Handbook for Chemical Process Research and Development 2nd Edition by Wenyi Zhao 1032259272 9781032259277

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ISBN 10: 1032259272

ISBN 13: 9781032259277

Author: Wenyi Zhao

This fully updated second edition reflects the significant changes in process chemistry since the first edition and includes more common process issues such as safety, cost, robustness, and environmental impact. Some areas have made notable progress such as process safety, stereochemistry, new reagents and reagent surrogates. Forty years ago there were few process research and development activities in the pharmaceutical industry, partly due to the simplicity of drug molecules. With increasing structural complexity especially the introduction of chiral centers into drug molecules and stricter regulations, process R&D has become one of the critical departments for pharmaceutical companies. Features: This unique volume now in its second edition is designed to provide readers with an unprecedented strategy and approach which will help chemists and graduate students develop chemical processes in an efficient manner. Promotes an industrial mindset concerning safety and commercial viability when developing methods. The author discusses development strategies with case studies and experimental procedures. Focuses on mechanism-guided process development which provides readers with practical strategies and approaches. Addresses more common process issues such as safety, cost, robustness, and environmental impact. This book provides a new direction for scientists, researchers, and students in materials science and polymer chemistry who seek to better understand the chemistry behind conducting polymers and improve their performance for use in advanced energy applications.

Handbook for Chemical Process Research and Development 2nd Table of contents:

Chapter 1 Reaction Solvent Selection

1.1 Ethereal Solvents

1.1.1 Cyclopentyl Methyl Ether

1.1.1.1 Brook Rearrangement

1.1.1.2 N-Alkylation Reaction

1.1.2 Tetrahydrofuran

1.1.2.1 Grignard Reagent Formation

1.1.2.2 Bromination of Ketone

1.1.3 2-Methyl Tetrahydrofuran

1.1.3.1 Control of Impurity Formation

1.1.3.2 Enhancing Reaction Rate

1.1.3.3 Improving Layer Separation

1.1.4 Methyl tert-Butyl Ether

1.1.4.1 Chlorination Reaction

1.1.4.2 Darzens Reaction

1.1.5 Diethoxymethane and Dimethoxyethane

1.2 Protic Solvents

1.2.1 Methanol as a Solvent

1.2.1.1 Leak of Palladium Catalyst

1.2.1.2 Side Product Formation

1.2.1.3 Palladium-Catalyzed Methylation Reaction

1.2.2 Ethanol as a Solvent

1.2.2.1 Catalytic Reduction of Diaryl Methanol

1.2.2.2 SN2 Reaction

1.2.3 2-Propanol as a Solvent

1.2.3.1 Reaction of Acyl Hydrazine with Trimethylsilyl Isocyanate

1.2.3.2 Classical Resolution of Racemic Acid

1.2.3.3 Nickel-Catalyzed Addition Reaction

1.2.4 1-Pentanol

1.2.5 Ethylene Glycol

1.3 Water as Reaction Solvent

1.3.1 Iodination Reaction

1.3.2 Synthesis of Quinazoline-2,4-dione

1.3.3 Synthesis of Pyrrolocyclohexanone

1.3.4 Synthesis of Thiourea

1.3.5 Synthesis of Amide

1.3.6 Synthesis of 1,3/1,4-Diketones

1.4 Non-Polar Solvents

1.4.1 Condensation of Ketone with tert-Butyl Hydrazine Carboxylate

1.4.2 Acid-Catalyzed Esterification

1.5 Polar Aprotic Solvents

1.5.1 Acetone as a Solvent

1.5.1.1 Michael Addition Reaction with Acetone Cyanohydrin

1.5.1.2 SN2 Alkylation Reaction

1.5.1.3 Multi-Component Reactions

1.5.1.4 Amidation Reaction

1.5.2 Acetonitrile as a Solvent

1.5.2.1 Intramolecular Michael Addition Reaction

1.5.2.2 Synthesis of Imidazolines

1.5.2.3 Synthesis of α-Alkylated Ketones

1.5.2.4 Chlorosulfonylation Reaction

1.5.3 N,N-Dimethylformamide as a Solvent

1.5.3.1 Preparation of Alkyl Aryl Ether

1.5.3.2 Preparation of Bisaryl Ether

1.6 Halogenated Solvents

1.6.1 Dichloromethane

1.6.1.1 Reaction with Pyridine

1.6.1.2 Synthesis of Benzo[d]isothiazolone

1.6.2 1,2-Dichloroethane

1.6.3 Trifluoroacetic Acid

1.6.4 (Trifluoromethyl)benzene

1.6.5 Hexafluoroisopropanol

1.6.5.1 Selective Oxidation of Sulfide

1.6.5.2 Cycloaddition Reaction

1.7 Carcinogen Solvent

1.8 Other Solvents

1.8.1 DW-Therm

1.8.2 Dowtherm A

1.8.2.1 Synthesis of 6-Chlorochromene

1.8.2.2 Conrad–Limpach Synthesis of Hydroxyl Naphthyridine

1.8.2.3 Conrad–Limpach Synthesis of Quinolone

1.8.3 Polyethylene Glycol

1.8.4 Propylene Glycol Monomethyl Ether

1.8.5 Sulfolane

1.8.5.1 Bromination/Esterification

1.8.5.2 Fluorine-Exchange Reaction

1.8.6 Ionic Liquids

1.9 Mixture of Solvents

1.9.1 Aldol Condensation Reaction

1.9.2 Visible-Light Mediated Redox Neutral Reaction

1.10 Solvent-Free Reaction

Chapter 2 Reagent Selection

2.1 Inorganic Base

2.1.1 Sodium Bicarbonate

2.1.2 Potassium Carbonate

2.1.2.1 Boc Protection of Amino Group

2.1.2.2 Ring-Opening Iodination

2.1.3 Sodium Hydride

2.1.3.1 SN2 Reaction

2.1.3.2 Addition/Elimination Reaction

2.1.3.3 Nucleophilic Addition Reaction

2.1.4 LiOH/H2O2 Combination

2.1.4.1 Hydrolysis of Chiral Pentanoate

2.1.4.2 Hydrolysis of Chiral Propanoate

2.1.4.3 Hydrolysis of Chiral Amide

2.2 Organic Base

2.2.1 Trialkylamine

2.2.1.1 Diisopropylethylamine

2.2.1.2 Triethylamine

2.2.2 Imidazole

2.2.3 2,6-Dimethylpiperidine

2.2.4 2-(N,N-Dimethylamino)pyridine

2.2.5 Metal Alkoxide Base

2.2.5.1 Potassium tert-Pentylate

2.2.5.2 Lithium tert-Butoxide

2.2.5.3 Potassium tert-Butoxide

2.2.5.4 Potassium Trimethylsilanoate

2.2.5.5 Combination of Potassium tert-Butoxide with tert-Butyllithium

2.2.5.6 Sodium Methoxide

2.3 Reagents For Amide C(O)−N Bond Formation

2.3.1 CDI-Mediated Amide Formation

2.3.1.1 Preparation of Nicotinic Acid Amide

2.3.1.2 Preparation of Ureas

2.3.2 Thionyl Chloride-Mediated Amide Formation

2.3.2.1 Tetramethylurea-Catalyzed Acid Chloride Formation

2.3.2.2 N-Sulfinylaniline-Involved Amide Preparation

2.3.3 Boc2O-Mediated Amide Formation

2.3.4 Schotten–Baumann Reaction

2.3.5 Other Amide Formation Methods

2.3.5.1 Copper (II)-Catalyzed Transamidation

2.3.5.2 Cross-Coupling between Acyltrifluoroborates and Hydroxylamines

2.3.5.3 Catalytic Aminolysis of Ester

Chapter 3 Various Reagent Surrogates

3.1 Ammonia Surrogates

3.1.1 Ammonium Hydroxide

3.1.2 Ammonium Acetate

3.1.2.1 Condensation with β-Keto Amide

3.1.2.2 Condensation with Cyclohexanones

3.1.2.3 Consecutive Reductive Amination Reactions

3.1.3 Ammonium Chloride

3.1.4 Hydroxylamine Hydrochloride

3.1.4.1 Reductive Amination

3.1.4.2 Aromatization

3.1.5 O-Benzylhydroxylamine

3.1.6 Hydroxylamine-O-Sulfonic Acid

3.1.6.1 SN2 Reaction with Sulfinate

3.1.6.2 Reaction with Boronic Acid

3.1.7 Hexamethylene Tetramine

3.1.8 Acetonitrile

3.1.9 Chloroacetonitrile

3.1.10 tert-Butyl Carbamate

3.1.11 Diphenylmethanimine

3.1.12 α-Amino Acids

3.1.12.1 Glycine Hydrochloride

3.1.12.2 2,2-Diphenylglycine

3.1.13 Silylated Amines

3.1.14 Allylamines

3.1.15 Isoamyl Nitrite

3.1.16 1,2-Benzisoxazole

3.2 Carbon Monoxide Surrogates

3.2.1 N-Formylsaccharin

3.2.2 Paraformaldehyde

3.2.3 Molybdenum Carbonyl

3.2.4 Phenyl Formate

3.2.5 Benzene-1,3,5-Triyl Triformate (TFBen)

3.2.6 Formic Acid

3.3 Carbon Dioxide Surrogates

3.4 α-Hydroxysulfonates as Aldehyde Surrogates

3.4.1 Oxidation of Aldehyde to Acid

3.4.2 Reductive Amination

3.4.3 Diels–Alder Reaction

3.4.4 Strecker Reaction

3.4.5 Transaminase DKR of Aldehyde

3.4.6 Reduction of Aldehyde to Alcohol

3.5 Sulfur Dioxide Surrogate

3.5.1 Synthesis of Sulfones

3.5.2 Synthesis of Sulfoxides

3.5.3 Synthesis of Sulfonamides

3.6 Miscellaneous Surrogates

3.6.1 Methyl Iodide Surrogate

3.6.2 Cyanide Surrogates

3.6.2.1 2-Methyl-2-Phenyl Malononitrile (MPMN)

3.6.2.2 2-Cyanoisothiazolidine 1,1-Dioxide

3.6.3 Ethylene Surrogates

Chapter 4 Modes of Reagent Addition: Control of Impurity Formation

4.1 Direct Addition

4.1.1 Sonogashira Reaction

4.1.2 Michael Reaction

4.1.3 Fisher Indole Synthesis

4.1.4 Amide Formation

4.1.4.1 EEDQ-Promoted Amide Formation

4.1.4.2 CDI-Promoted Amide Formation

4.1.5 Thioamide Formation

4.1.6 C–O Bond Formation

4.1.6.1 SRN2 Reaction

4.1.6.2 Mitsunobu Reaction

4.2 Reverse Addition

4.2.1 Grignard Reaction

4.2.1.1 Reaction with Alkyl Aryl Ketone

4.2.1.2 Grignard Reaction with Aldehydes

4.2.1.3 Reaction of Grignard Reagent with Ester

4.2.2 Copper-Catalyzed Epoxide Ring Opening

4.2.3 Nitration Reaction

4.2.4 Cyclization Reaction

4.2.5 Amide Formation

4.2.5.1 CDI-Promoted Amide Formation

4.2.5.2 Phenyl Chloroformate-Promoted Urea Formation

4.2.6 Reduction of Ketone to Hydrocarbon

4.2.7 1,3-Dipole-Involved Reactions

4.2.7.1 Addition–Elimination/Cyclization

4.2.7.2 [3+2] Cycloaddition

4.3 Other Addition Modes

4.3.1 Sequential Addition

4.3.2 Portionwise Addition

4.3.2.1 Cyclization

4.3.2.2 Deoxychlorination

4.3.3 Slow Release of Starting Material/Reagent

4.3.3.1 Synthesis of Urea

4.3.3.2 Preparation of Alkylamine

4.3.4 Alternate Addition

4.3.5 Concurrent Addition

4.3.5.1 Bromination Reaction

4.3.5.2 Difluoromethylation

4.3.5.3 Diels–Alder Reaction

Chapter 5 Process Optimization with Additives

5.1 Acid Additives

5.1.1 Hydrochloric Acid

5.1.1.1 SNAr Reaction

5.1.1.2 Deoxychlorination

5.1.2 Phosphoric Acid

5.1.3 Sulfuric Acid

5.1.3.1 Iodination Reaction

5.1.3.2 Chlorination Reaction with N-Chlorosuccinimide

5.1.3.3 Chlorination Reaction with Phosphorus Trichloride

5.1.3.4 Hydrogenation Reaction

5.1.4 Methanesulfonic Acid

5.1.5 Acetic Acid

5.1.5.1 Condensation Reaction

5.1.5.2 SN2 Reaction

5.1.5.3 Mitsunobu Reaction

5.1.6 Benzoic Acid

5.1.7 Trifluoroacetic Acid

5.1.8 Toluenesulfonic Acid

5.2 Base Additives

5.2.1 Potassium Carbonate

5.2.2 Sodium Hydrogen Carbonate

5.2.3 Diisopropylethylamine

5.2.3.1 Neutralizing AcOH/Replacing Ammonia

5.2.3.2 Stabilizing Intermediate

5.2.4 1,4-Diazabicyclo[2.2.2]octane

5.2.5 N,N’-Dimethylethylenediamine

5.2.6 Potassium tert-Butoxide

5.2.7 Sodium Methoxide

5.2.7.1 Increasing Reaction Rate

5.2.7.2 Improving Product Yield

5.2.8 Sodium Acetate

5.2.8.1 Trapping Hydrogen Iodide

5.2.8.2 Trapping Hydrogen Chloride

5.2.8.3 Improving Conversion

5.2.9 Sodium Acrylate

5.3 Inorganic Salts

5.3.1 Lithium Chloride

5.3.1.1 Increasing Reaction Rate

5.3.1.2 Improving Stereoselectivity

5.3.1.3 Improving Conversion

5.3.2 Lithium Bromide

5.3.3 Sodium Bromide

5.3.3.1 Lowering Reaction Temperature

5.3.3.2 Improving Product Yield

5.3.4 Magnesium Chloride

5.3.5 Magnesium Bromide

5.3.6 Calcium Chloride

5.3.6.1 Reaction with NaBH4

5.3.6.2 Trapping Fluoride

5.3.7 Zinc Chloride

5.3.8 Zinc Acetate

5.4 Assortment of Scavengers

5.4.1 Catechol as Methyl Cation Scavenger

5.4.2 Anisole as Quinone Methide Scavenger

5.4.3 Ethyl Acetate as Hydroxide Scavenger

5.4.4 Ethyl Trifluoroacetate as Hydroxide Scavenger

5.4.5 Ethyl Trifluoroacetate as Benzylamine Scavenger

5.4.6 Ethyl Pivalate as Hydroxide Scavenger

5.4.7 Trimethyl Orthoformate as Water Scavenger

5.4.8 Thionyl Chloride as Water Scavenger

5.4.9 1-Hexene

5.4.9.1 As HCl Scavenger

5.4.9.2 As Diimide (NH=NH) Scavenger

5.4.10 Epoxyhexene as HBr Scavenger

5.4.11 Acetic Anhydride as Aniline Scavenger

5.4.12 Amberlite CG50 as Ammonia Scavenger

5.4.13 3-Pentanone as HCN Scavenger

5.5 Other Additives

5.5.1 Imidazole

5.5.2 Triethylamine Hydrochloride

5.5.3 Methyl Trioctylammonium Chloride

5.5.4 Chlorotrimethylsilane

5.5.4.1 Julia Olefination

5.5.4.2 Michael Addition

5.5.5 Chlorotriethylsilane

5.5.6 Bis(trimethylsilyl)acetamide

5.5.7 Water

5.5.7.1 Wadsworth–Emmons Reaction

5.5.7.2 O-Alkyation

5.5.7.3 Methylation Reaction

5.5.7.4 Enolization Reaction

5.5.7.5 Pyrazole Synthesis

5.5.7.6 Copper-Mediated Intramolecular Cyclization

5.5.7.7 Crystallization-Induced Dynamic Resolution of Amine

5.5.8 Hydroquinone

5.5.8.1 Preclusion of Oxidation

5.5.8.2 Preclusion of Polymerization

5.5.9 Trimethyl Borate

5.5.10 Isobutanoic Anhydride

5.5.11 1,1-Dimethyl-2-Phenylethyl Acetate

5.5.12 Alcohols

5.5.12.1 Ethanol

5.5.12.2 2-Propanol

5.5.12.3 tert-Butanol

5.5.12.4 Ethylene Glycol

5.5.12.5 1,2-Propanediol

5.5.12.6 Neopentyl Glycol

5.5.13 1,4-Dioxane

5.5.14 Benzotriazole

5.5.15 1-Hydroxybenzotriazole

5.5.16 1,4-Dibromobutane

5.5.17 Diethanolamine

5.5.17.1 Improving Selectivity

5.5.17.2 Boranate Ester Exchange

5.5.18 Trimethyl Phosphite

5.5.19 Diethyl Phosphite

5.5.20 4-Trifluoromethyl Benzaldehyde

Chapter 6 Process Optimization of Catalytic Reactions

6.1 Suzuki–Miyaura Reaction

6.1.1 Catalyst Poisoning

6.1.1.1 Catalyst Poisoning by Sulfhydryl Group

6.1.1.2 Catalyst Poisoning by Unknown Impurities

6.1.2 Catalyst Precipitation

6.1.3 Instability of Arylboronic Acids

6.1.3.1 Buchwald’s Precatalyst

6.1.3.2 Tridentate Ligand

6.1.3.3 Alternative Negishi Coupling Reaction

6.1.3.4 Alternative Kumada Coupling Reaction

6.1.3.5 Using Protecting Group

6.1.3.6 Using Trifluoroborate Salt

6.1.4 Problems Associated with Base

6.1.4.1 Protodeboronation

6.1.4.2 Formation of Carbamate

6.1.5 Dimer Impurity

6.1.5.1 Reducing Arylboronic Acid Concentration

6.1.5.2 Reducing Free Pd(II) Concentration

6.2 Negishi Reaction

6.2.1 Poor Product Yield

6.2.2 Thick Reaction Mixture

6.3 Heck Reaction

6.3.1 Enhancing Palladium-Catalyst Stability

6.3.2 Improving Selectivity

6.4 Sonogashira Reaction

6.4.1 Reducing Palladium-Catalyst Loading

6.4.2 Improving Reactivity

6.5 Catalytic Deprotection

6.5.1 Debenzylation

6.5.1.1 Catalyst Poisoning

6.5.1.2 Erosion of Chiral Purity

6.5.2 Catalytic Removal of Cbz Group

6.5.2.1 Impurity Formation

6.5.2.2 Pd(OAc)2/Charcoal System

6.6 Catalytic Hydrogenation

6.6.1 Reduction of Nitro Group

6.6.1.1 Palladium-Catalyzed Hydrogenation

6.6.1.2 Nickel-Catalyzed Hydrogenation

6.6.1.3 Platinum-Catalyzed Hydrogenation

6.6.1.4 Catalytic Transfer Hydrogenation

6.6.2 Reduction of Pyridine Ring

6.6.3 Reduction of α,β-Unsaturated Compounds

6.6.4 Enantioselective Reduction of Quinolines

6.6.5 Reduction of Nitrile

6.6.6 Reduction of Azide

6.7 Other Catalytic Reactions

6.7.1 Cu(I)-Catalyzed Reaction

6.7.2 Decarboxylative Bromination

6.7.3 Formation of Acid Chloride

6.7.4 Catalytic Dechlorination

6.7.5 Two-Phase Reactions

6.7.5.1 Enhancement of Reaction Rate

6.7.5.2 Suppressing Side Reactions

6.7.5.3 Reducing the Amount of Toxic Sodium Cyanide

6.7.5.4 Replacing DMSO Solvent in SNAr Reaction

6.7.5.5 Two-Phase Reactions without PTC

6.7.6 Deoxybromination

6.7.7 Regioselective Chlorination

6.7.8 Regioselective Magnesiation

6.7.9 Amide Preparation

6.7.9.1 NaOMe as Catalyst

6.7.9.2 HOBt as Catalyst

6.7.10 Synthesis of Indole

6.7.11 N-Methylation Reaction

6.7.12 Baylis−Hillman Reaction

6.7.13 Catalytic Wittig Reaction

6.7.14 Palladium-Catalyzed Rearrangement

Chapter 7 Process Optimization of Problematic Reactions

7.1 Temperature Effect

7.1.1 Metal–Halogen/Hydrogen Exchange

7.1.1.1 Magnesium–Bromine Exchange

7.1.1.2 Lithium–Bromine Exchange

7.1.1.3 Lithium–Hydrogen Exchange

7.1.2 Ring Expansion

7.1.3 Synthesis of Pyrazole

7.1.4 Synthesis of Oxadiazole

7.1.5 Cross-Coupling Reaction

7.1.6 Vilsmeier Reaction

7.1.7 Oxidative Hydrolysis

7.2 Pressure Effect

7.2.1 Nitrile Reduction

7.2.2 [3+2]-Cycloaddition

7.3 Low Product Yields

7.3.1 Incomplete Reactions

7.3.1.1 Poor Mass Transfer

7.3.1.2 Undesired Physical Properties

7.3.1.3 High Flow Rate of Nitrogen

7.3.2 Loss of Product During Isolation

7.3.3 Side Reactions of Starting Materials

7.3.3.1 Decomposition of N-Oxide

7.3.3.2 Decomposition of Hydrazone

7.3.3.3 Hydrolysis of Chlorotriazine

7.3.4 Side Reactions of Intermediates

7.3.4.1 Sandmeyer Reaction

7.3.4.2 Hofmann Rearrangement

7.3.4.3 Tosylation/Amination Reactions

7.3.4.4 Synthesis of Cyclic Sulfimidate

7.3.4.5 Cyclization/Ring Expansion

7.3.4.6 Michael Addition

7.3.5 Side Reactions of Products

7.3.5.1 Decomposition of Amide

7.3.5.2 Side Reactions of 1,4-Isochromandione

7.3.5.3 Side Reactions of Oxirane

7.4 Reaction Problems Associated With Impurities

7.4.1 Residual MTBE

7.4.2 Residual Water

7.4.2.1 Bromination Reaction

7.4.2.2 SNAr Fluorination Reaction

7.4.2.3 Copper-Catalyzed C−N Bond Formation

7.4.3 Residual Oxygen

7.4.3.1 Oxidative Dimerization

7.4.3.2 Oxidation of Phenylenediamine

7.4.4 Residual Zinc

7.5 Reactions With Poor Selectivity

7.5.1 CIDR to Improve cis/trans Selectivity

7.5.2 Two-Step Process to Mitigate Racemization

7.5.3 Reduction of Carboxylic Acid

7.5.4 Sacrificial Reagent in Regioselective Acetylation

7.5.5 Converting Side Product to Product

7.5.6 Enamine Exchange

7.5.7 Carry-Over Approach

7.5.8 Friedel–Crafts Reaction

7.5.9 Reduction of Carbon–Carbon Double Bond

7.5.10 Reduction of Nitrile

7.6 Protecting Group

7.6.1 Acetyl Group

7.6.2 Trimethylsilyl Group

7.6.2.1 Protection of Terminal Alkyne

7.6.2.2 Protection of Enolate

7.6.2.3 Protection of Hydroxyl Group

7.6.3 Cyanoethyl Group

7.6.4 Benzhdryl Group

7.7 Polymerization Issues

7.7.1 Polymerization of Chloroacetyl Chloride

7.7.2 Polymerization of Acid Chloride

7.7.3 Polymerization of Chloroacrylonitrile

7.7.4 Polymerization of Enone

7.7.5 Polymerization of Pentasulfide

7.8 Activation of Functional Groups

7.8.1 Activation of Aniline Nitrogen

7.8.2 Activation of Amide

7.8.3 Activation of Lactol

7.8.4 C–H Bond Activation

7.9 Deactivation of Functional Groups

7.9.1 Deactivation of Amino Group

7.9.2 Deactivation of Sulfonyl Chloride

7.10 Optimization of Telescoped Process

Chapter 8 Hazards of Oxidation and Reduction Reactions

8.1 Oxidation Reactions

8.1.1 Oxidation of Olefins

8.1.1.1 Oxidation with mCPBA

8.1.1.2 Oxidation with Sodium Perborate

8.1.1.3 Oxidation with Ozone

8.1.1.4 Oxidation with KMnO4

8.1.1.5 Oxidation with 9-BBN/H2O2-NaOH

8.1.2 Oxidation of Alcohols

8.1.2.1 Py·SO3/DMSO System

8.1.2.2 Ac2O/DMSO System

8.1.2.3 TFAA/DMSO/TEA System

8.1.2.4 TEMPO/NaOCl System

8.1.2.5 RuCl3/NaOCl System

8.1.2.6 Sulfinimidoyl Chloride

8.1.2.7 2-Amadamantane N-Oxide/CuCl

8.1.3 Oxidation of Aldehydes to Acids

8.1.4 Oxidation of Sulfides to Sulfoxides

8.1.5 Oxidation of Sulfides to Sulfones

8.1.5.1 Oxidation with Oxone

8.1.5.2 Oxidation with Sodium Perborate

8.1.5.3 Oxidation with Sodium Periodate

8.1.5.4 Oxidation with NaOCl

8.1.5.5 Oxidation with H2O2/Na2WO4

8.1.5.6 Oxidation with TMSCl/KNO3

8.1.6 Other Oxidative Reactions

8.1.6.1 Dakin Oxidation

8.1.6.2 Hydroxylation

8.1.6.3 Oxidation of Phosphite

8.2 Reduction Reactions

8.2.1 Reduction with NaBH4-Based Agents

8.2.1.1 Reduction of Acids

8.2.1.2 Reduction of Esters

8.2.1.3 Reduction of Amides

8.2.1.4 Reduction of Imine

8.2.2 Reduction with Borane

8.2.2.1 BH3·THF Complex

8.2.2.2 BH3·DMS Complex

8.2.2.3 BH3·Amine Complex

8.2.3 Reduction with Lithium Aluminum Hydride

Chapter 9 Other Hazardous Reactions

9.1 Catalytic Cross-Coupling Reactions

9.1.1 Heck Reaction

9.1.2 Negishi Cross-Coupling Reaction

9.2 Blaise Reaction

9.3 Ritter Reaction

9.4 Hydrogen–Lithium Exchange

9.5 Halogenation Reactions

9.5.1 Chlorination Reaction

9.5.2 Fluorination Reactions

9.5.2.1 Deoxyfluorination

9.5.2.2 Hydrofluorination of Aziridines

9.5.2.3 Electrophilic Fluorination

9.5.3 Deoxychlorination

9.5.3.1 Deoxychlorination of Triazinone

9.5.3.2 Deoxychlorination of Quinazolone

9.5.3.3 Deoxychlorination of Triazine

9.5.3.4 Deoxychlorination of 4,6-Dihydroxypyrimidine

9.5.3.5 Deoxychlorination of 6,7-Dihydrothieno[3.2-d]pyrimidine-2,4-diol

9.5.3.6 Deoxychlorination of 6-Chlorophthalazin-1-ol

9.6 Thiocyanation

9.7 Gas-Involved Reactions

9.7.1 Boc Protection

9.7.2 N-Acetylation

9.7.3 Boc Deprotection

9.7.3.1 Selective Deprotection with TFA

9.7.3.2 Deprotection with NaOH

9.7.4 N-tert-Butylamide Formation

9.7.5 Deprotection of N-tert-Butyl Group

9.7.6 Decarboxylative Ethoxide Elimination

9.7.7 Deprotonation

9.7.8 SN2 Reaction

9.7.9 Chlorination Reaction

9.8 Darzens Reaction

9.9 Hofmann Rearrangement

9.10 Friedel–Crafts Reaction

Chapter 10 Hazardous Reagents

10.1 Diazonium Salts

10.1.1 Hydrolysis of Diazonium Salt

10.1.2 Diazonium Salt-Involved Cyclization

10.1.3 Nitroindazole Formation

10.1.4 Synthesis of Trifluoromethyl-Substituted Cyclopropanes

10.1.5 Sandmeyer Reaction

10.2 Azide Compounds

10.2.1 Nucleophilic Displacement

10.2.1.1 Synthesis of 3,4-Dihydropyrrole

10.2.1.2 Synthesis of 3-(1,2-Diarylbutyl) Azide

10.2.1.3 Preparation of Aryl (Alkyl) Azides

10.2.2 Nucleophilic Addition

10.2.2.1 Synthesis of Tetrazole

10.2.2.2 Synthesis of Triazole

10.2.2.3 Synthesis of Carbamate

10.2.2.4 Curtius Rearrangement

10.3 Hydrazine

10.3.1 Wolff–Kishner Reduction

10.3.1.1 Reduction of Asymmetric Ketone

10.3.1.2 Reduction of Symmetric Ketone

10.3.1.3 Synthesis of Indazole

10.3.1.4 Synthesis of Pyrazole

10.3.1.5 Preparation of Alkylamine

10.3.2 Preparation of Aryl (or Alkyl) Hydrazines and Related Reactions

10.3.2.1 Preparation of 5-Hydrazinoquinoline

10.3.2.2 Synthesis of Aminopyrazole

10.3.2.3 Fischer Indole Synthesis

10.4 Hydroxylamine

10.5 Oxime

10.6 N-Oxide

10.7 Nitro Compounds

10.7.1 Preparation of Nitro Compounds by Nitration

10.7.1.1 NaNO3/TFA/TFAA Nitration System

10.7.1.2 KNO3/TFA Nitration System

10.7.1.3 Use of Acetyl Nitrate

10.7.1.4 NaNO3/Py∙SO3 System

10.7.1.5 Stepwise Nitration

10.7.1.6 Use of Chlorotrimethylsilane and Nitrate Salt

10.7.1.7 Metal-Catalyzed Nitration

10.7.1.8 N-Nitro Intermediate Rearrangement

10.7.2 Hazardous Reactions of Nitro Compounds

10.7.2.1 Unstable Nitrophenate

10.7.2.2 Accumulation of Reactant

10.8 Volatile Organic Compounds

10.8.1 Ethylene Oxide

10.8.2 Acetylene

10.8.3 Halogenated Methyl Ethers

10.8.3.1 Bis(bromomethyl)ether

10.8.3.2 Chloromethyl Ethyl Ether

10.8.4 Methyl Iodide

10.8.4.1 N-Methylation of Heterocycles

10.8.4.2 N-Methylation of Amide

10.8.4.3 N-Methylation of 2-Methoxypyridine Derivative

10.8.5 Methyl Bromide

10.9 High Energy Compounds

10.9.1 5-Hydroxybenzofurazan

10.9.2 1-Hydroxybenzotriazole (HOBt)

10.9.2.1 Ethyl Acetate/Water Two-Phase System

10.9.2.2 Replacement of HOBt with 2-Hydroxypyridine

10.9.2.3 Replacement of HOBt with 2-Chloro-4,6-dimethoxy-1,3,5-triazine

10.10 Toxic Compounds

10.10.1 Zinc Cyanide

10.10.2 Potassium Ferrocyanide

10.10.3 Acetone Cyanohydrin

10.10.3.1 Epoxide Opening

10.10.3.2 Michael Addition

10.11 Corrosive Reagent

Chapter 11 Grignard Reagent and Related Reactions

11.1 Preparation of Grignard Reagents

11.1.1 Use of Chlorotrimethylsilane

11.1.1.1 Preparation of 4-Fluoro-2-methylphenylmagnesium Bromide

11.1.1.2 Preparation of (4-(2-(Pyrrolidin-1-yl)ethoxy)phenyl)magnesium Bromide

11.1.2 Use of Diisobutylaluminum Hydride

11.1.3 Use of Diisobutylaluminum Hydride/Iodine

11.1.4 Use of Grignard Reagents

11.1.4.1 Use of MeMgCl

11.1.4.2 Use of EtMgBr

11.1.4.3 Use of Heel

11.1.5 Use of Alkyl Halides

11.1.5.1 Use of Iodomethane

11.1.5.2 Use of 1,2-Dibromoethane

11.1.6 Halogen–Magnesium Exchange

11.1.6.1 Preparation of Trifluoromethyl Substituted Aryl Grignard Reagents

11.1.6.2 Preparation of N-Methylpyrazole Grignard Reagent

11.1.6.3 Preparation of (4-Bromonaphthalen-1-yl)magnesium Chloride

11.1.6.4 Magnesium-ate Complex

11.1.6.5 Alkylmagnesium Alkoxides

11.2 Reactions of Grignard Reagents

11.2.1 Reactions with Ketones

11.2.1.1 Vinyl Grignard Reagents

11.2.1.2 Aryl Grignard Reagents

11.2.1.3 Methylmagnesium Bromide

11.2.2 Reaction with Acid Chloride

11.2.3 Reaction with Dimethylformamide

11.2.4 Reaction with Weinreb Amide

11.2.5 Michael Addition

11.2.6 Reaction with Epoxide

11.2.7 Other Grignard Reagent-Involved Reactions

11.2.7.1 Ramberg−Bäcklund Reaction

11.2.7.2 Synthesis of Chiral δ-Ketoamides

11.2.7.3 Access to o-Quinone Methide Intermediates

Chapter 12 Challenging Reaction Intermediates

12.1 Effect of Intermediates

12.1.1 In Telescoping Steps

12.1.2 In Designing Synthetic Route

12.1.3 In Agitation

12.1.4 In Product Isolations/Purifications

12.1.4.1 Pictet–Spengler Reaction

12.1.4.2 Imide Reduction

12.1.5 In Improving Product Yields

12.1.5.1 Amide Formation

12.1.5.2 Synthesis of Hydroxybenzisoxazole

12.1.5.3 Synthesis of Vinyl Bromide

12.1.6 In Improving Operational Profile

12.2 Monitoring Intermediates

12.2.1 Direct Monitoring Intermediate

12.2.2 Indirect Monitoring Intermediates

12.2.2.1 Derivatization of Acylimidazolide

12.2.2.2 Derivatization of N-Methylene Bridged Dimer

Chapter 13 Protecting Groups

13.1 Protection of Hydroxyl Group

13.1.1 Prevention of Side Reactions

13.1.1.1 Friedel–Crafts Alkylation

13.1.1.2 Removal of Trifluoromethanesulfonyl Group

13.1.1.3 SN2 Reaction

13.1.2 Increasing Catalyst Activity

13.1.3 Separation of Diol Diastereomers

13.1.4 Developing Telescoped Process

13.2 Protection of Amino Group

13.2.1 Protection with (4-Nitrophenyl)sulfonyl Group

13.2.2 Protection with 2,5-Hexanedione

13.2.3 Protection with Aldehyde

13.2.4 Protection with 4-Methyl-2-Pentanone

13.2.5 Protection with Methylene Group

13.2.6 Protection with tert-Butyloxycarbonyl Group

13.2.7 Protection with 2,2,6,6-Tetramethylpiperidin-1-yloxycarbonyl Group

13.2.8 Protection with Trimethylsilyl Group

13.3 Protection of Carboxylic Acid

13.4 Protection of Aldehydes and Ketones

13.4.1 Protection of Aldehyde

13.4.2 Protection of Ketones

13.4.2.1 Protection with Methanol

13.4.2.2 Protection with Ethylene Glycol

13.4.2.3 Using Internal Protection Approach

13.5 Protection of Acetylene

13.6 Unusual Protecting Groups

13.6.1 Boron-Containing Protecting Groups

13.6.1.1 Borane Complex

13.6.1.2 Boronic Acids

13.6.2 N-Nitro Protecting Group

13.6.2.1 Regioselective Nitration

13.6.2.2 Activation of Aniline

13.6.3 Halogen as Protecting Group

13.6.3.1 Bromine Protecting Group

13.6.3.2 Chlorine Protecting Group

Chapter 14 Telescope Approach

14.1 Improving Process Safety

14.1.1 Chloroketone Intermediate

14.1.2 Lachrymatory Chloromethacryate Intermediate

14.1.3 Chloromethyl Benzoimidazole

14.1.4 Pyridine N-Oxide

14.1.5 Benzyl Bromide

14.1.6 Methyl Iodide

14.2 Processing Problematic Intermediates

14.2.1 Oily Intermediates

14.2.2 Hygroscopic Intermediate Solid

14.2.3 Hygroscopic Amine Salt

14.2.4 High Water-Soluble Intermediate

14.2.5 Unstable Intermediates

14.2.5.1 Heteroaryl Chloride

14.2.5.2 Toluenesulfonate Intermediate

14.2.5.3 Aldehyde Intermediates

14.2.5.4 Unstable Alkene Intermediates

14.2.5.5 Unstable β-Hydroxyketone

14.3 Improving Filtration

14.3.1 Preparation of Amide

14.3.2 Synthesis of β-Nitrostyrene

14.4 Telescoping Catalytic Reactions

14.4.1 Imine Reduction/Debenzylation

14.4.2 Debromination/Suzuki Cross-Coupling Reaction

14.5 Improving Overall Product Yields

14.5.1 Synthesis of Spirocyclic Hydantoin

14.5.2 Transition Metal-Catalyzed Cross-Coupling Reaction

14.6 Reduction in Processing Solvents

14.6.1 Toluene as the Common Solvent

14.6.2 DMF as the Common Solvent

14.6.3 EtOAc as the Common Solvent

14.6.4 THF as the Common Solvent

14.6.5 EtOH/THF as the Common Solvent

14.7 Other Telescope Processes

14.7.1 Bromination/Isomerization Reactions

14.7.2 Fisher Indole Synthesis/Ring Rearrangemet

14.7.3 Ylide Formation/Wittig Reaction/Cycloaddition

14.7.4 Overman Rearrangement

14.7.5 Acylation/Reduction/O-Alkylation/Bromination

14.7.6 Synthesis of (–)-Oseltamivir

14.8 Limitation of The Telescope Approach

14.8.1 Lack of Purity Control

14.8.2 Poor Product Yield

14.8.3 Lack of Compatibility

Chapter 15 Design of New Synthetic Route

15.1 Improving Process Safety

15.1.1 Toxic Reagents and Intermediates

15.1.1.1 Trimethylsilyl Cyanide as Cyanide Source

15.1.1.2 CuCN in Sandmeyer Reaction

15.1.1.3 Toxic Reagent (HF)

15.1.1.4 Toxic Benzyl Halides

15.1.1.5 Phosphorus Oxychloride

15.1.1.6 Sulfonyl Chloride Intermediate

15.1.2 High Energy Reagents

15.1.2.1 Azide-Involved Cycloaddition

15.1.2.2 Diazonium Salt-Involved Indazole Formation

15.1.2.3 Lithium Aluminum Hydride Reduction

15.1.3 Undesired Reaction Conditions

15.1.3.1 Acylation Reaction

15.1.3.2 SNAr Reaction

15.2 Improving Product Yield

15.2.1 Cycloaddition Reaction

15.2.2 Resolution/Amide Formation/Cyclization

15.2.3 Chlorine Replacement

15.2.4 Wittig Reaction

15.3 Improving Reaction Selectivity

15.3.1 Chlorination

15.3.2 Iodination

15.3.3 N-Alkylation Reaction

15.3.4 Formation of Seven-Membered Ring

15.4 Other Route Design Strategies

15.4.1 Using Less Expensive Starting Material

15.4.2 Using Convergent Approach

15.4.2.1 Decarboxylative Cross-Coupling Reaction

15.4.2.2 Synthesis of Chiral Amide

15.4.3 Step-Economy Synthesis

15.4.3.1 Synthesis of Keto–Sulfone Intermediate

15.4.3.2 Synthesis of Bendamustine

15.4.4 Atom-Economy Synthesis

15.4.4.1 Synthesis of Carboxylic Acid

15.4.4.2 Stereoselective Synthesis of Diol

15.4.5 Alternating Bond-Formation Order

15.4.6 Minimizing Oxidation Stage Change

15.4.6.1 Minimizing Nitrogen Oxidation Stage Adjustment

15.4.6.2 Minimizing Carbon Oxidation Stage Adjustment

15.4.7 Coupling Reagent-Free Amide Formation

15.4.8 Preventing Etching of Glass Reactor

Chapter 16 Stereochemistry

16.1 Asymmetric Synthesis

16.1.1 Asymmetric Catalysis

16.1.1.1 Desymmetrization of Anhydride

16.1.1.2 Asymmetric Reduction of Enone

16.1.1.3 Sharpless Asymmetric Dihydroxylation

16.1.1.4 Enantioselective Alkylation

16.1.1.5 Enantioselective Protonation of Enamines

16.1.1.6 CuH-Catalyzed Synthesis of 2,3-Disubstituted Indolines

16.1.1.7 CuH-Catalyzed Synthesis of Chiral Amines

16.1.2 Chiral Pool Synthesis

16.1.2.1 Condensation of Indoline with Benzaldehyde

16.1.2.2 Claisen Rearrangement

16.1.3 Use of Chiral Auxiliaries

16.1.3.1 Diastereoselective Diels–Alder Reaction

16.1.3.2 Diastereoselective Synthesis of Boronic Acid

16.1.3.3 Synthesis of Chiral (S)-Pyridyl Amine

16.1.3.4 Synthesis of L-Carnitine

16.2 Kinetic Resolution

16.2.1 Hydrolytic Kinetic Resolution of Epoxide

16.2.2 Resolution of Diol via Stereoselective Esterification

16.2.3 Resolution of Phosphine Ligand via Stereoselective Ligand Exchange

16.2.4 Resolution of Diastereomeric Mixture via Salt Formation

16.3 Enzymatic Resolution

16.3.1 Resolution of Esters

16.3.1.1 Resolution of Methyl Piperidine-4-Carboxylate

16.3.1.2 Resolution of Ethyl α-Amino Acetate

16.3.1.3 Resolution of Diazepane Acetate

16.3.2 Resolution of Amino Acids

16.3.3 Resolution Secondary Alcohols

16.4 Separation With Chiral Chromatography

16.5 Classical Resolution

16.5.1 Resolution of Racemic Acid

16.5.2 Resolution of Racemic Bases

16.5.2.1 Use of Optical Pure tert-Leucine Derivative

16.5.2.2 Use of di-p-Toluoyl-D-Tartaric Acid

16.5.2.3 Use of bis((S)-Mandelic Acid)-3-Nitrophthalate

16.5.3 Resolution of Ketone

16.5.4 Resolution of Racemic Ammonium Salt

16.5.5 Diastereomer Salt Break

16.5.6 Examples of Diastereomeric Salts

16.6 Dynamic Kinetic Resolution

16.6.1 DKR via Imine Intermediates

16.6.1.1 3,5-Dichlorosalicylaldehyde Catalyst

16.6.1.2 2-Hydroxy-6-(hydroxymethyl)benzaldehyde Catalyst

16.6.1.3 Picolinaldehyde Catalyst

16.6.1.4 DRK without Catalyst

16.6.1.5 Iridium-Involved DKR

16.6.2 DKR via Enolate Intermediates

16.6.2.1 Enolization with Base

16.6.2.2 Enolization without Base

16.6.3 DKR via Diastereomeric Salt Formation

16.6.4 DKR of Six-Membered Ring Systems

16.6.4.1 Epimerization of cis-Isomer to trans-Isomer

16.6.4.2 Isomerization of Cyclohexane Derivative

16.6.4.3 Fischer Indole Synthesis

16.6.5 DKR via Reversible Bond Formation

16.6.5.1 Reversible C−C Bond Formation

16.6.5.2 Reversible C−N Bond Formation

16.6.5.3 Reversible C−O Bond Formation

16.6.5.4 Reversible C−S Bond Formation

16.6.6 Other DKR Methods

16.6.6.1 Bromide-Catalyzed DKR

16.6.6.2 Resolution of Sulfoxide

16.6.6.3 Dynamic Kinetic Isomerization via Ir-Catalyzed Internal Redox Transfer Hydrogenation

16.6.6.4 Vinylogous Dynamic Kinetic Resolution

16.6.7 Various DKR Examples

Chapter 17 Various Quenching Strategies

17.1 Acidic Quenching

17.1.1 Removal of Magnesium Salts

17.1.1.1 Reaction of Grignard Reagent with Weinreb Amide

17.1.1.2 Weinreb Amide Formation

17.1.2 Removal of Zinc

17.2 Basic Quenching

17.2.1 Suppressing Thiadiazole Isomerization

17.2.2 Prevention of Etching Glass Reactor

17.2.2.1 Quenching with Sodium Bicarbonate

17.2.2.2 Quenching with Sodium Hydroxide

17.3 Anhydrous Quenching

17.3.1 Removal of Zinc By-Product

17.3.2 Avoiding Insoluble Organic Mass

17.3.3 Avoiding Degradation of Product

17.3.3.1 Use of Ethyl Acetate

17.3.3.2 Use of Diisopropylethylamine

17.3.4 Decomposition of Excess Reagent

17.3.4.1 Use of Methanol

17.3.4.2 Use of Silicon Dioxide

17.4 Oxidative Quenching

17.4.1 Oxidation of Hydrogen Iodide

17.4.2 Oxidation of Pinacol

17.5 Reductive Quenching

17.5.1 Restroying tert-Butyl Hydroperoxide

17.5.2 Destroying Hydrogen Peroxide

17.5.3 Destroying Oxone

17.5.4 Destroying Halogens

17.5.4.1 Use of Ascorbic Acid to Destroy Bromine

17.5.4.2 Use of Ascorbic Acid to Destroy Iodine

17.6 Disproportionation Quenching

17.7 Reverse Quenching

17.7.1 Control of Impurity Formation

17.7.1.1 Preparation of Ketone

17.7.1.2 Preparation of Aldehyde

17.7.1.3 Grignard Reaction

17.7.2 Removal of Excess Reagent

17.7.3 Increase in Conversion

17.7.4 Suppressing Product Hydrolysis

17.7.5 Prevention of Product Decomposition

17.7.6 Prevention of Emulsion

17.7.6.1 Copper-Catalyzed Amination

17.7.6.2 Lithium Aluminum Hydride Reduction

17.7.7 Prevention of Exothermic Runaway

17.8 Concurrent Quenching

17.9 Double Quenching

17.9.1 Acetone/HCl Combination

17.9.1.1 Ketone Reduction

17.9.1.2 SNAr Reaction

17.9.2 Acetone/Citric Acid Combination

17.9.3 Acetone/MeOH/H2O Combination

17.9.4 Ethyl Acetate/Water Combination

17.9.5 Ethyl Acetate/Tartaric Acid Combination

17.9.6 Ethyl Acetate/Aqueous Sodium Bicarbonate Combination

17.9.7 Isopropanol/Citric Acid Combination

17.9.8 Methyl Formate/Aqueous HCl Combination

17.10 Reactive Quenching

Chapter 18 Various Isolation and Purification Strategies

18.1 Extraction

18.1.1 Aqueous Extractions

18.1.1.1 Use of Methyl tert-Butyl Ether

18.1.1.2 Use of 2-Methyltetrahydrofuran

18.1.1.3 Use of Ethyl Acetate

18.1.1.4 Use of Dodecane

18.1.1.5 Use of n-Butanol

18.1.2 Anhydrous Extraction

18.1.2.1 Heptane/Acetonitrile System

18.1.2.2 Heptane–Cyclohexane/N-Methyl-2-pyrrolidone System

18.1.3 Double Extraction

18.2 Direct Isolation

18.2.1 Use of Cooling

18.2.1.1 Direct Isolation from Isopropanol

18.2.1.2 Direct Isolation from Ethyl acetate

18.2.1.3 Direct Isolation from Isopropyl Acetate

18.2.1.4 Direct Isolation from Acetonitrile

18.2.2 Use of Anti-Solvent

18.2.2.1 Adding Water to Acetic Acid

18.2.2.2 Addition of Water to Dimethylformamide

18.2.2.3 Addition of Water to Dimethylacetamide

18.2.2.4 Addition of Water to Dimethylsulfoxide

18.2.2.5 Addition of Methanol to Dimethylsulfoxide

18.2.3 Use of Cooling and Anti-Solvent

18.2.3.1 Isolation of Sonogashira Product

18.2.3.2 Isolation of 6-Chlorophthalazin-1-ol

18.2.3.3 Isolation of SNAr Product

18.2.4 Use of Neutralization

18.2.5 Use of Salt Formation

18.2.6 Other Direct Isolation Approaches

18.2.6.1 Direct Drop Process

18.2.6.2 Removal of By-Product by Direct Drop Approach

18.3 Filtration Problems

18.3.1 Metal-Related Filtration Problems

18.3.1.1 Copper-Related Filtration Problems

18.3.1.2 TiCl4-Related Problems

18.3.2 Small Particle Size

18.3.2.1 Addition of Acetic Acid

18.3.2.2 Addition of Isopropanol

18.3.2.3 Temperature Control

18.3.2.4 Polymorph Transformation

18.3.3 Low-Melting Solid

18.4 Purification Strategies

18.4.1 Use of Salt Formation

18.4.1.1 Hydrochloric Acid Salts

18.4.1.2 Acetic Acid Salt

18.4.1.3 (R)-Mandelate Salt

18.4.1.4 L-Tartaric Acid Salt

18.4.1.5 2-Picolinic Acid Salt

18.4.1.6 Toluenesulfonic Acid Salts

18.4.1.7 Sodium Salt

18.4.1.8 Potassium Salt

18.4.1.9 Magnesium Salt

18.4.1.10 Dicyclohexylamine Salts

18.4.1.11 Quaternary Salt

18.4.2 Derivatization

18.4.2.1 Isolation/Purification of Aldehydes

18.4.2.2 Isolation/Purification of Amine

18.4.2.3 Isolation/Purification of Diol

18.4.2.4 Isolation/Purification of Amino Diol

18.4.3 Various Approaches for Impurity Removal

18.4.3.1 Removal of Ammonium Chloride

18.4.3.2 Removal of 9-BBN

18.4.3.3 Removal of Acetic Acid

18.4.3.4 Removal of (1E,3E)-Dienol Phosphate

18.5 Crystallization

18.5.1 Seed-Induced Crystallization

18.5.1.1 Avoiding Uncontrolled Crystallization

18.5.1.2 Avoiding Oiling Out

18.5.1.3 Control of Exothermic Crystallization

18.5.1.4 Control of Polymorph

18.5.2 Reactive Crystallization

18.5.2.1 Deprotection/Salt Formation

18.5.2.2 Enamine Preparation

18.5.2.3 Free Acid Formation

18.5.2.4 Boc Protection

18.5.2.5 Limitations of Reactive Crystallization

18.5.3 Other Crystallization Approaches

18.5.3.1 Addition of Water

18.5.3.2 Addition of Polymer

18.5.3.3 Crystallization from Extraction Solvent

18.5.3.4 Three-Solvent System

18.5.3.5 Derivatization

18.5.3.6 Control of Crystal Size Distribution

18.5.3.7 Cocrystallization

Chapter 19 Methods for Residual Metal Removal

19.1 Removal of Residual Palladium

19.1.1 Crystallization

19.1.1.1 Crystallization in the Presence of Cysteine

19.1.1.2 Crystallization in the Presence of N-Acetylcysteine

19.1.2 Extraction

19.1.2.1 Liquid–Liquid Transportation

19.1.2.2 Extractive Precipitation

19.1.3 Adsorption

19.1.3.1 Activated Carbon

19.1.3.2 MP–TMT

19.1.3.3 Deloxan THP-II

19.1.3.4 Smopex 110

19.1.4 Distillation

19.1.5 Other Methods

19.1.5.1 Adsorption–Crystallization

19.1.5.2 Adsorption–TMT Wash

19.1.5.3 Protecting Group

19.1.5.4 Salt Formation

19.1.6 Conclusion

19.2 Removal of Residual Copper

19.2.1 Use of Aqueous Ammonia

19.2.2 Use of Thiourea

19.2.3 Use of 2,4,6-Trimercaptotriazine

19.3 Removal of Residual Rhodium

19.3.1 Use of Smopex-234

19.3.2 Use of Ecosorb C-941

19.4 Removal of Residual Ruthenium

19.4.1 Use of Activated Carbon

19.4.2 Use of Supercritical Carbon Dioxide

19.5 Removal of Zinc

19.5.1 Extraction with Trisodium Salt of EDTA

19.5.2 Use of Ethylenediamine

19.6 Removal of Magnesium

19.7 Removal of Aluminum

19.7.1 Use of Triethanolamine

19.7.2 Use of Crystallization

19.8 Removal of Iron and Nickel

19.8.1 Removal of Iron

19.8.2 Removal of Nickel

Chapter 20 Methods for Impurity Removal

20.1 Removal of Fluoride

20.1.1 Use of Aqueous Wash

20.1.2 Use of CaCl2

20.1.3 Use of CaCO3

20.2 Removal of Iodide

20.3 Removal of High-Boiling Dipolar Aprotic Solvents

20.3.1 Wash with Aqueous Solution

20.3.2 Extraction with Heptane

20.4 Removal of Triphenylphosphine Oxide

20.4.1 Wash with Ethyl Acetate

20.4.2 Precipitation of Ph3PO with MgCl2

20.4.3 Precipitation of Ph3PO with ZnCl2

20.4.4 Precipitation of Ph3PO with Heptane

20.5 Use of Sodium Bisulfate

20.5.1 Removal of Methacrylic Acid from Acid Product

20.5.2 Removal of Alcohol from Aldehyde Product

20.5.3 Removal of Excess Formaldehyde

20.5.4 Removal of Ketone Intermediate

20.6 Removal of Excess Reagents

20.6.1 Use of Dimethylamine to Remove Excess Formaldehyde

20.6.2 Use of N-Methylpiperazine to Remove Boc Anhydride

20.6.3 Use of CO2 to Remove Excess Piperazine

20.6.4 Use of Succinic Anhydride to Remove 1-(2-Pyrimidyl)piperazine

20.6.5 Use of Pivalaldehyde to Remove 4-Chlorobenzylamine

20.6.6 Use of DABCO to Remove Benzyl Bromide

20.6.7 Use of Aqueous Ammonia to Remove Diethyl Sulfate

20.6.8 Use of Hydrogen Peroxide to Oxidize Ph3P

20.7 Conversion of Impurity to Starting Material

20.8 Conversion of Impurity to Product

20.8.1 Deoxychlorination

20.8.2 Cycloaddition Reaction

20.9 Removal of Other Impurities

20.9.1 Removal of Polymeric Material

20.9.2 Use of Sodium Periodate to Remove Diol

20.9.3 Use of Phenylboronic Acid to Remove Diol

20.9.4 Use of Sodium Dithionate to Reduce Nitro Group

20.9.5 Use of Polymeric Resin to Remove Hydrazide

Chapter 21 Pharmaceutical Salts

21.1 Salts of Basic Drug Substances

21.1.1 Hydrochloride Salts

21.1.2 Hemisulfate Salt

21.1.3 Citric Acid Salt

21.1.4 Various Pharmaceutical Salts

21.2 Salts of Acidic Drug Substances

21.2.1 Use of Inorganic Bases

21.2.1.1 Sodium Salts

21.2.1.2 Potassium Salts

21.2.1.3 Calcium Salts

21.2.1.4 Various Inorganic Salts

21.2.2 Use of Organic Bases

Chapter 22 Solid Form

22.1 Polymorphism

22.1.1 Control of Polymorph by Seeding

22.1.1.1 Use of Direct Addition

22.1.1.2 Use of Reverse Addition

22.1.2 Control of Polymorph by Temperature

22.1.3 Control of Polymorph by Slurrying

22.1.4 Control of Polymorph by Aging

22.1.5 Control of Polymorph by Adding Polymer

22.1.6 Polymorph Transformation

22.2 Cocrystals

22.2.1 Cocrystal with L-Phenylalanine

22.2.2 Cocrystal with L-Pyroglutamic Acid

22.2.3 Cocrystal with Phosphoric Acid

22.2.4 Cocrystal with L-Proline

22.2.5 Cocrystal with Adipic Acid

22.3 Api Particle Size

22.4 Amorphous Solids

22.4.1 Use of Spray Drying

22.4.2 Use of Solvent-Induced Method

22.4.3 Use of Hot-Melt Extrusion

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