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_5671_Библиотеки_им_академика_М_И_Перельмана
.pdf
CH
Ph
3
cholest erol
ArSO2NHNH
CH
Ph
3
Route B
https://t.me/medicina_free
O
O
Colecalciferol 111
3
CH
3
2
CH
H
3
H
H H
O
CH
CH
3
CH
CH
3
3
H
CH
CH
3
3
CH
H
3
O
H H
O
CH
H
CH
3
3
O
Ph Cl
CH
Ph
CH
3
CH
3
H
3
H H
HO
In Route B, the 7,8- alkene is formed by elimination of hydrogen bromide from 7- bromocholesteryl benzoate. (Draw the
structure of a side product which is also formed in this elimination.) 7-
Bromocholesteryl benzoate is formed by bromination of cholesteryl benzoate. (List the options for brominating reagent and reaction conditions and the ratio of 7αbromocholesteryl benzoate to 7β- bromocholesteryl benzoate associated with each option.) Cholesteryl benzoate is formed
from cholesterol. Cholesterol is isolated from sheep wool grease.
3
O
O
CH
3
H H
CH
3
Ph
CH
H
CH
3
CH
CH
3
3
H
CH
CH
3
3
CH
H
3
O
H H
O
Br
C112
CH
Ph
3
cholesterol
CH
https://t.me/medicina_free
3
CH
3
H
CH
O
O
H
3
H H
O
CH
3
CH
CH
3
3
H
H H
CH
CH
3
3
H
CH
CH
3
Ph Cl
HO
Extended Discussion
7- Dehydrocholesterol can also be formed by fermentation (Route C). List the pros and cons for the three routes to
7-
dehydrocholesterol.
Cyclizine
Medicines for Pain and Palliative Care/Medicines for Other Common Symptoms in Palliative Care
3
N
N
Tertiary amines are ubiquitous in drug structures. A tertiary amine is often formed by
alkylation of a secondary 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. Cyclizine is manufactured in one step. The tertiary amine near the center of the molecule is formed by chloride displacement from chlorodiphenylmethane (benzhydryl chloride) by 1-
CH
3
N
N
Cl
methylpiperazine.
CH
3
N
N
H
Cyclophosphamide 113
ON
Cl
Cl
ON
ON
https://t.me/medicina_free
Cyclophosphamide
Antineoplastics and Immunosuppressives/Cytotoxic and Adjuvant Medicines
A phosphoric acid amide is often formed from a phosphoryl chloride and a primary or
secondary amine. A phosphoric acid ester is often formed from a phosphoryl chloride
and an alcohol.
O N
P
H
Discussion. Cyclophosphamide is a 1 : 1mixture of the (R)- and (S)- enantiomers. The (S)- enantiomer has the higher
therapeutic index. The tetrahydrophosphoramidic dichloride with 3phorus oxychloride with bis(2-
2H- 1,3,2- oxazaphosphorine- 2- oxide is formed in the final step by the reaction of the
amino- 1- propanol. The phosphoramidic dichloride is formed by the reaction of phos-
chloroethyl)amine hydrochloride.
O N
P
Cl
Cl
H
Cl Cl
HO NH
O N
P
Cl
Cl
Cl
2
HN
HCl
Cl
Extended Discussion
Cyclophosphamide is also formed from the same starting materials using the same disconnections in the reverse order. List
the pros and cons for both routes. Is one route preferred?
Cl
Cl
Cl
HN
HCl
O N
P
H
Cl
O Cl
P
ONH
HO NH
2
C114
HN
O
O
2
HN
2
D-serine
HO
OH
NH
https://t.me/medicina_free
Cycloserine
Anti-Infective Medicines/Antibacterials/Antituberculosis Medicines
A chiral carbon in a single- enantiomer molecule is often delivered in a starting material.
NH
Discussion. Cycloserine has been manufactured by fermentation (Streptomyces garyphalussive orchidaceus) and by chemi-
cal synthesis from of 3–chloro-
- alanine methyl ester hydrochloride with hydroxylamine hydrochloride. 3–Chloro- - alanine methyl ester
hydrochloride is formed from -
serine (Fischer Esterification). - Serine is produced by fermentation.
serine. In the chemical synthesis, the isoxazolidinone ring is formed in the final step by the reaction
serine methyl ester hydrochloride. - Serine methyl ester hydrochloride is formed from
O
NH
2
O
CH3O
O
NH
2
HCl
Cl
CH
O
O
3
NH
HCl HO
OH
CH3OH
O
2
NH
OH
Extended Discussion
Alternative routes to cycloserine utilize protection and deprotection of the amino group in the conversion of - serine to
cycloserine. Draw the structures of the retrosynthetic analysis of one of these alternative routes. List the pros and cons for
both routes.
Cytarabine
Antineoplastics and Immunosuppressives/Cytotoxic and Adjuvant Medicines
N
O
N
OH
O
2
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.
Cytarabine 115
HO
NH
https://t.me/medicina_free
Discussion. Cytarabine is formed by hydrolysis of 2,2′- O- anhydro(1- β- - arabinofuranosyl)cytosine. The anhydronucleo-
side is formed from cytidine.
O
OH
2
N
N
OH
O
HO
OH
NH
N
N
O
O
HO
O
5'
3'
OH
cytidine
NH
2
N
2
N
O
2'
OH
Extended Discussion
Cytidine can be converted to a 2,2′- O- anhydro(1- β- - arabinofuranosyl)cytosine by other routes which require an addi-
tional step to release the 3′ and 5′alternative route from cytidine to cytarabine. List the pros and cons for both routes and select one route as the preferred
route.
hydroxyl groups of cytarabine. Draw the structures of the retrosynthetic analysis of one
116
O
3
3
O
O
2
O
https://t.me/medicina_free
D
Dacarbazine
Antineoplastics and Immunosuppressives/Cytotoxic and Adjuvant Medicines
A highly reactive/unstable functional group in the target molecule is best formed
NH
2
N
N
N
H
N
CH
N
CH
last in the synthetic sequence.
Discussion. The unusual triazene functional group is unstable/highly reactive. Triazenes must be protected from light and
fragment to form diazonium salts and amines in the presence of Bronsted acids or alkylating agents.
The N- aryltriazene is formed by reaction of the aryldiazonium salt with dimethylamine. The diazonium salt is formed by
diazotization of 5-
N
N
H
aminoimidazole-4- carboxamide.
NH
2
CH
N
CH
3
3
N
N
NH
2
N
N
H
N
(CH3)2NH
N
N
N
H
NH
NH
2
The carboxamide is formed by hydrolysis of the nitrile. The amine is formed from the carboxamide (Hofmann
Rearrangement). 4- Cyano- 1H- imidazole- 5- carboxamide is formed by hydrolysis of 4,5- dicyanoimidazole. 4,5- Dicyanoimidazole
is formed from triethyl orthoformate and diaminomaleonitrile.
Routes to Essential Medicines: A Workbook for Organic Synthesis, First Edition. Peter J. Harrington.
© 2022 John Wiley & Sons, Inc. Published 2022 by John Wiley & Sons, Inc.
Companion website: www.wiley.com/go/Harrington/routes_essential_medicine
Daclatasvir 117
O
2
H
O
CH
2
temozolomide
CH
CH3O
3
3
https://t.me/medicina_free
NH
2
N
N
CN
N
CN
NH
NH
N
H
2
N
H
CN
NH
2
H
N
H
N CN
2
O
N
HC(O CH2CH3)
N
CN
H2N
CN
Extended Discussion
Temozolomide is used to treat some brain cancers and is the first- line treatment for glioblastoma multiforme. Draw the
structures of a retrosynthetic analysis of this important drug.
3
N
N
N
N
N
NH
O
Daclatasvir
Anti- infective Medicines/Antiviral Medicines/Antihepatitis Medicines/Medicines for Hepatitis C/NS5A Inhibitors
O
HN
3
CH
A 2,5- disubstituted imidazole is formed by reaction of an α- acyloxyketone with ammonium acetate. The four C-N bonds
O
N
N
3
N
H
of the imidazole ring are formed in the reaction.
H
N
N
CH
N
3
CH
O
NH
O
OCH
D118
CH3O
Br
3
3
https://t.me/medicina_free
Discussion. In a preferred route, the identical components on the left and right of the central C-C bond are introduced in
the same step. The amide is formed by r
final step. The pyrrolidine is released by deprotection of the tertreaction of the αthe α-
bromoketone by N- ( tert- butoxycarbonyl)- - proline (Boc- - proline).
HN
CH
3
CH
N
H
N
Boc
N
N
acyloxyketone with ammonium acetate. The α- acyloxyketone is formed by bromide displacement from
O
O
N
N
3
N
H
N
H
N
H
eaction of the pyrrolidine with N- (methoxycarbonyl)- - valine (Moc- - valine) in the
butyl (Boc) carbamate. The imidazole ring is formed by
H
N
N
H
N
H
N
N
H
N
N
Boc
N
CH
3
N
O
O
NH
OCH
3
HO
O
O
Moc-L-valine
CH
CH
OCH
NH
3
3
CH
3
3
Boc
O
N
OO
Br
O
O
O
O
N
Boc
O
Br
HO
Boc-L-proline
N
Boc
O
The α- bromoketone is formed by bromination of the ketone. 4,4′- Diacetylbiphenyl is formed by the palladium- catalyzed
coupling of 4′-
bromoacetophenone and the arylboronic acid or arylboronate ester derived from 4′- bromoacetophenone
(Suzuki–Miyaura Coupling). (Evaluate the acylation of biphenyl as an alternative route to 4,4′-
O
O
CH
3
CH
Br
O
CH
Br
CH
CH
CH
3
O
3
3
3
O
B
O
3
O
CH
diacetylbiphenyl.)
CH
3
O
3
CH
3
CH
3
CH
3
CH
O
O
O
BB
O
CH
CH
CH
CH
3
3
Br
3
O
CH
3
Dapsone 119
O O
H
2
2
O O
O
O
https://t.me/medicina_free
Extended Discussion
Draw the structures of a retrosynthetic analysis of an alternative Suzuki–Miyaura Coupling route to daclatasvir.
Dapsone
Anti- infective Medicines/Antibacterials/Antileprosy Medicines
Sulfur is encountered in organic synthesis in oxidation states ranging
S
N NH
Discussion. The second amino group is formed by reduction of the nitro group in the final step. The amino group is released by
hydrolysis of the acetamide. The diarylsulfone is formed by oxidation of the diarylsulfide. The amino group of
4- amino- 4′- nitrodiphenylsulfide is protected as the acetamide. 4- Amino- 4′- nitrodiphenylsulfide is formed by displacement of chloride from 1reduction from 1-
chloro- 4- nitrobenzene by 4- aminothiophenol. 4- Aminothiophenol is formed by chloride displacement and nitro group
chloro- 4- nitrobenzene.
−2
from S
to S+6. Diarylsulfones (S+2) are often formed by oxidation of
diarylsulfides (S
−2
).
S
H2N NH
O
O
S
O2N NH
S
N NH
2
Cl
2
3
OCH
O2N NH
O2N NH
2
O
O
S
CH
3
S
2
OO
CH
3
O CH
3
O2N
HS
NH
Cl
2
NO
2
D120
H
CH
CH
CH
CH
O
CH
CH
https://t.me/medicina_free
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to dapsone. List the pros and cons for both routes
and select one route as the preferred route.
Darunavir
Anti- infective Medicines/Antiviral Medicines/Antiretrovirals/Protease Inhibitors
3
O O
3
S
NH
2
N
HO
NH
O
H
O
A β- amino alcohol with a chiral β- C is often formed from an α-
amino acid if the configuration and β- substituent of the β- amino
alcohol match the configuration and α-
amino acid.
α-
substituent of a common
O
O
Discussion. The carbamate is formed from the amine and the N- succinimidyl carbonate in the final step. The amine is
released by cleavage of the tertthe 4-
nitrosulfonamide.
3
O O
3
HO
S
N
NH
O
butoxycarbonyl (Boc) protecting group. The 4- aminosulfonamide is formed by reduction of
3
O O
NH
2
O
H
O
H
O
CH
3
HO
S
N
NH
2
O
O
N
O
NH
2
H
O
O
H
O
CH
3
O O
3
HO
S
N
NHBoc
CH
3
O O
NH
2
CH
3
HO
S
N
NHBoc
NO
2
Соседние файлы в папке Библиотека им академика М.И. Перельмана