Chemistry and creativity: Advanced Practical Medicinal Chemistry
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Advanced Practical Medicinal Chemistry
The ‘art and skill’ for the preparation of ‘newer drug molecules’ is a pivotal creative and anexceptionally great intellectual exercise that essentially serves as a fulcrum to plethora of specificareas of scientific research, ranging from the most applied to the most academic. Accordingly,
the medicinal chemist, organic chemist, biologist, pharmacologist, biochemist,
biotechnologist, phytochemist, genetic engineer, materials scientist, and polymer scientist, in
an university or an industry, all must have genuinely encountered with the most challenging
and intricate task of performing a reaction ultimately leading to an entirely new organic preparation
exhibiting certain specific actions on the biological system to combat diseases in the
ailing human beings.
Invariably, the wonderful ‘magic’ of modern organic synthesis, based on host of documented
theories, hypothesis, organic name reactions (ONRs) amalgamated with logistic, scientific
and assertive reaction mechanism(s), in fact, genuinely paved the way of complicated, notso-
easy, cumbersome course of reactions much simpler and understandable.
The advent of ever-more sophisticated and many supportive modern analytical techniques,
such as : UV, IR, NMR, MS, ORD, CD, AAS, FES, GC, HPLC and the hyphenated
techniques as well, have tremendously enhanced the confidence of medicinal chemists to such a
magnitude as to maximize both the chances of success rate and probability factor.
Besides, the use of organic and inorganic chemicals employed as reactants, catalysts,
medium of reaction, purifying substances etc., are not only harmful but also hazardous in nature.
Nevertheless, the various conditionalities of critical and specific reactions are sometimes
articulated and spelled out so meticulously that one has to follow them just like ‘gospel truth’,
to accomplish the right synthesis, and hence, the right product.
It is, however, pertinent to mention here that the UG and PG students, associated with
the myth and reality of ‘drug synthesis’ should make an honest attempt to carry out a particular
synthesis of a drug substance with a most tried and tested methodical, scientific and rational
approach, so that one may get reproducible results under a particular reaction in a seamless
manner.
The copious volumes of textbooks, scientific research journals, monographs, review articles
on related topics like : organic chemistry of drug synthesis, chiral chemistry, drug design,
principles of medicinal chemistry, organic medicinal and pharmaceutical chemistry, and medicinal
chemistry provide ample evidence and scope to suggest that the comprehensive in-depth
knowledge together with utmost specialized state-of-the-art know-how of the various techniques
is an absolute necessity and basic requirement to have a real understanding with regard to the
practical aspects of ‘Medicinal Chemistry’.
In ‘Advanced Practical Medicinal Chemistry’, an attempt has been made to stress
the much needed requirement of both undergraduate and graduate students specializing in the
field of Pharmaceutical Chemistry to learn how to synthesize ‘drugs’ in the laboratory. Unfortunately,
the common available textbooks ordinarily referred to by the Pharmacy Students
mostly deal with the synthesis of pure ‘organic compounds’ ; and hence, do not provide the
real and much needed subject matter relevant to a budding ‘Medicinal Chemist’.
The ‘Advanced Practical Medicinal Chemistry’ comprises of four major chapters
that are intimately associated with specific emphasis on the synthesis of a broad range of some
typical and selected ‘drugs’ commonly found in the therapeutic armamentarium.
Chapter-1 deals with ‘Safety in a Chemical Laboratory‘. It consists of various aspects,
namely : guard against personal safety ; conduct in a chemistry laboratory ; neatness and cleanliness
; after-hours working ; guidelines for accident or injury ; storage of chemicals/reagents in
a chemical laboratory ; glass ware ; waste disposal ; an ideal chemistry laboratory ; and toxicity
and hazards of chemicals/reagents.
Chapter-2 consists of ‘Drug Synthesis’. First, aspect being—‘Conceptualization of a Synthesis‘
viz., prime considerations in designing synthesis ; the Synthon Approach ; reaction
specificity. Secondly, Reaction Variants, viz., structural variants ; interchangeability of functional
moiety ; selectivity in reactions ; protection of functional moieties ; elimination of functional
moieties ; annealation reactions ; fragmentation reactions. Thirdly, Stereochemistry, viz.,
nucleophilic substitutions (SN2), ionic additions to C-C double bonds ; catalytic hydrogenation ;
acid or base promoted enolization of compounds, reductions of cyclohexane ; and cycloadditions.
Chapter-3 comprises of ‘Performing the Reactions’. The wide range of latest laboratory
techniques invariably employed in a reasonably well equipped chemical research laboratory or
a chemical laboratory for actually performing the specifically desired reactions and other equally
important operational measures have been dealt with in an explicit and lucid manner. The
various aspects included in this chapter are, namely : solvent stills (with continuous still collecting
head)-reactions performed at elevated temperatures-large scale reaction and slow addition
of reagents-low temperature reactions-reaction above room temperature using a condensermechanical
stirrer-mechanical shaker-crystallization at low temperature-distillation under reduced
pressure-small scale distillation-performing the reaction, and -photolysis.
Chapter-4 i.e., the last chapter, has been exclusively devoted to—‘Synthesis of Medicinal
Compounds’ which vary in length from the single-stage reaction to the multi-stage or projecttype
synthesis. In fact, it is the backbone of the present textbook and specially designed to
inculcate the sense of creativity, learning the art of synthesis, and above all inject the spirit of
zeal and enthusiasm amongst the ‘medicinal chemists’ to tackle most synthesis-related problems
with great ease, confidence and fervour. It embraces ‘three’ specific areas of interest
confined to the ‘synthesis of drugs’, such as :
(a) Types of Chemical Reactions e.g., acetylation methods-benzoylation methodssulphonation
methods-bromination methods-condensation reactions ; and diazotization and
coupling reactions ;
(b) Organic Name Reactions (ONRs) e.g., Bart reaction-Diel’s-Alder reaction-Friedel-
Craft’s reaction-Fries reaction-Grignard reaction-Hoesch reaction-Perkin reaction-Mannich
reaction-Michael reaction, and Reimer-Tieman reaction ;
(c) Selected Medicinal Compounds : It includes the synthesis of forty selected medicinal
compounds having a wide variety of therapeutic action(s).
An intensive and extensive care has been exercised painstakingly and meticulously to
discuss in details each and every medicinal compound under the above mentioned three categories
i.e., (a) through (c) in a particular original style of presentation that essentially includes :
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chemical structure-synonym(s)/chemical name(s)-theory-chemicals required-procedure-precautions-
recrystallization-theoretical yield/practical yield-physical parameters-uses, and -questions
for viva-voce.
A subtle, but no less profound effect of this completely new approach as given in the
‘Advanced Practical Medicinal Chemistry’ comprising of syntheses totalling eighty selected
‘drug substances’ would not only benefit the undergraduate and graduate students in
Pharmaceutical Chemistry in Indian Universities and other developing countries as well, but
also go a along way to help the esteemed teachers involved in the handling of such courses who
always genuinely felt the dire necessity of such a compilation for the ‘academics’ in particular.
The ‘medicinal chemists’ involved in ‘Bulk Drug Manufacturing Operations’ may also
find this presentation as a handy reference book in the domain of their ever expanding and
demanding profession.
In case, the above outlined objectives have been duly achieved, actual users of this textbook
must be able to accomplish their synthetic problems with greater ease and confidence.
Synthesis of ‘Medicinal Compounds’ is not only satisfying but also exciting, and provides an
ample opportunity to explore an individual’s inherent talent and enormous strength of ‘real
creativities’
Ashutosh Kar
Advanced Practical Medicinal Chemistry
1.1. Introduction 1
1.2. Guard Against Personal Safety 2
1.2.1. Protective Coat 2
1.2.2. Protection for Eyes 2
1.2.3. Conduct in a Chemistry Laboratory 3
1.2.4. Neatness and Cleanliness 3
1.2.5. After-Hours Working 6
1.2.6. Guidelines for Accident or Injury 6
1.2.7. Storage of Chemicals/Reagents in a Chemical Laboratory 7
1.2.8. Glassware 8
1.2.9. Waste Disposal 9
1.2.10. An Ideal Chemistry Laboratory 9
1.2.11. Toxicity and Hazards of Chemicals Reagents 10
2.1. Introduction 15
2.2. Conceptualization of a Synthesis 15
2.2.1. Prime Considerations in Designing Synthesis 16
2.2.2. The Synthon Approach 17
2.2.3. The Retro-Synthetic Approach 18
2.2.4. Materials Required 19
2.2.5. Reaction Specificity 20
2.2.6. Purity and Yield 21
2.3. Reaction Variants 21
2.3.1. Structural Variants 21
2.3.2. Interchangeability of Functional Moiety 22
2.3.3. Selectivity in Reactions 27
2.3.4. Protection of Functional Moieties 28
2.3.5. Elimination of Functional Moieties 31
2.3.6. Annelation Reactions 32
2.3.7. Fragmentation Reactions 34
2.4. Stereochemistry 37
2.4.1. The Chiral Centre 37
2.5. Summary 43
3.1. Introduction 45
I. Solvent Stills 46
II. Reactions Performed at Elevated Temperatures 49
III. Large Scale Reactions and Slow Addition of Reagents 50
IV. Low Temperature Reactions 50
V. Reactions above Room Temperature Using a Condenser 54
VI. Mechanical Stirrers 56
VII. Mechanical Shakers 57
VIII. Sonication 58
IX. Crystallization at Low Temperature 59
X. Distillation Under Reduced Pressure 60
XI. Small Scale Distillation 62
XII. Performing the Reaction 62
XIII. Photolysis 64
4.1. Acetylation Methods 67
4.1.1. Introduction 67
4.1.2. Synthesis of Medicinal Compounds 71
4.1.2.1. Acetanilide 71
4.1.2.2. Aspririn 75
4.1.2.3. Acetylacetone 80
4.1.2.4. Phenacetein 83
4.1.2.5. Acetylcysteine 86
4.1.2.6. Paracetamol 88
4.2. Benzoylation Methods 90
4.2.1. Introduction 90
4.2.2. Synthesis of Medicinal Compounds 93
4.2.2.1. Benzoyl Glycine 93
4.2.2.2. N-Benzoyl-beta-alanine 95
4.2.2.3. Flavone 97
4.2.2.4. Benzoyl Peroxide 100
4.2.2.5. Benzoyl Benzoate 103
4.3. Sulphonylation Methods 105
4.3.1. Introduction 105
4.3.1.1. Similarity with Benzoylation 106
4.3.1.2. Dissimilarity with Benzoylation 106
4.3.2. Synthesis of Medicinal Compounds 107
4.3.2.1. Dichloramine-T 108
4.3.2.2. Chloramine-T 112
4.4. Bromination Methods 115
4.4.1. Introduction 115
4.4.1.1. Mechanism of Bromination 115
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4.4.2. Synthesis of Medicinal Compounds 116
4.4.2.1. para-Bromoacetanilide 116
4.4.2.2. para-Bromophenol 118
4.4.2.3. 2′, 4′, 5′, 7′-Tetrabromofluorescein 121
4.5. Condensation Reactions 125
4.5.1. Claisen Condensation 125
4.5.2. Sorbic Acid 128
4.5.3. Pechman Condensation 130
4.6. Diazotization and Coupling Reactions 133
4.6.1. Phenyl-azo-beta-naphthol 136
4.6.2. 5-Diazouracil 139
4.6.3. Dimethyl-p-phenylenediamine 140
4.7. Organic Name Reactions (ONRs) 145
4.7.1. Bart Reaction 145
4.7.1.1. Phenylarsonic Acid 146
4.7.2. Diels-Alder Reaction 149
4.7.2.1. 9, 10-Dihydroanthracene-9, 10-endo-αβ-succinic anhydride 150
4.7.3. Friedal-Craft’s Reaction 150
4.7.3.1. Acetophenone 153
4.7.3.2. p-Methylacetophenone 158
4.7.3.3. Anthrone 160
4.7.4. Frie’s Reaction 165
4.7.4.1. p-Hydroxypropiophenone 166
4.7.5. Grignard Reaction 168
4.7.5.1. Benzoic acid 169
4.7.5.2. Triphenylcarbinol 172
4.7.6. Hoesch Reaction (or Houben-Hoesch Reaction) 175
4.7.6.1. Floropione 176
4.7.6.2. Resacetophenone 179
4.7.7. Perkin Reaction 181
4.7.7.1. Cinnamic acid 182
4.7.7.2. Coumarin 185
4.7.8. Mannich Reaction 187
4.7.8.1. Metamfepramone 188
4.7.8.2. Garmine 190
4.7.9. Michael Reaction 192
4.7.9.1. 5, 5-Dimethyl-1, 3-cyclohexanedione 193
4.7.9.2. Tricarballylic Acid 195
4.7.10. Reiner-Tiemann Reaction 200
4.7.10.1. para-Anisaldehyde 201
4.7.10.2. Salicylaldehyde 203
4.8. Selected Medicinal Compounds 206
4.8.1. Acyclovir 207
4.8.2. Acetaminophen 209
4.8.3. Busulfan 211
4.8.4. Buthiazide 213
4.8.5. Benzocaine 216
4.8.6. Coumarin-3-carboxylic acid 221
4.8.7. Chlormezanone 226
4.8.8. Chlorpropamide 229
4.8.9. Clotrimazole 231
4.8.10. Diazoxide 233
4.8.11. Diclofenac Sodium 236
4.8.12. 5, 5-Diphenyl Hydantoin (Phenytoin) Sodium 239
4.8.13. Ethamivan 242
4.8.14. Etofylline Clofibrate 243
4.8.15. Fenbufen 246
4.8.16. Flumethiazide 248
4.8.17. Guaifensin 250
4.8.18. Guanethidine Sulphate 252
4.8.19. Haloprogin 255
4.8.20. Hepronicate 257
4.8.21. Indomethacin 259
4.8.22. Isocarboxazid 262
4.8.23. Isoniazid 264
4.8.24. Ketotifen 266
4.8.25. Loxapine 269
4.8.26. Mazindol 272
4.8.27. Methyldopa 275
4.8.28. Metronidazole 277
4.8.29. Naproxen 279
4.8.30. Niclosamide 281
4.8.31. Oxaceprol 283
4.8.32. Oxyfedrine 285
4.8.33. Phensuximide 286
4.8.34. Povidone Iodine 288
4.8.35. Ritodrine 290
4.8.36. Simethicone 292
4.8.37. Ticrynafen 294
4.8.38. Tocainide 298
4.8.39. Trimethoprim 300
4.8.40. Zipeprol 304
