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
Mp
a(A cm)-OH
Bo
Bo
Bo
Bo
OH
2
O
O
H
https://t.me/medicina_free
Mpa
Dexamethasone 131
Acm-OH
Z-Tyr-O H H-Tyr-OH
H-P he -OBn H-P he -OH
c-Gln-OH H-Gln-OH
c-Asn -OH
c-Cys(Acm)-OH H-Cys(Acm)-OH H-Cys-OH
c-D-Arg-OH H-D-Arg-OH H-DL-Arg-OH H-Arg-
H-Asn-OH
Z -Cl
Bn-OH
(Boc)
(Boc)
(Boc)
O
2
O
2
(Boc)
O
2
O
Acm-OH
Extended Discussion
Draw a scheme for the retrosynthetic analysis of one alternative solution- phase synthesis of desmopressin. Add any new
acronyms used in the alternative synthesis to the table. List the pros and cons for both of the solution-
phase syntheses.
Dexamethasone
Medicines for Pain and Palliative Care/Medicines for Other Common Symptoms in Palliative Care
Antiallergics and Medicines Used in Anaphylaxis
Antineoplastics and Immunosuppressives/Hormones and Antihormones
Gastrointestinal Medicines/Antiemetic Medicines
Specific Medicines for Neonatal Care/Medicines Administered to the Mother
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. A steroid with a 16α- methyl substituent is often formed by coppermethylmagnesium halide to a 16-
3
catalyzed conjugate addition of a
ene- 20- one.
HO
CH
CH
3
H
3
F
H
OH
O
CH
D132
O
O
O
3
O
https://t.me/medicina_free
Discussion. Dexamethasone is manufactured in seven steps from pregna- 1,4,9(11),16- tetraene- 3,20- dione, 13 steps from
16-
dehydropregnenolone acetate, and 16 steps from diosgenin. Diosgenin is a phytosteroid sapogenin isolated from the
tubers of Dioscorea wild yam.
The C21 alcohol is released by hydrolysis of the acetate ester in the final step. The acetate ester is formed by bromide
displacement by acetate. The α-
bromoketone is formed by α- bromination of the ketone.
O
HO
HO
CH
CH
CH
3
H
3
F
3
F
H
O
CH
3
H
H
CH
OH
OH
3
CH
CH
O
OH
Br
3
3
OH
HO
CH
3
F
O
HO
CH
3
F
O
CH
3
H
H
O
CH
3
H
H
OH
OH
CH
CH
CH
O
CH
3
3
3
Fluorine is introduced at C9 on the α- face by ring- opening of the 9β,11- epoxide with hydrogen fluoride. The methyl
group is introduced at C16 on the α16-
alkene (Grignard Reaction). The α- alcohol at C17 is then formed by α- oxidation of the C20ketone. Methylmagnesium
bromide is formed from bromomethane. The 9β,11mohydrin is formed in situ by hydrolysis of the formate ester. The bromohydrin formate is formed from the 9(11)pregna-
1,4,9(11),16- tetraene- 3,20- dione.
face by copper- catalyzed conjugate addition of a methylmagnesium bromide to the
epoxide is formed from the bromohydrin. The 11β- alcohol of the bro-
alkene of
Dexamethasone 133
O
O
3
O
O
O
https://t.me/medicina_free
HO
CH
3
F
O
CH
3
CH3MgBr
O
H N
H
H
CH
CH
H
CH
OH
CH
3
O
3
CH
3
3
CH
3
H
H
OH
CH
3
CH
O
CH
H
O
CH
3
3
O H
O
CH
3
Br
O
CH
CH
3
3
H
H
O
CH3Br
O
CH
CH
3
CH
3
3
CH
H
3
H
3
The 9(11)- alkene is formed by elimination of the methanesulfonate formed in situ from the 11α- alcohol. The 16- alkene
is released by deoxygenation of the 16α,174-
ene- 3- one. The 11α- alcohol is formed by microbial oxidation. The 4- ene- 3- one is formed by oxidation of the C3 alcohol
followed by double bond migration. The 16α,17acetate. The acetate ester is hydrolyzed under the epoxidation conditions.
epoxide. The 1,4- diene- 3- one is formed by microbial dehydrogenation of the
epoxide is formed by epoxidation of the 16- alkene of 16- dehydropregnenolone
D134
O
O
O
O
3
O
16-dehydropregnenolone acetate
https://t.me/medicina_free
HO
CH
CH
CH
3
H
3
H
CH
SO2CH
O
CH
3
CH
3
H
3
H
H
3
O
O
CH
CH
3
H
3
H
3
O
HO
CH
3
HH
O
CH
3
H
H
O
O
CH
CH
3
3
CH
3
HO
CH
3
H
O
CH
H
H
CH3SO2Cl
3
CH
O
CH
3
CH
3
O
CH
H
3
CH
3
O
H
O
O
CH
CH
3
3
O
CH
HO
H
3
CH
O
3
O
H H
H
CH
H
3
H
The 16- alkene of 16- dehydropregnenolone acetate is formed from diosone by β- elimination. Diosone is formed by oxidation of the 20(22)genin with acetic anhydride. The three-
alkene of pseudodiosgenin- 3,26- diacetate. Pseudodiosgenin 3,26- diacetate is formed by reaction of dios-
step synthesis of 16- dehydropregnenolone acetate from diosgenin by acetylation,
oxidation, and elimination is known as the Marker Degradation.
CH
CH
CH
CH
CH
3
diosgenin
O
3
3
β
https://t.me/medicina_free
135Dexamethason
3
O
3
CH
H
3
O
H
O
3
H
CH
3
O
CH
3
O
CH
O
O
3
CH
O
O
3
H
3
H
H
diosone
CH
H
CH
3
H
3
O
CH
3
CH
O
O
CH
O
3
CH
3
O
3
O
H
H
H
pseudodiosgenin-3,26-diacetate
21
CH
3
O
26
22
CH
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 a retrosynthetic analysis of an alternative route to dexamethasone via 3β,17α- dihydroxy-
16α- methyl- 5α- pregnan- 20- one.
HO
,17α-dihydroxy-16α-methyl-5α-pregnan-20-one
CH
H
H
3
H H
CH
CH
3
3
OH
CH
D136
CH
O
Cl
CH
Cl
CH
Cl
CH
https://t.me/medicina_free
Diazepam
Medicines for Pain and Palliative Care/Medicines for Other Common Symptoms in Palliative Care
Anticonvulsants/Antiepileptics
Medicines for Mental and Behavioral Disorders/Medicines for Anxiety Disorders
3
N
N
A 5- aryl- 1,3- dihydro- 2H- 1,4- benzodiazepin- 2- one is often formed in two steps from a
2-
aminobenzophenone, chloroacetyl chloride, and ammonia/hexamethylenetetramine.
Discussion. The diazepine ring is closed in the final step by imine formation. The amine is formed by displacement of chloride from
the α-
chloroamide by ammonia. The α- chloroamide is formed from chloroacetyl chloride and 5- chloro- 2- methylaminobenzophen
one. 5-
Chloro- 2- methylaminobenzophenone is formed by N- methylation of 2- amino- 5- chlorobenzophenone. (List the methylating
agents, reaction conditions, and yields.)
3
N
O
N
Cl
3
N
O
NH
O
2
Cl
3
O
N
O
Cl
Three routes to 2- amino- 5- chlorobenzophenone are well- known. In Route A, the benzophenone is formed from 4- chloroaniline and
benzoyl chloride (Friedel–Crafts Acylation). In Route B, the benzophenone is formed from 4- chloroaniline and benzonitrile (Sugasawa
Reaction). In Route C, the b enzophenone is formed by reduction of 5- chloro- 3- phenyl- 2,1- benzisoxazole (5- chloro- 3- phenylanthranil).
5- Chloro- 3- phenylanthranil is formed from 4- chloronitrobenzene and phenylacetonitrile.
CH
NH
3
Cl
NH
CH3X
2
O
O
Cl
Cl
O
Diethylcarbamazine 137
Cl
Cl
RouteA
Cl
O
3
CH
3
https://t.me/medicina_free
RouteB
RouteC
NH
NH
NH
2
O
Cl
2
O
Cl
2
O
Cl Cl
NH
NH
2
OCl
2
CN
NO
N
O
2
CN
Extended Discussion
List the pros and cons for the three routes to 2- amino- 5- chlorobenzophenone. Is one route preferred?
Diethylcarbamazine
Anti- infective Medicines/Anthelminthics/Antifilarials
An unsymmetrical urea is often formed by the reaction of an amine with a
CH2CH
N N
N
CH2CH
3
carbamoyl chloride. The carbamoyl chloride is formed by the reaction of an
amine with phosgene.
D138
R
RouteA
H H
RouteC
CH
https://t.me/medicina_free
Discussion. The unsymmetrical urea is formed from 1- methylpiperazine and N,N- diethylcarbamoyl chloride (Route A) or from N,N-
diethylamine and 4- methylpiperazinecarbonyl chloride (Route B). The carbamoyl chlorides are formed from the amines and
phosgene.
outeB
CH
CH
O
CH2CH
N N
N
3
CH2CH
3
3
CH
N
3
O
CH2CH
3
N N
N
3
CH2CH
3
CH
N
3
NH
O
N
NH(C H2CH3)
2
Cl
Cl
O
CH
N
CH2CH
3
CH2CH
Cl Cl
N
3
3
O
NH
Diethylcarbamazine is formed by reductive methylation of N,N- diethylpiperazine- 1- carboxamide in the final step of
Route C. The carbamate is formed from piperazine and N,N-
diethylcarbamoyl chloride.
O
CH2CH
N N
N
3
CH2CH
3
3
HN
O
O
N N
CH2CH
CH2CH
3
3
Cl
Extended Discussion
List the pros and cons for the three routes and select one route as the preferred route.
HN
O
NH
CH2CH
N
CH2CH
3
3
Dihydroartemisinin
CH
OH
CH
3
CH
CH
3
dihydroartemisinin artemisinin
https://t.me/medicina_free
Anti- infective Medicines/Antiprotozoal Medicines/Antimalarial Medicines/For Curative Treatment
Dihydroartemisinin 139
H
3
A cyclic hemiacetal can be formed by the reduction of the carbonyl carbon of a
lactone. If the hemiacetal has a propensity to ring- open, further reduction of the
O
3
O
O
H
O
H
CH
aldehyde to a primary alcohol is likely.
Discussion. Dihydroartemisinin (artenimol or DHA) is semisynthetic. It is manufactured by reduction of artemisinin.
Artemisinin is a natural product isolated from the plant Artemisia annua or sweet wormwood.
CH
H
O
3
H
CH
O
OH
3
O
O
H
O
H
CH
CH
3
3
H
O
3
O
O
H
O
An alternative supply of artemisinin is manufactured in four steps from artemisinic acid. In the last step, the aldehyde,
hydroperoxide, ketone, and carboxylic acid assemble to form artemisinin. The hydroperoxide is formed in situ by reaction
of the aldehyde with triplet oxygen. The aldehyde and ketone are formed by cleavage of an allylic hydroperoxide (Hock
Rearrangement). The allylic hydroperoxide is formed from the alkene (Ene Reaction). The alkene, dihydroartemisinic
acid, is formed by reduction of artemisinic acid. Artemisinic acid is a natural product also isolated from the plant A. annua
or sweet wormwood. An alternative supply of artemisinic acid is produced from sugar by yeast fermentation.
D140
CH
CH
3
dihydroartemisinic acid artemisinic acid
CH
Cl
Cl
https://t.me/medicina_free
CH
3
3
HOO
O
O
H
O
artemisinin
HO
H
O
3
O
OHC
HOO
HO
H
CH
CH
3
3
O
CH
3
H
CH
H
3
HO
CH
3
O
CH
H
3
CH
3
O
H
CH
3
OHC
HO
O
CH
3
H
CH
H
H
3
CH
3
H
H
CH
O
CH
3
H
H
H
HO
CH
3
O
O
Extended Discussion
Dihydroartemisinin is usually isolated from methanol–water. Drying the wet solid under vacuum at 15–25 °C affords dihydroartemisinin of very high purity (>99.9%) but some degradation is observed when the drying temperature is increased to
50 °C. Draw the structures of two degradation products.
Diloxanide Furoate
Anti- infective Medicines/Antiprotozoal Medicines/Antiamoebic and Antigiardiasis Medicines
O
O
O
Discussion. There are just two steps in the synthesis of diloxanide furoate. The ester is formed in the final step from
2-
furoyl chloride and the phenol. The acid chloride is formed from 2- furoic acid. The amide is formed from
4- methylaminophenol (the hydrogen sulfate salt is called metol) and dichloroacetyl chloride.
3
N
Amides are ubiquitous in drug structures. Amide formation
from an amine and acid chloride, anhydride, ester, or carboxylic acid is often very efficient.
O
Соседние файлы в папке Библиотека им академика М.И. Перельмана