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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5671_Библиотеки_им_академика_М_И_Перельмана
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Clomifene
Cl
CH
CH
CH
Cl
HO
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Hormones, Other Endocrine Medicines and Contraceptives/Ovulation Inducers
An alkene conjugated to three aromatic rings is often
formed by dehydration of an alcohol.
CH
3
Clomifene 101
3
N
O
Discussion. Clomifene is manufactured as a mixture of the (E)- and (Z)- alkenes. The (E)- alkene, also called the trans-
alkene (refers to the relationship of the unsubstituted phenyl substituents), has the desired estrogenic activity. The chloroalkene is formed by chlorination and dehydrochlorination of the alkene in the final step. The alkene is formed by
dehydration of the tertiary alcohol. The tertiary alcohol is formed by addition of benzylmagnesium chloride to the ketone
(Grignard Reaction). Benzylmagnesium chloride is formed from benzyl chloride. The ether is formed by displacement of
chloride from 2-
3
3
chloro- N,N- diethylethanamine by 4- hydroxybenzophenone (Williamson Ether Synthesis).
ClCH
N
O
CH
CH
3
N
3
O
CH
3
N
3
CH
3
CH
N
3
OH
O
CH
CH
3
3
O
O
MgCl
N
Cl
O
C102
Cl
CH
3
10
11
CH
Cl
H
Cl
Cl
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Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to clomifene that does not involve a Grignard
Reaction. Include the structures of the retrosynthetic analysis of any organic starting material(s) from petrochemical or
biochemical raw materials.
Clomipramine
Medicines for Mental and Behavioral Disorders/Medicines Used for Obsessive Compulsive Disorders
membered rings are often formed by ring expansion of six-
Sevenmembered rings.
N
3
N
CH
Discussion. 3- Chloro- 10,11- dihydrodibenzo[b,f]azepine displaces chloride from 3- chloro- N,N- dimethylpropan- 1- amine
in the final step. The 10,11-
dihydrodibenzo[b,f]azepine is formed by reduction of 3- chlorodibenzo[b,f]azepine.
5
N
3
N
CH
3
3
Cl
CH
3
N
CH
N
H
3
Cl
Cl
N
H
The azepine ring is formed from (3- chloro- 9,10- dihydroacridin- 9- yl)methanol by a ring expansion. (3- Chloro- 9,10- dihyd
roacridin-
9- yl)methanol is formed by reduction of the ethyl 3- chloroacridine- 9- carboxylate. The ester is formed from the
acid chloride, the acid chloride from the acid, and the acid from the nitrile. The nitrile is formed by displacement of the
chloride at C9 of 3,9- dichloroacridine by cyanide. The reaction of 2- anilino- 4- chlorobenzoic with phosphorous oxychloride
results in formation of the acridine ring and replacement of the oxygen at C9 by chlorine. 2- Anilino- 4- chlorobenzoic acid
is formed from by displacement of the chloride at C2 of 2,4- dichlorobenzoic acid by aniline (Ullmann–Goldberg
Reaction).
HO
N
H
N
Cl
O
N
OCH2CH
3
Clopidogrel 103
S
O
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O
Cl
N
Cl
N
NaCN
Extended Discussion
Cl
Cl
HO
O
HN
OH
N
O
Cl
Cl
HO
NH
CN
N
O
Cl
2
Cl
Cl
Design a new synthesis of clomipramine using a transition metal- catalyzed reaction to form the azepine ring. Draw the
structures of the retrosynthetic analysis. Include the structures of the retrosynthetic analysis of any organic starting
material(s) from petrochemical or biochemical raw materials.
Clopidogrel
Cardiovascular Medicines/Antithrombotic Medicines/Anti- Platelet Medicines
Thiophene reacts with nthiophene is often formed by the reaction of 2electrophile.
Cl
H
N
OCH
3
Discussion. Clopidogrel, the (S)- enantiomer, is separated from the racemic mixture by resolution in the final step. The
byproduct mixture rich in the (R)- enantiomer is recycled: the (R)- enantiomer is converted back to the racemic mixture. The α-
amino ester is formed from the α- bromo ester by bromide displacement with 4,5,6,7- tetrahydrothieno[3,2- c]pyridine.
butyllithium to form 2- lithiothiophene. A 2- substituted
lithiothiophene with an
C104
3
S
O
S
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Cl
Cl
N
S
H
OCH
O
3
Cl
OCH
O
3
N
Br
NH
OCH
3
The α- bromo ester is formed by bromination of the ester. Methyl 2- chlorophenylacetate is formed by methoxycarbonylation of 2-
chlorobenzyl chloride.
O
Cl
Br Cl
OCH
O
3
OCH
3
Cl
Cl
CO
CH
OH
4,5,6,7- Tetrahydrothieno[3,2- c]pyridine is formed from 2- (thiophen- 2- yl)ethanamine and formaldehyde (Pictet–
Spengler Reaction). The amine is formed from the alcohol. (List all the options for reagents and conditions for this con-
version. List the yield associated with each option.) 2-(Thiophen-2-yl)ethanol is formed by reaction of thiophene with
ethylene oxide.
O
H H
O
NH
S
S
NH
2
S S
OH
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to clopidogrel. List the pros and cons for both
approaches and select one route as the preferred route.
Cloxacillin
3
3
O
O
HO
H
H
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Anti- Infective Medicines/Antibacterials/Beta- Lactam Medicines
Cloxacillin 105
Cl
Penicillins are produced by fermentation or are semisynthetic. A semisynthetic penicillin is often formed by acylation of the amine of
6-
aminopenicillanic acid (6- APA). 6- APA is produced from penicillin G
N
(benzylpenicillin) by enzyme-
mediated hydrolysis of the side- chain
amide.
H
S
N
CH
CH
OH
CH
H
N
3
O
O
Discussion. Cloxacillin is semisynthetic. The side- chain amide bond is formed in the final step by reaction of an amine
with an acid chloride. The amine, 6-
aminopenicillanic acid (6- APA), is formed by enzyme- mediated hydrolysis of the side
chain amide of penicillin G. Penicillin G (benzylpenicillin) is produced by the fungus P. chrysogenum.
The acid chloride is formed from the carboxylic acid. The carboxylic acid is formed by ester hydrolysis. Ethyl 3- (2- chlorophe
nyl)-
5- methylisoxazole- 4- carboxylate is formed by condensation of 2- chloro- N- hydroxybenzimidoyl chloride with ethyl ace-
toacetate. The benzimidoyl chloride is formed by chlorination of the oxime. The oxime is formed from 2-
Cl
O
CH
N
Cl
H2N
O
3
H
S
CH
3
N
O
6-APA
CH
3
OH
O
Cl
N
O
CH
3
H
H
N
O
O
S
CH
3
N
O
OH
CH
3
chlorobenzaldehyde.
Cl
N
O
CH
3
Cl
N
OH
O
Cl
N
O
CH
3
Cl
O
OCH2CH
O
HO
3
CH
Cl
N
Cl
O
O
3
OCH2CH
3
C106
Cl
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Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to 3- (2- chlorophenyl)- 5- methylisoxazole- 4- carb
oxylic acid. Include the structures of the retrosynthetic analysis of any organic starting material(s) from petrochemical or
biochemical raw materials. List the pros and cons for both routes and select one route as the preferred route.
Clotrimazole
Anti- Infective Medicines/Antifungal Medicines
N
A benzylic C─N bond is often formed by displacement of a leaving group by a nitrogen
nucleophile.
N
Discussion. Clotrimazole is manufactured in just two steps. A benzylic hydroxyl group is replaced by imidazole in the
final step. The benzyl alcohol, (2- chlorophenyl)diphenylmethanol, is formed from the benzyl chloride in the water workup
of the reaction of 2-
chlorobenzotrichloride with benzene (Friedel–Crafts Alkylation).
N
N
N
H
N
OH
CCl
3
Cl
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to (2- chlorophenyl)diphenylmethanol. List the
pros and cons for both routes and select one route as the preferred route.
Cl
Cl
Clozapine 107
H
CH
3
Cl
CH
Cl
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Clozapine
Medicines for Mental and Behavioral Disorders/Medicines Used in Psychotic Disorders
A 5H-dibenzo[b.e][1,4]diazepine is often formed from a diphenylamine.
N
N
N
N
Discussion. The C11 chloride of 8,11-dichloro-5H-dibenzo[b.e][1,4]diazepine is displaced by 1- methylpiperazine in the final
step. The imino chloride is formed from the amide. The diazepine ring is formed when the amide is formed from the amine and
carboxylic acid. The amine is formed by nitro group reduction. The diphenylamine is formed by displacement of halide (X=Cl,
Br) from 1,4Reaction). (Draw structures for the retrosynthetic analysis of 1chemical raw materials.)
dichloro- 2- nitrobenzene or 1- bromo- 4- chloro- 2- nitrobenzene by anthranilic acid (Ullmann–Goldberg
bromo- 4- chloro- 2- nitrobenzene from petrochemical or bio-
Cl
3
N
N
N
HN
NO
N
H
O
N
H
O
OH
2
Cl
CH
N
N
H
Cl
3
Cl
N
Cl
N
H
O
NH
Cl
NO
2
OH
2
N
H
O
HO
N
H
X
X=Cl,Br
H2N
C108
CH3O
HO
3
CH
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Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to clozapine which does not use anthranilic
acid as a starting material. Include the structures of the retrosynthetic analysis of any organic starting material(s)
from petrochemical or biochemical raw materials. List the pros and cons for both routes and select one route as the
preferred route.
Codeine
Medicines for Pain and Palliative Care/Opioid Analgesics
A single- enantiomer molecule with multiple chiral carbons is often formed by
modification of a natural product which has most or all of the chiral carbons
already in place.
O
N
H
CH
Discussion. Codeine is an opium poppy alkaloid but most codeine is manufactured by O- methylation of another opium poppy
alkaloid, morphine. Morphine has three sites likely to react with iodomethane or dimethyl sulfate. Selective Oaccomplished with trimethylphenylammonium chloride. (N,N-
dimethylaniline separated from codeine?) Trimethylphenylammonium chloride is formed from N,N- dimethylaniline and
N,N-
Dimethylaniline is a byproduct of the O- methylation. How is
methylation is
chloromethane.
CH3Cl
CH
O
3
N
H
HO
CH
HO
2
O
3
HO
10
morphine
CH
N
H
CH
3
3
3
CH
3
N
Cl
CH
3
CH
3
N
Extended Discussion
Morphine is prone to oxidation. Draw the structures of three impurities in codeine which result from morphine
oxidation.
Colecalciferol
HO
CH
3
HO
CH
3
cholesterol
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Vitamins and Minerals
Colecalciferol 109
CH
3
3
H
CH
CH
3
A singleoften formed by modification of a natural product which has
most or all of the chiral carbons already in place.
enantiomer molecule with multiple chiral carbons is
H
Discussion. Colecalciferol (cholecalciferol, vitamin D3) is a semisynthetic secosteroid (seco from Latin secare “to cut”).
Colecalciferol is produced by cleavage of the B-
3
CH
3
H
9
8
H
7
19
3
1
CH
HO
ring of the steroid natural product cholesterol.
CH
3
3
19
CH
3
1
3
9
H
CH
3
CH
3
H
H
8
H
7
CH
CH
3
Colecalciferol (vitamin D3) is formed from pre- vitamin D3. Pre- vitamin D3 is formed by UV- photoirradiation of pro- vitamin
(7- dehydrocholesterol). Low conversion in the UV- photoirradiation step minimizes the formation of two side products.
D
3
(Draw structures for and name these side products. How is 7- dehydrocholesterol separated from the UV- photoirradiation
product mixture?) 7- Dehydrocholesterol is formed by hydrolysis of the ester of 7- dehydrocholesteryl benzoate.
C110
3
O
Ph
H
CH
3
H
CH
Ph
3
RouteA
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3
CH
3
H
H
CH
CH
3
3
CH
3
CH
CH
3
3
H
CH
CH
3
H
O
CH
3
CH
3
CH
3
H H
O
pro-vitamin D
7-dehydrocholesterol
HO
pro-vitamin D
CH
CH
3
3
CH
3
H
3
CH
CH
3
3
3
H
CH
CH
3
O
H H
There are two routes to 7- dehydrocholesteryl benzoate from cholesterol. In Route A, the 7,8- alkene is formed from the
p- toluenesulfonyl hydrazone (Bamford–Stevens Reaction). The hydrazone is formed from 7- oxocholesteryl benzoate
7(7-
ketocholesteryl benzoate) and p- toluenesulfonyl hydrazide. 7- Oxocholesteryl benzoate is formed by oxidation of choles-
teryl benzoate. Cholesteryl benzoate is formed from cholesterol.
3
CH
3
CH
3
CH
3
3
H
H H
CH
3
CH
3
NH
NHSO2Ar
CH
CH
3
H
H
CH
3
O
CH
H H
O
O
Ph
O
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