Overcoming Synthetic Challenges in Medicinal Chemistry

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