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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5949_Библиотеки_им_академика_М_И_Перельмана
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HO
O
SH
OH
OH
HO
HO
H
O
O
N
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Sulfadiazine and Silver Sulfadiazine 411
OH
O S
S
O
O
S
O O
S
O
OH
OH
SH
O S
HO
HO
HO OH
S
S
O
O
O
O
O O
S
O
OH
OH
O
HO
HO
O S
S
O
O
S
O O
S
O
Extended Discussion
Hydrogen sulfide is a poisonous, flammable, and corrosive gas. List alternative sulfur- containing reagents used to
make thiols.
Sulfadiazine and Silver Sulfadiazine
Anti- infective Medicines/Antiprotozoal Medicines/Antipneumocystosis and Antitoxoplasmosis Medicines
Dermatological Medicines(topical)/Anti- infective Medicines
O
N S
2
AgN
A sulfonamide is often formed by the reaction of a sulfonyl chloride with an amine.
Discussion. Silver sulfadiazine is formed from sulfadiazine. The amino group of sulfadiazine is released in the final step by
hydrolysis of the acetamide. The sulfonamine is formed by a reaction of 4- acetylaminobenzenesulfonyl chloride
(N- acetylsulfanilyl chloride) with 2- aminopyrimidine.
O
N
N
H2N S
N
HN
S412
O
N
CH
O
N
OCH
H2N
OCH
H
N
OCH
H
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O
S
N
HN
N
H2N
S
AgN
O
N
H2N
N
O
O
3
HN
O
O
S
N
CH
3
HN
HN
O
O
S
N
Cl
H2N
N
Extended Discussion
Draw the structures of the retrosynthetic analysis of an alternative route to sulfadiazine from 4- nitrobenzenesulfonyl chloride (nosyl chloride). Include the structures of the retrosynthetic analysis of nosyl chloride from petrochemical or biochemical raw materials. List the pros and cons for both routes and select one route as the preferred route.
Sulfadoxine
Anti- infective Medicines/Antiprotozoal Medicines/Antimalarial Medicines/For Curative Treatment
3
CH3O
O O
S
N
N
H
A sulfonamide is often formed by reaction of a sulfonyl chloride with an amine.
Discussion. The amino group of sulfadoxine is released in the final step by hydrolysis of the acetamide. The sulfonamine is
formed by the reaction of the aminopyrimidine with 4- acetylaminobenzenesulfonyl chloride (N- acetylsulfanilyl chloride).
3
CH3O
O O
N
S
N
H
N
O
N
2
CH
3
N
H
CH3O
O O
S
N
H
OCH
3
O Cl
CH
3
N
O O
S
CH3O
H2N
N
N
3
N
Sulfamethoxazole 413
N
3
CH
H
3
O
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4- Amino- 5,6- dimethoxypyrimidine is formed from 4,6- dichloro- 5- methoxypyrimidine by displacement of one chloride by
ammonia then displacement of the remaining chloride by methanol. The 4,6- dichloropyrimidine is formed from
the pyrimidine- 4,6- dione. 5- Methoxy- 4,6- pyrimidinedione is formed by the reaction of dimethyl methoxymalonate with formamidine acetate (Pinner Pyrimidine Synthesis). Dimethyl methoxymalonate is formed in two steps from methyl methoxyacetate and dimethyl oxalate (mixed Claisen Condensation).
3
H2N
O
CH3O
OCH
3
CH3OH
CH3O
H2N
3
NH
H2N
OCH
3
N
N
O
O
OCH
Cl
N
N
CH3O
O
H
CH3O
Cl N
O
OCH
O
OCH
3
Cl
CH3O
O
OCH
CH3O
O
3
OCH
N
N
3
O
H
O
OCH
3
O
Extended Discussion
Draw the structures of a retrosynthetic analysis of an alternative route to sulfadoxine from 4- aminobenzenesulfonamide (sulfanilamide). Include the structures of the retrosynthetic analysis of sulfanilamide from petrochemical or biochemical raw
materials. List the pros and cons for both routes. Is one route preferred?
Sulfamethoxazole
Anti- infective Medicines/Antibacterials/Other Antibacterials
Anti- infective Medicines/Antiprotozoal Medicines/Antipneumocystosis and Antitoxoplasmosis Medicines
N
2
Discussion. The amino group of sulfamethoxazole is released in the final step by hydrolysis of the acetamide. The sulfonamide is formed by the reaction of 3- amino- 5- methylisoxazole with 4- acetylaminobenzenesulfonyl chloride (N- acetylsulfanilyl
chloride).
O
S
HN
N
O
CH
A 3- aminoisoxazole is often formed by Hofmann Rearrangement of a
carboxamide.
S414
OCH2CH
O
O
CH
H
O
3
O
3
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O
N
2
S
HN
HN S
CH
3
O
N
O
CH
3
O
O
Cl
HN S
CH
3
O
H2N
N
O
CH
HN
O
N
O
CH
3- Amino- 5- methylisoxazole is formed by hydrolysis of the ethyl carbamate. The ethyl carbamate is formed from the amide
(Hofmann Rearrangement). The amide is formed from the ester. Ethyl 5- methylisoxazole- 3- carboxylate is formed from ethyl
2,4- dioxopentanoate (ethyl acetopyruvate). Ethyl acetopyruvate is formed by the condensation of acetone with diethyl oxalate
(mixed Claisen Condensation).
3
NH
2
HN
O
N
3
O
CH
3
N
O
CH
3
O
NH
2
N
CH
3
O
N
OCH2CH
3
CH
O O
3
O
OCH2CH
3
CH
O
3
CH
3
CH3CH2O
O
OCH2CH
3
O
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to 3- amino- 5- methylisoxazole. 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 to 3- amino- 5- methylisoxazole and select one route as the preferred route.
Sulfasalazine
OH
HO
3
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Gastrointestinal Medicines/Anti- inflammatory Medicines
Sulfasalazine 415
O
O
N
S
NH
N
N
An azo compound is often formed by the coupling of an aromatic
diazonium salt with a phenol or aniline.
O
Discussion. The azo compound is formed in the final step by azo coupling of the diazonium salt with the essential medicine salicylic acid. The diazonium salt is formed from the aniline (sulfapyridine). The amino group of sulfapyridine is released by hydrolysis
of the acetamide. The sulfonamide is formed by reaction of 2- aminopyridine with 4- acetylaminobenzenesulfonyl chloride
(N- acetylsulfanilyl chloride).
O
O
N
S
N
N
NH
HO
O
X
O
N
S
N N
NH
OH
O
OH
O
HO
N
O
O
S
NH
sulfapyridine
NH
2
N
NH
2
N
O
O
S
Cl
O
O
S
NH
NH
CH
O
NH
CH
3
O
Extended Discussion
Draw the structures of a retrosynthetic analysis of an alternative route to sulfasalazine from 2- bromopyridine. List the pros
and cons for both routes and select one route as the preferred route.
S416
CH
CH
H
HO
CH
CH
H
HO
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Suramin
Anti- infective Medicines/Antiprotozoal Medicines/Antitrypanosomal Medicines/African Trypanosomiasis/
Medicines for the Treatment of First Stage African Trypanosomiasis
3
O
N
O
NH
S
3
SO3H
H
SO3H
H
H
N
N
O
3
O
N
H
HO3S
HO3S
HN
O
SO
3
A symmetrical urea is often efficiently formed by the reaction of an amine with phosgene.
Discussion. The final step in the “outside- in” synthesis of suramin is the formation of the symmetrical urea by the reaction of the amine with phosgene.
3
O
N
O
H
H
H
N
N
O
O
NH
3
N
H
O
HN
SO3H
S
3
SO3H
HO3S
HO3S
SO
3
O
CH
HO3S
NH
3
O
HN
Cl
O
Cl
SO3H
NH
2
HO3S
The 3- aminobenzamide is formed by reduction of the 3- nitrobenzamide. The 3- nitrobenzamide is formed from the amine
and 3- nitrobenzoyl chloride. The 3- amino- 4- methylbenzamide is formed by reduction of the 4- methyl- 3- nitrobenzamide. The
4- methyl- 3- nitrobenzamide is formed from the amine and 4- methyl- 3- nitrobenzoyl chloride. 8- Aminonaphthalene- 1,3,5- trisul
fonic acid is formed by the reduction of 8- nitronaphthalene- 1,3,5- trisulfonic acid. 8- Nitronaphthalene- 1,3,5- trisulfonic acid is
formed by nitration of naphthalene- 1,3,5- trisulfonic acid.
HO
S
2
O
HO
O
Cl
Cl
O
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3
HO3S
O
NH
SO3H
HN
CH
Suramin 417
CH
3
O
HO3S
NH
3
O
HN
SO3H
NH
2
NO
HO3S
O
CH
3
HO3S
HO3S
S NO
3
HO3S
NH
SO3H
NH
2
SO3H
NH
2
O
NO
Cl
2
HO3S
CH
3
Cl
NO
2
HO3S
HO3S
HO3S
2
SO3H
O
NH
SO3H
HO3S
HO3S
NO
CH
2
SO3H
3
3- Nitrobenzoyl chloride is formed from 3- nitrobenzoic acid. 4- Methyl- 3- nitrobenzoyl chloride is formed from 4-methyl-
3-nitrobenzoic acid.
O
NO
CH
NO
O
NO
CH
NO
2
3
2
2
HO
3
HO
2
O
S418
CH
3
3
3
CH
CH
O
CH
O
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Suxamethonium Chloride
Muscle Relaxants (Peripherally- Acting) and Cholinesterase Inhibitors
3
3
N
3
Cl
O
O
O
Cl
CH
N
CH
CH
Esters are common in drug structures and intermediates
leading to drug structures. An ester is often formed from
an alcohol and acid chloride, anhydride, another ester,
or a carboxylic acid.
Discussion. The quaternary ammonium salt is formed in the final step by alkylation of the tertiary amine with chloromethane.
The succinic acid diester is formed by transesterification from dimethyl succinate and 2- dimethylaminoethanol.
CH
CH
CH
CH
3
3
N
3
O
Cl
CH
3
O
N
3
O
O
O
O
O
Cl
CH
3
N
CH
3
CH
3
CH3Cl
CH
3
N
CH
3
O
O
OCH
3
HO
3
O
N
CH
CH
3
3
Extended Discussion
Draw the structures of the retrosynthetic analysis of an alternative route to suxamethonium chloride from succinyl chloride. List the pros and cons for both routes and select one route as the preferred route.
CH
3
T
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Tamoxifen
Antineoplastics and Immunosuppressives/Hormones and Antihormones
An alkene conjugated to three aromatic rings is often
O
CH
N
formed by dehydration of an alcohol.
419
3
CH
3
Discussion. Tamoxifen is the (Z)- or trans- alkene. Tamoxifen is crystallized from the mixture of (E)- and (Z)- alkenes.
Tamoxifen is then also formed by isomerization of the (E)-
alkene. The mixture of (E)- and (Z)- alkenes is formed by dehydration of a tertiary alcohol. The tertiary alcohol is formed by the addition of an arylmagnesium bromide to 1,2-Diphenyl1-butanone (Grignard Reaction).
Routes to Essential Medicines: A Workbook for Organic Synthesis, First Edition. Peter J. Harrington.
© 2022 John Wiley & Sons, Inc. Published 2022 by John Wiley & Sons, Inc.
Companion website: www.wiley.com/go/Harrington/routes_essential_medicine
T420
CH
CH
3
Br
CH
3
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O
3
N
CH
CH
3
O
CH
N
CH
3
3
CH
3
O
O
3
OH
N
CH
CH
3
3
CH
BrMg
3
O
N
CH
CH
3
3
The arylmagnesium bromide is formed from 2- (4- bromophenoxy)- N,N- dimethylethanamine. The ether C─O bond is
formed by chloride displacement from 2-
chloro- N,N- dimethylethanamine by 4- bromophenol (Williamson Ether
Synthesis).
3
N
Mg
Cl
O
N
CH
CH
3
3
Br
O
N
CH
CH
3
3
CH
OH
3
Br
1,2-Diphenyl-1-butanone is formed by α–alkylation of2- phenylacetophenone (deoxybenzoin) with bromoethane.
O
CH
O
CH3CH
Br
2
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