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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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Ritonavir 391
3
CH
3
CH
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CH
N
S
3
CH
3
S
S
N
O
O
HN O
OH
CH
3
N
HN
H
N
O
CH
O
CH
3
3
NH
2
X O
2
OH
3
5
The amide bond at C5 is formed from the carboxylic acid and amine in the final step.
NH
N
3
CH
S
N
CH
3
N
H
NH
2
CH
CH
3
3
HO
2
O
L-valine
3
CH
N
3
S
O
HN O
OH
CH
N
3
CH
3
N
S
S
S
N
O
CH
3
N
HN O
OH
HN
H
N
O
CH
3
O
CH
3
NH
2
HO
CH
3
N
HN
O
CH
O
CH
3
The carboxylic acid is formed by hydrolysis of the methyl ester. The urea is formed by the reaction of the 4- nitrophenyl
carbamate with the secondary amine. The carbamate is formed from - valine methyl ester and 4- nitrophenyl
chloroformate.
R392
HO
CH
3
3
3
3
CH
c
N
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3
CH
CH
3
CH
3
S
CH
3
CH
3
S
S
N
3
N
CH
3
N
HN
O
CH
3
O
CH
CH3O
3
CH
3
N
HN
O
CH
N
CH
3
N
H
OAr
OAr
NH
O
2
CH
3
CH
3
Cl
O
CH
3
CH3O
3
HN
O
CH
3
O
CH
3
CH3O
O
The secondary amine, 2- isopropyl- 4- (methylaminomethyl)isothiazole, is formed by chloride displacement from
4- (chloromethyl)- 2- isopropylthiazole by methylamine. The thiazole is formed by the condensation of thioisobutyramide
and 1,3- dichloroacetone. The thioamide is formed from isobutyramide.
Cl
SH2N
CH
Cl
OH2N
CH
CH
3
CH
CH3NH
CH
3
NH
N
CH
3
S
CH
3
3
2
Cl
N
O
S
CH
The amine for the ritonavir final step is released by hydrolysis of the tert- butyl carbamate (Boc) at C5. The carbamate at C2
is formed by the reaction of a 4- nitrophenyl carbonate with the amine at C2.
S
O
ArO O
NH
2
OH
NHBo
S
O
HN O
OH
N
HN O
NH
2
N
S
O
OH
NHBoc
Ritonavir 393
ArO O
Bn Bn
Bn Bn
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The carbonate is formed from 5- (hydroxymethyl)thiazole and 4- nitrophenyl chloroformate. 5- (Hydroxymethyl)thiazole is
formed by hydrogenolysis of the 2- chlorothiazole. 2- Chloro- 5- (hydroxymethyl)thiazole is formed by hydrolysis of 2- chloro-
5- chloromethylthiazole.
N
O
S
OAr
O
N
OH
S
Cl
Cl
N
OH
S
N
Cl
Cl
S
The amine at C2 of the ritonavir scaffold is released from the tertiary amine by hydrogenolysis. The primary amine at C5 is
protected as the tert- butyl carbamate (Boc). The alcohol of (2S,3S,5S)- 5- amino- 2- (dibenzylamino)- 1,6- diphenylhexan- 3- ol
is formed by reduction of the ketone and the ketone is formed by reduction of the enone. (Name three diastereomers which
are also formed in this two- reduction sequence. Identify the downstream process intermediate which is upgraded to remove
diastereomer impurities.) The enone is formed by addition of benzylmagnesium chloride to the nitrile (Grignard
Reaction
). Benzylmagnesium chloride is formed from benzyl chloride. The nitrile is formed by condensation of acetonitrile with the benzyl ester (mixed Claisen Condensation). The ester, (S)- benzyl 2- (dibenzylamino)- 3- phenylpropanoate,
is formed by N- and O- alkylation of - phenylalanine with benzyl chloride. - Phenylalanine is produced by fermentation.
NH
2
N
N
OH
NHBoc
Bn Bn
OH
NHBoc
Bn Bn
N
O
NH
2
N
O
NH
OH
NH
2
(Boc)2O
2
R394
O
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Bn Bn
N
O
CN
MgCl
Bn Bn
CH3CN
N
O
O
Bn
Cl
L-phenylalanine
NH
2
OH
Cl
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to ritonavir from (2S,3S,5S)- 5- amino- 2(dibenzylamino)- 1,6- diphenylhexan- 3- ol. List the pros and cons for both routes and select one route as the preferred
route.
HO
HO
OH
3
3
S
OH
3
3
OH
CH
3
3
CH
3
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Salbutamol
Medicines Acting on the Respiratory Tract/Antiasthmatic and Medicines for Chronic Obstructive Pulmonary Disease
395
H
N
CH
CH
CH
3
or ketone.
Discussion. Salbutamol is a 1 : 1mixture of the (R)- and (S)- enantiomers. In the final step, the primary alcohol and phenol
are released by hydrolysis of the 4H- 1,3- benzodioxin. The secondary amine is formed by hydrogenolysis of the tertiary amine.
The secondary alcohol is formed by the reduction of the ketone. The tertiary amine is formed by bromide displacement from
2- bromo- 1- (2,2- dimethyl- 4H- 1,3- benzodioxin- 6- yl)ethanone by N- benzyl- tert- butylamine.
A benzylic alcohol is often formed by the reduction of an aldehyde
H
N
CH
CH
CH
3
Ph
N CH
CH
CH
3
3
CH
HO
3
H
N
HO
OH
N CH
O
O
CH
Ph
CH
CH
3
CH
3
3
3
CH
3
3
CH
CH
3
CH
3
CH
O
O
3
O
O
O
3
O
3
CH
Routes to Essential Medicines: A Workbook for Organic Synthesis, First Edition. Peter J. Harrington.
O
© 2022 John Wiley & Sons, Inc. Published 2022 by John Wiley & Sons, Inc.
Companion website: www.wiley.com/go/Harrington/routes_essential_medicine
O
Br
Ph
HN CH
CH
CH
3
3
3
S396
CH
O
OH
3
3
OH
CH
CH
3
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The 4H- 1,3- benzodioxin is formed by the reaction of the diol with 2- methoxypropene. The primary alcohol of 2- bromo4′- hydroxy- 3′- (hydroxymethyl)acetophenone is formed by the reduction of the aldehyde. The acetophenone is formed from
salicylaldehyde and bromoacetyl bromide (Friedel–Crafts Acylation).
O
Br
Br
3
CH
Br
O
O
3
O
O
OCH
3
CH
O
Br
H
HO
H
HO
HO
3
HO
O
Br
salicylaldehyde
Extended Discussion
In one alternative route to salbutamol, the β–amino alcohol is formed by ring- opening an epoxide with tert- butylamine.
The epoxide is formed from the bromohydrin. The bromohydrin is formed by the reduction of the α- bromoketone. List the
pros and cons for both routes. Which route is preferred?
3
CH
3
CH
HO
3
H
N
CH
CH
CH
3
HO
H
N
O
CH
CH
3
CH
3
3
CH
3
CH
O
O
3
OH
Br
CH
3
CH
O
O
3
O
H2N CH
O
CH
3
CH
3
3
O
Br
O
O
Simeprevir
3
OCH
CH
CH
OCH
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Anti- infective Medicines/Antiviral Medicines/Antihepatitis Medicines/Medicines for Hepatitis C/Protease Inhibitors
Simeprevir 397
3
CH
3
N
O
O
N
3
NH
O
N
S
O
O
N
H
CH
CH
O
S
Amides are often efficiently formed by the reaction of an amine with
an acid chloride, anhydride, ester, or
3
carboxylic acid.
Discussion. Five disconnections reveal the five components of simeprevir and the modular nature of the synthesis.
OCH
3
CH
3
3
CH
3
OH
N
CH
CH
3
3
N
S
N
CH
CH
3
3
HO
O
N
S
O
O
O
O
3
O
N
NH
O
S
N
H
CH
HO
O
O
3
N
H
OH
H
N
2
OH
O
O
S
H2N
(NOTE: The heterocyclic ether will be represented as OAr until the ether is disconnected.)
The N- acylsulfonamide is formed in the final step by the reaction of an acylating agent with cyclopropanesulfonamide. The acylating agent is formed in situ from the cyclopropanecarboxylic acid. (Draw the structure of the acylating
agent.) The cyclopropanecarboxylic acid is formed by ester hydrolysis. The cis- alkene of the macrocyclic ring is formed
by olefin metathesis (Grubbs Reaction).
S398
OAr
CH
OAr
OAr
OAr
O
3
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CH
O
O
NH
N
3
O
OH
O
O
O
O
O
3
O
N
NH
O
S
N
H
S
H2N
CH
OAr
O
O
O
NH
N
3
O
OCH
3
CH
N
3
OAr
O
NH
O
OCH
3
One amide is formed by the reaction of the amine, methyl (1R,2S)- 1- amino- 2- vinylcyclopropane- 1- carboxylate, with the
carboxylic acid. The carboxylic acid is formed by hydrolysis of the methyl ester. The C-O bond of the ether is formed with inversion of the stereochemistry from the 4- hydroxyquinoline and the secondary alcohol (Mitsunobu Reaction).
CH
CH
3
3
O
N
OAr
O
NH
O
OCH
O
N
3
CH
3
O
OCH
OH
OH
H2N
3
CH
3
O
OCH
3
N
OCH
3 O
N
O
CH
N
3
OCH
3
O
HO
N
S
CH
CH
3
Simeprevir 399
O
CH
HO
O
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The secondary alcohol and methyl ester are both formed by ring- opening the lactone with methanol. The amide is
formed by the reaction of N-methyl-5-hexen-1-amine with (R,R)- 3- oxo- 2- oxabicyclo[2.2.1]heptan- 5- carboxylic acid.
OH
CH
3
N O
OCH
O
O
O
N
O
CH3OH
3
CH
3
O
HN
CH
3
O
OH
The (R,R)- lactone is produced by resolution. The racemic lactone is formed by cyclization of 4- hydroxy- trans- 1,2- cyclop
entanedicarboxylic acid. The secondary alcohol is formed by the reduction of the ketone. The diacid is formed by hydrolysis
of the diester. The ketone is formed by cyclization of the 1,6- diacid and decarboxylation of the resulting β- ketoacid.
The 1,6- diacid is formed by oxidative cleavage of the cyclohexene. The cyclohexene is formed by cycloaddition of
1,3- butadiene and dimethyl fumarate (Diels- Alder Reaction). 1,3- Butadiene is formed by thermolysis of 3- sulfolene.
O
O
O
O
O
O
OH
O
R,RR,R S,S
Followingonlythe R,Rstructures:
OH
HO
OH
OO
O
O
OH
O
3
O
OCH
O
HO
OH
O
O
HO OH
OO
O
CH3O OCH
OO
O
3
S
O O
CH3O
3
O
OCH
3
O
O
OCH
3
CH3O
S400
H
CH
CH
Cl
Br
H
3
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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.
N
2
O O
S
CH
CH
CH
3
CH
3
CH
3
3
NH
3
2
O O
S
Cl
3
O O
N
H
O O
S
Cl
CH
CH
3
3
3
1,3-propanesultone
S
N
H
OO
S
O
Cleavage of the tert- butyl carbamate releases key component methyl (1R,2S)- 1- amino- 2- vinylcyclopropanecarboxylate.
The (1R,2S)- enantiomer of the carbamate is separated from the racemic mixture by a selective enzyme- mediated hydrolysis
of the (1S,2R)- ester. The carbamate is formed from the amine. The amine is formed by hydrolysis of the benzaldehyde
imine. The cyclopropane ring is formed by the reaction of methyl glycine benzaldehyde imine with trans- 1,4- dibromo- 2butene. (Draw the structures for four possible stereoisomeric cyclopropane products. Assign (R/S) configurations to the
chiral carbons. This ring- forming reaction is diastereoselective. Identify the desired/isolated products.) The imine is formed
from methyl glycine and benzaldehyde.
3
(Boc)2O
H2N
O
OCH
O
N
2
OCH
3
BocH N
O
OCH
3
Boc
NH
O
OCH
H
Ph
O
N
H
N- Methyl- 5- hexen- 1- amine is formed by hydrolysis of the trifluoroacetamide. The trifluoroacetamide is formed by bromide displacement from 6- bromo- 1- hexene by N- methyltrifluoroacetamide. 6- Bromo- 1- hexene is formed by hydrogen
bromide elimination from 1,6- dibromohexane. N- Methyltrifluoroacetamide is formed from ethyl trifluoroacetate and
methylamine.
OCH
H
H
H
O
O
3
Ph N
Br
OCH
Ph
3
H
O
H2N
OCH
3
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