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Full Description
Collection of 150 synthetic problems in medicinal chemistry offering mechanistic insights into complex reactions and potential pitfalls in drug synthesis
Overcoming Synthetic Challenges in Medicinal Chemistry is a comprehensive collection of around 150 challenging organic reactions in medicinal chemistry, drawn from the author's work experience and recent journal and patent publications. Problems are arranged by the structure of the reaction product to make it easier for the reader to find the information needed.
In this book, readers will find information on:
General terms and concepts in synthetic organic chemistry and medicinal chemistry
Specific reactions leading to desired products or unexpected side products
Step-by-step mechanisms, experimental procedures, literature information, and applications for each reaction
Ways to reduce mistakes in synthetic work and optimize product synthesis
Overcoming Synthetic Challenges in Medicinal Chemistry serves as a valuable guide for organic chemists, professionals, and job candidates in the pharmaceutical industry, as well as graduates and lecturers at university, helping them grasp complex reactions and gain insight into potential pitfalls and side reactions in drug synthesis.
Contents
Preface xv
Abbreviations xix
1 Opinions and Suggestions 1
1.1 Be a "Doctor," Not Just a "Drug Fetcher" 1
1.2 Synthetic Organic Chemistry: Still as Much an Art as a Science 1
1.3 Synthetic Organic Chemistry Is an Experimental Science under the Guidance of Theory 2
1.4 Reduce Mistakes in Your Synthetic Work 2
1.5 Your Knowledge, Experience, and Skills Can Never Be Too Much 3
1.6 What Is a Mistake? 4
1.7 Beyond Experience: Combining Literature and Insight for Optimal Synthetic Design 6
1.8 Improve Your Decision-Making Ability 6
1.9 Know the Mechanism of the Reactions You Perform 7
1.10 Always Learn Something from the Reaction You Performed 8
1.11 Knowing Reaction Mechanisms Alone Doesn't Make an Excellent Chemist—But It's Essential 8
1.12 Patents Do Not Tell You the Full Story of Chemistry 8
1.13 Summarize Your Work After Completing a Synthesis 9
1.14 Two Examples 9
References 12
2 General Terms and Concepts in Synthetic Organic Chemistry 13
2.1 Reaction Mechanism 13
2.2 Approaches to Draw Reaction Mechanism 13
2.2.1 Linear Way: Catalytic and Noncatalytic Reactions 14
2.2.2 Cyclic Way: Catalytic Reactions 14
2.3 Desired Product 14
2.4 Unexpected Product 14
2.5 Side Reaction 15
2.6 Side Product and By-product 15
2.7 Impurity 15
2.8 Theoretical Yield, Percentage Yield (Yield), Net Yield, and Overall Yield 16
2.9 Intermediate 16
2.10 Transition State 17
2.11 Species 17
2.12 Free Radical 17
2.13 Stoichiometric Reaction 17
2.14 Catalytic Reaction 17
2.15 Material Balance 17
2.16 Electron Balance 18
2.17 Nucleophile 18
2.18 Electrophile 18
2.19 Acid 18
2.20 Base 18
2.21 Acidity and pK a 19
2.22 Acid-Base Reaction 19
2.23 Reaction Selectivity 20
2.24 Chemoselectivity 20
2.25 Regioselectivity 21
2.26 Stereoselectivity 21
2.27 Iteroselectivity 23
2.28 One-pot Synthesis/Telescoping Process 25
2.29 Cascade Reaction 27
2.30 Multicomponent Reaction 29
2.31 Flow Chemistry 29
2.32 Atom Economy 30
2.33 Green Chemistry 31
2.34 Partial Synthesis, Total Synthesis, and Formal Synthesis 32
2.35 Linear Synthesis and Convergent Synthesis 34
2.36 Divergent Synthesis 36
2.37 Click Chemistry 36
2.38 Parallel Synthesis 37
2.39 Solid-phase Synthesis 38
2.40 Combinatorial Chemistry 38
2.41 Process Chemist versus Medicinal Chemist 39
References 40
3 General Terms and Concepts in Medicinal Chemistry 43
3.1 What Is a Drug? 43
3.2 Drug Discovery 43
3.3 Medicinal Chemistry 44
3.4 Drug Target 45
3.5 Enzyme 45
3.6 Receptor 46
3.7 Inhibitor 47
3.8 Activator 48
3.9 Drug Design 48
3.10 Ligand-based Drug Design 49
3.11 Structure-based Drug Design 50
3.12 Lipinski's Rule of Five 50
3.13 Lead Compound 51
3.14 Hit-to-Lead 52
3.15 High-Throughput Screening 52
3.16 Pharmacophore 52
3.17 Affinity, Efficacy, and Potency 53
3.18 Structure-Activity Relationship 54
3.19 Partition Coefficient and Log P/Clog P 54
3.20 Drug Candidate 55
3.21 Preclinical Studies 55
3.22 Toxicity 56
3.23 Pharmacokinetics and Pharmacodynamics 56
3.24 Absorption, Distribution, Metabolism, and Excretion 56
3.25 Bioavailability 57
3.26 Pharmacology 58
3.27 Formulation 58
3.28 Active Pharmaceutical Ingredient 59
3.29 Drug Stability 59
3.30 Prodrugs 60
3.31 Deuterium-containing Drug 61
3.32 Antibody Drug Conjugates 62
3.33 Good Laboratory Practice 62
3.34 Good Manufacturing Practice 63
3.35 Chemistry, Manufacturing, and Controls 64
3.36 Contract Research Organization 65
3.37 Investigational New Drug Application 65
3.38 Clinical Trials 65
3.39 New Drug Application 66
References 67
4 Mechanism Problems from Reactions Give Expected Products 71
4.1 Formation of Noncyclic Compounds 71
Problem 1: t-BuOK Promoted Isomerization of Terminal Alkyne to Internal Alkyne 71
Problem 2: Dimerization of Terminal Aziridines to (E)-but-2-ene-1,4-diamines 72
Problem 3: Thiourea-Mediated Conversion of Alcohols to Alkylhalides 74
Problem 4: Oxidative Decarboxylation of N-Aroylglycines with Lead(IV) Acetate 76
Problem 5: Preparation of Aromatic Amines Promoted by DDQ and Ph 3 P 78
Problem 6: Conversion of Alkyl Aryl Ketones to α-Arylalkanoic Acids Using DPPA 80
Problem 7: Synthesis of β-Aryl-α-Keto Acid from Benzaldehyde and Hydantoin 82
Problem 8: α-Amination of Amides 83
Problem 9: α-Oxidation of Amides 85
Problem 10: Tsunoda Reagent for Mitsunobu Reaction 87
Problem 11: Preparation of Arylacetonitriles from Arylbromides 89
Problem 12: Transformation of Aromatic Bromides into Aromatic Nitriles 90
Problem 13: Preparation of Nitriles from Carboxylic Acid by Smiles Rearrangement 91
Problem 14: Synthesis of Disubstituted Malononitriles 92
Problem 15: Preparation of 2-Arylacetonitriles from Aromatic Ketones 95
Problem 16: Synthesis of Aminophosphonate by Birum-Oleksyszyn Reaction 97
Problem 17: Synthesis of Primary Sulfonamide by using N-Sulfinyl-O- (tert-butyl)hydroxylamine 98
4.2 Formation of Hydrazine Derivatives 101
Problem 18: Preparation of Hydrazines from Amines by Using Oxaziridines 101
Problem 19: Preparation of Hydrazines from Alcohols 102
Problem 20: Synthesis of Arylacetohydrazonoyl Cyanide 103
4.3 Formation of Cyclic Alkane and Derivatives 105
4.3.1 Cyclopropane 105
Problem 21: Preparation of Methyl (1S,5R)-2-oxo-3- oxabicyclo[3.1.0]hexane-1-carboxylate 105
Problem 22: Synthesis of Cyclopropylamines 107
Problem 23: Formation of Cyclopropane by Dialkylation of Active Methylene 109
Problem 24: A Tandem Cyclopropanation Ring-Expansion Reaction 111
4.3.2 Cyclobutane 115
Problem 25: Synthesis of 3-Ethylbicyclo[3.2.0]hept-3-en-6-one 115
4.3.3 Cyclopentane 117
Problem 26: Preparation of cis-2-(Methoxycarbonyl)cyclopentane-1- carboxylic Acid 117
Problem 27: Rearrangement of Furfuryl Alcohol to 4-Hydroxy-2-cyclopen-tenone 119
4.3.4 Cycloheptane 120
Problem 28: Preparation of Homobenzylic Ketones by 1,2-shift in 1,1'-disubstituted Olefins 120
4.4 Formation of Aromatic Compounds 122
Problem 29: Formation of Hexasubstituted Benzene Ring by Cyclization 122
Problem 30: Vicarious Nucleophilic Substitution of Hydrogen in Aromatic Nitro Compounds 124
Problem 31: Synthesis of Tetralone from 1-Naphthol and
1,2-Dichlorobenzene 125
4.5 Formation of Nonaromatic Heterocycles 126
4.5.1 Lactone 126
Problem 32: Preparation of Thiolactone from Lactone 126
Problem 33: Preparation of D-Erythronolactone from Erythorbic Acid 129
Problem 34: Synthesis of L-lyxonolactone-2,3-O-isopropylidene 129
Problem 35: Thermal Rearrangement of Ozonides 131
4.5.2 Hydrofuran 133
Problem 36: Preparation of 2,2-Dimethyl-5-phenylfuran-3(2H)-one by a Rearrangement 133
Problem 37: Decarboxylative Elimination of β-Hydroxycarboxylic Acid 134
4.5.3 Tetrahydropyran 137
Problem 38: Construction of Fosdenopterin Core by Viscontini Reaction 137
4.5.4 Pyrrolidine 138
Problem 39: Formation of 2,5-Dibenzyltetrahydropyrrolo[3,4-c] pyrrole-1,3-dione 138
Problem 40: Synthesis of trans-3-substituted Proline Derivatives 139
Problem 41: Preparation of 5,5-Dimethyl-3-methylene-1-(prop-1-en-2-yl) pyrrolidin-2-one 141
Problem 42: Synthesis of Heteroaromatic-Fused Pyrrolidines via Cyclopropane Ring-Opening Reaction 144
Problem 43: Synthesis of Spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-one 146
4.5.5 Piperidine 148
Problem 44: Synthesis of (2S,4R)-4-Hydroxypipecolic Acid from Homoallyl Alcohol 148
Problem 45: Preparation of a Spiropiperidine 151
Problem 46: Dealkylation of Tertiary Amine with DEAD 153
Problem 47: A Novel Synthesis of δ-Keto -ɑ-amino Acids 155
Problem 48: Construction of Morphine Core by Acid Promoted Cyclization 157
Problem 49: Preparation of 8a-Phenyloctahydroquinolin-4a(2H)-ol 159
Problem 50: Preparation of an Octahydroquinolizine 160
Problem 51: Preparation of a Chromeno[3,2-i]quinolizine 162
4.5.6 Imidazoline 163
Problem 52: Preparation of Phenytoins from Benzils 163
4.5.7 Oxazolidine 164
Problem 53: Preparation of a Chiral (R)-5-(Hydroxymethyl)-3-aryloxazolidin-2-one 164
4.5.8 Tetrahydropyrimidine 166
Problem 54: Synthesis of Tetrahydropyrimidinol 166
4.5.9 Diazepine 167
Problem 55: Synthesis of 2,3,4,5-Tetrahydro-1Hbenzo[e][1,4]diazepine 167
4.5.10 Trioxane 170
Problem 56: Formation of 1,2,4-Trioxanes from Cyclic Peroxides and Carbonyl Compounds 170
Problem 57: Synthesis of 1,2,4-Trioxanes from 4-Alkylphenols and Aldehydes 172
Problem 58: A Key Step for Industrial-Scale Synthesis of Artemisinin (Qinghaosu) 173
4.6 Formation of Monocyclic Aromatic Heterocycles 175
4.6.1 Oxathiolane 175
Problem 59: Synthesis of Substituted 1,3-Oxathiolane 175
4.6.2 Pyrrole 177
Problem 60: Preparation of Pyrrole-2-Aldehyde from Pyrrole-2-t-butyl ester 177
Problem 61: Synthesis of 2-Formylpyrroles from Pyridinium Iodide Salts 179
Problem 62: Preparation of 2-Aminopyrroles 180
Problem 63: Synthesis of 3-(3,4-Dihydro-2H-pyrrol-5-yl)pyridine (Myosmine) 182
Problem 64: Formation of Substituted Pyrrole by Cyclization of γ-ketonitrile 183
4.6.3 Thiophene 186
Problem 65: Synthesis of Trisubstituted Thiophene 186
4.6.4 Pyrrol-2-one 188
Problem 66: Preparation of Spiro 1H-Pyrrol-2(5H)-ones by One-Pot Multicomponent Reaction 188
4.6.5 Pyridine 191
Problem 67: A General Preparation of Pyridines via the Annulation of Ketones 191
Problem 68: Conversion of Benzenes to Pyridines by ipso-selective Nitrene Internalization 192
Problem 69: Synthesis of Multisubstituted Pyridines via HFIP Catalyzed Cyclization 197
Problem 70: Preparation of Multisubstituted Pyridine 199
Problem 71: Preparation of 4-Perfluoroalkylpyridines 201
Problem 72: C-2 Amination of Pyridine 203
Problem 73: C-2 Amination of Pyridine N-oxide Derivatives 205
Problem 74: Nucleophilic Cyanation of Pyridines 207
Problem 75: Synthesis of 2-Arylpyridines from Acetophenones 209
Problem 76: Preparation of penta-substituted Pyridone 211
4.6.6 Imidazole 212
Problem 77: Formation of 2,4-disubstituted Imidazole 212
Problem 78: Synthesis of Substituted 2-Aryl-N-benzylbenzimidazoles 213
Problem 79: Preparation of 1-Isopropenyl-1,3-dihydro-2Hbenzo[d]imidazol-2-one 216
4.6.7 Isoxazole 217
Problem 80: Formation of 5-Chloro-3-phenylbenzo[c]isoxazole 217
Problem 81: Preparation of Isoxazoles from Nitro Compounds and Oxetanes 219
4.6.8 Thiazole 221
Problem 82: Preparation of Thiazole by Thiourea 221
Problem 83: Preparation of Thiazole from Sulfoxide During Ceftibuten Synthesis 223
4.6.9 Pyrazole 224
Problem 84: Synthesis of Trifluoromethylpyrazoles 224
Problem 85: Preparation of Pyrazole by Sulfur Extrusion 226
Problem 86: Synthesis of 4-(3-Aminopropyl)-5-amino-1-methylpyrazole 227
4.6.10 Pyrimidine 229
Problem 87: Formation of 5-Hydroxypyrimidin-4(3H)-one by 3,3-sigmatropic Rearrangement 229
Problem 88: Regioselective Chlorination of 1-Methylpyrimidine-2,4,6(1H,3H,5H)-trione 231
Problem 89: An Industrial Synthesis of Orotic Acid 232
Problem 90: 2-Thioxo-2,3-dihydropyrimidin-4(1H)-one to Pyrimidine-2,4(1H,3H)-dione 234
Problem 91: Preparation of N,N'-Dicyclohexylbarbituric Acid from dcc and Malonic Acid 235
4.6.11 Pyrazine 237
Problem 92: Synthesis of Ethyl 3-(trifluoromethyl) pyrazine-2-carboxylate 237
4.6.12 Triazole 239
Problem 93: Preparation of [1,2,4]Triazolo[1,5-a]pyridin-2-amine 239
4.6.13 Oxadiazole 240
Problem 94: Formation of 1,3,4-Oxadiazole 240
Problem 95: Preparation of 1,2,4-Oxadiazole 241
4.6.14 Thiadiazole 243
Problem 96: Formation of 1,2,4-Thiadiazole 243
4.6.15 Triazine 245
Problem 97: Synthesis of 1,2,3-Triazines 245
4.7 Formation of Bicyclic and Polycyclic Aromatic Heterocycles 248
4.7.1 Indole 248
Problem 98: Formation of 2,3-Disubstituted Indole 248
Problem 99: A Novel Synthesis of Indoles by Vinyl Grignard Reagent with Nitroarenes 250
Problem 100: Deprotection of 2-Hydroxylethyl from Indole Derivative 252
4.7.2 Indolizine 254
Problem 101: Access to 2-Iodoindolizines via Iodine-Mediated Cyclization of 2-pyridylallenes 254
4.7.3 Quinolone 254
Problem 102: Oxidative Rearrangement of Carboline to Quinolone 254
4.7.4 Indazole 257
Problem 103: A Special Cadogan Reductive Cyclization-Preparation of Indazole 257
Problem 104: Preparation of Indazoles from 2-Methylanilines 259
Problem 105: Synthesis of 7-aza-Indazoles by Diels-Alder/Retro-Diels- Alder Cascade 260
Problem 106: Synthesis of Indazole by Davis-Beirut Reaction 262
4.7.5 Quinazoline 265
Problem 107: Synthesis of Quinazolines 265
Problem 108: Carbon Dioxide Mediated Synthesis of Quinazoline-2,4(1H,3H)-dione 266
Problem 109: Synthesis of 3-Alkylquinazolin-4-ones Promoted by Mukaiyama Reagent 269
Problem 110: Dimroth Rearrangement in the Preparation of Gefitinib and Erlotinib 270
4.7.6 Thienoquinolizine 272
Problem 111: A [3+2] Cycloaddition Followed by Sulfur Extrusion 272
4.7.7 Pyridopyrimidine 273
Problem 112: An Extended Dimroth Rearrangement Catalyzed by MeONa 273
4.7.8 Pyrrolopyrimidine 274
Problem 113: One-Pot Synthesis of 2-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl) acetates 274
4.7.9 Pyrazolopyrimidine 276
Problem 114: Cyclization of Diazo Compound with Aldehyde 276
4.8 Miscellaneous 277
4.8.1 Steroid 277
Problem 115: Formation of Cyclopropane Ring in a Nucleophile Substitution on Steroid 277
Problem 116: Preparation of 21-Hydroxypregna-4,9(11), 16-triene-3,20-dione-21-acetate 280
4.8.2 Macrolide 281
Problem 117: An Ascomycin Rearrangement 281
4.8.3 Gibberellin 283
Problem 118: An Acyloin Rearrangement in Gibberellin 283
4.8.4 Cannabicitran 284
Problem 119: Formation of Cannabicitran During the Synthesis of Cannanbichromene 284
4.8.5 Serratezomine 287
Problem 120: Transformation of Serratinine into Serratezomine A 287
4.8.6 Vincamine 288
Problem 121: Preparation of Vincamine from Tabersonine 288
References 290
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products 305
5.1 Formation of Noncyclic Alkane and Derivatives 306
5.1.1 Alcohol 306
Problem 122: An Unexpected Impurity from a Grignard Reaction 306
Problem 123: Formation of a Dimer Impurity in the Development of Delafloxacin 308
Problem 124: Formation of an Amidino-Diol Side Product 310
5.1.2 Amine 312
Problem 125: Formation of Ketoamine During Semmler-Wolff Aromatization 312
Problem 126: Formation of an Aniline Impurity by Smiles Rearrangement 314
5.2 Formation of Cyclic Alkane and Derivatives 316
5.2.1 Cyclopropane 316
Problem 127: Formation of a Cyclopropane Impurity 316
5.3 Formation of Aromatic Compounds 318
5.3.1 Benzene 318
Problem 128: Formation of an Undesired Substituted Benzene Side Product 318
5.4 Formation of Nonaromatic Heterocycles 320
5.4.1 Aziridine 320
Problem 129: Formation of an Aziridine-a Neighboring Group Participated Cyclization 320
5.4.2 Pyrrolidine 323
Problem 130: Formation of Ring-contracted Side Product During Fluorination 323
5.4.3 Piperidine 326
Problem 131: An Unusual DAST-Mediated Rearrangement 326
5.4.4 Tetrahydropyrazine 329
Problem 132: Formation of an Unexpected Tetrahydropyrazine Product 329
5.4.5 Tetrahydropyrimidine 332
Problem 133: Formation of Impurities During a CDI-promoted Cyclization 332
5.4.6 Oxazepane 334
Problem 134: An Unusual Stevens Rearrangement Catalyzed by Acid 334
5.4.7 Tetrahydroquinoline 336
Problem 135: Formation of Unexpected Tetrahydrobenzoquinoline Side Product in a Hydrogenation 336
5.5 Formation of Monocyclic Aromatic Heterocycles 338
5.5.1 Pyrrole 338
Problem 136: Formation of an Amino Pyrrole Impurity 338
5.5.2 Pyridine 341
Problem 137: Pyridyl Walks to Hydroxyl from Sulfone During an Alkylation 341
5.5.3 Pyrazole 343
Problem 138: Ring Expansion by [3 + 2] Cycloaddition During the Synthesis of Pyrazoles 343
5.5.4 Oxazole 346
Problem 139: Formation of 2-(2,6-difluorophenyl)-4-(p-tolyl)oxazole as an impurity 346
Problem 140: Formation of an Oxazoline Impurity in the Synthesis of a M1 Agonist 349
5.5.5 Triazole 351
Problem 141: Formation of Dimethylcarbamoyl-OBt in a HBTU-promoted Amide Preparation 351
5.5.6 Tetrazole 353
Problem 142: Formation of a Tetrazole Impurity Caused by Acetone 353
5.5.7 Diazepine 355
Problem 143: Accidental Discovery of Librium 355
5.6 Formation of Bicyclic Aromatic Heterocycles 356
5.6.1 Benzofuran 356
Problem 144: Formation of Two Benzofuran Side Products During the Synthesis of Morin 356
5.6.2 Benzoxazolinone 361
Problem 145: Formation of Undesired Benzoxazolinone from N,2-Dihydroxybenzamide 361
5.6.3 Quinoline 363
Problem 146: Formation of Quinoline-4-carboxylic Acids by Pfitzinger Reaction Conditions 363
Problem 147: Formation of a Tricyclic Impurity During Alkylation of 8-hydroxyquinoline 365
5.6.4 Naphthyridine 368
Problem 148: Unexpected Formation of a Dibenzo[c,f]-2,7-naphthyridine-3,6-diamine 368
5.6.5 Pteridine 370
Problem 149: Formation of Two Pteridine Impurities During a Synthesis of Dexrazoxane 370
5.7 Miscellaneous 372
5.7.1 Steroid 372
Problem 150: Formation of Impurity F of Clobetasol Propionate 372
Problem 151: Formation of a 24-Methylene Steroidal Impurity 373
5.7.2 Terramycin 375
Problem 152: An Unusual Reaction of Terramycin with Methyl Iodide 375
5.7.3 Cephem 376
Problem 153: Degradation of Cephem Intermediate 376
References 378
Index 383
