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
Epinephrine 161
HO
HO
OH
O
O
Cl
2
HO
HO
HO
Ph
HO
HO
OH
HO
HO
HO
OH
HO
HO
O
https://t.me/medicina_free
NHCH3HO
HO
NHCH
HO
3
HO
CH3NH
In Route B, the secondary amine is released by hydrogenolysis of the benzyl group of the tertiary amine in the final step.
(What reaction conditions are required to avoid hydrogenolysis of the benzyl alcohol?) The (R)- alcohol is formed by asymmetric hydrogenation of the ketone. The α- aminoketone is formed by chloride displacement by N- benzylmethylamine.
HO
HO
OH
O
NHCH
N
Ph
CH
3
HO
HO
HO
3
OH
N
CH
3
Ph
O
HN
Cl
CH
3
In Route C, the (R)- alcohol is formed by resolution of the racemic alcohol. (How is the undesired (S)- alcohol converted
to the racemic alcohol?) The racemic alcohol is formed by hydrogenation of the ketone. The α- aminoketone is formed by
chloride displacement by methylamine.
NHCH
3
HO
HO
O
NHCH
3
HO
O
2- Chloro- 3′,4′- dihydroxyacetophenone is formed from catechol and chloroacetyl chloride (Fries Rearrangement).
Cl HO
Cl
HO
catechol
NHCH
3
Cl
CH3NH
2
O
Cl
E162
HO
CH
3
HO
3
ergosterol
CH
https://t.me/medicina_free
Extended Discussion
List the pros and cons for the three routes to epinephrine.
Ergocalciferol
Vitamins and Minerals
CH
3
A single- enantiomer molecule with multiple chiral carbons is often formed by modification of a natural product
CH
which has most or all of the chiral carbons already in
place.
3
CH
CH
3
3
H
H
Discussion. Ergocalciferol (calciferol, vitamin D2) is semisynthetic. The secosteroid ergocalciferol is produced by cleavage
of the B- ring of the steroid natural product ergosterol.
CH
CH
3
3
H
3
CH
3
9
H
7
19
10
3
1
Ergocalciferol (vitamin D2) is formed from pre- vitamin D2. Pre- vitamin D2 is formed by UV- photoirradiation of pro-
vitamin D
(ergosterol). Low conversion in the UV- photoirradiation step minimizes the formation of two side products.
2
(Draw structures for and name these side products. How is ergosterol separated from the UV- photoirradiation product
mixture?) Ergosterol is produced by fermentation.
CH
HO
3
19
CH
1
10
35
9
3
H H
CH
3
CH
3
H
7
CH
3
CH
CH
3
Ergometrine 163
HO
3
ergosterol
CH
H
HO
CH
O
https://t.me/medicina_free
CH
CH
H
CH
HO
HO
3
CH
3
3
CH
3
CH
3
H H
CH
3
CH
3
H
pre-vitamin D
CH
3
CH
3
pro-vitamin D
CH
3
CH
CH
CH
CH
3
3
CH
3
3
H
2
H
2
3
3
H
Ergometrine
Oxytocics and Antioxytocics/Oxytocics
3
CH
3
N
H
N
N
H
Discussion. Ergometrine (ergonovine) is accessible by isolation of the alkaloid from field ergot, by fermentation, and by semisynthesis. In the semisynthesis, the amide is formed in the final step from the carboxylic acid (lysergic acid) and (S)- 2- amino-
1- propanol (- alaninol). (List the coupling agents used and the yield of ergometrine associated with each coupling agent.)
Lysergic acid is formed from an ergot alkaloid by amide hydrolysis or from the fermentation product paspalic acid by isomerization. (Draw the structure of side product isolysergic acid also formed by paspalic acid isomerization. How is isolysergic acid
separated from lysergic acid?)
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.
E164
HO
O
er
er
er
α
β
2
3
HO
O
https://t.me/medicina_free
CH
O
3
N
H
O R
H
N
HO
R
1
gotamine CH
gocristine CH(CH3)
gocornine
3
CH(CH
-ergocryptine CH(CH3)
-ergocryptine CH(CH3)
3)2
N
2
N
O
R
CH2Ph
CH2Ph
2
CH(CH3)
CH2CH(CH3)
2
CH(CH3)CH2CH
CH
H
3
CH
HO
3
CH
3
N
H
HO
NH
2
N
H
N
H
lysergic acid
O
O
N
H
1
H
or
R
2
2
2
N
H
HO
O
CH
3
N
H
H
N
H
paspalic acid
Estradiol Cypionate
Hormones, Other Endocrine Medicines and Contraceptives/Contraceptives/Injectable Hormonal Contraceptives
A single- enantiomer molecule with multiple chiral
O
CH
3
H
H
H
Discussion. Estradiol cypionate is manufactured in three steps from estrone and in six steps from the plant sterol
β- sitosterol. The final step is hydrolysis of the C3 ester of the 3,17- diester. The 3,17- diester is formed by reaction of estradiol
with 3- cyclopentylpropionyl chloride. Estradiol is formed by reduction of estrone. Estrone is formed by A- ring aromatization
from androsta- 1,4- diene- 3,17- dione ethylene glycol ketal (acetal). The acetal is formed from androsta- 1,4- diene- 3,17- dione
(boldione). Androsta- 1,4- diene- 3,17- dione is formed by microbial oxidation/side chain degradation of phytosterols (plant
sterols) including β- sitosterol.
carbons is often formed by modification of a natural
product which has most or all of the chiral carbons
already in place. Steroids with an aromatic A ring are
often formed from androsta-
1,4- diene- 3,17- dione
which is produced by microbial oxidation/side chain
degradation of a phytosterol.
HO
3
β
CH
O
CN
https://t.me/medicina_free
Estradiol Cypionate 165
O
3
O
HO
H
H
H
H
CH
O
3
O
H
H
O
O
Cl
OH
CH
3
H
H
H
H
H
HO
estradiol
HO
CH
OH
H
3
H
CH
H
O
3
O
HO
estrone
3
19
1
A
4
CH
H
CH
O
3
CH
3
H
H
CH
O
3
O
H
O
CH
3
CH
3
18
H
3
H
CH
H
20
3
H
17
CH
CH
3
-sitosterol
3- Cyclopentylpropionyl chloride is formed from the carboxylic acid. 3- Cyclopentylpropionic acid (cypionic acid) is formed
from 3- (2- oxocyclopentyl)propionitrile by reduction of the ketone and hydrolysis of the nitrile. 3- (2- Oxocyclopentyl)propionitrile is formed by addition of an imine or enamine of cyclopentanone to acrylonitrile (Michael Addition).
O
O
O
O
CN
Cl
OH
E166
CH
HO
OH
3
CH
OH
HO
OH
https://t.me/medicina_free
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to 3- cyclopentylpropionic acid.
Ethambutol
Anti- infective Medicines/Antibacterials/Antituberculosis Medicines
A beta-amino alcohol with a primary α- C is often formed by reduc-
H
3
N
H
N
CH
Discussion. The 1,2- diamine is formed by chloride displacement from 1,2- dichloroethane by the primary amine
(S)- 2- amino- 1- butanol. (Draw the structures of likely side products of this reaction. How is the procedure designed to
minimize the formation of these side products? How are these side products separated from ethambutol?) (S)- 2- Amino1- butanol is produced by resolution. The unwanted (R)- 2- amino- 1- butanol can be racemized and the racemate returned
to the resolution.
tion of a beta-nitro alcohol.
CH
HO
3
Cl
NH
Cl
2
HO
H
3
N
H
N
CH
3
CH
HO
3
NH
2
Extended Discussion
(S)- 2- Amino- 1- butanol is also formed from an inexpensive proteinogenic amino acid. Identify one amino acid and outline the route
from the amino acid to (S)- 2- amino- 1- butanol.
Ethinylestradiol
Hormones, Other Endocrine Medicines and Contraceptives/Contraceptives/Oral Hormone Contraceptives
CH
3
H
H
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. Steroids with an aromatic A
ring are often formed from androsta- 1,4- diene- 3,17- dione which is
produced by microbial oxidation/side chain degradation of a
phytosterol.
Ethionamide 167
HO
-sitosterol
O
CH
3CH2
S NH
2
https://t.me/medicina_free
Discussion. Ethinylestradiol is manufactured in four steps from the plant sterol β- sitosterol. The tertiary alcohol at C17 is
formed by addition of a metal acetylide to the C17ketone of estrone in the final step. (List the reagents and conditions used
to form the metal acetylide and the associated yield of ethinylestradiol.) Estrone is formed by A- ring aromatization from
androsta- 1,4- diene- 3,17- dione ethylene glycol ketal (acetal). The acetal is formed from androsta- 1,4- diene- 3,17- dione
(boldione). Androsta- 1,4- diene- 3,17- dione is formed by microbial oxidation/side chain degradation of phytosterols (plant
sterols) including β- sitosterol.
HC C H
CH
OH
3
CH
O
3
CH
O
3
H
estrone
19
1
A
3
4
H
CH
CH
H
O
CH
3
18
H
3
H
CH
H
20
3
H
17
H
3
H
CH
H
CH
3
CH
3
3
H
H
CH
OH
3
H
HO
O
H
HO
O
CH
3
H
H
HO
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to estrone. List the pros and cons for both routes.
Ethionamide
Anti- infective Medicines/Antibacterials/Antituberculosis Medicines
N
Discussion. Three functional group interconversions at the end of the sequence convert the ester to the thioamide.
Thethioamide is formed from the nitrile, the nitrile is formed by dehydration of the amide, and the amide is formed from
the ester.
Hydrogen at C2 and/or C6 of a pyridine ring is often introduced by hydrogenolysis of a
chlorine substituent. The chloropyridine is formed from the pyridone.
E168
CH
3
2
3
CH
https://t.me/medicina_free
CH
3
S NH
2
2
N
3
CH
2
CN
NCH
CH
3
O NH
2
2
NCH
O OCH2CH
CH
NCH
The simplicity of ethionamide and the ester precursor suggests an unusual retrosynthetic strategy: functional groups are
added to construct the pyridine ring
. After the pyridine ring is formed, the functional groups are replaced by hydrogen.
Chlorine at C6 is removed by hydrogenolysis. The ester is formed from the acid chloride. The chloropyridine and acid chloride are formed from the pyridone and carboxylic acid. The 2- pyridone- 4- carboxylic acid is formed by decarboxylation of
the 2- pyridone- 3,4- dicarboxylic acid. The dicarboxylic acid is formed by hydrolysis of an ester at C4 and a nitrile at C3. The
pyridine ring is formed by reaction of cyanoacetamide and a β- diketone. The β- diketone is formed from 2- butanone and
diethyl oxalate (mixed Claisen Condensation).
CH3CH2OH
O OCH2CH
3
O OCH2CH
3
O Cl
2
3CH2
NCH3CH
O OH
CH3CH
2
O OCH2CH
CN
N
H
O
3
2
Cl
3
2
O OH
OH
O
CN
O
N
H
O
CH3CH2O
O OCH2CH
O
CH
3
CH3CH
O
2
3
CH3CH
N
H
O
3
O OCH2CH
2
3
O
CH3CH
O
2
H2N
Extended Discussion
Adding functional groups which are not in the target molecule results in a nine- step synthesis of this simple molecule.
Draw the structures of the retrosynthetic analysis of an alternative route to ethionamide from 2- ethylpyridine. Include the
structures of the retrosynthetic analysis of 2- ethylpyridine from petrochemical or biochemical raw materials. List the pros
and cons for the two routes and select one route as the preferred route.
Etonogestrel 169
NH
O
O
CH
O
2CH3
3
CH
O
O
CH
https://t.me/medicina_free
Ethosuximide
Anticonvulsants/Antiepileptics
A succinimide is often formed from the succinic acid and ammonia.
3CH2
CH
3
Discussion. Ethosuximide is a 1 : 1mixture of (R)- and (S)- enantiomers. The succinimide is formed by heating the ammo-
nium succinate. (Ethosuximide is often distilled at reduced pressure. List the reported boiling points and pressures. What is
the melting point of ethosuximide?) The ammonium succinate is formed in situ from the succinic acid. The succinic acid is
formed by hydrolysis and decarboxylation of ethyl 2,3- dicyano- 3- methylpentanoate. Ethyl 2,3- dicyano- 3- methylpentanoate
is formed by addition of cyanide to ethyl 2-cyano-3-methyl-2-pentenoate (Michael Addition). Ethyl 2-cyano-3-methyl2-pentenoate (E/Z mixture) is formed by condensation of ethyl cyanoacetate and 2- butanone (Knoevenagel Condensation).
O
3
O
O
OH
OH
OCH2CH
3
3CH2
NC
CH
ONH
NH
CH3CH
2
3
O
O
CH
3
O
O
NC
OCH
2CH3
4
ONH
4
OCH2CH
CH3CH
2
CH
NC
3
O
CH3CH
CH3CH
2
CH
CN
3
2
CH
3
KCN
CH
CH
Etonogestrel
Hormones, Other Endocrine Medicines and Contraceptives/Contraceptives/Implantable Contraceptives
3
H
H
H
OH
Steroids with an ethyl group at C13 on the gonane structure are often
manufactured by total synthesis. The gonane is constructed from
6- methoxy- 1- tetralone, vinyl chloride, and 2- ethyl- 1,3- cyclopentanedione
(Torgov–Smith Synthesis). Chirality at C13 is established by microbial
reduction of a 2,2-disubstituted-1,3-cyclopentanedione intermediate.
H
E170
CH
CH
O
HO
https://t.me/medicina_free
Discussion. Etonogestrel is manufactured in eight steps from 13β- ethylgon- 4- ene- 3,17- dione, in 13 steps from 13- ethyl-
3- methoxygona- 1,3,5(10),8,14- pentaen- 17β- ol acetate, and in 18 steps from 6- methoxy- 1- tetralone.
The 4- ene- 3- one of etonogestrel is released in the final step by hydrolysis of the C3 acetal and migration of the double
bond. The tertiary alcohol at C17 is formed by addition of a metal acetylide to the C17ketone. The C17ketone is formed
by oxidation of the secondary alcohol. The C11ketone is converted to the C11methylene (Wittig Reaction). (List other
reagents and conditions used to convert the C11ketone to the C11methylene.) The C17ketone of the 11,17- dione is
protected as/reduced to the secondary alcohol. The C3 ketone of the 3,11,17- trione is protected as an acetal. The
C11 ketone is formed by oxidation of the C11 α- alcohol. The C11 α- alcohol is formed by microbial oxidation of
13β- ethylgon- 4- ene- 3,17- dione.
O
O
Ph3PCH
3
H H
CH
3
OH
OH
3
H H
4
5
3
11 13
9
8
H H
6
CH
3
17
OH
H H
O
O
O
HC CH
H H
H H
O
CH
3
I
3
O
OH
O
O
H H
H H
H H
CH
O
H H
3
O
O
O
CH
3
O
H H
H H
H H
OH
O
H H
O
CH
O
3
O
CH
3
O
HO
H H
H H
O
O
H H
H H
Соседние файлы в папке Библиотека им академика М.И. Перельмана