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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5429_Библиотеки_им_академика_М_И_Перельмана
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Ribavirin 381
O
O
3
3
3
CH
O
O
OH
O
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Discussion. The ribavirin carboxamide is formed from the methyl ester in the final step. The three alcohols on the sugar are
released by transesterification. The C-N bond is formed by displacement of the C1 acetate of β- - ribofuranose 1,2,3,5- tetraacetate
by methyl 1,2,4- triazole- 3- carboxylate.
NH
2
HO
OH
N
N
N
HO
O
OH
OH
N
N
O
OH
O
OCH
3
N
O
3
N
N
O
O
O
O
O
CH
O
CH
CH
O
3
O
O
CH
O
3
O
O
O
O
CH
OCH
3
N
O
OCH
N
N
CH
N
3
H
O
3
Methyl 1,2,4- triazole- 3- carboxylate is formed from the carboxylic acid (Fischer Esterification). 1,2,4- Triazole-
3- carboxylic acid is formed from 5- amino- 1,2,4- triazole- 3- carboxylic acid via the diazonium salt. 5- Amino- 1,2,4- triazole-
3- carboxylic acid is formed by condensation of aminoguanidine bicarbonate with oxalic acid.
O
N
N
N
H
H
N NHNH
2
CH3OH
OCH
3
OH
N
N
N
H
O
NH
HO
OH
2
O
OH
N
N
2
N
N
H
H2N
N
N
N
H
Extended Discussion
Draw the structures of a retrosynthetic analysis of one alternative route to methyl 1,2,4- triazole- 3- carboxylate. 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 methyl 1,2,4- triazole- 3- carboxylate and select one route as the preferred route.
R382
CH
CH
3
3
CH
CH
CH
CH
CH
CH
3
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Rifabutin
Anti- infective Medicines/Antibacterials/Antituberculosis Medicines
3
CH3O
3
HO
O
CH
3
O
CH
O
CH
OH
CH
3
3
O
3
O
OH
3
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
O
O
NH
NH
N
CH
3
N
CH
CH
already in place. The rifamycins are often formed by
modification of rifamycin S. Rifamycin S is formed from
the fermentation product rifamycin B.
Discussion. Rifabutin is formed by reaction of 3-amino-4-deoxy-4-iminorifamycin S with 1- isobutyl- 4- piperidinone.
3- Amino- 4- deoxy- 4- iminorifamycin S is formed from 3- aminorifamycin S. 3- Aminorifamycin S is formed by b romide displacement from 3- bromorifamycin S. 3- Bromorifamycin S is formed by bromination of r ifamycin S.
3
CH3O
CH
3
CH
3
OH
3
O
3
HO
O
CH
3
O
CH
3
CH
OH
3
O
O
CH
3
O
OH
3
HO
O
CH
3
CH
3
CH3O
3
O
CH
3
O
O
CH
3
O
O
CH
NH
NH
N
N
OH
O
NH
3
O
CH
NH
NH
2
CH
3
CH
3
NO
CH
3
Rifabutin 383
rifamycin S
CH
CH
CH
CH
3
CH
CH
CH
3
rifamycin S
CH
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CH
3
CH3O
3
CH3O
3
HO
O
CH
3
O
CH
OH
CH
3
3
O
O
CH
O
CH
3
CH
3
OH
3
CH
3
HO
O
O
CH
3
O
O
CH
3
O
OH
OH
O
O
CH
O
O
3
HO
O
CH
O
CH
NH
NH
2
3
3
O
CH3O
CH
3
O
O
CH
3
3
CH
3
CH
3
OH
3
OH
3
O
O
CH
NH
Br
O
O
O
CH
3
NH
3
4
Rifamycin S is formed by hydrolysis of rifamycin O. Rifamycin O is formed by oxidation of rifamycin B. Rifamycin B is
produced by fermentation.
HO
O
3
CH3O
O
CH
O
O
CH
CH
OH
CH
3
3
3
3
3
OH
3
O
O
CH
NH
O
O
R384
3
CH
CH
3
CH
3
CH
CH
3
CH
CH
CH
rifamycin O
CH
CH
3
CH
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3
CH3O
CH
3
CH
3
OH
3
3
HO
O
CH
3
O
CH
OH
CH
3
3
O
OH
3
HO
O
CH
O
O
CH
NH
3
3
O
CH3O
CH
3
O
OH
OH
3
O
CH
NH
O
OO
O
CH
3
O
O
O
CH
3
rifamycin B
O
O
OH
Extended Discussion
Draw the structures of the retrosynthetic analysis of an alternative route to 3- aminorifamycin S. List the pros and cons for
both routes. Is one route preferred?
Rifampicin
Anti- infective Medicines/Antibacterials/Antituberculosis Medicines
3
CH3O
3
HO
O
CH
3
O
CH
O
CH
OH
CH
3
3
O
O
OH
OH
OH
3
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
O
NH
CH
3
N
N
N
CH
in place. The rifamycins are often formed by modification of rifamycin S. Rifamycin S is formed from the
f
ermentation product rifamycin B.
Discussion. The rifampicin hydrazone is formed by reaction of rifamycin oxazine with 1- amino- 4- methylpiperazine. Rifamycin
oxazine is formed by reaction of rifamycin S with 1,3,5- tri- tert- butylhexahydro- 1,3,5- triazine and paraformaldehyde.
3
CH3O
3
HO
O
O
CH
3
CH
CH
3
OH
3
O
O
CH
O
OH
OH
OH
3
O
CH
3
NH
N
N
N
CH
Rifampicin 385
rifamycin S
CH
CH
CH
CH
CH
3
rifamycin S
CH
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CH
3
CH3O
3
CH3O
3
HO
O
CH
3
CH
OH
3
O
OH
OH
3
O
CH
3
NH
CH
3
N
N
CH
CH
3
CH
3
CH
3
NCH
CH
3
CH
3
3
N
O
O
CH
3
CH
HO
O
CH
CH
OH
3
O
ONCH
O
CH
3
3
OH
3
O
O
CH
CH
3
CH
NH
CH
3
3
O
O
CH
3
O
4
O
O
H H
H2N
3
3
CH
CH
3
3
CH
N
3
3
3
Rifamycin S is formed by hydrolysis of rifamycin O. Rifamycin O is formed by oxidation of rifamycin B. Rifamycin B is
produced by fermentation.
3
CH3O
3
HO
O
CH
3
O
CH
OH
CH
3
3
O
O
CH
3
O
OH
3
O
O
CH
NH
O
R386
CH
CH
rifamycin O
CH
CH
3
CH
CH
CH
CH
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3
CH3O
3
HO
O
CH
3
O
CH
OH
CH
3
3
OH
3
O
CH
O
O
CH
NH
3
3
O
CH3O
O
OO
O
CH
3
O
O
O
Rifapentine
Anti- infective Medicines/Antibacterials/Antituberculosis Medicines
3
CH3O
3
HO
O
CH
3
OH
CH
OH
3
O
OH
3
O
CH
3
NH
HO
CH
CH
O
3
CH
OH
CH
3
3
rifamycin B
3
3
OH
OH
3
O
CH
NH
O
O
O
OH
CH
3
N
O
O
CH
3
OH
O
N
N
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. The rifamycins are often formed by modification of rifamycin S.
Rifamycin S is formed from the fermentation product rifamycin B.
Discussion. The rifapentine hydrazone is formed by the reaction of rifamycin oxazine with 1- amino- 4- cyclopentylpipera
zine. Rifamycin oxazine is formed by the reaction of rifamycin S with 1,3,5- tri- tert- butylhexahydro- 1,3,5- triazine and
paraformaldehyde.
Rifapentine 387
rifamycin S
CH
CH
CH
CH
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CH
3
CH3O
3
CH3O
O
3
HO
O
CH
3
OH
CH
OH
3
O
OH
3
O
CH
3
NH
CH
3
N
O
OH
CH
3
CH
CH
OH
O
CH
3
3
OH
3
O
OH
CH
3
HO
O
O
N
CH
N
3
NH
3
CH3O
CH
3
O
O
CH
3
CH
HO
O
CH
CH
OH
3
O
ONCH
O
CH
3
3
OH
3
O
O
CH
CH
3
CH
NH
CH
3
3
O
O
CH
3
O
4
O
O
H H
H2N
3
3
3
CH
N
CH
3
3
3
CH
N
CH
3
CH
3
N
NCH
CH
3
N
CH
3
CH
3
3
R388
CH
CH
rifamycin O
3
CH
2
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Rifamycin S is formed by hydrolysis of rifamycin O. Rifamycin O is formed by oxidation of rifamycin B. Rifamycin B is
produced by fermentation.
3
CH3O
CH
3
CH3O
3
HO
O
CH
3
O
CH
OH
CH
3
3
OH
3
O
O
CH
3
NH
O
O
CH
3
O
O
rifamycin S
CH
HO
O
CH
O
CH
OH
CH
3
3
CH
3
3
OH
3
HO
O
CH
O
O
CH
NH
3
3
O
CH3O
CH
CH
CH
OH
CH
3
3
CH
3
3
OH
OH
3
O
CH
NH
O
O
O
OO
O
CH
3
O
O
O
CH
3
rifamycin B
O
O
OH
1- Amino- 4- cyclopentylpiperazine is formed by reduction of the nitrosopiperazine. The nitrosopiperazine
is formed by nitrosation of 1- cyclopentylpiperazine. 1- Cyclopentylpiperazine is formed from cyclopentanone and
piperazine by reductive amination.
N
N
NH
N
N
NO
N
N
H
O
H
N
N
H
Risperidone 389
O
3
F
O
2
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Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to 1- cyclopentylpiperazine. 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 1- cyclopentylpiperazine.
Risperidone
Medicines for Mental and Behavioral Disorders/Medicines Used in Psychotic Disorders
N
Tertiary amines are ubiquitous in drug structures. A tertiary amine is often formed by alkylation of a secondary
O
N
N
CH
N
amine. The alkylation is most efficient when the amine
is used in excess and the carbon with the leaving group
(Cl, Br, I, OTs, OMs) is primary or benzylic.
Discussion. The tertiary amine is formed in the final step by chloride displacement by the piperidine. The 6,7,8,9- tetrahy
dro- 4H- pyrido[1,2- a]pyrimidin- 4- one is formed by reduction of the 4H- pyrido[1,2- a]pyrimidin- 4- one. 3- (2- Chloroethyl)-
2- methyl- 4H- pyrido[1,2- a]pyrimidin- 4- one is formed from 2- aminopyridine and α- acetyl- γ- butyrolactone (Pinner
Pyrimidine Synthesis
).
N
O
N
N
N
CH
O
N
3
F
O
N
N
The isoxazole ring of 6- fluoro- 3- (4- piperidinyl)benzo[d]isoxazole is formed by intramolecular displacement of fluoride by
the oxime. The oxime is formed from the ketone. The piperidine is released by amide hydrolysis. The ketone is formed from
1,3- difluorobenzene and the acid chloride (Friedel Crafts Acylation). The acid chloride is formed from the carboxylic
acid. 1- Acetylpiperidine- 4- carboxylic acid is formed by the reaction of piperidine- 4- carboxylic acid (isonipecotic acid) with
acetic anhydride.
HN
CH
F
O
Cl
3
N
N
CH
Cl
3
CH
O
3
N
O
O
NH
R390
O
3
3
OH
3
CH
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O
N
N F
HN
F
HN
F
O F
F
O
HN
O F
O
F
NO
CH
3
F
O
OH
OH
HN
CH
O
O
O
CH
CH
Cl
N
3
F
CH
N
3
O
Extended Discussion
Draw structures of a retrosynthetic analysis of one route to 1,3- difluorobenzene from petrochemical or biochemical raw
materials.
Ritonavir
Anti- infective Medicines/Antiviral Medicines/Antiretrovirals/Protease Inhibitors
Amides, carbamates, and ureas are often efficiently
formed from amines: an amide is formed by acylation
with an acid chloride, anhydride, ester or carboxylic
acid, a carbamate is formed by acylation with a
chloroformate or carbonate, and a urea is formed by
acylation with a carbamate.
N
CH
3
CH
S
N
O
CH
3
3
S
O
HN O
OH
N
CH
3
HN
H
N
O
Discussion. Disconnection of the C-N bonds of the amide, carbamate, and urea reveals the key components of ritonavir.
The two primary amines of (2S,3S,5S)- 2,5- diamino- 1,6- diphenylhexan- 3- ol suggest the N- protection–deprotection strategy
will be an important feature of an efficient ritonavir synthesis.
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