17 1.2.5.1 CDI-Promoted Amide Formation ....................................... 17 1.2.5.2 Phenyl Chloroformate–Promoted Urea Formation ............ 18 vii

viii

Contents

1.2.6

Reduction of Ketone to Hydrocarbon................................................. 18 (I) Problematic Addition Order .......................................................... 19 (II) Chemistry Diagnosis .................................................................... 19 (III) Solutions .....................................................................................20 Procedure ............................................................................................20 1.2.7 1,3-Dipole-Involved Reactions ...........................................................20 1.2.7.1 Addition–Elimination/Cyclization .....................................20 1.2.7.2 [3+2]-Cycloaddition ............................................................ 21 1.3 Other Addition Modes ..................................................................................... 23 1.3.1 Sequential Addition ............................................................................ 23 (I) Problematic Addition Sequence .................................................... 23 (II) Solutions (to Control the Concentration of CDMT) .................... 23 Procedure ............................................................................................ 23 1.3.2 Portionwise Addition ..........................................................................24 1.3.2.1 Cyclization ..........................................................................24 1.3.2.2 Dehydrochlorination ...........................................................25 1.3.3 Slow Release of Starting Material/Reagent .......................................26 1.3.3.1 Synthesis of Urea ................................................................26 1.3.3.2 Preparation of Alkylamine .................................................28 1.3.4 Alternate Addition ..............................................................................28 (I) Chemistry Diagnosis ..................................................................... 29 (II) Solutions ...................................................................................... 29 1.3.5 Concurrent Addition ........................................................................... 29 1.3.5.1 Bromination Reaction ......................................................... 29 1.3.5.2 Difluoromethylation ............................................................ 31 1.3.5.3 Diels–Alder Reaction.......................................................... 32 Notes........................................................................................................................... 32

Chapter 2

Process Optimization ................................................................................................. 35 2.1

Addition of Additives ...................................................................................... 35 2.1.1 Acid Additives .................................................................................... 35 2.1.1.1 Hydrochloric Acid .............................................................. 35 2.1.1.2 Sulfuric Acid....................................................................... 38 2.1.1.3 Acetic Acid ......................................................................... 41 2.1.1.4 Benzoic Acid as Amine Stabilizer...................................... 45 2.1.1.5 Trifluoroacetic Acid ............................................................ 45 2.1.1.6 Toluenesulfonic Acid ..........................................................46 2.1.2 Base Additives .................................................................................... 48 2.1.2.1 Potassium Carbonate .......................................................... 48 2.1.2.2 Sodium Hydrogen Carbonate ............................................. 49 2.1.2.3 Diisopropylethylamine ....................................................... 50 2.1.2.4 1,4-Diazabicyclo[2.2.2]octane ............................................ 52 2.1.2.5 Potassium tert-Butoxide...................................................... 53 2.1.2.6 Sodium Methoxide.............................................................. 55 2.1.2.7 Sodium Acetate................................................................... 57 2.1.2.8 Sodium Acrylate .................................................................60 2.1.3 Inorganic Salts .................................................................................... 61 2.1.3.1 Lithium Salts....................................................................... 61 2.1.3.2 Sodium Bromide ................................................................. 62

ix

Contents

2.2

2.1.3.3 Magnesium Salts ................................................................. 63 2.1.3.4 Calcium Chloride................................................................ 67 2.1.3.5 Zinc Chloride ...................................................................... 68 2.1.4 Assortment of Scavengers .................................................................. 68 2.1.4.1 Catechol as Methyl Cation Scavenger ................................ 68 2.1.4.2 Anisole as Quinone Methide Scavenger ............................. 69 2.1.4.3 Carboxylic Esters ................................................................ 70 2.1.4.4 Thionyl Chloride as Water Scavenger ................................ 73 2.1.4.5 1-Hexene as HCl Scavenger ................................................ 74 2.1.4.6 Epoxyhexene as HBr Scavenger ......................................... 76 2.1.4.7 Acetic Anhydride as Aniline Scavenger ............................. 77 2.1.4.8 Amberlite CG50 as Ammonia Scavenger........................... 77 2.1.5 Other Additives .................................................................................. 77 2.1.5.1 Imidazole ............................................................................ 78 2.1.5.2 Triethylamine Hydrochloride ............................................. 79 2.1.5.3 Methyl Trioctylammonium Chloride..................................80 2.1.5.4 TMSCl (or BF3 · Etherate) ................................................... 81 2.1.5.5 Water ................................................................................... 82 2.1.5.6 Hydroquinone ..................................................................... 85 2.1.5.7 B(OMe)3 in Borane Reduction of Acid ............................... 86 2.1.5.8 Isobutanoic Anhydride ....................................................... 87 2.1.5.9 1,1-Dimethyl-2-Phenylethyl Acetate ................................... 87 2.1.5.10 Alcohols .............................................................................. 88 2.1.5.11 1,4-Dioxane.........................................................................92 2.1.5.12 Benzotriazole ...................................................................... 93 2.1.5.13 1-Hydroxybenzotriazole ..................................................... 93 2.1.5.14 1,4-Dibromobutane .............................................................94 2.1.5.15 Diethanolamine .................................................................. 95 Approaches to Optimize Catalytic Reactions ................................................. 95 2.2.1 Suzuki–Miyaura Reaction .................................................................. 95 2.2.1.1 Catalyst Poison ...................................................................97 2.2.1.2 Precipitation of Palladium Catalyst .................................. 100 2.2.1.3 Instability of Arylboronic Acids ....................................... 101 2.2.1.4 Problems Associated with Base ........................................ 105 2.2.1.5 Dimer Impurity ................................................................. 107 2.2.2 Catalytic Deprotection ..................................................................... 109 2.2.2.1 Debenzylation ................................................................... 109 2.2.2.2 Catalytic Removal of Cbz Group ..................................... 110 2.2.3 Catalytic Hydrogenation................................................................... 112 2.2.3.1 Reduction of Nitro Group ................................................. 112 2.2.3.2 Reduction of Pyridine Ring .............................................. 113 2.2.3.3 Reduction of Cyano Group ............................................... 114 2.2.3.4 Reduction of Imine Intermediate...................................... 114 2.2.3.5 Catalytic Hydrogenation of Azide .................................... 115 2.2.4 Other Catalytic Reactions ................................................................ 115 2.2.4.1 Negishi Cross-Coupling Reaction .................................... 115 2.2.4.2 Cu(I)-Catalyzed Grignard Reaction ................................. 116 2.2.4.3 Decarboxylative Bromination ........................................... 117 2.2.4.4 Sulfonylation Reaction ...................................................... 118 2.2.4.5 Preparation of Acid Chloride............................................ 119 2.2.4.6 Catalytic Dechlorination................................................... 120

x

Contents

2.3

Temperature and Pressure .............................................................................120 2.3.1 Temperature Effect ...........................................................................120 2.3.1.1 Metal–Hydrogen/Halogen Exchange................................120 2.3.1.2 Cyclization Reactions .......................................................123 2.3.1.3 Cross-Coupling Reaction ..................................................126 2.3.1.4 Vilsmeier Reaction ...........................................................127 2.3.1.5 Oxidative Hydrolysis ........................................................128 2.3.1.6 Reduction of Ester ............................................................128 2.3.1.7 Michael Addition ..............................................................129 2.3.1.8 Amide Formation..............................................................130 2.3.2 Pressure Effect .................................................................................131 2.3.2.1 Nitrile Reduction ..............................................................131 2.3.2.2 [3+2]-Cycloaddition ..........................................................132 2.4 Other Approaches ..........................................................................................133 2.4.1 Low Product Yield ...........................................................................133 2.4.1.1 Incomplete Reaction .........................................................133 2.4.1.2 Loss of Product during Isolation ......................................136 2.4.1.3 Side Reactions of Starting Materials ................................137 2.4.1.4 Side Reactions of Intermediates .......................................139 2.4.1.5 Side Reactions of Products ...............................................145 2.4.2 Problems Associated with Impurities ..............................................151 2.4.2.1 Residual Zn .......................................................................151 2.4.2.2 Residual MTBE ................................................................152 2.4.2.3 Residual Water ..................................................................153 2.4.2.4 Residual Oxygen ...............................................................155 2.4.3 Reactions with Poor Selectivity........................................................158 2.4.3.1 CIDR to Improve cis/trans Selectivity .............................158 2.4.3.2 Two-Step Process to Mitigate Racemization ....................158 2.4.3.3 Reduction of Carboxylic Acid ..........................................159 2.4.3.4 Sacrificial Reagent in Regioselective Acetylation ............160 2.4.3.5 Protecting Group ..............................................................161 2.4.3.6 Functional Group in SNAr Reaction .................................166 2.4.3.7 Enamine Exchange ...........................................................167 2.4.3.8 Carryover Approach .........................................................169 2.4.4 Miscellaneous Reaction Problems ...................................................169 2.4.4.1 Friedel–Crafts Reaction....................................................169 2.4.4.2 Reduction of C–C Double Bond .......................................170 2.4.4.3 Reduction of Nitrile ..........................................................171 2.4.4.4 Polymerization Issues .......................................................172 2.4.4.5 Activation of Functional Groups ......................................175 2.4.4.6 Deactivation of Functional Groups ...................................178 2.4.4.7 Side Reactions with Excess of Reagent ............................180 2.4.4.8 Optimization of Telescoped Process ................................181 Notes.........................................................................................................................184 Chapter 3

Hazardous Reactions ................................................................................................193 3.1

Oxidation Reactions ......................................................................................193 3.1.1 Oxidation of Olefins .........................................................................193 3.1.1.1 Oxidation with mCPBA ....................................................193 3.1.1.2 Oxidation with Sodium Perborate ....................................194

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3.2

3.3

3.1.1.3 Oxidation with Ozone ....................................................... 194 3.1.1.4 Oxidation with KMnO4 .................................................... 197 3.1.2 Oxidation of Alcohols to Aldehydes or Ketones .............................. 197 3.1.2.1 SO3 ∙ Py/DMSO System..................................................... 198 3.1.2.2 Ac2O/DMSO System ........................................................200 3.1.2.3 TFAA/DMSO/TEA System ............................................. 201 3.1.2.4 TEMPO/NaOCl System ................................................... 201 3.1.2.5 RuCl3/NaOCl System .......................................................203 3.1.2.6 Sulfinimidoyl Chloride .....................................................204 3.1.3 Oxidation of Aldehydes to Acids .....................................................204 Procedure ..........................................................................................205 3.1.4 Oxidation of Sulfides to Sulfoxides..................................................205 3.1.5 Oxidation of Sulfides to Sulfones.....................................................205 3.1.5.1 Oxidation with Oxone.......................................................205 3.1.5.2 Oxidation with Sodium Perborate ....................................206 3.1.5.3 Oxidation with Sodium Periodate ....................................207 3.1.5.4 Oxidation with NaOCl ......................................................208 3.1.5.5 Oxidation with H2O2/Na2WO4 ..........................................208 3.1.5.6 Oxidation with TMSCl/KNO3 ..........................................209 3.1.6 Other Oxidative Reactions ...............................................................209 3.1.6.1 Dakin Oxidation ...............................................................209 3.1.6.2 Hydroxylation ................................................................... 210 3.1.6.3 Oxidative Cyclization ....................................................... 211 3.1.6.4 Oxidation of Phosphite ..................................................... 211 Reduction Reactions ...................................................................................... 212 3.2.1 Boron-Based Reductive Reactions ................................................... 212 3.2.1.1 Reduction with NaBH4...................................................... 212 3.2.1.2 Reduction with Borane ..................................................... 219 3.2.2 Reduction with Lithium Aluminum Hydride ................................... 226 Procedure .......................................................................................... 226 Nitrogen-Involved Hazardous Reactions ....................................................... 227 3.3.1 Diazonium Salts ............................................................................... 227 3.3.1.1 Hydrolysis of Diazonium Salt ........................................... 227 3.3.1.2 Diazonium Salt–Involved Cyclization .............................. 228 3.3.1.3 Nitroindazole Formation................................................... 229 3.3.1.4 Synthesis of Trifluoromethyl-Substituted Cyclopropanes..... 230 3.3.1.5 Sandmeyer Reaction ......................................................... 230 3.3.2 Azide Compounds ............................................................................ 232 3.3.2.1 Nucleophilic Displacement ............................................... 233 3.3.2.2 Nucleophilic Addition....................................................... 236 3.3.3 Hydrazine ......................................................................................... 243 3.3.3.1 Wolff–Kishner Reduction ................................................. 243 3.3.3.2 Synthesis of Indazole ........................................................ 245 3.3.3.3 Synthesis of Pyrazole........................................................ 245 3.3.3.4 Synthesis of Triazole......................................................... 245 3.3.3.5 Preparation of Dihydropyridazinone ................................246 3.3.3.6 Preparation of Phthalazin-1-ol ..........................................246 3.3.3.7 Preparation of Alkylamine ............................................... 247 3.3.4 Preparation of Aryl (or Alkyl) Hydrazines and Related Reactions ......247 3.3.4.1 Preparation of 5-Hydrazinoquinoline ...............................248 3.3.4.2 Synthesis of Aminopyrazole............................................. 249

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Contents

3.3.4.3 Fischer Indole Synthesis ................................................... 250 3.3.4.4 Preparation of Alkylhydrazine ......................................... 250 3.3.5 Hydroxylamine ................................................................................. 251 3.3.6 Oxime ............................................................................................... 252 Procedure .......................................................................................... 252 3.3.7 N-Oxide ............................................................................................ 253 3.3.8 Nitro Compounds ............................................................................. 254 3.3.8.1 Preparation of Nitro Compounds by Nitration ................. 254 3.3.8.2 Hazardous Reactions of Nitro Compounds ...................... 259 3.3.9 Ritter Reaction..................................................................................260 (I) Ritter Reaction Incident............................................................... 261 (II) Solutions .................................................................................... 261 3.4 Other Hazardous Reactions and Reagents .................................................... 261 3.4.1 Other Hazardous Reactions.............................................................. 261 3.4.1.1 Heck Reaction ................................................................... 261 3.4.1.2 Negishi Cross-Coupling Reaction .................................... 262 3.4.1.3 Blaise Reaction ................................................................. 262 3.4.1.4 Hydrogen/Metal Exchange ............................................... 263 3.4.1.5 Halogenation Reactions ....................................................264 3.4.1.6 Dehydrochlorination .........................................................266 3.4.1.7 Thiocyanation ................................................................... 270 3.4.1.8 Gas-Involved Reactions .................................................... 271 3.4.1.9 Darzens Reaction .............................................................. 277 3.4.2 Hazardous Reagents ......................................................................... 278 3.4.2.1 Volatile Organic Compounds ........................................... 278 3.4.2.2 High-Energy Compounds ................................................. 283 3.4.2.3 Toxic Compounds ............................................................. 286 Notes......................................................................................................................... 289 Chapter 4

Catalytic Reactions................................................................................................... 297 4.1

4.2 4.3 4.4 4.5

4.6

Two-Phase Reactions ..................................................................................... 297 4.1.1 Nucleophilic Substitution Reactions ................................................ 297 4.1.1.1 Enhancement of SN2 Reaction Rate.................................. 297 4.1.1.2 Replacement of DMSO in SNAr Reaction ........................ 298 4.1.1.3 Reduction of Amounts of Toxic Sodium Cyanide ............ 299 4.1.1.4 Controls of Impurity Formation ....................................... 299 4.1.2 Oxidation of Di-tert-Dutylphosphite ................................................300 Dehydrobromination...................................................................................... 301 Procedure ....................................................................................................... 301 Regioselective Chlorination........................................................................... 301 Procedure .......................................................................................................302 Regioselective Deprotonation ........................................................................302 Procedure .......................................................................................................302 Amide Preparation ........................................................................................ 303 4.5.1 NaOMe as Catalyst ........................................................................... 303 Procedure .......................................................................................... 303 4.5.2 HOBt as Catalyst ..............................................................................304 Procedure ..........................................................................................304 Synthesis of Indole ........................................................................................ 305 Procedure ....................................................................................................... 305

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Contents

4.7

N-Methylation Reaction.................................................................................306 Procedure .......................................................................................................306 4.8 Baylis–Hillman Reaction ..............................................................................307 Procedure .......................................................................................................307 4.9 Catalytic Wittig Reaction ..............................................................................307 4.10 Negishi Cross-Coupling Reaction .................................................................307 4.11 Catalytic Hydrogenations ..............................................................................308 4.11.1 Chemoselective Hydrogenation ........................................................308 4.11.1.1 Using P(OPh)3 Additive ....................................................309 4.11.1.2 Nickel-Catalyzed Reduction .............................................309 4.11.2 Catalytic Transfer Hydrogenation .................................................... 310 4.11.2.1 Metal-Catalyzed Reductions ............................................ 310 4.11.2.2 Organocatalytic Transfer Hydrogenation ......................... 312 4.12 Palladium-Catalyzed Rearrangement............................................................ 313 Procedure ....................................................................................................... 314 Notes......................................................................................................................... 314 Chapter 5

Grignard Reagent and Related Reactions ................................................................ 317 5.1

5.2

Preparation of Grignard Reagent................................................................... 317 5.1.1 Use of Chlorotrimethylsilane ........................................................... 317 5.1.1.1 Preparation of 4-Fluoro-2-Methylphenylmagnesium Bromide ............................................................................ 317 5.1.1.2 Preparation of (4-(2-(Pyrrolidin-1-yl)ethoxy)phenyl) magnesium Bromide ......................................................... 318 5.1.2 Use of Diisobutylaluminum Hydride ............................................... 318 Procedure .......................................................................................... 319 5.1.3 Use of Diisobutylaluminum Hydride/Iodine.................................... 319 Procedure .......................................................................................... 319 5.1.4 Use of Grignard Reagent .................................................................. 320 5.1.4.1 Use of MeMgCl ................................................................ 320 5.1.4.2 Use of EtMgBr .................................................................. 321 5.1.4.3 Use of Heel ....................................................................... 322 5.1.5 Use of Alkyl Halides ........................................................................ 323 5.1.5.1 Iodomethane ..................................................................... 323 5.1.5.2 1,2-Dibromoethane ........................................................... 323 5.1.6 Halogen–Magnesium Exchange ....................................................... 323 5.1.6.1 Preparation of Trifluoromethyl Substituted Aryl Grignard Reagents ............................................................ 324 5.1.6.2 Preparation of N-Methylpyrazole Grignard Reagent........ 325 5.1.6.3 Preparation of (4-Bromonaphthalen-1-yl)Magnesium Chloride ............................................................................ 325 5.1.6.4 Magnesium-Ate Complex ................................................. 326 Reactions of Grignard Reagents .................................................................... 327 5.2.1 Reactions with Ketones .................................................................... 327 5.2.1.1 Vinyl Grignard Reaction................................................... 327 5.2.1.2 Aryl Grignard Reaction .................................................... 328 5.2.1.3 Grignard Reaction of Methylmagnesium Bromide .......... 330 5.2.2 Reaction with Acid Chloride ............................................................ 331 Procedure .......................................................................................... 331 5.2.3 Reaction with Amide........................................................................ 331

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Contents

5.2.4 5.2.5

Michael Addition .............................................................................. 333 Reaction with Epoxide ..................................................................... 333 (I) Chemistry Diagnosis ................................................................... 334 (II) Solutions .................................................................................... 334 5.2.6 Cross-Coupling Reactions ................................................................ 334 5.2.6.1 Suzuki Coupling Reaction ................................................ 334 5.2.6.2 Iron-Catalyzed Coupling Reaction ................................... 336 Notes......................................................................................................................... 336 Chapter 6

Challenging Reaction Intermediates ........................................................................ 339 6.1

Effect of Intermediates .................................................................................. 339 6.1.1 In Telescoping Steps ......................................................................... 339 6.1.2 In Designing Synthetic Steps ........................................................... 339 6.2 Intermediate in the Product Isolation ............................................................ 342 6.2.1 Counter Ion Exchange ...................................................................... 342 (I) Problems ...................................................................................... 343 (II) Solutions .................................................................................... 343 6.2.2 Pictet–Spengler Condensation..........................................................344 Procedure ..........................................................................................344 6.2.3 Amide Reduction.............................................................................. 345 6.3 Multiple Reaction Stages ...............................................................................346 Procedure ....................................................................................................... 347 6.4 Intermediate in the Process Development ..................................................... 347 6.4.1 Indirect Monitoring of the Intermediate .......................................... 347 6.4.1.1 Derivatization of Acylimidazolide ................................... 347 6.4.1.2 Derivatization of N-Methylene Bridged Dimer ................348 6.4.2 Direct Monitoring of the Intermediate ............................................. 349 Notes......................................................................................................................... 350 Chapter 7

Protecting Groups .................................................................................................... 351 7.1

7.2

Protection of Hydroxyl Group ....................................................................... 351 7.1.1 Prevention of Side Reactions ............................................................ 351 7.1.1.1 Friedel–Crafts Alkylation................................................. 351 7.1.1.2 Removal of Trifluoromethanesulfonyl Group................... 352 7.1.2 Increasing Catalyst Activity ............................................................. 352 7.1.3 Selection of Protecting Group .......................................................... 354 7.1.3.1 Protection of Hydroxyphenylboronic Acid ....................... 354 7.1.3.2 Protection of Iodobutanol ................................................. 354 7.1.3.3 Protection of 1-Hydroxypropan-2-yl Methanesulfonate ... 354 7.1.4 Protection of Diol for Separation of anti- and syn-Diols ................. 356 Procedure .......................................................................................... 356 Protection of Amino Group ........................................................................... 357 7.2.1 Protection of Indole Nitrogen ........................................................... 357 Procedure .......................................................................................... 358 7.2.2 Epoxide Ring Opening ..................................................................... 358 7.2.3 Formation of Imines ......................................................................... 359 7.2.3.1 Protection of Amine with Aryl Aldehyde ........................ 359 7.2.3.2 Protection of Amine with 4-Methyl-2-Pentanone ............ 359 7.2.4 Indirect Protection............................................................................360 Procedure .......................................................................................... 361

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Contents

7.3 7.4

Protection of Carboxylic Acid ....................................................................... 361 Protection of Aldehydes and Ketones ........................................................... 362 7.4.1 Protection of Ketone with Dimethyl Ketal....................................... 363 7.4.2 Dioxolane.......................................................................................... 363 7.4.3 Deprotection of Acetal .....................................................................364 7.5 Protection of Acetylene .................................................................................364 7.6 Unusual Protecting Groups ........................................................................... 365 7.6.1 Boron-Containing Protecting Group................................................ 365 7.6.1.1 Borane Complex ............................................................... 365 7.6.1.2 Boronic Acid ..................................................................... 366 7.6.2 N-Nitro Protecting Group................................................................. 367 7.6.2.1 Regioselective Nitration .................................................... 367 7.6.2.2 Activation of Aniline ........................................................ 368 7.6.3 Halogen as Protecting Group ........................................................... 368 7.6.3.1 Bromine Protecting Group ............................................... 368 7.6.3.2 Chlorine as Protecting Group ........................................... 370 7.7 Protecting Group Migration .......................................................................... 371 Notes......................................................................................................................... 371 Chapter 8

Reaction Solvents ..................................................................................................... 373 8.1

8.2

Ethereal Solvents ........................................................................................... 373 8.1.1 Cyclopentyl Methyl Ether ................................................................ 374 8.1.1.1 Brook Rearrangement ....................................................... 374 8.1.1.2 N-Alkylation Reaction ...................................................... 375 8.1.2 Tetrahydrofuran ................................................................................ 376 8.1.2.1 Grignard Reagent Formation ............................................ 376 8.1.2.2 Bromination of Ketone ..................................................... 376 8.1.3 2-Methyl Tetrahydrofuran ................................................................ 377 8.1.3.1 Control of Impurity Formation ......................................... 377 8.1.3.2 Improving Reaction Rate .................................................. 378 8.1.3.3 Improving Layer Separation ............................................. 379 8.1.4 Methyl tert-Butyl Ether .................................................................... 380 8.1.4.1 Chlorination Reaction ....................................................... 380 8.1.4.2 Darzens Reaction .............................................................. 381 8.1.5 Diethoxymethane and Dimethoxyethane ......................................... 381 Protic Solvents ............................................................................................... 381 8.2.1 Reaction of Acyl Hydrazine with Trimethylsilyl Isocyanate ........... 381 8.2.2 Amide Formation ............................................................................. 382 Procedure .......................................................................................... 382 8.2.3 Catalytic Reduction of Diaryl Methanol .......................................... 383 (I) Reaction Problems....................................................................... 383 (II) Solutions .................................................................................... 383 8.2.4 Catalytic Debenzylation ................................................................... 383 (I) Reaction Problems....................................................................... 384 (II) Solutions .................................................................................... 384 Procedure .......................................................................................... 384 8.2.5 Catalytic Reduction of Nitro Group ................................................. 384 8.2.5.1 Leak of Palladium Catalyst .............................................. 384 8.2.5.2 Side Product Formation .................................................... 385 8.2.5.3 Classic Resolution of Acid ................................................ 385 8.2.6 SN2 Reaction ..................................................................................... 386

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8.3

Water as a Reaction Solvent .......................................................................... 386 8.3.1 Iodination Reaction .......................................................................... 386 Procedure .......................................................................................... 386 8.3.2 Synthesis of Quinazoline-2,4-Dione ................................................ 387 Procedure (for Synthesis of 58a) ...................................................... 387 8.3.3 Synthesis of Pyrrolo Cyclohexanone................................................ 388 Procedure .......................................................................................... 388 8.3.4 Synthesis of Thiourea ....................................................................... 389 (I) Reaction Problems....................................................................... 389 (II) Solutions .................................................................................... 389 8.4 Nonpolar Solvents.......................................................................................... 389 8.4.1 Condensation of Ketone with tert-Butyl Hydrazine-Carboxylate ..... 390 Procedure .......................................................................................... 390 8.4.2 Acid-Catalyzed Esterification .......................................................... 390 8.5 Polar Aprotic Solvents ................................................................................... 391 8.5.1 Decarboxylative Blaise Reaction...................................................... 391 8.5.2 Michael Addition Reaction............................................................... 391 8.5.2.1 Acetone as a Solvent ......................................................... 391 8.5.2.2 Acetonitrile as a Solvent ................................................... 392 8.5.3 SNAr Reaction .................................................................................. 393 8.5.3.1 Preparation of Alkyl Aryl Ether ....................................... 393 8.5.3.2 Preparation of Bisaryl Ether ............................................. 393 8.6 Halogenated Solvents .................................................................................... 394 8.6.1 Dichloromethane .............................................................................. 394 8.6.1.1 Reaction with Pyridine ..................................................... 394 8.6.1.2 Synthesis of Benzo[d]isothiazolone.................................. 394 8.6.2 Trifluoroacetic Acid.......................................................................... 396 (I) Problems ...................................................................................... 396 (II) Solutions .................................................................................... 396 Procedure .......................................................................................... 397 8.6.3 (Trifluoromethyl)benzene ................................................................. 397 8.6.4 Hexafluoroisopropanol ..................................................................... 398 8.7 Carcinogen Solvent ........................................................................................ 399 8.8 Other Solvents ............................................................................................... 399 8.8.1 DW-Therm ........................................................................................ 399 8.8.2 Dowtherm A ..................................................................................... 399 8.8.2.1 Synthesis of 6-Chlorochromene ....................................... 399 8.8.2.2 Conrad–Limpach Synthesis of Hydroxyl Naphthyridine .....400 8.8.3 Polyethylene Glycol ..........................................................................400 8.8.4 Propylene Glycol Monomethyl Ether ............................................... 401 Procedure .......................................................................................... 401 8.8.5 Sulfolane........................................................................................... 401 8.8.6 Ionic Liquid ......................................................................................402 8.9 Solvent-Free Reaction ....................................................................................403 Procedure .......................................................................................................403 Notes.........................................................................................................................403 Chapter 9

Base Reagent Selection ............................................................................................407 9.1

Inorganic Base ...............................................................................................407 9.1.1 Sodium Bicarbonate .........................................................................407

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Contents

9.1.2 9.1.3 9.1.4

Potassium Carbonate ........................................................................407 Sodium Hydride ...............................................................................407 Combination of LiOH with H2O2 .....................................................408 9.1.4.1 Hydrolysis of Chiral Ester ................................................408 9.1.4.2 Hydrolysis of Chiral Amide.............................................. 410 9.2 Organic Base ................................................................................................. 410 9.2.1 Trialkylamine ................................................................................... 410 9.2.1.1 Diisopropylethylamine ..................................................... 411 9.2.1.2 Triethylamine.................................................................... 412 9.2.2 Imidazole .......................................................................................... 414 Procedure .......................................................................................... 414 9.2.3 2,6-Dimethylpiperidine .................................................................... 414 9.2.4 2-(N,N-Dimethylamino)pyridine ...................................................... 415 9.2.5 Metal Alkoxide Base ........................................................................ 415 9.2.5.1 Potassium tert-Pentylate ................................................... 415 9.2.5.2 Lithium tert-Butoxide ....................................................... 418 9.2.5.3 Potassium tert-Butoxide.................................................... 419 9.2.5.4 Combination of Potassium tert-Butoxide with tert-Butyllithium ............................................................... 421 9.2.5.5 Sodium Methoxide............................................................ 422 Notes......................................................................................................................... 422 Chapter 10 Reagents for Amide Formation ................................................................................ 425 10.1 CDI-Mediated Amide Preparation ................................................................ 425 10.1.1 Preparation of Amide ....................................................................... 425 Procedure .......................................................................................... 426 10.1.2 Preparation of Ureas ......................................................................... 426 10.1.2.1 In the Absence of a Base .................................................. 426 10.1.2.2 Activation via N-Methylation ........................................... 426 10.2 Thionyl Chloride-Mediated Amide Preparation ........................................... 426 10.2.1 Preparation of Acid Chloride ........................................................... 426 Procedure .......................................................................................... 428 10.2.2 N-Sulfinylaniline-Involved Amide Preparation ............................... 429 10.3 Boc2O-Mediated Amide Preparation ............................................................ 430 10.4 Schotten–Baumann Reaction ........................................................................ 431 Procedure ....................................................................................................... 431 10.5 Other Methods ............................................................................................... 431 10.5.1 Copper (II)-Catalyzed Transamidation ............................................ 431 10.5.2 Cross-Coupling between Acyltrifluoroborates and Hydroxylamines ............................................................................... 436 Notes......................................................................................................................... 437 Chapter 11 Various Reagent Surrogates ..................................................................................... 439 11.1 Ammonia Surrogates ..................................................................................... 439 11.1.1 Ammonium Hydroxide .................................................................... 439 Procedure ..........................................................................................440 11.1.2 Ammonium Acetate .........................................................................440 11.1.2.1 Condensation with Aldehyde ............................................440 11.1.2.2 Condensation with Ketone ................................................440

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Contents

11.1.3 11.1.4

Ammonium Chloride ..................................................................... 442 Hydroxylamine Hydrochloride ...................................................... 442 11.1.4.1 Reaction with Aldehyde.................................................. 442 11.1.4.2 Reaction with Ketone...................................................... 442 11.1.5 O-Benzylhydroxylamine ................................................................ 443 11.1.6 Hydroxylamine-O-Sulfonic Acid................................................... 443 11.1.6.1 SN2 Reaction of with Sulfinate ....................................... 443 11.1.6.2 Reaction with Boronic Acid ........................................... 443 11.1.7 4-Methylbenzenesulfonamide........................................................444 11.1.8 Hexamethylenetetramine ...............................................................444 11.1.9 Acetonitrile .................................................................................... 445 Procedure .......................................................................................446 11.1.10 Chloroacetonitrile ..........................................................................446 11.1.11 tert-Butyl Carbamate ..................................................................... 447 11.1.12 Diphenylmethanimine ................................................................... 447 Procedure ....................................................................................... 447 11.1.13 tert-Butylcarbamidine ....................................................................448 Procedure .......................................................................................449 11.1.14 Silylated Amines as Ammonia Equivalents .................................. 450 Procedure (for the Preparation of 56) ............................................ 451 11.1.15 Allylamines as Ammonia Equivalents .......................................... 451 Procedure ....................................................................................... 452 11.2 Carbon Monoxide Surrogates ........................................................................ 453 11.2.1 N-Formylsaccharin ........................................................................ 453 11.2.2 Paraformaldehyde .......................................................................... 453 11.2.3 Molybdenum Carbonyl .................................................................. 453 11.3 Aldehyde Surrogates...................................................................................... 454 11.3.1 Sodium Bisulfite............................................................................. 454 11.3.1.1 Oxidation of Aldehyde to Acid ....................................... 454 11.3.1.2 Reductive Amination ...................................................... 455 11.3.1.3 Diels–Alder Reaction...................................................... 456 11.3.1.4 Strecker Reaction ............................................................ 457 11.3.1.5 Transaminase DKR of Aldehyde .................................... 457 11.3.2 Sulfur Dioxide Solution ................................................................. 458 Procedure ....................................................................................... 458 11.4 Sulfur Dioxide Surrogate............................................................................... 459 11.4.1 Synthesis of Alkyl Aryl Sulfones .................................................. 459 11.4.2 Synthesis of Sulfonamides ............................................................. 459 Notes......................................................................................................................... 459 Chapter 12 Telescope Approach ................................................................................................. 461 12.1 Hazardous Intermediates and Toxic Reagents .............................................. 461 12.1.1 Chloroketone Intermediate ............................................................ 461 Procedure ....................................................................................... 461 12.1.2 Lachrymatory Chloromethacrylate Intermediate .......................... 462 12.1.3 Chloromethyl Benzimidazole ........................................................ 462 Procedure ....................................................................................... 463 12.1.4 Pyridine N-Oxide ...........................................................................464 12.1.5 Benzyl Bromide .............................................................................465

Contents

xix

12.2 Hygroscopic and Oily Intermediate ..............................................................465 12.2.1 Oily Intermediates ............................................................................466 Procedure ..........................................................................................466 12.2.2 Hygroscopic Solid ............................................................................ 467 12.2.3 Amine Hydrochloride Salt ............................................................... 467 Procedure ..........................................................................................469 12.2.4 High Water-Soluble Intermediate .....................................................469 12.3 Filtration Problem .......................................................................................... 470 12.3.1 Preparation of Amide ....................................................................... 470 12.3.2 Synthesis of β-Nitrostyrene .............................................................. 470 Procedure .......................................................................................... 471 12.4 Unstable Intermediates .................................................................................. 472 12.4.1 Heteroaryl Chlorides ........................................................................ 472 Procedure .......................................................................................... 472 12.4.2 Toluenesulfonate Intermediate ......................................................... 473 12.4.3 Aldehyde Intermediates ................................................................... 474 12.4.3.1 Reduction/Grignard-Type Reaction .................................. 474 12.4.3.2 Oxidation/Wittig Reaction ............................................... 474 12.4.4 Unstable Alkene Intermediates ........................................................ 474 12.4.4.1 Diels–Alder Reaction........................................................ 474 12.4.4.2 Acrylate Formation/Heck Coupling ................................. 476 12.4.4.3 Protection/Heck Reaction/Deprotection .......................... 477 12.4.5 Unstable β-Hydroxyketone ............................................................... 478 Procedure .......................................................................................... 479 12.5 Expensive Catalyst.........................................................................................480 12.5.1 Imine Reduction/Debenzylation ......................................................480 Procedure ..........................................................................................480 12.5.2 Palladium-Catalyzed Debromination/Suzuki Cross-Coupling Reaction ............................................................................................ 481 Procedure .......................................................................................... 482 12.6 Improvement of Overall Yields ..................................................................... 482 12.6.1 Synthesis of Spirocyclic Hydantoin ................................................. 482 Procedure .......................................................................................... 482 12.6.2 Synthesis of Diaryl Compound ........................................................484 12.7 Reduction in Processing Solvents.................................................................. 485 12.7.1 Toluene as the Common Solvent ...................................................... 485 12.7.2 DMF as the Common Solvent .......................................................... 485 Procedure .......................................................................................... 485 12.7.3 EtOAc as the Common Solvent ........................................................ 486 12.7.3.1 Acid Activation/Hydrazide Formation/Triazolone Formation.......................................................................... 486 12.7.3.2 Reduction/Acid Activation/Acylation ............................... 488 12.7.4 THF as the Common Solvent ........................................................... 489 Procedure .......................................................................................... 490 12.7.5 EtOH/THF as the Common Solvent ................................................ 490 Procedure .......................................................................................... 490 12.8 Solvent Exchange........................................................................................... 491 12.9 Other Telescope Processes ............................................................................ 492 12.9.1 Bromination/Isomerization Reactions ............................................. 492 12.9.2 Fisher Indole Synthesis/Ring Rearrangement .................................. 492

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Contents

12.9.3

Ylide Formation/Wittig Reaction/Cycloaddition ............................ 493 Procedure......................................................................................... 493 12.9.4 Overman Rearrangement ................................................................ 494 Procedure ......................................................................................... 495 12.9.5 Nitro Reduction/Reductive Amination/Dehalogenation ................. 495 Procedure ......................................................................................... 496 12.9.6 Michael Addition/Elimination/Cycloaddition ................................. 496 12.9.7 Synthesis of Aryl Bromide .............................................................. 497 12.9.8 Synthesis of Lactam ........................................................................ 497 Procedure ......................................................................................... 497 12.9.9 Synthesis of (–)-Oseltamivir............................................................ 499 12.10 Limitation of the Telescope Approach .......................................................... 501 12.10.1 Lack of Purity Control..................................................................... 501 12.10.2 Poor Product Yields ......................................................................... 501 12.10.3 Lack of Compatibility...................................................................... 503 Notes.........................................................................................................................504 Chapter 13 Stereochemistry........................................................................................................ 507 13.1 Asymmetric Synthesis ...................................................................................507 13.1.1 Asymmetric Catalysis .....................................................................507 13.1.1.1 Desymmetrization of Anhydride ..................................... 507 13.1.1.2 Asymmetric Reduction of Enone ....................................509 13.1.1.3 Sharpless Asymmetric Dihydroxylation.......................... 510 13.1.1.4 Enantioselective Alkylation............................................. 511 13.1.1.5 Asymmetric Cross-Benzoin Addition ............................. 511 13.1.1.6 CuH-Catalyzed Stereoselective Synthesis of 2,3-Disubstituted Indolines ............................................. 512 13.1.2 Chiral Pool Synthesis ...................................................................... 512 13.1.2.1 Generation of a New Chiral Center ................................. 512 13.1.2.2 Transfer of Chiral Center ................................................ 514 13.1.3 Use of Chiral Auxiliaries ................................................................ 515 13.1.3.1 Diastereoselective Diels–Alder Reaction ........................ 515 13.1.3.2 Diastereoselective Synthesis of Boronic Acid ................. 515 13.1.3.3 Synthesis of Chiral (S)-Pyridyl Amine ........................... 516 13.2 Kinetic Resolution ......................................................................................... 517 13.2.1 Classical Resolution......................................................................... 518 13.2.1.1 Resolution of Racemic Acid ............................................ 518 13.2.1.2 Resolution of Racemic Base ............................................ 519 13.2.1.3 Enantiomeric Enrichment................................................ 522 13.2.1.4 Diastereomer Salt Break .................................................. 522 13.2.1.5 Examples of Diastereomeric Salts ................................... 523 13.2.2 Enzymatic Resolution ...................................................................... 523 13.2.2.1 Resolution of Esters ......................................................... 525 13.2.2.2 Resolution of Amino Acids ............................................. 528 13.2.2.3 Resolution Secondary Alcohols ...................................... 529 13.2.3 Other Resolution Methods ............................................................... 529 13.2.3.1 Stereoselective Ligand Exchange .................................... 529 13.2.3.2 Diastereomer Salt Formation........................................... 530

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xxi

13.2.3.3 Stereoselective Esterification of Racemic Diol ................ 530 13.2.3.4 Chiral Chromatographic Separation................................. 532 13.3 Dynamic Kinetic Resolution ......................................................................... 533 13.3.1 Dynamic Kinetic Resolution via Imine Intermediate ...................... 533 13.3.1.1 Aldehyde-Catalyzed Dynamic Kinetic Resolution .......... 533 13.3.1.2 Enantioselective Synthesis of Azabicyclic Rings ............. 535 13.3.1.3 Asymmetric Synthesis of Chiral Amines ......................... 537 13.3.2 Dynamic Kinetic Resolution via Proton Transfer ............................ 537 13.3.2.1 Ketone Reduction ............................................................. 537 13.3.2.2 Racemization of Nitrile .................................................... 539 13.3.2.3 Formation of Diastereomeric Salt.....................................540 13.3.2.4 Epimerization of cis-Isomer to trans-Isomer ................... 541 13.3.2.5 Isomerization of Cyclohexane Derivative......................... 542 13.3.2.6 Fischer Indole Synthesis ................................................... 543 13.3.3 Dynamic Kinetic Resolution via Reversible Bond Formation .........544 13.3.3.1 Reversible C−C Bond Formation......................................544 13.3.3.2 Reversible C−N Bond Formation......................................544 13.3.3.3 Reversible C−O Bond Formation ..................................... 547 13.3.3.4 Reversible C−S Bond Formation ...................................... 547 13.3.4 Other Resolution Methods................................................................ 548 13.3.4.1 Bromide-Catalyzed Dynamic Kinetic Resolution ............ 548 13.3.4.2 Resolution of Sulfoxide..................................................... 549 13.3.4.3 Resolution of Dihydropyrazole Carboxylate .................... 549 13.3.4.4 Dynamic Kinetic Resolution via C–C σ-Bond Rotation.......................................................................550 13.3.4.5 Dynamic Kinetic Isomerization via Ir-Catalyzed Internal Redox Transfer Hydrogenation ........................... 550 13.3.5 Various Dynamic Kinetic Resolution Examples .............................. 550 Notes......................................................................................................................... 555

Chapter 14 Design of New Synthetic Route ............................................................................... 561 14.1 Process Safety................................................................................................ 561 14.1.1 Toxic Reagents and Products............................................................ 561 14.1.1.1 Cyanogen Bromide ........................................................... 561 14.1.1.2 Hydrogen Cyanide (HCN) Evolution................................ 561 14.1.1.3 Toxic Reagent–Hg(OAc)2 .................................................. 563 14.1.1.4 Toxic Reagent–PBr3 ..........................................................564 14.1.1.5 Toxic Reagent–Hydrogen Fluoride HF ............................. 565 14.1.1.6 Toxic Benzyl Halides ........................................................ 565 14.1.1.7 Lachrymatory 2-(Benzo[d])[1,3]dioxol-5-yl-2Bromoacetic Acid ............................................................. 566 14.1.1.8 Phosphorus Oxychloride ................................................... 567 14.1.1.9 Sulfonyl Chloride Intermediate ........................................ 568 14.1.2 High-Energy Reagents ..................................................................... 569 14.1.2.1 Azide-Involved Cycloaddition .......................................... 569 14.1.2.2 Diazonium Salt-Involved Indazole Formation.................. 570 14.1.2.3 Lithium Aluminum Hydride Reduction ........................... 570

xxii

Contents

14.1.3

14.2

14.3

14.4

14.5

14.6

14.7

14.8

14.9

14.10

14.11

Undesired Reaction Conditions ...................................................... 572 14.1.3.1 Acylation Reaction ........................................................ 572 14.1.3.2 SNAr Reaction ................................................................ 573 Process Costs ................................................................................................. 574 14.2.1 Expensive Starting Materials ......................................................... 574 14.2.1.1 Using Fluorine-Free Starting Material .......................... 574 14.2.1.2 Using Convergent Approach.......................................... 575 14.2.2 Expensive Reagents ........................................................................ 577 14.2.2.1 Kumada Coupling.......................................................... 577 14.2.2.2 Cross-Coupling Reaction............................................... 578 14.2.2.3 Chiral Acid in Amide Preparation ................................ 579 Low Product Yields ....................................................................................... 579 14.3.1 Cycloaddition Reaction .................................................................. 580 14.3.2 Resolution and Grignard Reaction ................................................. 580 14.3.3 Resolution/Amide Formation/Cyclization...................................... 581 14.3.4 Chlorine Replacement .................................................................... 581 Procedure ........................................................................................ 582 Convergent Approach .................................................................................... 584 14.4.1 Decarboxylative Cross-Coupling Reaction .................................... 584 14.4.2 Synthesis of Chiral Amide ............................................................. 586 Multicomponent Reaction ............................................................................. 587 14.5.1 Construction of Piperidinone Structure ......................................... 587 14.5.2 Construction of Pyrimidinone Structure ........................................ 587 Step-Economy Synthesis ............................................................................... 587 14.6.1 Synthesis of Keto-Sulfone Intermediate ........................................ 587 14.6.2 Synthesis of Bendamustine ............................................................ 588 Atom-Economic Synthesis ............................................................................ 589 14.7.1 Synthesis of Carboxylic Acid ......................................................... 589 14.7.2 Stereoselective Synthesis of Diol ................................................... 590 Problematic Intermediates ............................................................................. 592 14.8.1 Unstable Alkyne ............................................................................. 592 14.8.2 Oily Intermediates .......................................................................... 592 14.8.2.1 Alkyl Alcohols .............................................................. 593 14.8.2.2 N-Acylpiperidine Derivatives ........................................ 593 Reaction Selectivity ....................................................................................... 594 14.9.1 Iodination ....................................................................................... 594 14.9.2 N-Alkylation Reaction.................................................................... 595 14.9.3 Formation of Indole Derivative ...................................................... 595 14.9.4 Formation of Seven-Membered Ring ............................................. 597 Residual Metals ............................................................................................. 598 14.10.1 C−N Bond Formation .................................................................... 598 14.10.2 C−C Bond Formation .................................................................... 598 14.10.3 Formation of C–C/C–N Bonds ...................................................... 598 Reagents and Conditions ................................................................600 Minimum Oxidation Stage Change ...............................................................600 14.11.1 Minimizing Nitrogen Oxidation Stage Adjustment .......................600 14.11.2 Minimizing Carbon Oxidation Stage Adjustment .........................600 14.11.2.1 Synthesis of Carboxylate Ester ......................................600 14.11.2.2 Synthesis of Alkyl Chloride .......................................... 601

Contents

xxiii

14.12 Coupling Reagent–Free Amide Formation ...................................................602 14.13 Etching of Glass Reactors .............................................................................603 Procedure (Route II, Production of 312) .......................................................604 Notes.........................................................................................................................604

Chapter 15 Reaction Workup ......................................................................................................607 15.1 Various Quenching Strategies .......................................................................607 15.1.1 Acidic Quenching .............................................................................607 15.1.1.1 Removal of Magnesium Salt .............................................607 15.1.1.2 Removal of Zinc By-Products ..........................................608 15.1.2 Basic Quenching...............................................................................609 15.1.2.1 Prevention of Thiadiazole Isomerization ..........................609 15.1.2.2 Prevention of Etching Glass Reactor ................................ 610 15.1.3 Anhydrous Quenching ..................................................................... 611 15.1.3.1 Removal of Zinc By-Products .......................................... 611 15.1.3.2 Avoidance of Insoluble Organic Mass .............................. 611 15.1.3.3 Avoidance of Degradation of Product .............................. 612 15.1.3.4 Decomposition of Excess Reagent.................................... 614 15.1.4 Oxidative Quenching........................................................................ 614 (I) Problematic Iodine ...................................................................... 615 (II) Solutions .................................................................................... 615 15.1.5 Reductive Quenching ....................................................................... 615 15.1.5.1 Triethylphosphite .............................................................. 615 15.1.5.2 Sodium Bisulfite ............................................................... 616 15.1.5.3 Ascorbic Acid ................................................................... 616 15.1.6 Disproportionation Quenching ......................................................... 617 Procedure .......................................................................................... 618 15.1.7 Reverse Quenching........................................................................... 618 15.1.7.1 Control of Impurity Formation ......................................... 618 15.1.7.2 Removal of Excess Reagent .............................................. 620 15.1.7.3 Increase in Conversion...................................................... 620 15.1.7.4 Prevention of Product Hydrolysis ..................................... 621 15.1.7.5 Prevention of Product Decomposition .............................. 622 15.1.7.6 Prevention of Emulsion..................................................... 622 15.1.7.7 Prevention of Exothermic Runaway ................................. 623 15.1.8 Concurrent Quenching ..................................................................... 624 (I) Problems ...................................................................................... 624 (II) Solutions .................................................................................... 624 15.1.9 Double Quenching............................................................................ 625 15.1.9.1 Acetone/HCl Combination ............................................... 625 15.1.9.2 Acetone/Citric Acid Combination .................................... 626 15.1.9.3 Acetone/MeOH/H2O ........................................................ 627 15.1.9.4 Ethyl Acetate/Water Combination .................................... 628 15.1.9.5 Ethyl Acetate/Tartaric Acid .............................................. 628 15.1.9.6 Ethyl Acetate/Aqueous Sodium Bicarbonate.................... 628 15.1.9.7 Isopropanol/Citric Acid .................................................... 629 15.1.9.8 Methyl Formate/Aqueous HCl .......................................... 630

xxiv

Contents

15.2 Direct Isolation .............................................................................................. 630 15.2.1 Cooling of Reaction Mixture ........................................................... 630 15.2.1.1 Direct Isolation from 2-Propanol...................................... 630 15.2.1.2 Direct Isolation from Isopropanol Acetate ....................... 631 15.2.1.3 Direct Isolation from Ethyl Acetate.................................. 631 15.2.1.4 Direct Isolation from Acetonitrile .................................... 632 15.2.2 Addition of Antisolvent .................................................................... 632 15.2.2.1 Adding Water to Acetic Acid............................................ 632 15.2.2.2 Addition of Water to DMF................................................ 633 15.2.2.3 Addition of Water to DMAc ............................................. 634 15.2.2.4 Addition of Water to DMSO ............................................. 635 15.2.2.5 Addition of Methanol to DMSO ....................................... 635 15.2.3 Cooling/Addition of Antisolvent ...................................................... 636 15.2.3.1 Isolation of Sonogashira Product ...................................... 636 15.2.3.2 Isolation of 6-Chlorophthalazin-1-ol ................................ 637 15.2.3.3 Isolation of 6-(pyridin-2-ylmethoxy)-1Hpyrazolo[3,4-b]pyrazine .................................................... 637 15.2.4 Neutralization ................................................................................... 638 Procedure .......................................................................................... 638 15.2.5 Salt Formation .................................................................................. 639 Procedure .......................................................................................... 639 15.2.6 Miscellaneous Approaches...............................................................640 15.2.6.1 Direct Drop Process..........................................................640 15.2.6.2 Direct Removal Approach ................................................ 641 15.3 Purification Strategies ................................................................................... 642 15.3.1 Extraction ......................................................................................... 642 15.3.1.1 Methyl tert-Butyl Ether Extraction ................................... 642 15.3.1.2 Ethyl Acetate Extraction ................................................... 643 15.3.1.3 Dodecane Extraction ........................................................644 15.3.1.4 n-Butanol Extraction......................................................... 645 15.3.1.5 Anhydrous Extraction ....................................................... 645 15.3.1.6 Double Extraction .............................................................646 15.3.2 Salt Formation .................................................................................. 647 15.3.2.1 Basic Organic Amines ...................................................... 647 15.3.2.2 Organic Acids ................................................................... 655 15.3.2.3 Quaternary Salt .................................................................664 15.3.3 Derivatization ...................................................................................666 15.3.3.1 Isolation/Purification of Aldehydes ..................................666 15.3.3.2 Isolation/Purification of Diol ............................................ 671 15.3.3.3 Isolation/Purification of Amino Diol ............................... 671 15.3.3.4 Isolation/Purification of Amine ........................................ 671 15.3.4 Removal of Impurities ...................................................................... 672 15.3.4.1 Removal of Ammonium Chloride .................................... 672 15.3.4.2 Removal of 9-BBN ........................................................... 673 15.3.4.3 Removal of Acetic Acid .................................................... 674 15.3.4.4 Selective Hydrolysis Approach ......................................... 675 15.4 Crystallization ............................................................................................... 676 15.4.1 Seed-Induced Crystallization ........................................................... 677 15.4.1.1 Avoiding Uncontrolled Crystallization ............................. 678 15.4.1.2 Avoiding Oiling Out .........................................................680

Contents

xxv

15.4.1.3 Control of Exothermic Crystallization ............................. 682 15.4.1.4 Polymorph Control ........................................................... 683 15.4.2 Various Other Crystallization Approaches ...................................... 683 15.4.2.1 Reactive Crystallization.................................................... 683 15.4.2.2 Addition of Water ............................................................. 687 15.4.2.3 Crystallization from Extraction Solvent ........................... 688 15.4.2.4 Three-Solvent System ....................................................... 689 15.4.2.5 Derivatization ...................................................................690 15.4.2.6 Control of Crystal Size Distribution .................................690 15.4.2.7 Cocrystallization............................................................... 691 15.5 Filtration Problems ........................................................................................ 693 15.5.1 Metal-Related Filtration Problems ................................................... 693 15.5.1.1 Copper-Related Problems ................................................. 693 15.5.1.2 TiCl4-Related Problems .................................................... 694 15.5.1.3 Aluminum-Related Problems ........................................... 694 15.5.2 Small Particle Size ........................................................................... 695 15.5.2.1 Addition of Acetic Acid .................................................... 695 15.5.2.2 Addition of 2-Propanol ..................................................... 697 15.5.2.3 Temperature Control ......................................................... 698 15.5.2.4 Polymorph Transformation ............................................... 699 15.5.3 Low-Melting Solid............................................................................700 Procedure ..........................................................................................700 15.6 Removal of Residual Palladium ....................................................................700 15.6.1 Crystallization .................................................................................. 701 15.6.1.1 Crystallization of Suzuki Reaction Product ..................... 701 15.6.1.2 Crystallization in the Presence of Additives .................... 701 15.6.2 Extraction ......................................................................................... 706 15.6.2.1 Liquid–Liquid Transportation .......................................... 706 15.6.2.2 Extractive Precipitation .................................................... 710 15.6.3 Adsorption ........................................................................................ 712 15.6.3.1 Activated Carbon .............................................................. 712 15.6.3.2 MP-TMT ........................................................................... 713 15.6.3.3 Deloxan THP-II ................................................................ 717 15.6.3.4 Smopex 110 ....................................................................... 717 15.6.4 Distillation ........................................................................................ 718 Procedure .......................................................................................... 718 15.6.5 Miscellaneous Methods.................................................................... 718 15.6.5.1 Adsorption–Crystallization .............................................. 718 15.6.5.2 Adsorption and TMT Wash .............................................. 719 15.6.5.3 Protecting Group .............................................................. 719 15.6.5.4 Salt Formation .................................................................. 720 15.6.6 Conclusion ........................................................................................ 721 15.7 Removal of Other Metals .............................................................................. 721 15.7.1 Removal of Copper........................................................................... 721 15.7.1.1 Aqueous Ammonia ........................................................... 722 15.7.1.2 Thiourea ............................................................................ 723 15.7.1.3 2,4,6-Trimercaptotriazine ................................................. 723 15.7.2 Removal of Rhodium ....................................................................... 725 15.7.2.1 Smopex-234 ...................................................................... 725 15.7.2.2 Ecosorb C-941 .................................................................. 725

xxvi

Contents

15.7.3 Removal of Ruthenium..................................................................... 726 15.7.3.1 Activated Carbon ........................................................... 726 15.7.3.2 Supercritical Carbon Dioxide ........................................ 726 15.7.4 Removal of Zinc ............................................................................... 726 15.7.4.1 Extraction with Trisodium Salt of EDTA ...................... 726 15.7.4.2 Use of Ethylenediamine ................................................. 728 15.7.5 Removal of Magnesium.................................................................... 729 Procedure .......................................................................................... 729 15.7.6 Removal of Aluminum ..................................................................... 730 15.7.6.1 Use of Triethanolamine ................................................. 730 15.7.6.2 Use of Crystallization .................................................... 731 15.7.7 Removal of Iron and Nickel ............................................................. 731 15.7.7.1 Removal of Iron ............................................................. 731 15.7.7.2 Removal of Nickel.......................................................... 732 15.8 Removal of Impurities ................................................................................... 732 15.8.1 Extractive Wash................................................................................ 733 15.8.1.1 Aqueous Wash................................................................ 733 15.8.1.2 Organic Wash ................................................................. 735 15.8.2 Precipitation Approach ..................................................................... 737 15.8.2.1 Precipitation of Product ................................................. 737 15.8.2.2 Precipitation of By-Product ........................................... 739 15.8.3 Use of Additives ............................................................................... 740 15.8.3.1 Application of NaHSO3.................................................. 740 15.8.3.2 Application of CaCl2 ...................................................... 744 15.8.3.3 Application of CaCO3 .................................................... 745 15.8.3.4 Application of N-Methylpiperazine ............................... 745 15.8.3.5 Application of Dimethylamine ...................................... 746 15.8.3.6 Application of Sodium Periodate ................................... 747 15.8.3.7 Application of Hydrogen Peroxide................................. 748 15.8.3.8 Application of Phenylboronic Acid ................................ 749 15.8.3.9 Application of CO2 ......................................................... 751 15.8.3.10 Application of Succinic Anhydride ............................... 751 15.8.3.11 Application of Pivaldehyde ............................................ 751 15.8.3.12 Application of Benzyltributylammonium Chloride ....... 753 15.8.3.13 Application of Sodium Dithionate ................................. 754 15.8.3.14 Application of Polymeric Resin ..................................... 755 15.8.3.15 Application of Aqueous Ammonia ................................ 756 15.8.3.16 Application of DABCO.................................................. 756 15.8.4 Transformation of Impurity to Starting Material or Product ........... 757 15.8.4.1 Transformation to Starting Material .............................. 757 15.8.4.2 Transformation to Product ............................................. 758 Notes......................................................................................................................... 760 Chapter 16 Pharmaceutical Salts ................................................................................................ 769 16.1 Common Acids in the Salt Formation ........................................................... 769 16.2 Hydrochloride Salts ....................................................................................... 770 Procedure ....................................................................................................... 770 16.3 Various Pharmaceutical Salts ........................................................................ 773

Contents

xxvii

16.4 Salts of Acidic Drug Substances ................................................................... 773 16.4.1 Potassium Salts ................................................................................. 773 16.4.1.1 Potassium Salt of 1,5-Naphthyridin-4(1H)-one................ 773 16.4.1.2 Potassium Salt of Amide .................................................. 780 16.4.2 Calcium Salts.................................................................................... 780 16.4.2.1 Salt Exchange from Sodium to Calcium Salt ................... 780 16.4.2.2 Salt Exchange from Ammonium to Calcium Salt ............ 781 16.4.3 Various Inorganic Salts .................................................................... 781 16.4.4 Salts with Organic Bases .................................................................. 781 Notes......................................................................................................................... 784 Chapter 17 Solid Form ................................................................................................................ 787 17.1 Polymorphism................................................................................................ 787 17.1.1 Control of Polymorph by Seeding .................................................... 788 Procedure .......................................................................................... 788 17.1.2 Control of Polymorph by Temperature ............................................ 788 17.1.2.1 Hydrolysis of Butyl Ester .................................................. 788 17.1.2.2 Deprotection of Diol ......................................................... 790 17.1.3 Control of Polymorph via Slurrying................................................. 791 Procedure .......................................................................................... 791 17.1.4 Control of Polymorph by Aging ....................................................... 791 17.2 Cocrystals ...................................................................................................... 792 17.2.1 Cocrystal with l-Phenylalanine ....................................................... 792 Procedure .......................................................................................... 793 17.2.2 Cocrystal with l-Pyroglutamic Acid................................................ 793 Procedure .......................................................................................... 793 17.2.3 Cocrystal with Phosphoric Acid....................................................... 794 Procedure .......................................................................................... 794 17.3 Hydrates ......................................................................................................... 794 Procedure ....................................................................................................... 795 17.4 API Particle Size ........................................................................................... 795 Notes......................................................................................................................... 796 Index .............................................................................................................................................. 799

Preface Forty years ago, there was little process research and development (R&D) activities in the pharmaceutical industry partially due to the simplicity of the drug molecules. Over the past decades, however, considerable attention has been paid to the process R&D of chemical synthesis for largescale production. With increasing structural complexity, especially the introduction of chiral centers into drug molecules and in order to comply with the regulations set by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), process R&D has become one of the critical departments for pharmaceutical companies. The scale-up of synthetic organic chemistry from laboratory glassware to large reaction vessels is by no means a simple linear process. Large-scale operations are expected to lead to expanded time scale, poor heat transfer, insufficient mixing, and loss of temperature control, which may potentially result in runaway reactions. Therefore, the process R&D in pharmaceutical industry requires integration of a broad range of disciplines, including, but not limited to, synthetic organic chemistry, physical organic chemistry, analytical chemistry, chemical engineering, regulatory compliance, and plant operation. The key responsibility of process chemists is to develop chemical processes that are feasible for manufacturing pharmaceutical intermediates and final drug substances (active pharmaceutical ingredients [APIs]) for support of clinical studies and, eventually, for commercial production. A good chemical process shall meet all key elements: low cost, available raw materials and reagents, simple workup, robustness, high throughput (fast reaction with high concentration), good product purity, and minimum environmental impact.

P.1

EVALUATION OF PROCESS

Generally, the medicinal chemistry route serves as the starting point for most process development programs, though it is normally designed to be divergent and to allow access to a variety of targets in small quantities. The first activity in developing a chemical process is to evaluate the existing medicinal process. The initial evaluation of the route will be based on the following criteria: safety, economics, environmental impact (green chemistry), and legal issues.

P.1.1

PROCESS SAFETY

Among various factors that need to be addressed appropriately during process R&D in laboratories, process safety is the most important aspect in the chemical process development. “If a route cannot be scaled up safely, then it should not be scaled up at all.”1 Process safety refers to (a) thermal and reactive hazards and (b) health hazards. The thermal or reactive hazards associated with process and operator safety include reactions with gas evolution and the possibility of thermal runaway and explosion and reactions that involve shock or heatsensitive and pyrophoric, flammable, or corrosive materials. It is important to have a hazard assessment for a given process, particularly when using materials or intermediates without an available material safety data sheet (MSDS). Early thermal decomposition data such as differential scanning calorimetry (DSC) can give an indication of operating limits for a particular process. For commercially available materials, MSDS is a valuable safety data. MSDS also provides important information of chemicals with health hazards.

xxix

xxx

P.1.2

Preface

PROCESS COST

Process costs depend largely on the following aspects: materials, labor, equipment, and waste disposal. In general, raw materials, intermediates, reagents, and solvents are comprised of 20%– 80% of the total cost of a given process. An economic process will use less expensive, commercially available materials as much as possible. Quite often the cost and availability of raw materials can be one of the major considerations in the synthetic route selection (see Chapter 14). Fortunately, due to the development of new synthetic methodologies and catalysis systems, more chemical compounds are available in bulk quantity at affordable prices. Therefore, the limitation of raw materials has diminished, which gives process chemists more freedom in devising chemical processes. Some reagents can be generated in situ, and hydrogen chloride, for example, is frequently prepared especially when HCl is needed in requisite amount and under dry-reaction conditions.2 Obviously, less labor intense processes are preferred, for example, chromatographic purification is not an ideal process on a large scale due to the burden of intensive labor. As per reduction of process cost, the one-pot process is frequently employed to minimize process wastes, time-consuming isolations, and handling losses. In addition, cryogenic reactions or reactions that require high temperature or pressure should be avoided as much as possible. These reaction conditions usually need special equipment and large amounts of energy, which, in turn, will increase process costs.

P.1.3

ENVIRONMENTAL IMPACT

Green chemistry addresses environmentally benign chemical synthesis, encouraging the design of chemical processes that minimize the use and generation of hazardous substances. Paul Anastas and John Warner developed the 12 green chemistry principles.3 The concept of atom economy4 for organic reactions proposed by Trost addresses that a maximum number of atoms of reactants should end up in products. Thus, an ideal reaction would incorporate all of the atoms of the reactants with limited wastes, which, in turn, effectively reduces environmental pollution and improves efficiency. Most chemical processes, however, produce products and wastes at the same time. These chemical wastes will, to a certain extent, have negative environmental impacts. Roger Sheldon, Professor Emeritus of Biocatalysis and Organic Chemistry at Delft University of Technology, the Netherlands, developed the concept of environmental factors (E-factors)5 to assess the environmental footprint of chemical processes. The E-factor is defined as “kg of total waste”/“kg of product.” Due to the complexity of the drug substance and tight quality regulations, pharmaceutical companies are more focused on the manufacture of molecules and the quality of the products. Therefore, the pharmaceutical industry faces a great challenge as well as an opportunity to reduce environmental impact. Green chemistry encourages the use of more sustainable chemistry and provides some benchmarking data. Accordingly, significant improvement has been made. For instance, the process (shown in Equation P.1)6 developed by Pfizer uses the Baylis–Hillman reaction in the synthesis of allyl alcohol, an intermediate for sampatrilat (an inhibitor of zinc metalloprotease). The inherently environmentally friendly, atom-efficient Baylis−Hillman reaction not only incorporates all the atoms of the two starting materials into the product, but it also adds environmental benefit since it allows the simple reuse of the 3-quinuclidinol and generated much less waste stream. 3-quinuclidinol (0.25 equiv)

O CO2tBu +

H

H

H2O/MeCN

OH

(P.1) CO2tBu

xxxi

Preface Me

Me

O O S N

ClSO3H

O

N Me

O H2N

Me N N

O 2N

H2 Pd/C

Me

Me N N

HN N

(a) CDI/EtOAc (b) tBuOK

2 O

EtOAc 3

O CO2H

N-methyl piperazine

CO2H 1

O

Me O

H 2N

Me N N

(c) Citric acid

H2N

Me

N

Me

•

HO

4

Me

O S N O

HO2C

CO2H CO2H

Sildenafil citrate

SCHEME P.1

Scheme P.17 demonstrates a highly convergent synthesis of sildenafil citrate, the active ingredient in Viagra, which was launched in early 1998. In this commercial manufacture route, the molecules, 2 and 3, were put together by a hydrogenation, activation, and acylation sequence in one pot using ethyl acetate (Class 3 solvent) as solvent. The single solvent for the three telescoped steps allows easy solvent recovery. This environmentally benign synthesis of sildenafil citrate has an E-factor of 6, which is significantly less than the industry standard (25–100). Consequently, the amount of waste produced per year is extremely low (just 6 kg of waste per kilogram of the product).8

P.1.4

CONTROLLED SUBSTANCES AND LEGAL ISSUES

Any chemicals that can be used for illicit drug refinement are controlled by governments and constantly monitored by the International Narcotics Control Board (INCB). Licenses are often required for the possession, supply, and manufacture of these chemicals. For example, (+)-pseudoephedrine (Figure P.1) has many applications; it is used as a resolving agent, ligand, and intermediate in organic synthesis. (+)-Pseudoephedrine is, however, a regulated chemical in the UK and the United States. International governments also tightly control chemicals that can be used in the production of chemical weapons. Notable examples include phosgene and cyanogen chloride. In the development stage, intellectual property (IP) issues should be avoided or resolved as early as possible.

Me

FIGURE P.1

NHMe OH

The chemical structure of (+)-pseudoephedrine.

xxxii

P.2

Preface

DESIGN OF NEW SYNTHETIC ROUTES

At the end of a process evaluation, a decision has to be made whether the existing process needs to be redesigned. When designing new synthetic routes, a rule of thumb should be followed: • • • • • • •

P.2.1

Use commercially available and less expensive materials. Use catalytic systems. Limit protecting group manipulations. Use convergent routes over linear ones. Use addition reactions. Use multicomponent reactions (MCRs). Use tandem or cascade processes, etc.

MATERIALS AND REAGENTS

The selection of starting materials and reagents is primarily based on process safety, cost, and commercial availability. Introducing atom-economical reagents into a process can potentially reduce costs and downstream wastes. For instance, similar reaction profiles were obtained when bromination of aminopyrazole 5 with either N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin (DBH), or N-bromoacetamide (Equation P.2).9 N H2N

N

N

DBH

Br

(P.2)

DMF/MeCN

H2N

5

N 6

Compared with NBS and DBH, N-bromoacetamide was more expensive and not readily available on scale. DBH was selected as the bromination reagent due to its robust solution stability in dimethyl formamide (DMF)/MeCN. It should be noted that both bromine atoms in DBH were utilized in this bromination reaction, making the process atom economical.

P.2.2

CATALYTIC SYSTEMS

A catalytic reaction proceeds through a transition state with lower activation energy, resulting in a higher reaction rate than an uncatalyzed reaction under otherwise the same reaction conditions. Thereby a catalytic reaction can be performed at relatively mild conditions, which is desired in large-scale production in terms of process costs and safety. Catalytic reactions are considered environmentally friendly due to the reduced amount of waste generated, as opposed to stoichiometric reactions. Classical olefinations, such as the Wittig reaction and Julia olefination, employ ketones or aldehydes as starting materials that are typically prepared by oxidation of the corresponding alcohols. A direct catalytic olefination of alcohols was realized using the thermally stable Ru-pincer catalyst (Equation P.3).10 This approach represents a step-economical synthesis, which avoids the alcohol oxidation step. R

O2 S

R2

Ru catalyst R1

OH

R1

R2

(P.3)

Phase-transfer catalysis is a process in which a reaction proceeds in heterogeneous media. Enantioselective fluorination of allylic alcohols was effected using chiral anion phase–transfer

xxxiii

Preface

catalyst (Equation P.4).11 This new method allows the fluorination reaction to be conducted in nonpolar media (p-xylene/ethylcyclohexane) at room temperature using insoluble Selectfluor as the fluorine reagent and tolylboronic acid as the in situ directing group.

iPr

iPr O O iPr P iPr HO O

1-Ad

1-Ad

R΄ R

P.2.3

R΄

SelectFluor R

p-tolylboronic acid

OH

OH

(P.4)

F

PROTECTING GROUPS

Chemoselective transformation via protection of functional groups is one of the standard tools in the total synthesis of natural products, and a large number of protecting groups12 have been developed to fulfill the chemoselective construction of complex molecules. The protecting group has to be stable enough under certain reaction conditions and, at the end, the deprotection has to be selective. For instance, the synthesis of natural products, (±)-basiliolide B, involved transformation of 7 → 8 that contains nine synthetic steps, including cyclopropane ring opening, oxidation, olefination, Achmatowicz ring expansion, methylation, another olefination, oxidation of ketal to lactone, base-promoted double-bond migration to form 2-pyrone, and Diels–Alder cycloaddition (Scheme P.2).13 While the allylic protecting group in 7 survived in all nine chemical transformations, the removal of the allylic group in 8 had to be selective without damaging other existing ester functionalities. To that end, a palladium-catalyzed deprotection protocol was adopted. However, these protecting/deprotecting manipulations render processes less efficient. Efforts in limiting protection/deprotection operations or protecting group-free synthesis14 led to the development of various strategies (see Chapter 7).

OH O

O

O O

Me

O

MeO

9 steps

O

O

I

Me

O Me Me 7

Me MeO

8 O O

O Me

O Me

CO2Me

Basiliolide B

SCHEME P.2

CO2Me

xxxiv

P.2.4

Preface

CONVERGENT SYNTHESIS

Convergent synthesis allows the coupling of advanced intermediates at the later stage of synthesis, which not only shortens processing times but also provides a better opportunity to remove impurities. For example, a convergent synthesis (Route II, Scheme P.3) of SDZ NKT343, a human NK-1 tachykinin receptor antagonist developed by Novartis, avoided the formation of three impurities (13–15) generated from the linear synthesis (Route I, Scheme P.3).15 Consequently, this convergent process allowed chromatography-free preparation of the drug substance on a large scale.

P.2.5

ADDITION AND SUBSTITUTION REACTIONS

In general, addition reactions are preferred over elimination reactions, as additions will build up molecular skeletons while eliminations will lose fragments of molecules that, in most cases, become O BocHN

O HCl • H2N

OH 2 steps

(I)

9

N Me

Bn

2 steps

11

N C O

H N

O Chromatography

O Bn N Me

O N H NO2

Bn N Me

HCl • HN

10

NO2

O

H N

O

N

SDZ NKT343

O O

OH

Cl

Me

O

O (II)

N

N H

10

Me N-benzyldimethylamine toluene, –20°C to –25°C

NO2 12

O

O Me

H N

N H

O N H NO2

O

Ph O

N

N H NO2

13

Me

Me O O

O

H N

N 15

SCHEME P.3

H N

O Bn N Me

N

14

O N H

Ph

xxxv

Preface

wastes. Addition reactions are limited to compounds that have unsaturated bonds, such as carbon– carbon double bonds, triple bonds, or carbonyl groups. Most organic transformations can be regarded as substitution reactions, in which X in the reactants RX is replaced by Y to form products RY (Equation P.5). Depending on reactants, these substitution reactions can generally be classified into nucleophilic substitution, electrophilic substitution, and free-radical substitution. Substitution reactions are inherently more balanced transformations, given that the replacement occurs between two compatible pieces in terms of mass. R–X + Y

(P.5)

R–Y + X

Besides traditional aromatic substitution reactions, transition metal–catalyzed cross-coupling reactions (Equation P.6) are extensively applied in the pharmaceutical industry owing to the recent development on organometallic chemistry. Pd R–Pd–R΄

R–X R΄–Y

P.2.6

R–R΄

(P.6)

ONE-POT SYNTHESIS

The one-pot process is an economically favorable method by performing a series of bond-formation steps in a single reaction vessel without isolation of intermediates. The use of one-pot synthesis can greatly improve the process efficiency by minimizing isolation and purification steps. The current development of one-pot synthesis is summarized in a review article16 that highlights various telescoping techniques, such as MCR,17 cascade (or domino)18 reaction, and tandem19 reaction. Chapter 12 provides useful information regarding these telescoping strategies and their application in the chemical process development.

P.3

PROCESS OPERATION

Although the advent of flow chemistry has brought much attention recently, most chemical processes in the pharmaceutical industry are developed based on batchwise operation. The way of mixing starting materials, reagents, catalysts, etc., in the presence of a solvent (in most cases) has a direct impact on the outcome of a given reaction. As a consequence, it affects not only the product yield and purity but also the thermodynamic behavior and process safety. There are several motivations for developing semibatch processes, such as control of reactant concentration to improve the selectivity of a reaction, avoidance of accumulation of reactants, and control of heat production of reactions (exothermic reactions). Most exothermic reactions are conducted in a semibatch fashion in order to mitigate the exothermic event and prevent a runaway reaction from occurring. Chapter 1 discusses the details of addition-related processing issues and various methods that are frequently used in the pharmaceutical industry.

P.4 PROCESS OPTIMIZATION Prior to scaling up, a number of process parameters need to be identified so that reactions can be carried out under optimal conditions. These parameters include the mode of addition of starting materials/reagents/solvents, temperature, solvent/concentration, pressure (for some cases), agitation rate, etc.

P.4.1

REACTION TEMPERATURE

A reaction temperature is established based primarily on the reaction rate and impurity profile. Ideally, the reaction temperature should be within the −20°C to 100°C range, too low or too high will

xxxvi

Preface

require additional energy and time at scale and sometimes special equipment is needed. Generally, a high reaction temperature will lead to poor selectivity, thereby forming impurities. Large jumps in temperature should be avoided.

P.4.2

SOLVENT AND CONCENTRATION

Several solvent evaluation tools20 are developed as solvent selection guides. Solvents shall be selected and assessed based on three general aspects: (a) toxicity (including carcinogenicity, mutagenicity, reprotoxicity, skin absorption/sensitization), (b) process safety (including flammability, emission, static charge, and potential for peroxide formation), and (c) environmental and regulatory considerations (including ecotoxicity, ground water contamination, and ozone depletion potential). Class 3 solvents, as proposed in the International Conference on Harmonization (ICH) guidelines, are preferred, especially at the end of the synthesis because of their low toxic potential (see Chapter 8). In general, high-concentration reactions are desired because not only do the reactions at high concentrations afford high throughput, but they also produce less downstream wastes. Anhydrous reaction conditions can be reached by using anhydrous reagents and solvents. In addition, azeotropic distillation is the most commonly used technique to remove moisture from a reaction system. In the case of the presence of temperature-sensitive species, a moisture scavenger, such as acetic anhydride, is employed.

P.4.3

ISOLATION AND PURIFICATION

Direct isolation and extractive workup are two commonly used isolation approaches. Direct isolation is preferred over extractive workup in terms of process wastes, processing times, and costs. An isolated reaction product usually needs to be purified in order to meet a predetermined purity criteria. The purification methods include distillation, recrystallization/precipitation, and column chromatography. Owing to the intensive labor requirement, column chromatography is generally not recommended in large scale. Obviously, the product yield and quality, including chiral and chemical purity and solid form (for solid materials), are two important parameters in determining the efficiency of a given process. Generally, reaction product yields of around 100% are considered quantitative, yields between 90% and 100% are considered excellent, yields between 80% and 90% are considered very good, yields between 60% and 80% are considered good, yields between 40% and 50% are considered moderate, and yields below 40% are considered poor.21 A product failing to meet the predetermined purity criteria may contain impurities, such as residual processing solvents, undesired products, or metals (see Chapter 15 for various isolation/purification strategies).

P.5

CONCLUSION

This book is designed to provide readers with unprecedented R&D approaches, which will help process chemists and graduate students who plan to become industrial chemists to develop chemical processes in an efficient manner. Based on the mechanism-guided process development (MPD) strategy, this book consists of 17 chapters, and each chapter contains numerous case studies. Each case study focuses on a mechanistic diagnosis of reaction problems, giving readers an opportunity of independent thinking and ultimately the ability to solve process problems in the real world.

Preface

xxxvii

NOTES 1. Blacker, A. J.; Williams, M. T. Pharmaceutical Process Development, Current Chemical and Engineering Challenges, Ch. 5, Royal Society of Chemistry: Cambridge, UK, 2011, p. 92. 2. (a) Luo, F.-T.; Jeevanandam, A. Tetrahedron Lett. 1998, 39, 9455. (b) Connolly, T. J.; Considine, J. L.; Ding, Z.; Forsatz, B.; Jennings, M. N.; MacEwan, M. F.; McCoy, K. M.; Place, D. W.; Sharma, A.; Sutherland, K. Org. Process Res. Dev. 2010, 14, 459. (c) Connolly, T. J.; Constantinescu, A.; Lane, T. S.; Matchett, M.; McGarry, P.; Paperna, M. Org. Process Res. Dev. 2005, 9, 837. (d) Peters, R.; Waldmeier, P.; Joncour, A. Org. Process Res. Dev. 2005, 9, 508. 3. Anastas, P. T.; Warner, J. C. Green Chemistry, Theory and Practice, Oxford University Press: New York, 1988. 4. Trost, B. Science 1991, 54, 1471. 5. Sheldon, R. A. Chem. Ind. 1992, 56, 903. 6. Dunn, P. J.; Hughes, M. L.; Searle, P. M.; Wood, A. S. Org. Process Res. Dev. 2003, 7, 244. 7. (a) Dunn, P. J. Org. Process Res. Dev. 2005, 9, 88. (b) Dale, D. J.; Dunn, P. J.; Golightly, C.; Hughes, M. L.; Levett, P. C.; Pearce, A. K.; Searle, P. M.; Ward, G.; Wood, A. S. Org. Process Res. Dev. 2000, 4, 17. (c) Dunn, P. J.; Wood, A. S. European Patent, EP 0 812845, 1997. 8. Dunn, P. J.; Galvin, S.; Hettenbach, K. Green Chem. 2004, 6, 43. 9. Itoh, T.; Kato, S.; Nonoyama, N.; Wada, T.; Maeda, K.; Mase, T.; Zhao, M. M.; Song, J. Z.; Tschaen, D. M.; McNamara, J. M. Org. Process Res. Dev. 2006, 10, 822. 10. Srimani, D.; Leitus, G.; Ben-David, Y.; Milstein, D. Angew. Chem. Int. Ed. 2014, 53, 11092. 11. Zi, W.; Wang, Y.-M.; Toste, F. D. J. Am. Chem. Soc. 2014, 136, 12894. 12. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons: New York, 1999. 13. Min, L.; Zhang, Y.; Liang, X.; Huang, J.; Bao, W.; Lee, C.-S. Angew. Chem. Int. Ed. 2014, 53, 11294. 14. Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404. 15. Prashad, M.; Prasad, K.; Repic, O.; Blacklock, T. J. Org. Process Res. Dev. 1999, 3, 409. 16. Zhao, W.; Chen, F.-E. Curr. Org. Synth. 2012, 9, 873. 17. (a) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123. (b) Ugi, I. Pure Appl. Chem. 2001, 73, 187. (c) Zhu, J.; Bienaime, H. Multicomponent Reactions, Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2005. 18. For reviews on cascade reactions in organic synthesis, see: (a) Tietze, L. F. Chem. Rev. 1996, 96, 115. (b) Tietze, L. F.; Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967. 19. (a) Nemoto, T.; Kakei, H.; Gnanadesikan, V.; Tosaki, S.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 14544. (b) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J. Am. Chem. Soc. 2002, 124, 13390. (c) Denmark, S. E. Thorarensen, A. Chem. Rev. 1996, 96, 137. (d) Winkler, J. D. Chem. Rev. 1996, 96, 167. (e) Ryu, I.; Sonoda, N.; Curran, D. P. Chem. Rev. 1996, 96, 177. (f) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem. Int. Ed. 2006, 45, 7134. 20. Curzons, A. D.; Constable, D. C.; Cunningham, V. L. Clean Prod. Process 1999, 1, 82. (b) JimenezGonzalez, C.; Curzons, A. D.; Constable, D. J. C.; Cunningham, V. L. Clean Technol. Environ. Pol. 2005, 7, 42. (c) Capello, C.; Fischer, U.; Hungerbuhler, K. Green Chem. 2007, 9, 917. 21. Vogel, A. I.; Tatchell, A. R.; Furnis, B. S.; Hannaford, A. J.; Smith, P. W. G. Vogel’s Textbook of Practical Organic Chemistry, 5th ed., Longman Scientific & Technical: London, UK, 1989.

List of Abbreviations ACE-Cl API ARC 9-BBN BDMAEE BHT BINAP Boc BOP BQ mCBA mCBPO Cbz CDI CDMT CIDR CLD CMCS COBC mCPBA CPME CSA CSD CSI CTP DABCO DABSO 1,2-DAP DAS DAST DBDMH DBH DBN DBU DCE DCH DCM DEA DEAD DEAN DEG DEM DEMS Deoxo-Fluor DFI DHP DIAD

1-Chloroethyl chloroformate Active pharmaceutical ingredient Accelerating rate calorimeter 9-Borabicyclo[3.3.1]nonane Bis[2-(N,N-dimethylamino)ethyl] ether Butylated hydroxy toluene (2,6-bis(1,1-dimethylethyl)-4-methylphenol) 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl tert-Butyloxycarbonyl (Benzotriazol-1-yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate 1,4-Benzoquinone m-Chlorobenzoic acid m-Chlorobenzoyl peroxide Benzyloxycarbonyl 1,1-Carbonyl diimidazole 2-Chloro-4,6-dimethoxy-1,3,5-triazine Crystallization-induced dynamic resolution Chord length distribution Chloromethyl chlorosulfate Continuous oscillatory baffled crystallizer m-Chloroperbenzoic acid Cyclopentyl methyl ether Camphorsulfonic acid Crystal size distribution N-Chlorosulfonylisocyanate 4-Chlorothiophenol 1,4-Diazabicyclo[2.2.2]octane 1,4-Diazabicyclo[2.2.2]octane (DABCO)–sulfur dioxide charge-transfer complex 1,2-Diaminopropane Dipolar aprotic solvent Diethylaminosulfur trifluoride Dibromodimethylhydantoin 1,3-Dibromo-5,5-dimethylhydantoin 1,5-Diazabicyclo[4.3.0]non-5-ene 1,8-Diazabicyclo[5.4.0]undec-7-ene Dichloroethane 1,3-Dichloro-5,5-dimethylhydantoin Dichloromethane Diethanolamine Diethyl azodicarboxylate N,N-Diethylaniline Diethylene glycol Diethoxymethane Diethoxy(methyl)silane Bis(2-methoxyethyl)aminosulfur trifluoride 2,2-Difluoro-1,3-dimethylimidazolidine 3,4-Dihydro-2H-pyran Diisopropyl azodicarboxylate xliii

xliv

DIBAL-H DIC DIPEA DIPT DKR DMAc DMAP DMC DMCC DME DMEDA DMF DMI DMP 2,2-DMP DMPU DMS DMSO DPEphos DPPA DPPB DPPE DSC DTA DTAD DTBP DTTA DVS EDC EDCI EDTA EEDQ EH&S EMA EPA FBRM FDA Fmoc FTIR GSK HATU HBTU HDMT HFIP HKR HMDS HMTA HNB HOAt HOBt

List of Abbreviations

Diisobutylaluminum hydride 1,3-Diisopropylcarbodiimide Diisopropylethylamine Diisopropyl tartrate Dynamic kinetic resolution Dimethylacetamide 4-Dimethylaminopyridine Dimethyl carbonate Dimethylcarbamoyl chloride Dimethoxyethane N,N-Dimethylethylenediamine Dimethyl formamide Dimethylimidazolidinone Dess–Martin periodinane 2,2-Dimethoxypropane 1,3-Dimethyl tetrahydropyrimidin-2(1H)-one Dimethyl sulfide Dimethyl sulfoxide Bis[(2-diphenylphosphino)phenyl]ether Diphenylphosphoryl azide 1,4-Bis(diphenylphosphino)butane 1,2-Bis(diphenylphosphino)ethane Differential scanning calorimetry Differential thermal analysis Di-tert-butyl azodicarboxylate 2,6-Di-tert-butyl pyridine Di-p-toluoyl-tartaric acid Dynamic vapor sorption 1-Ethyl-3-(3-dimethyl-aminopropyl)carbodiimide 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride Ethylenediamine tetraacetic acid 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline Environment, health, and safety European Medicines Agency Environmental Protection Agency Focused beam reflectance measurement Food and Drug Administration Fluorenylmethyloxycarbonyl Fourier transform infrared spectroscopy GlaxoSmithKline Pharmaceuticals 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate 2-Hydroxy-4,6-dimethoxy-1,3,5-triazine Hexafluoro-2-propanol Hydrolytic kinetic resolution Hexamethyldisilazane Hexamethylenetetramine 2-Hydroxy-5-nitrobenzaldehyde 1-Hydroxy-7-azabenzotriazole 1-Hydroxybenzotriazole

List of Abbreviations

HOSu HPLC HSA HWE IBCF ICH IMS INCB IPA IPAc IPE LAH LC/MS LDA LiHMDS LiTMP MCR MEK MEMCl MeTHF MIBK MIDA MPD MP-TMT MPV MSA MSDS MTBE NBS NCP NCS NFSI NIS NMM NMO NMP P-BiAA PBPB PBS PCC PCP P-EDA PEPPSI L-PGA PGIs PGME PICB PKA PLE PMB PMP

N-Hydroxysuccinimide High-performance liquid chromatography Hydroxylamine-O-sulfonic acid Horner–Wadsworth–Emmons olefination Isobutyl chloroformate International Conference on Harmonization Industrial methylated spirit International Narcotics Control Board 2-Propanol Isopropyl acetate Diisopropyl ether Lithium aluminum hydride Liquid chromatography/mass spectrometry Lithium diisopropylamide Lithium bis(trimethylsilyl)amide Lithium 2,2,6,6-tetramethylpiperidin-1-ide Multicomponent reaction Methyl ethyl ketone 2-Methoxyethoxymethyl chloride 2-Methyl tetrahydrofuran Methyl isobutyl ketone N-Methyl iminodiacetic acid Mechanism-guided process development Macroporous polystyrene-2,4,6-trimercaptotriazine Meerwein–Ponndorf–Verley reduction Methanesulfonic acid Material safety data sheet Methyl tert-butyl ether N-Bromosuccinimide N-Chlorophthalimide N-Chlorosuccinimide N-Fluorobenzenesulfonimide N-Iodosuccinimide N-Methylmorpholine N-Methylmorpholine N-oxide N-Methyl-2-pyrrolidone Polymer-supported bis(2-aminoethyl)-amine Pyridinium bromide perbromide Phosphate buffered saline Pyridinium chlorochromate Purity control point Polymer-supported ethylenediamine Pyridine-enhanced precatalyst preparation stabilization and initiation l-Pyroglutamic acid Potential genotoxic impurities Propylene glycol monomethyl ether 2-Picoline borane Porcine kidney Pig liver esterase p-Methoxybenzyl p-Methoxyphenyl

xlv

xlvi

PNB PPTS PSD PTAB PTC P-TriAA PVE PVM PYBOP RCM R&D RSST SAS SNAr SN1 SN 2 T3P TATP TBAB TBACl TBAF TBHP TBS TCAN TCCA TDA TEA TEAB TEBA TEMP TEMPO TFA TFB TFE TFFH TGA THF THP TIPS TMDS TMEDA TMG TMM TMP TMS TMSCl TMSCN TMSI TMT TMU TPPMS

List of Abbreviations

p-Nitrobenzyl Pyridinium p-toluenesulfonate Particle size distribution Phenyltrimethyl ammonium tribromide Phase-transfer catalyst Polymer-supported tris(2-aminoethyl)-amine Propyl vinyl ether Particle vision measurement (Benzotriazol-1-yloxy)-trispyrrolidinophosphonium hexafluorophosphate Ring-closing metathesis Research and development Reactive system screening tool Sodium anthraquinone-2-sulfonate Aromatic nucleophilic substitution Nucleophilic unimolecular substitution Nucleophilic two-molecular substitution n-Propanephosphonic acid cyclic anhydride Triacetone triperoxide Tetrabutylammonium bromide Tetrabutylammonium chloride Tetrabutylammonium fluoride tert-Butyl hydroperoxide tert-Butyldimethylsilyl Trichloroacetonitrile Trichloroisocyanuric acid Tris(3,6-dioxaheptyl)amine Triethylamine Tetraethylammonium bromide Triethylbenzylammonium chloride 2,2,6,6-Tetramethylpiperidine 2,2,6,6-Tetramethyl-1-piperidine-N-oxide Trifluoroacetic acid (Trifluoromethyl)benzene Trifluoroethanol N,N,N΄,N΄-Tetramethylfluoroformamidinium hexafluorophosphate Thermogravimetric analysis Tetrahydrofuran Tetrahydropyran Triisopropylsilyl Tetramethyl disiloxane Tetramethylethylenediamine Tetramethyl guanidine Trimethylenemethane 2,2,6,6-Tetramethylpiperidine Trimethylsilyl Chlorotrimethylsilane Trimethylsilyl cyanide Iodotrimethylsilane Trimercaptotriazine (or trithiocyanuric acid) Tetramethyl urea Sodium 3-(diphenylphosphino)benzenesulfonate

List of Abbreviations

TPPTS TRIS p-TSA UHP VOC WFE XRPD XtalFluor-E XtalFluor-M

3,3′,3″-Phosphanetriyltris(benzenesulfonic acid) trisodium salt Tris(hydroxymethyl)aminomethane para-Toluenesulfonic acid Urea–hydrogen peroxide Volatile organic compound Wiped film evaporation X-ray powder diffraction Diethylaminodifluorosulfinium tetrafluoroborate Difluoro(morpholino)sulfonium tetrafluoroborate

xlvii

Modes of Reagent Addition

1 Control of Impurity Formation

There are two types of impurities: the process impurity and the degradation (of the product) impurity. The former is generated from the manufacturing process and can be carried through the process to the final API if the isolation/purification is not effective. The latter refers to the decomposition of the product during the processing or storage. In general, two strategies are used to address impurity issues, that is, minimizing the impurity formation and removing the impurity from the product. One of the challenges in the process development is to suppress side reactions. Side products can be generated at three different reaction stages as shown in Figure 1.1. During the early reaction stage, side products are usually produced via competitive side reactions. For instance, a regioisomer may be generated due to poor regioselectivity. At this stage, the mechanism for the formation of side products appears to be relatively simple, as there are no intermediates or products involved. Given that a reaction involves an intermediate, impurities may arise from side reactions of the intermediate. Reducing the level and the number of impurities at the intermediate stage is a formidably challenging task due to the fact that the intermediate, being formed in situ, can participate in a number of competitive side reactions in addition to the desired reaction pathway. Further reactions of the desired product would occur at the final stage such as hydrolysis of an ester group in the product during the aqueous workup. Nonetheless, undesired side products can be minimized through optimization of reaction conditions, such as temperature, pressure, and solvent. In addition to the control of the reaction temperature and pressure, modes of reagent additions are valuable tools that are frequently used by process chemists to control impurity formation. Not only can an addition sequence significantly improve the impurity profile of a given process, especially for impurities generated during the early and intermediate stages, it would also mitigate exothermic runaway reactions. This chapter reveals various opportunities for the optimization of addition sequences including direct addition (DA), reverse addition (RA), sequential addition, portionwise addition, alternate addition, and concurrent addition (CA). Many case studies include the Grignard reaction, the amide formation, the nitration and cyclization, and the Sonogashira reaction. Charging starting materials, reagents, and solvents into a reaction vessel in proper order has substantial effects on the process safety and impurity profile. In addition, an appropriate addition order will result upon reducing the batch volume and improving the reaction selectivity. Basically, there are four modes of additions: In the first mode of addition, the starting material, reagent, and solvent are added one after another without control of the addition order and rate. This “all in” addition mode shall be avoided as an exothermic reaction can create a thermal runaway situation at large scales where heat removal rates are much slower compared to the laboratory reaction. In order to manipulate reactions in a safe and a controllable manner, in many cases, reactions have to be run in a semibatch manner, that is, charging the starting material, followed by introducing the reagent (and vice versa). The semibatch operation can be performed by a DA1 or an RA. DA is a way of conducting a reaction by adding a reagent to a mixture of starting material and solvent in a dose-controlled manner; in contrast, RA is to add the starting material to the mixture of the reagent and solvent. The final mode of addition is the CA in which the starting material and reagent are introduced simultaneously. Each mode of addition can be further differentiated into three categories: solid addition, liquid addition, and gas addition. Addition of solids to a reactor containing flammable solvents should be avoided as the electron static of the solid dust may ignite the flammable solvents. Therefore, solids 1

2

Handbook for Chemical Process Research and Development A

+

B

The early stage

[C]

Product

The intermediate stage

The final stage

Side products

FIGURE 1.1 The formation of side products at three reaction stages.

should be charged as a solution or slurry if the solids are not fully soluble or be charged into the inert reactor first. Liquid addition is the most commonly used method to introduce the starting material and reagent into the reactor. In the liquid addition, the reagent (or the starting material) (either in solid, liquid, or gas state) is usually dissolved in an appropriate solvent and, if the reagent is liquid, addition as neat may be used. Addition of gas directly is less common except in the catalytic hydrogenation.

1.1

DIRECT ADDITION

As a development approach, the DA is commonly used to improve process safety by controlling the heat release rate. In addition, an impurity profile can also be improved by controlling the concentration of reagents via addition rate.

1.1.1

SONOGASHIRA REACTION

The Sonogashira reaction is a valuable tool for functionalizing aromatic and heteroaromatic halides with a versatile acetylene functional group.2 One of the common difficulties in the Sonogashira reaction is the polymerization of acetylene, particularly when the cross-coupling reaction is conducted at an elevated temperature, as in the case of aromatic bromides or chlorides are used as starting materials. (I) Problematic “All-In” Conditions • Mixing 1 with 2 (1.1–1.3 equiv) in the presence of BuNH2 (1.2 equiv) and CuI (2 mol%)/ PPh3 (4 mol%)/Pd2(dba)3 (0.5 mol%) in DMPU, then heating at 70°C (Equation 1.1).3 • Scale: 100 g. • Observations: Abrupt temperature rise to 145°C along with a formation of dark polymeric materials. OH H 2 O Br 1

Pd2(dba)3 CuI, PPh3, BuNH2

OH

O

(1.1)

Solvent 3

(II) Solutions–Semibatch Conditions (DA) • Addition of 2 in NMP over 1 h to a mixture of 1, BuNH2 (1.2 equiv), CuI (4 mol%), and Pd(PPh3)4 (2 mol%) in NMP at 50°C. • The product 3 was isolated in a yield of 74% with little polymerization.

3

Modes of Reagent Addition

Remarks (a) The polymerization of the accumulated acetylene is exothermic, which is a big safety concern on a large scale. The DA addition sequence and temperature (50°C) are crucial in controlling the concentration of acetylene at a relatively low level in the reaction system. (b) In order to remove the residual palladium and copper from the product, the workup included washing the product solution with a diluted aqueous ammonium hydroxide, followed by treating the solution with silica bond-thiol and activated carbon. As a result, the residual metals in the product 3 are 120−150 ppm of Pd and