Handbook for Chemical Process Research and Development

842 Pages·2017·13.38 MB·English

by  Wenyi Zhao

Handbook for
Chemical Process
Research and
Development
Handbook for
Chemical Process
Research and
Development
Wenyi Zhao
CRC Press
Taylor & Francis Group
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Boca Raton, FL 33487-2742
© 2017 by Wenyi Zhao
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Version Date: 20160819
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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
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ook 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 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 S 1 Reaction .......................................................................8
RN
1.1.6.2 Mitsunobu Reaction ..............................................................9
1.2 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
Contents ix
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 BF · Etherate) ...................................................81
3
2.1.5.5 Water ...................................................................................82
2.1.5.6 Hydroquinone .....................................................................85
2.1.5.7 B(OMe) in Borane Reduction of Acid ...............................86
3
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
2.2 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 S Ar Reaction .................................166
N
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
Contents xi
3.1.1.3 Oxidation with Ozone .......................................................194
3.1.1.4 Oxidation with KMnO ....................................................197
4
3.1.2 Oxidation of Alcohols to Aldehydes or Ketones ..............................197
3.1.2.1 SO ∙ Py/DMSO System .....................................................198
3
3.1.2.2 AcO/DMSO System ........................................................200
2
3.1.2.3 TFAA/DMSO/TEA System .............................................201
3.1.2.4 TEMPO/NaOCl System ...................................................201
3.1.2.5 RuCl /NaOCl System .......................................................203
3
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 H O /Na WO ..........................................208
2 2 2 4
3.1.5.6 Oxidation with TMSCl/KNO ..........................................209
3
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
3.2 Reduction Reactions ......................................................................................212
3.2.1 Boron-Based Reductive Reactions ...................................................212
3.2.1.1 Reduction with NaBH......................................................212
4
3.2.1.2 Reduction with Borane .....................................................219
3.2.2 Reduction with Lithium Aluminum Hydride ...................................226
Procedure ..........................................................................................226
3.3 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