106,99 €
Mehr erfahren.
- Herausgeber: Wiley-VCH
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
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.
Sie lesen das E-Book in den Legimi-Apps auf:
Seitenzahl: 685
Veröffentlichungsjahr: 2025
Ähnliche
Table of Contents
Cover
Table of Contents
Title Page
Copyright
Preface
Abbreviations
Chapter 1: Opinions and Suggestions
1.1 Be a “Doctor,” Not Just a “Drug Fetcher”
1.2 Synthetic Organic Chemistry: Still as Much an Art as a Science
1.3 Synthetic Organic Chemistry Is an Experimental Science under the Guidance of Theory
1.4 Reduce Mistakes in Your Synthetic Work
1.5 Your Knowledge, Experience, and Skills Can Never Be Too Much
1.6 What Is a Mistake?
1.7 Beyond Experience: Combining Literature and Insight for Optimal Synthetic Design
1.8 Improve Your Decision-Making Ability
1.9 Know the Mechanism of the Reactions You Perform
1.10 Always Learn Something from the Reaction You Performed
1.11 Knowing Reaction Mechanisms Alone Doesn’t Make an Excellent Chemist—But It’s Essential
1.12 Patents Do Not Tell You the Full Story of Chemistry
1.13 Summarize Your Work After Completing a Synthesis
1.14 Two Examples
References
Chapter 2: General Terms and Concepts in Synthetic Organic Chemistry
2.1 Reaction Mechanism
2.2 Approaches to Draw Reaction Mechanism
2.3 Desired Product
2.4 Unexpected Product
2.5 Side Reaction
2.6 Side Product and By-product
2.7 Impurity
2.8 Theoretical Yield, Percentage Yield (Yield), Net Yield, and Overall Yield
2.9 Intermediate
2.10 Transition State
2.11 Species
2.12 Free Radical
2.13 Stoichiometric Reaction
2.14 Catalytic Reaction
2.15 Material Balance
2.16 Electron Balance
2.17 Nucleophile
2.18 Electrophile
2.19 Acid
2.20 Base
2.21 Acidity and pK
a
2.22 Acid–Base Reaction
2.23 Reaction Selectivity
2.24 Chemoselectivity
2.25 Regioselectivity
2.26 Stereoselectivity
2.27 Iteroselectivity
2.28 One-pot Synthesis/Telescoping Process
2.29 Cascade Reaction
2.30 Multicomponent Reaction
2.31 Flow Chemistry
2.32 Atom Economy
2.33 Green Chemistry
2.34 Partial Synthesis, Total Synthesis, and Formal Synthesis
2.35 Linear Synthesis and Convergent Synthesis
2.36 Divergent Synthesis
2.37 Click Chemistry
2.38 Parallel Synthesis
2.39 Solid-phase Synthesis
2.40 Combinatorial Chemistry
2.41 Process Chemist versus Medicinal Chemist
References
Chapter 3: General Terms and Concepts in Medicinal Chemistry
3.1 What Is a Drug?
3.2 Drug Discovery
3.3 Medicinal Chemistry
3.4 Drug Target
3.5 Enzyme
3.6 Receptor
3.7 Inhibitor
3.8 Activator
3.9 Drug Design
3.10 Ligand-based Drug Design
3.11 Structure-based Drug Design
3.12 Lipinski’s Rule of Five
3.13 Lead Compound
3.14 Hit-to-Lead
3.15 High-Throughput Screening
3.16 Pharmacophore
3.17 Affinity, Efficacy, and Potency
3.18 Structure–Activity Relationship
3.19 Partition Coefficient and Log
P
/Clog
P
3.20 Drug Candidate
3.21 Preclinical Studies
3.22 Toxicity
3.23 Pharmacokinetics and Pharmacodynamics
3.24 Absorption, Distribution, Metabolism, and Excretion
3.25 Bioavailability
3.26 Pharmacology
3.27 Formulation
3.28 Active Pharmaceutical Ingredient
3.29 Drug Stability
3.30 Prodrugs
3.31 Deuterium-containing Drug
3.32 Antibody Drug Conjugates
3.33 Good Laboratory Practice
3.34 Good Manufacturing Practice
3.35 Chemistry, Manufacturing, and Controls
3.36 Contract Research Organization
3.37 Investigational New Drug Application
3.38 Clinical Trials
3.39 New Drug Application
References
Chapter 4: Mechanism Problems from Reactions Give Expected Products
4.1 Formation of Noncyclic Compounds
4.2 Formation of Hydrazine Derivatives
4.3 Formation of Cyclic Alkane and Derivatives
4.4 Formation of Aromatic Compounds
4.5 Formation of Nonaromatic Heterocycles
4.6 Formation of Monocyclic Aromatic Heterocycles
4.7 Formation of Bicyclic and Polycyclic Aromatic Heterocycles
4.8 Miscellaneous
References
Chapter 5: Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products
5.1 Formation of Noncyclic Alkane and Derivatives
5.2 Formation of Cyclic Alkane and Derivatives
5.3 Formation of Aromatic Compounds
5.4 Formation of Nonaromatic Heterocycles
5.5 Formation of Monocyclic Aromatic Heterocycles
5.6 Formation of Bicyclic Aromatic Heterocycles
5.7 Miscellaneous
References
Index
End User License Agreement
Guide
Cover
Table of Contents
Title Page
Copyright
Preface
Abbreviations
Begin Reading
Index
End User License Agreement
Pages
i
ii
xv
xvi
xvii
xviii
xix
xx
xxi
xxii
xxiii
xxiv
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337
338
339
340
341
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381
382
383
384
385
386
387
388
389
390
391
392
393
Overcoming Synthetic Challenges in Medicinal Chemistry
Mechanistic Insights and Solutions
Tongshuang Li
Author
Dr. Tongshuang Li
Wuxi AppTec
3912 Trust Way
Hayward
CA, 94545 USA
Cover Design: Wiley
Cover Images: © Unconventional/Shutterstock, Courtesy of Tongshuang Li, Adapted from Org. Process Res. Dev., 2021, 25, 1943, Elliott, L.D.; Booker-Milburn, K. I.; Lennox, A. J. J.
Library of Congress Card No.: applied for
British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the British Library.
Bibliographic information published by the Deutsche Nationalbibliothek
The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at http://dnb.d-nb.de.
Print ISBN: 9783527355273
ePDF ISBN: 9783527852635
ePub ISBN: 9783527852628
oBook ISBN: 9783527852642
© 2026 WILEY-VCH GmbH, Boschstraße 12, 69469 Weinheim, Germany ((or Ernst & Sohn GmbH, Rotherstraße 21, 10245 Berlin, Germany))
All rights reserved (including those of translation into other languages, text and data mining and training of artificial technologies or similar technologies). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.
The manufacturer’s authorized representative according to the EU General Product Safety Regulation is WILEY-VCH GmbH, Boschstr. 12, 69469 Weinheim, Germany, e-mail: [email protected].
While the publisher and the authors have used their best efforts in preparing this work, including a review of the content of the work, neither the publisher nor the authors make any representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.
Preface
If you read a book or article and find yourself agreeing with every single point without a single question or doubt, it might indicate that you’re not thinking critically and you have been brain washed. True growth comes from recognizing what you don’t know—without acknowledging your own ignorance, progress becomes impossible.
When applying for a position as a synthetic chemist or medicinal chemist, you can expect to be questioned about reaction mechanisms during the interview process. These mechanistic problems are typically not taken directly from textbooks but are often drawn from the interviewer’s own research experiences. This was certainly the case for me when I interviewed for such roles in pharmaceutical companies after completing my postdoctoral research. A solid understanding of organic reaction mechanisms is a fundamental skill for any synthetic organic chemist. It is essential not only for designing synthesis routes and experimental procedures but also for troubleshooting and resolving synthetic challenges effectively.
The fundamental reactions and named reactions in organic chemistry, along with their mechanisms, have been extensively covered in numerous textbooks and monographs. These mechanisms are also readily accessible through online platforms such as Wikipedia, Google, the Organic Chemistry Portal, and YouTube videos. However, when it comes to specific reactions in published synthetic routes, their mechanisms are not always straightforward to identify or comprehend. This often depends on the chemist’s knowledge and experience. In many instances, understanding the mechanisms behind the formation of unexpected products, side products, or even impurities can significantly aid chemists in addressing challenges in their research. With these points in mind, this book compiles a selection of intriguing and challenging mechanism problems in organic reactions, particularly within the realm of medicinal chemistry, drawing from my experience and the literature I have studied.
Many of the reactions featured in this book are key steps in the synthesis of target compounds, while others involve the formation of side products, unexpected products, or impurities. I have made an effort to avoid including examples that have already been covered in other books. The primary goal of this book is to assist organic chemists, professionals, and students in deepening their understanding of reaction mechanisms. For mechanisms reported in the literature, I have redrawn them in a more accessible format to enhance clarity for readers. Additionally, I have offered my own perspectives on certain mechanisms that I find questionable in the literature. For reactions, particularly those described in patents, where mechanisms are not provided, I have proposed mechanistic explanations based on my understanding. I strongly encourage readers to attempt drawing their own mechanisms before consulting my proposed answers.
Certainly, whether derived from the literature or proposed by me, the mechanisms should not be considered the only possible explanations or the “definitive answers.” You are encouraged to develop your own mechanisms, provided they offer a reasonable and logical explanation for the reaction.
Needless to say, this book is not an encyclopedia and it does not aim to cover all reaction mechanisms in organic synthesis. For example, some common, hotly cited, or frontier organic reactions, such as transition metal catalyzed coupling, catalytic asymmetric reactions, photo-promoted reactions, and electrochemical reactions, are barely included.
I would like to extend my appreciation to the original publishers for experimental procedures for granting permission to use in this book. The publishers include the American Chemical Society, Elsevier, the Royal Society of Chemistry, John Wiley & Sons, Springer Nature, the American Association for the Advancement of Science, and Oxford University Press. I would like to thank all inventors for patent literatures cited in this book.
Errors occasionally creep into any book, so it should not be surprising if you find mistakes in this one. If you do find any, feel free to discuss them with me. I would welcome any comments from readers, especially those suggestions that would make the book of greater value to the reader.
I would like to express my sincere gratitude to my mentors, students, and colleagues throughout my university studies, teaching, research, and career in the pharmaceutical industry.
I deeply appreciate Wiley editors Dr. Anne Brennführer, Priyadarshini Natarajan and Haridharini Velayoudame for helping me turning my ideas into this book.
Finally, I wish to thank my family members for their continual support and understanding.
Tongshuang Li
Hayward, CA, USA
June 2025
《付梓感怀》
菊花绽放深秋, 红梅香自苦寒。蒙父母言行教诲, 得各任恩师真传。集平生经历见闻, 受中西思想浇灌。融古今圣贤智慧, 于个人粗浅拙见。出首部学术专著, 甘愿做引玉之砖。意启迪同辈后生, 续科学创造新篇。限本人才疏学浅, 有错误纰漏难免。望各位专家学者, 不吝啬斧正纠偏！
《Reflections Upon My Manuscript’s Publication》
Chrysanthemums bloom proud in autumn’s snow,
Plum fragrance crystallizes winter’s blow.
Nurtured by parental virtues stern and bright,
Humbled beneath mentors’ scholarly light.
Ten thousand miles of wisdom fill my gaze,
East-West philosophies through my brush convey.
A hundred schools’ essence within me flows,
Lone quill stirs waves where silent paper glows.
May this crude work spark jade-carved replies,
To nurture magnolia beneath new skies.
Let younger waves surge where old currents crest,
Fresh voices shake academia’s hallowed nest.
Though keenly aware my borrowed insights show,
Joy finds me when errors meet your chisel’s glow.
Abbreviations
3CL protease
3-chymotrypsin-like protease
5-HT
5-hydroxytryptamine or serotonin
5-HT4
5-hydroxytryptamine receptor 4
ABN
2-aminobenzonitrile
ACC inhibitor
acetyl-CoA carboxylase inhibitor
AD
Alzheimer’s disease
ADC
antibody–drug conjugate
ADME
absorption, distribution, metabolism, and excretion
AI
artificial intelligence
AIDS
acquired immunodeficiency syndrome
ALK
anaplastic lymphoma kinase
AMPA
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
ANRORC
addition of the nucleophile, ring opening, and ring closure
APIs
active pharmaceutical ingredients
ATC
apricitabine
ATPase
adenosine 5′-triphosphatase
ATR
ataxia telangiectasia and Rad3-related
AUC
area under the plasma drug concentration–time curve
BACE
beta-amyloid cleaving enzyme
BCC
basal-cell carcinoma
BLA
biologic license application
BMS
Bristol–Myers Squibb Company
Boc
tert-butoxycarbonyl or tert-butyloxycarbonyl
BPR
back-pressure regulator
brsm
based on recovered starting material
BSA
N,O-bis-(trimethylsilyl)acetamide
BTK
Bruton’s tyrosine kinase
BTP
2-bromo-3,3,3-trifluoroprop-1-ene
BTPP
tert-butylimino-tri(pyrrolidino)phosphorane
Bus
tert-butylsulfonyl
CB1
cannabinoid receptor 1
CBC
cannanbichromene
CBTC
cannabicitran
Cbz
benzyl carbamate
Cbz-Cl
benzyl chloroformate
CCR5
cysteine-cysteine chemokine receptor 5
CD45
lymphocyte common antigen, a protein tyrosine phosphatase
CDI
carbonyldiimidazole
CFTR
cystic fibrosis transmembrane conductance regulator
cGMP
cyclic guanosine monophosphate-specific phosphodiesterase
Chk
checkpoint kinase
CMBP
cyanomethylenetributylphosphorane
CMC
chemistry, manufacturing, and controls
CNS
central nervous system
COVID-19
coronavirus disease 2019
COX
cyclooxygenase
CRF1
corticotropin-releasing factor receptor 1
CRO
contract research organization
CuAAC
Cu(I)-catalyzed azide-alkyne cycloaddition
CXCR4
C-X-C chemokine receptor type 4
CYP1A2
cytochrome P450 1A2
CYP2B6
cytochrome P450 2B6
CYP2C19
cytochrome P450 2C19
CYP2C9
cytochrome P450 2C9
CYP3A
cytochrome P450, family 3, subfamily A
DABCO
1,4-diazabicyclo[2.2.2]octane
DAST
diethylaminosulfur trifluoride
DBU
1,8-diazabicyclo[5.4.0]undec-7-ene
DCC
N,N′-dicyclohexylcarbodiimide
DCHU
N,N′-dicyclohexyl urea
DCM
dichloromethane
DDQ
2,3-dichloro-5,6-dicyano-1,4-benzoquinone
DEAD
diethyl azodicarboxylate
DCE
dichloroethane
DED
dry eye disease
Deoxo-Flour
bis(2-methoxyethyl)aminosulfur trifluoride
DEPT
distortionless enhancement by polarization transfer
DGAT-1
diacyl glycerolacyl transferase-1
DHA
dihydroartemisinin
DI
deionized
DIAD
diisopropyl azodicarboxylate
DIHD
diisopropyl hydrazine-1,2-dicarboxylate
DIPA
diisopropylamine
DIPEA
N,N-diisopropylethylamine
DMA
dimethylacetamide
DMAD
dimethyl acetylenedicarboxylate
DMAP
4-dimethylaminopyridine
DMB
2,4-dimethoxybenzyl
DMBNH2
2,4-dimethoxybenzylamine
DMF
dimethylformamide
DMF-DMA
N,N-dimethylformamide dimethyl acetal
DMMN
dimethylmalononitrile
DMPK
drug metabolism and pharmacokinetics
DMSO
dimethyl sulfoxide
DMTU
1,3-dimethylthiourea
DNA
deoxyribonucleic acid
DNBSA
2,4-dinitrobenzenesulfonamide
DOAC
direct oral anticoagulant
DOE
design of experiment
DPP4
dipeptidyl peptidase-4
DPPA
diphenylphosphoryl azide
DQF-COSY
double quantum-filtered COSY
ERR1
estrogen-related receptor 1
EUA
emergency use authorization
FAK
focal adhesion kinase
FCC
flush column chromatography
FDA
Food and Drug Administration of the United States
GAs
gibberellins
GC-MS
gas chromatography-mass spectrometry
GK-GKRP
glucokinase-glucokinase regulatory protein
GLP
Good Laboratory Practices
GMP
Good Manufacturing Practices
GPCR
G protein-coupled receptor
GPLR
G protein-linked receptor
GPR17
G protein-coupled receptor 17
H2L
hit to lead
HBTU
hexafluorophosphate benzotriazole tetramethyluronium
HCV
hepatitis C virus
HFIP
hexafluoroisopropanol
HIV
human immunodeficiency virus
HMG-CoA
3-hydroxy-3-methylglutaryl (HMG) coenzyme A
HPLC
high-performance liquid chromatography
HRMS
high-resolution mass spectrometry
HSDD
hypoactive sexual desire disorder
HTS
high-throughput screening
IND
Investigational New Drug Application
IP6K
inositol hexakisphosphate kinase
IUPAC
International Union of Pure and Applied Chemistry
JAK
Janus kinase
LED
light emitting diode
LNO
2,6-lutidine N-oxide
LO
lead optimization
LSF
late stage functionalization
MCL-1
myeloid cell leukemia-1
mCPBA
meta-chloroperoxybenzoic acid
MCR
multi-component reaction
MDM2
mouse double minute 2
MEK
mitogen-activated protein kinase
MMA
methyl methacrylate
MP
melting point
MRSA
methicillin-resistant
Staphylococcus aureus
MTBE
methyl tert-butylether, tert-butylmethyl ether
NBC
N-bromocaprolactam
NBS
N-bromosuccinimide
NCS
N-chlorosuccinimide
NDA
new drug application
NMM
N-methylmorpholine
NMP
N-methyl-2-pyrrolidone
NMPAC
National Medical Products Administration of China
NMR
nuclear magnetic resonance
NtRTI
nucleotide reverse transcriptase inhibitor
OA
orotic acid
OECD
Organization for Economic Cooperation and Development
OLM
olmesartan medoxomil
PARP
poly (ADP-ribose) polymerase
PD
pharmacodynamics
PDE IV
phosphodiesterase-4
PDE-V
phosphodiesterase V
PDGFR
platelet-derived growth factor receptors
PFA
perfluoroalkoxy, Teflon
®
PFA
PK
pharmacokinetics
Plk
polo-like kinase
Plk1
polo-like kinase 1
PNP
peripheral neuropathic pain
PPAR
peroxisome proliferator–activated receptor
PTFE
polytetrafluoroethylene
PTLC
preparative thin layer chromatography
QSAR
quantitative structure-activity relationship
RCM
ring-closing metathesis
RNA
ribonucleic acid
ROCK1
rho-associated kinase isoform 1
RRT
relative retention time
SAR
structure–activity relationship
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SHP2
Src homology-2 domain-containing protein tyrosine phosphatase-2
TBAF
tetra-n-butylammonium fluoride
TBDPS
tert-butyldiphenylsilyl
TBHP
tert-butyl hydroperoxide
TBME
tert-butylmethyl ether
t-BuONSO
N-sulfinyl-O-(tert-butyl)hydroxylamine
TEA
triethylamine
TFA
trifluoroacetic acid
TFAA
trifluoroacetic anhydride
THF
tetrahydrofuran
TIPS
triisopropylsilyl
TLC
thin layer chromatography
TMP
2,2,6,6-tetramethylpiperidine
TMSCl
trimethylsilyl chloride or chlorotrimethylsilane
TMSOTf
trimethylsilyl trifluoromethanesulfonate
TPP
tetraphenylporphyrin
TPS
tert-butyldiphenylsilyl, TBDPS
TRK
tropomyosin receptor kinase
TRPV1
transient receptor potential cation channel subfamily V member 1
TV
target validation
USP
upstream processing
UV
ultraviolet
VEGFR
vascular endothelial growth factor receptor
