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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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Paclitaxel 331
3
O
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CH
3
O
O
10
CH
O
NH
3'
2'
3
O
13
O
CH
CH
OH
OH
CH
3
3
7
3
H
O
O
H
O
CH
3
HO
O
O
O
CH
3
O
N
O
CH
3
O
O
CH
3
CH
OH
CH
3
3
H
O
OSi(CH2CH3)
H
O
O
CH
3
3
O
O
O
O
CH
3
O
O
O
CH
3
N
O
OH
HO
CH
3
CH
OH
OSi( CH2CH3)
CH
3
3
H
O
H
O
O
CH
3
O
O
P332
CH
10-deacetylbaccatin III
NH
O
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The acetate ester at C10 is formed by the reaction of the secondary alcohol with acetic anhydride. The C7 secondary
alcohol of 10-
deacetylbaccatin III (10- DAB) is protected as the triethylsilyl ether. 10- Deacetylbaccatin III is a diterpenoid
isolated from the leaves of the European yew Taxus baccata.
HO
O
O
O
CH
3
CH
O
3
CH
O
3
OH
OSi(CH2CH3)
CH
3
3
H
O
H
O
O
CH
O
O
HO
CH
3
3
3
O
CH
HO
CH
3
HO
O
CH
CH
3
3
CH
3
H
O
OH
O
3
O
Si(CH2CH3)
H
O
CH
3
3
O
O
O
CH
OH
3
(CH3CH2)3SiCl
CH
OH
3
CH
3
H
O
O
H
O
CH
3
CH
HO
3
O
The carboxylic acid, (4S)-
trans- 4,5- dihydro- 2,4- diphenyl- 5- oxazolecarboxylic acid, is formed by hydrolysis of the methyl
ester. The oxazolidine is formed by a reaction of (2R,3S)zimidate is formed from benzonitrile.
O
OH
N
O
N
O
OCH
O
O
3- phenylisoserine methyl ester with ethyl benzimidate. The ben-
2
OCH
3
OH
NH
OCH2CH
3
3
CH3CH2OH
CN
Paracetamol 333
OH
3
3
Ph
Ph
Br
HO
H
3
HO
H
HO
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In one preferred route to (2R,3S)- 3- phenylisoserine methyl ester, the ester is formed from the amide. The (2R,3S) -
and (2S,3R)reaction of racemic methyl cismohydrin. Methyl 3-
3- phenylisoserine amides are separated by resolution. The (2R,3S)- and (2S,3R)- amides are formed by
3- phenylglycidate with ammonia. Methyl cis- 3- phenylglycidate is formed from the bro-
bromo- 2- hydroxy- 3- phenylpropanoate is formed by the ring- opening of methyl trans- 3phenylglycidate by hydrogen bromide. Methyl trans- 3- phenylglycidate is formed by condensation of benzaldehyde and
methyl chloroacetate (Darzens Reaction). (Racemic methyl cisReaction. How much of the cis-
side product is present in the crude methyl 3- phenylglycidate? What is the fate of this
3- phenylglycidate is a side product of the Darzens
side product in the next step?)
NH
O
2
Ph
OH
OH
H H
Br
OH
H
Paracetamol
O
H H
O
H
O
OCH
OCH
O
O
OCH
H
3
2
OCH
OCH
Ph
Ph
3
3
H H
NH
2
OH
H
NH
2
Ph H
NH
2
Ph
O
O
Ph
NH
2
H
O
Cl
CH3OH
OH
H H
OCH
3
Ph
NH
2
NH
O
O
OCH
Ph H
3
H
O
O
H
OCH
3
H
Ph
O
O
O
H
Medicines for Pain and Palliative Care/Non- opiods and Non- steroidal Anti- inflammatory Medicines
Antimigraine Medicines/For Treatment of Acute Attack
Discussion. Paracetamol is manufactured in a single step by acetylation of 4- aminophenol with acetic anhydride.
N
N
CH
O
CH
3
O
Amides are ubiquitous in drug structures. Amide formation from an amine and
acid chloride, anhydride, ester, or carboxylic acid is often very efficient.
NH
2
CH
O
3
O
O
CH
3
P334
HO
H
HO
CH
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Extended Discussion
Paracetamol can also be formed in a single step from 1,4- hydroquinone and ammonium acetate. List the pros and cons of
both routes.
N
CH
3
O
OH
CH
O
NH
O
3
4
Paritaprevir
Anti- infective Medicines/Antiviral Medicines/Antihepatitis Medicines/Medicines for Hepatitis C/Other Antivirals
Amides are ubiquitous in drug structures. Amide formation from an amine and acid chloride, anhydride, ester,
or carboxylic acid is often very efficient.
3
N O
NN
O O
NH
O
N
NH
OO
H
S
HN
O
Paritaprevir 335
CH
CH
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Discussion. Some key disconnections reveal the six components of paritaprevir and the modular nature of the synthesis.
3
N O
NN
O O
NH
O
N
NH
OO
H
S
HN
O
H2N
3
NN
OH
O
OH
O
N
OH
HN
Cl
O O
S
H2N
OH
O
H2N
H
OH
O
P336
3
CH
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(NOTE: The phenanthridine will be represented as Ar until the ether is disconnected.)
The cyclopropanesulfonamide is introduced by N-
cyclopropanecarboxylic acid. The carboxylic acid is formed by ester hydrolysis. The cis-
acylation in the final step. The acylating agent is formed from the
alkene of the macrocyclic ring is
formed by olefin metathesis (Grubbs Reaction). The diene for olefin metathesis is assembled when the amide is formed
from the carboxylic acid and the pyrrolidine.
CH
3
N O
NN
O O
NH
O
N
NH
OO
S
HN
O
H
CH
3
OAr
NN
NH
N
O
OO
O O
S
H2N
OH
NH
O
H
3
OAr
NN
NH
O
N
OO
NH
OCH2CH
O
3
H
CH
3
NN
NH
O
OAr
N
OO
H
NH
OCH2CH
O
3
CH
3
OAr
NN
OH
NH
HN
O
O
O
OCH2CH
NH
O
H
Paritaprevir 337
O
HN
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The carboxylic acid component is formed from 5- methylpyrazine- 2- carboxylic acid and (S)- 2- amino- 8- nonenoic acid.
The (S)-
α- amino acid is formed by reductive amination of the α- ketoacid. The α- ketoacid is formed by hydrolysis of the α-
ketoester. Ethyl 2- oxo- 8- nonenoate is formed by the reaction of the alkylmagnesium bromide from 7- bromo- 1- heptene
with diethyl oxalate (Grignard Reaction).
CH
3
N
N
H
N
OH
O
O
OH
OCH2CH
O
O
O
CH
3
N
N
OH
H2N
OH
O
O
MgBr
OCH2CH
O
3
Br
O
3
CH3CH2O
The pyrrolidine is released by hydrolysis of the tert- butyl carbamate. The amide bond is formed from the proline carboxylic acid and the cyclopropanamine. The ether C–O bond is formed by nucleophilic displacement of chloride from
6- chlorophenanthridine by the alcohol of N- Boc- trans- 4- hydroxy- - proline.
OAr
OCH2CH
NH
O
H
Ar
O
OAr
BocN
BocN
3
O
O
H
NH
OCH2CH
O
3
H2N
H
OH
O
OCH2CH
O
Ar Cl
OH
BocN
OH
3
O
P338
H
H
3
CH
CH
Cl
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Cleavage of the tert- butyl carbamate releases the amine of ethyl (1R,2S)- 1- amino- 2- vinylcyclopropanecarboxylate. The
carbamate (1R,2S)(1S,2R)-
ester. The carbamate is formed from the amine. The amine is formed by hydrolysis of the imine. The cyclopropane
ring is formed by the reaction of ethyl glycine benzaldehyde imine with transfor four possible stereoisomeric cyclopropane products. Assign (R/S) configurations to the chiral carbons. This ring-
enantiomer is separated from the racemic mixture by selective enzyme- mediated hydrolysis of the
1,4- dibromo- 2- butene. (Draw the structures
forming
reaction is diastereoselective. Identify the desired/isolated products.) The imine is formed from glycine ethyl ester and
benzaldehyde.
O
OCH2CH
(Boc)2O
OCH2CH
3
Ph
O
N
2
OCH2CH
3
H
O
N
OCH2CH
BocH N
3
O
H
Ph N
OCH2CH
3
BocHN
O
O
H
OCH2CH
OCH2CH
3
PhCHO
H
2
H2N
3
H
O
N
Br
Br
Cyclopropanesulfonamide is formed from N- tert- butylcyclopropanesulfonamide. The cyclopropane ring is formed by
nucleophilic displacement of chloride by the sulfonamide dianion. The N-
tert- butylsulfonamide is formed from tert-
butylamine and the sulfonyl chloride. 3- Chloropropanesulfonyl chloride is formed from 1,3- propanesultone.
O O
S
H2N
CH
CH
CH
3
3
3
NH
O O
Cl
2
O O
CH
CH
S
3
3
3
Cl
S
N
H
1,3-propanesultone
S
CH
3
CH
3
OO
O
3
N
H
O O
S
6- Chlorophenanthridine is formed from 6(5H)- phenanthridinone. The phenanthridinone can be formed from
CH
OH
O
2
3
3
penicillin G (benzylpenicillin)
H
CH
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9-
fluorenone and hydrazoic acid (Schmidt Reaction).
339Penicillamine
N Cl
N
H
O
O
9-fluorenone
Extended Discussion
There are many potential routes to 7- bromo- 1- heptene. Draw the structures of a retrosynthetic analysis of one route.
Include the structures of the retrosynthetic analysis of any organic starting material(s) from petrochemical or biochemical
raw materials.
Penicillamine
Antidotes and Other Substances Used in Poisonings/Specific
Medicines for Diseases of Joints/Disease-
CH
3
HS
NH
3
A chiral carbon in a single- enantiomer molecule is often delivered in a starting material.
modifying Agents Used in Rheumatoid Disorders
Discussion. Penicillamine is semisynthetic. Penicillamine is released from a mercury complex by reaction with hydrogen
sulfide. The penicillamine mercury complex forms and precipitates when mercuric chloride is added to the mixture produced by hydrolysis of penicillin G (benzylpenicillin). Penicillin G is produced by the fungus Penicillium chrysogenum.
H
N
O
O
S
CH
N
HO
CH
O
HS
3
NH
3
OH
2
O
CH
Extended Discussion
A synthesis of penicillamine usually involves several steps, including a resolution and protection–deprotection of functional groups. Draw the structures of the retrosynthetic analysis of one resolution- based route to penicillamine.
(Penicillamine is often used as a chiral auxiliary for asymmetric synthesis. Is there an asymmetric synthesis of
penicillamine?)
P340
HN
2
O O
NH
2
O O
NC
H
furfural
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Pentamidine
Anti- infective Medicines/Antiprotozoal Medicines/Antipneumocystosis and Antitoxoplasmosis Medicines
Anti-
infective Medicines/Antiprotozoal Medicines/Antitrypanosomal Medicines/African Trypanosomiasis
An amidine is often formed by the reaction
of an imidate with ammonia or an amine.
An imidate is formed by the acidaddition of an alcohol to a nitrile.
NH
NH
Discussion. The amidine is formed in the final step by the reaction of the ethyl imidate with ammonia. The imidate is
formed by the addition of ethanol to the nitrile. The ether is formed by displacement of a primary bromide by the phenol
(Williamson Ether Synthesis).
catalyzed
HN
NH
2
HN
OCH2CH
O O
Extended Discussion
NH
NH
2
O O
NH
NC
OCH2CH
3
OH
3
CN
CH3CH2OH
Br Br
Draw the structures of the retrosynthetic analysis of an alternative route to 1,5- dibromopentane from biomass- derived
furfural. List the pros and cons of both routes to 1,5- dibromopentane. Is one route preferred?
O
O
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