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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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Anastrozole 21
O
NH
Cl
HCl
3
CH
N
N
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OCH2CH
OCH2CH
3
3
O
CH
O
3
O
OCH2CH
3
O
NH
2
OH
O
CH
CH
3
3
NH
CH
3
CH
3
NH
OK
O
CH
3
O
O
CH
O
3
CH
3
Cl
CH
3
Extended Discussion
Ampicillin is also manufactured from 6- APA and the acid chloride, (R)- α- phenylglycine chloride hydrochloride. List the
pros and cons for both routes and select one route as the preferred route.
2
O
Anastrozole
Antineoplastics and Immunosuppressives/Hormones and Antihormones
CH
3
3
C
N
N
C
N
CH
3
CH
Discussion. Each substituent on the central ring of anastrozole has a functional group (cyanide or 1,2,4- triazole) which is
likely introduced as a nucleophile. These features suggest disconnection strategies which have statistical product distribution
problems. In a preferred strategy, the most significant problem is addressed in the preparation of the starting material.
Bromide is displaced by 1,2,4- triazole in the final step. The bromomethyl group is formed by bromination of the methyl
group.
A phenylacetonitrile is often formed by displacement of a benzyl
chloride or bromide by cyanide.
A22
CN
CN
CN
N
N
N
CH
N
N
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CH
3
CH
3
C
CH
3
CH
3
C
CH
3
3
C
N
N
CH
C
CH
3
3
Br
CH
N
N
N
CH
C
CH
3
3
C
CH
CH
3
3
3
N
NH
Four methyl groups are added by α- alkylation of the nitriles with iodomethane. The nitriles are formed by bromide dis-
placement by sodium cyanide. The dibromide is formed by bromination of mesitylene.
CH
3
CH
3
CH
3
CH
3
CH3I
CN
Br
CH
CH
3
CH
3
CN
3
CH
CH
3
CN
3
CH
3
Br
CH
3
NaCN
Br
CH
3
Extended Discussion
CH
3
CH
3
Final product purity is critical when manufacturing a drug substance. To ensure high purity of the product, no side products which are difficult to separate from the product should form in the final step. This is not the case for the anastrozole
process. Explain. List the process details which ensure that anastrozole meets high purity specifications.
Artemether
CH
3
CH
3
CH
CH
3
artemether dihydroartemisinin artemisinin
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Anti- Infective Medicines/Antiprotozoal Medicines/Anti malarial Medicines/For Curative Treatment
Artemether 23
3
H
O
3
O
O
H
O
OC
H
CH
H
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.
Discussion. Artemether (β- artemether) is semisynthetic, it is manufactured in two steps from artemisinin. The methyl
acetal of β-
artemether is formed by the acid- catalyzed reaction of the hemiacetal (dihydroartemisinin) with methanol. The
hemiacetal of dihydroartemisinin is formed by reduction of the ester of artemisinin. Artemisinin is a natural product isolated from the plant Artemisia annua or sweet wormwood.
OCH
3
CH
3
H
CH
3
3
O
O
H
O
H
O
3
O
O
H
O
CH
OH
3
H
CH
3
CH3OH
CH
3
O
O
H
O
H
O
CH
H
O
3
H
CH
O
Artemisinin can also be manufactured in four steps from artemisinic acid. In the last step, a hydroperoxide is formed by
α- oxidation of an aldehyde with triplet oxygen. The aldehyde, hydroperoxide, ketone, and carboxylic acid then assemble to
form artemisinin. The aldehyde and ketone are formed by cleavage of an allylic hydroperoxide (Hock Rearrangement).
The allylic hydroperoxide is formed from dihydroartemisinic acid (Ene Reaction). Dihydroartemisinic acid is formed by
reduction of artemisinic acid. Artemisinic acid is a natural product also isolated from the plant A. annua or sweet wormwood. Artemisinic acid is also produced by fermentation.
A24
CH
CH
O
OH
CH
CH
3
dihydroa rtemisin ic acid artemisinicacid
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CH
3
3
HOO
O
O
H
O
artemisini n
HO
H
3
O
CH
3
H
CH
3
O
HOO
OHC
HO
O
CH
3
H
CH
H
3
HO
CH
3
O
CH
H
3
CH
3
O
H
CH
3
OHC
HO
O
CH
3
H
CH
H
H
CH
3
3
HO
O
CH
3
H
H
CH
O
CH
3
H
H
H
O
Extended Discussion
Draw the structures of four impurities which are likely to form in the conversion of dihydroartemisinin to artemether.
Artesunate
Anti- Infective Medicines/Antiprotozoal Medicines/Antimalarial Medicines/For Curative Treatment
3
H
O
O
3
O
H
O
O
H
CH
O
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 in place.
Artesunate 25
CH
CH
3
O
CH
CH
3
dihydroa rtemisin ic acid artemisinicacid
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Discussion. Artesunate is semisynthetic, and it is manufactured in two steps from artemisinin. The ester is formed by reaction
of the hemiacetal (dihydroartemisinin) with succinic anhydride. The hemiacetal of dihydroartemisinin is formed by reduction of the ester of artemisinin. Artemisinin is a natural product isolated from the plant A. annua or sweet wormwood.
H
3
O
3
CH
3
O
O
H
O
H
CH
O
3
O
O
H
O
O
OH
dihydroart emisinin
O
CH
3
H
O
CH
3
O
CH
H
3
O
O
H
CH
H
3
O
H
CH
O
OH
O
artemisinin
O
artesunate
Artemisinin is also manufactured in four steps from artemisinic acid. In the last step, a hydroperoxide is formed by αoxidation of an aldehyde with triplet oxygen. The aldehyde, hydroperoxide, ketone, and carboxylic acid then assemble to
form artemisinin. The aldehyde and ketone are formed by cleavage of an allylic hydroperoxide (Hock Rearrangement).
The allylic hydroperoxide is formed from the alkene (Ene Reaction). The alkene, dihydroartemisinic acid, is formed by
reduction of artemisinic acid. Artemisinic acid is a natural product also isolated from the plant A. annua or sweet wormwood. Artemisinic acid is also produced by fermentation.
H
3
O
3
O
CH
3
O
H
CH
3
H
O
O
O
HOO
OHC
HO
artemisinin
CH
H
3
CH
3
O
H
CH
3
OHC
HO
O
CH
3
H
H
CH
O
CH
3
HOO
HO
Extended Discussion
β- Artemether and α- artesunate are both formed from dihydroartemisinin. Draw the structures of a retrosynthetic analysis
of β- artesunate.
CH
3
H
CH
H
3
CH
3
H
H
H
HO
CH
3
O
O
CH
CH
3
H
CH
3
H
H
HO
3
O
A26
O
OHHO
HO
HO
HO
O
OH
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Ascorbic Acid
Vitamins and Minerals
H
O
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.
Discussion. Ascorbic acid (vitamin C) is semisynthetic. Ascorbic acid is formed from 2- keto- - gulonic acid.
Keto- - gulonic acid is produced by fermentation from - sorbose. - Sorbose is produced by fermentation from
2-
sorbitol.
HO
H
O
O
OHHO
HO
OH
2-keto-L-gulonic acid
OH
OH
O
OH
OH
OH
HO
OH
OH
L-sorbose
OH
O
OH
HO
OH
OH
D-sorbitol
Extended Discussion
Draw the structures of the retrosynthetic analysis of an alternative non- fermentation route to 2- keto- - gulonic acid from
- sorbose.
Atazanavir
CH
3
3
CH
OH NHBoc
N
NHBoc
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Anti- Infective Medicines/Antiviral Medicines/Antiretro virals/Protease Inhibitors
A β- amino alcohol with a primary β- C is often formed by ring-
N
opening of an epoxide by an amine.
CH
HN
CH
3
3
3
O
NH
OH HN O
O
N
CH
HN
CH
OCH
3
CH
3
OCH3O
Discussion. Two amides are formed with expensive N- (methoxycarbonyl)- - tertleucine (Moc- - tertleucine) in the final step.
The amine and hydrazine needed to form the amides are released by hydrolysis of tertA key C─N bond near the center of the molecule is formed by ring-
N
HN
N
CH
3
CH
3
CH
3
OCH3O
CH
HN
CH
3
3
3
OCH
NH
3
O
OH HN O
O
opening of an epoxide with a Boc- protected hydrazine.
H2N
OH NH
CH
CH
3
O
CH3O
N
H
Mo c-L -te rt leucine
butoxycarbonyl (Boc) protecting groups.
N
N
2
3
CH
3
OH
O
BocHN
N
BocHN
N
O
HN
A28
OH
CH
O
CH
CH
O
Cl
O
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Moc- - Tertleucine is formed from - tertleucine and methyl chloroformate. - Tertleucine is formed by an enzyme-
mediated reductive amination of trimethylpyruvic acid. The pyruvic acid is formed by oxidation of the
hydroxyacid. The α- hydroxyacid is formed from 1,1- dichloropinacolone by rearrangement and hydrolysis.
α1,1-
Dichloropinacolone is formed by α–chlorination of pinacolone.
CH
CH
3
3
3
O
NH
O
CH
CH
CH
3
3
OH
3
O
NH
2
CH
CH
CH
3
3
OH
3
O
OCl
OCH
3
Moc-L-tertleucine
CH
3
3
OH
3
OH
CH
3
O
CH
3
CH
OCH
3
3
CH
Cl
Cl
CH
CH
3
3
3
CH
3
O
The epoxide is formed from the chlorohydrin by nucleophilic displacement of chloride by oxygen. The chlorohydrin is
formed by reduction of the α-
chloroketone, N- ( tert- butoxycarbonyl)- 3(S)- amino- 1- chloro- 4- phenyl- 2- butanone. The αchloroketone is formed by reduction of the α,α- dichloroketone. The α,α- dichloroketone is formed from N- ( tertbutoxycarbonyl)- - phenylalanine methyl ester and dichloromethane.
BocH N
O
BocHN
The Boc- protected hydrazine is formed by reduction of the hydrazone. The hydrazone is formed by reaction of
the aldehyde with Boc- hydrazine. The aldehyde, 4- (2- pyridyl)benzaldehyde, is formed from 2- bromopyridine and
4- formylbenzeneboronic acid (Suzuki–Miyaura Coupling). The boronic acid is formed from 4- chlorobenzaldehyde
and trimethylborate via an acetal.
O
BocHN
OCH
O
CH2Cl
2
3
BocHN
Cl
Cl
Cl
OH
BocHN
Atracurium Besylate 29
OH
CH
CH
O
CH
CH
CH
3
OCH
3
3
3
3
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N
HN
NHBoc
CH3O OCH
B
3CH2
O
OCH2CH
N
N
N
Br
HO
B
N
NHBoc
H
O H
BocNHNH
2
O H
3
B(OCH3)
3
Cl
Cl
3
CH3CH2O
OCH2CH
3
OH
CH3CH2OH
Extended Discussion
In the route presented, the key C─N bond is formed by ring- opening of an epoxide. Draw the structures of the retrosynthetic analysis of an alternative route to atazanavir which forms the same key C─N bond but does not involve an epoxide
intermediate. List the pros and cons for both routes and select one route as the preferred route.
Atracurium Besylate
Muscle Relaxants (Peripherally Acting) and Cholinesterase Inhibitors
3
O
O
Ph
N
CH
SO
3
3
O
3
O
3
O
A tertiary amine is often formed by alkylation of a secondary amine.
Discussion. Atracurium besylate is produced as a mixture of 10 stereoisomers (label the four chiral centers in atracurium
besylate). The discussion will be limited to routes to one of the 10 stereoisomers, the (1R- cis, 1′R- cis)- isomer known as
cisatracurium besylate.
O
O
PhSO
N
CH
OCH
3
3
OCH
OCH
A30
CH3O
CH
CH
CH
OCH
3
3
3
3
CH
CH
CH
CH
(R)-tetrahydropapaverine
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In one preferred route, the quaternary salts are formed in the final step by reaction of the tertiary amines with methyl
benzenesulfonate (draw structures for two side products formed in this reaction. How is cisatracurium besylate separated
from the side products?) The tertiary amines are formed by conjugate addition of (R)-
tetrahydropapaverine to the acrylate.
O
3
O
3
O
3
O
3
CH
PhSO
3
3
N
O
3
O
3
N
O
O
cisatracuriumbesylate
O
O
O
O
O
O
PhSO
N
CH
N
OCH
3
3
OCH
OCH
OCH
3
OCH
3
OCH
3
O
O
3
Ph S
OCH
3
OCH
3
O
CH3O
NH
O
O
CH3O
CH3O
O
O
CH3O
(R)- Tetrahydropapaverine is formed by resolution of tetrahydropapaverine. Tetrahydropapaverine is formed by
reduction of dihydropapaverine. The dihydroisoquinoline ring of dihydropapaverine is formed from the amide
(Bischler–Napieralski Reaction). The amide is formed from 3,4- dimethoxyphenylacetic acid and
3,4- dimethoxyphenethylamine.
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