Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5949_Библиотеки_им_академика_М_И_Перельмана
.pdf
Beclomethasone Dipropionate 41
O
O
O
O
O
OH
O
https://t.me/medicina_free
O
CH
3
OH
H
CH
3
CH3CH2C(OCH3)
3
HO
CH
H
3
Cl H
O
CH
3
O
OCH
3
O
CH
CH2CH
3
3
HO
CH
3
Cl H
Chlorine is introduced at C9 on the α–face by ring- opening of the 9β,11- epoxide with hydrogen chloride. The 9β,11epoxide is formed from the bromohydrin. The 11β- alcohol of the bromohydrin is formed in situ by hydrolysis of the formate
ester. The 219(11)-
alkene. The 9(11)- alkene is formed by dehydration of the 11α- alcohol. The 21- alcohol is protected as a carbonate.
alcohol is also released by hydrolysis of the carbonate ester. The bromohydrin formate is formed from the
HO
CH
3
OH
OH
O
CH
3
OH
OH
CH
3
H
Cl H
CH
3
CH
H
3
CH
3
H
O
O H
O
CH
3
O
CH
3
OH
H
CH
O
O
OCH2CH
3
3
CH
3
O
CH
3
OH
H
CH
O
O
OCH2CH
3
3
O
Br H
O
O
HO
CH
3
CH
3
OH
H
CH
O
O
OCH2CH
3
3
HO
CH
H
H N
CH
CH
3
3
O
CH
3
H
3
OH
CH
OH
3
H
O
H
O
H
H
O
Cl OCH2CH
3
B42
O
O
Br
3
3
HO
https://t.me/medicina_free
The 11α- alcohol is formed by microbial oxidation. The C21 acetate ester is hydrolyzed during the microbial oxidation.
The 1,4by α-
diene- 3- one is formed from the 2α,4α- dibromo- 3- one by double elimination. The 2α,4α- dibromo- 3- one is formed
bromination of the C3 ketone. The C3 ketone is formed by oxidation of the 3β- alcohol of 16β- methylpregnane-
3β,17α,21- triol 21- acetate.
O
CH
HO
CH
3
H
3
H
H
O
O
CH
3
CH
H
3
H
H
O
OH
OH
CH
CH
OH
3
O
3
CH
3
H
O
O
CH
3
CH
3
H
O
CH
3
H
OH
CH
O
CH
3
H
O
CH
3
OH
H
CH
O
O
CH
3
H
Br
CH
O
3
OH
CH
H
3
CH
O
O
CH
3
3
The acetate ester is formed by displacement of bromide by acetate. The α- bromoketone is formed by α- bromination of
the C20ketone. The C20ketone is released by acetal hydrolysis. The 16β- methyl substituent is introduced by ring- opening
of the 16α,17- epoxide with methylmagnesium bromide (Grignard Reaction). Methylmagnesium bromide is formed from
bromomethane. The 5,6- alkene is reduced by catalytic hydrogenation. (What is the stereochemistry of the new chiral carbon at C5? Add this stereochemical feature to the structures in the retrosynthetic analysis.) The C20ketone is protected as
an acetal by reaction with ethylene glycol. The 16α,17- epoxide is formed by epoxidation of the 16- alkene of
16-
dehydropregnenolone acetate. The acetate ester is hydrolyzed under the epoxidation conditions.
H
H
Beclomethasone Dipropionate 43
HO
O
O
HO
HO
HO
16-dehydropregnenolone acetat e
https://t.me/medicina_free
O
CH
CH
3
H
3
OH
CH
O
CH
3
3
CH
3
CH
3
H
OH
CH
Br
3
O
H
CH
3
H
H
H
HO
O
CH
CH
3
3
OH
H
H
CH
3
CH
3
H
H
CH
OH
3
O
CH
O
3
CH
3
OH
H
CH
3
H
HO
CH
O
O
CH
3
H
3
CH
O
3
CH3MgBr
CH3Br
CH
CH
H
3
O
O
3
CH
3
O
H
H
H
H
HO
HO
OH
CH
O
CH
3
3
CH
O
CH
3
3
O
CH
H
3
CH
H
3
O
H
H
CH
3
O
H
H
The 16- alkene of 16- dehydropregnenolone acetate is formed from diosone by β- elimination. Diosone is formed by oxidation of the 20(22)- alkene of pseudodiosgenin- 3,26- diacetate. Pseudodiosgenin 3,26- diacetate is formed by reaction of diosgenin with acetic anhydride. The three- step synthesis of 16- dehydropregnenolone acetate from diosgenin by acetylation,
oxidation, and elimination is known as the Marker Degradation.
B44
CH
CH
CH
CH
3
diosgenin
https://t.me/medicina_free
3
O
CH
3
CH
H
3
O
H
3
O
H
CH
3
O
CH
3
O
CH
O
3
O
CH
O
3
O
H
3
H
H
O
O
diosone
CH
3
H
CH
3
H
3
O
H
H
H
pseudodiosgenin-3,26-diacetate
CH
CH
O
3
CH
O
3
O
CH
3
21
CH
3
O
26
CH
22
3
O
CH
O
3
O
O
CH
3
HO
H
CH
3
20
11
CH
1
2
3
4
5
H
3
9
H H
6
17
16
H
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to beclomethasone dipropionate via the
11β- trifluoroacetate intermediate.
Bedaquiline 45
O
CF
O
9α
e
Br
https://t.me/medicina_free
3
CH
O
CH
O
-chloro-11β,17α-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione11-trifluoroacetat
H
3
Cl
3
H
OH
CH
CH
3
3
Bedaquiline
Anti- infective Medicines/Antibacterials/Antituberculosis Medicines
A tertiary alcohol is often formed by addition of an organometallic reagent
RLi or RMX (M = Mg, Zn, X = Cl, Br, I) to a ketone.
N
CH3O
CH
N
3
OH
CH
3
Discussion. Bedaquiline, the (1R,2S)- enantiomer, is separated from a 1 : 1mixture of (1R,2S)- and (1S,2R)- enantiomers by
resolution in the final step. (Draw the structures of the chiral acids used for the resolution. What is the yield of bedaquiline
for the two- step resolution process associated with each chiral acid?) The addition of an alkyllithium to a ketone results in
a mixture of four stereoisomers. The undesired (1S,2S)- and (1R,2R)- enantiomers are separated from the mixture by crystallization. The desired (1R,2S)-
and (1S,2R)- enantiomers are then isolated by crystallization. (What is the highest diastereoselectivity for the addition reaction? What reagents and reaction conditions are associated with the highest diastereoselectivity?)
The alkyllithium is formed from 3- benzyl- 6- bromo- 2- methoxyquinoline. The β–dimethylamino ketone is formed from
1- acetonaphthone, formaldehyde, and dimethylamine (Mannich Reaction).
B46
Br
https://t.me/medicina_free
CH
3
N
4
CH
3
Br
N
CH3O
Br
3
N
OH
1
2
CH3O
(1R, 2S)
CH
N
3
OH
CH
3
CH
3
HO
CH
N
3
(1R, 2S) (1S, 2R)
CH
CH
3
3
N
O
H
H
Br
N
OCH
3
(CH3)2NH
CH
3
N
O
O
CH3O
The 2- methoxyquinoline is formed from the 2- chloroquinoline by chloride displacement. 3- Benzyl- 6- bromo- 2- chloroqu
inoline is formed from N- (4- bromophenyl)- 3- phenylp ropanamide, and N,N- dimethylformamide (Vilsmeier–Haack
Reaction). N- (4- Bromophenyl)- 3- phenylpropanamide is formed from 4- bromoaniline and the acid chloride. The acid
chloride is formed from 3- phenylpropanoic acid (dihydrocinnamic acid).
Bendamustine 47
H
Br
OH
3
Cl
Cl
https://t.me/medicina_free
Br
N
O
H
N(CH3)
2
N
OCH
3
Br
O
Br
NH
CH3OH
N
OCl
2
Cl
OHO
Extended Discussion
Bedaquiline is converted to a 1 : 1 salt with fumaric acid in the final step of the manufacturing process. Calculate the overall
yield of bedaquiline fumarate (1
waste?)
: 1) from 4- bromoaniline. (What percent of the 4- bromoaniline starting material is lost to
Bendamustine
Antineoplastics and Immunosuppressives/Cytotoxic and Adjuvant Medicines
A 2-
alkylbenzimidazole is often formed by the reaction of
O
N
N
N
CH
Discussion. The carboxylic acid is formed by ester hydrolysis in the final step. The bis- (2- chloroethyl)amine is formed
from the bis- (2- hydroxyethyl)amine. The bis- (2- hydroxyethyl)amine is formed by ring- opening of ethylene oxide by the
5- aminobenzimidazole.
a 1,2-
phenylenediamine with an acid chloride, anhydride,
ester or carboxylic acid.
B48
Cl
3
3
3
https://t.me/medicina_free
O
OH
Cl
N
N
N
CH
3
Cl
O
OCH2CH
Cl
N
N
N
CH
3
OH
O
OCH2CH
HO
N
N
N
CH
3
O
OCH2CH
O
H2N
N
N
CH
3
The 5- aminobenzimidazole is formed by reduction of the 5- nitrobenzimidazole. The ester is formed from the carboxylic
acid and ethanol (Fischer Esterification). The benzimidazole ring and the carboxylic acid both form in the reaction of N1methyl- 4- nitro- 1,2- phenylenediamine with glutaric anhydride. The phenylenediamine is formed by a selective reduction of
N- methyl- 2,4- dinitroaniline. The dinitroaniline is formed by the displacement of chloride from 1- chloro- 2,4-dinitrobenzene
by methylamine.
Benznidazole 49
O
H
3
O
2
O
N
https://t.me/medicina_free
O
OCH2CH
N
2
N
3
O2N
N
OCH2CH
N
CH
3
CH3CH2OH
N
2
N
N
CH
3
O2N
NH
2
NHCH
3
Extended Discussion
N
CH
3
O
OH
OO
O2N
3
NO
Cl
2
O2N
NO
2
NHCH
O
CH3NH
The selective reduction of one nitro group in a 2,4- dinitroaniline is a key step in the synthesis of bendamustine. (How selective
is this reduction?) Draw the structures of the retrosynthetic analysis of an alternative route to bendamustine which is based
on reduction of both nitro groups of a dinitroaromatic in the same step. List the pros and cons for both routes and select one
route as the preferred route.
Benznidazole
Anti- Infective Medicines/Antiprotozoal Medicines/Antitrypanosomal Medicines/American Trypanosomiasis
A 2- nitroimidazole is often formed from a 2- aminoimidazole via the
O2N
H
N
N
diazonium salt.
B50
N
O
CH
https://t.me/medicina_free
Discussion. The amide is formed in the final step by reaction of the ethyl ester with benzylamine. Ethyl 2-nitroimidazole1-ylacetate is formed from ethyl bromoacetate by bromide displacement by 2from 22,2-
aminoimidazole via the diazonium salt. 2- Aminoimidazole is formed from O- methylisourea and
dimethoxyethanamine. O- Methylisourea is formed from cyanamide and methanol.
nitroimidazole. 2- Nitroimidazole is formed
O2N
3CH2
O2N
H
N
N
N
O
N
O
O2N
CH3CH2O
NH
2
CH3O OCH
N
N
H
O
H2N
Br
N
N
H
H2N
H2N OCH
Extended Discussion
Why are anhydrous conditions preferred for the final two steps of the synthesis?
NH
3
NH2CN
3
CH
3
OH
Benzoyl Peroxide
Dermatological Medicines/Medicines Affecting Skin Differentiation and Proliferation
O
O
O
Discussion. Benzoyl peroxide is formed by reaction of benzoyl chloride with hydrogen peroxide.
O
O
O
O
O
Cl
O
Соседние файлы в папке Библиотека им академика М.И. Перельмана