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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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Lumefantrine 261
O
C
O
Cl
Cl
CH
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H
l
N
N
CH
3
CN
H
CH
Br
CH
3
3
Cl
NH
N
CN
CN
Extended Discussion
Estimate a yield of losartan potassium from 2- butyl- 4- chloro- 1H- imidazole- 5- carboxaldehyde for both routes. Show the
calculations. List the pros and cons for both routes. Is one route preferred?
Lumefantrine
Anti- infective Medicines/Antiprotozoal Medicines/Antimalarial Medicines/For Curative Treatment
CH
3
An alkene conjugated to three aromatic rings is
N
OH
3
Cl
often formed by dehydration of an alcohol.
Discussion. Lumefantrine is produced as a 1 : 1mixture of the (R)- and (S)- enantiomers of the (Z)- alkene. The alkene,
conjugated to three aromatic rings, is formed by dehydration of the secondary alcohol. Under the dehydration conditions,
the (E)- and (Z)- alkenes equilibrate and the (Z)- alkene crystallizes from the mixture. The secondary alcohol is formed by
condensation of the fluorene with 4- chlorobenzaldehyde (Knoevenagel Condensation). The β- amino alcohol is formed
by ring- opening of an epoxide by N,N- dibutylamine.
L262
CH
CH
O
Cl
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Cl
CH
OH
CH
Cl
Cl
CH
3
3
Cl
3
N
3
3
Cl
OH
CH
3
CH
Cl
3
Cl
Cl
Cl
CH
3
N
OH
Cl
HO
N
N
H
O
O
H
Cl
The epoxide is formed from the chlorohydrin. The chlorohydrin is formed by reduction of the α- chloroketone. The
chloroketone is formed from 2,7- dichlorofluorene and chloroacetyl chloride (Friedel–Crafts Acylation).
α2,7-
Dichlorofluorene is formed by chlorination of fluorene. (Draw the structures for side products which are likely to form
in the chlorination of fluorene. List the options for the chlorination reagent(s) and conditions and select one of the options
as the preferred option.) Fluorene is obtained from high- temperature coal tar.
OH
Cl
Cl Cl
O
Cl
Cl
Cl
O
Cl
Cl
Cl
Cl Cl
M
HO
OH
OH
OHOH
OH
HO
OHOH
e
e
D-glucose
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Mannitol
Diuretics
A single- enantiomer molecule with multiple chiral carbons is often formed by the modification of a natural
product which has most or all of the chiral carbons
already in place.
Discussion. Mannitol (- mannitol) is separated from a mixture of mannitol and sorbitol (- sorbitol). The mixture of mannitol and sorbitol is often formed by hydrogenation of a mixture of with a higher mannitol to sorbitol ratio is formed by hydrogenation of pure time, pressure, and mannitol: sorbitol ratio for hydrogenations of pure verted into mixtures of -
mannose and - glucose or - mannose, - fructose, and - glucose for use in the hydrogenation.
fructose and - glucose (invert sugar syrup). A mixture
fructose. (List the catalyst, solvent, temperature,
fructose.) - Fructose or - glucose can also be con-
263
HO
OH
OHOH
OH
O
D-fructose
OH
or
or
or
OH
D-fructose
D-glucose
D-fructose
D-mannos
D-glucose
D-mannos
D-fructose
D-glucose
OHOH
OH
HO
OH
HO
OHOH
OH
O
OH
OH
H
OH
OH
OHOH
OH
sorbitol
OHOH
OH
OH
OH
H
O
OH
OH
D-mannose
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
M264
H
O
3
O
H
O
O
2
O
Cl
Cl
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Mebendazole
Anti- infective Medicines/Intestinal Anthelminthics
O
N
N
OCH
NH
A benzimidazole is often formed from a
1,2-
benzenediamine.
Discussion. The benzimidazole ring is formed in the final step by the reaction of 3,4- diaminobenzophenone with Nmethoxycarbonyl- S- methylisothiourea. The isothiourea is formed from S- methylisothiouronium hemisulfate and methyl
chloroformate.
O
NH
OCH
3
CH
3
S
O
N
NH
O
NH
2
NH
2
SCH
O
3
HN N
OCH
3
H2N NH
Cl OCH
2
3
3,4- Diaminobenzophenone is formed by reduction of 4- amino- 3- nitrobenzophenone. 4- Amino- 3- nitrobenzophenone is formed from
4-
chloro- 3- nitrobenzophenone by chloride displacement by ammonia. 4- Chloro- 3- nitrobenzophenone is formed from
4-
chloro- 3- nitrobenzoyl chloride and benzene (Friedel–Crafts Acylation). The acid chloride is formed from the carboxylic acid.
NH
2
NH
2
Cl
O
NO
2
HO
NO
NH
2
2
NO
Cl
O
NO
2
Medroxyprogesterone Acetate 265
O
3
CH
O
O
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Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to 3,4- diaminobenzophenone. Include the structures of the retrosynthetic analysis of any organic starting material(s) from petrochemical or biochemical raw materials.
List the pros and cons for both routes and select one route as the preferred route.
Medroxyprogesterone Acetate
Hormones, Other Endocrine Medicines and Contraceptives/Contraceptives/Injectable Hormonal Contraceptives
Hormones, Other Endocrine Medicines and Contraceptives/Progestogens
CH
3
3
O
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
CH
H
3
H
CH
H
CH
3
place. A 6αby hydrogenation of the 6-
methyl- 4- ene- 3- one steroid is often formed
methylene- 4- ene- 3- one.
Discussion. In one preferred route, medroxyprogesterone acetate is manufactured in four steps from 17- α- acetoxyprogesterone, 11
steps from 16-
dehydropregnenolone acetate, and 14 steps from diosgenin. Diosgenin is a phytosteroid sapogenin isolated from the
tubers of Discorea wild yam.
In the final step, the α- methyl at C6 is formed by hydrogenation of the C6methylene. The C6methylene is formed by
elimination of Nhyde and N17-
α- acetoxyprogesterone with triethyl orthoformate. The 4- ene- 3- one of 17- α- acetoxyprogesterone is formed from
α- acetoxypregnenolone by oxidation of the secondary alcohol at C3 and migration of the double bond.
17-
methylaniline. The 6- aminomethyl group is formed by reaction of the 3- ethoxy- 3,5- diene with formalde-
methylaniline (Mannich Reaction). The 3- ethoxy- 3,5- diene is formed by reaction of the 4- ene- 3- one of
M266
CH
O
CH
O
O
O
O
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3
CH
3
O
CH
H
3
H
H
O
CH
3
CH
3
O
CH
O
CH
H
3
H
H
O
Ph
N
CH
3
O
CH
CH
3
3
H
O
CH
3
O
CH
CH
3
3
H
CH3CH2O
CH
H
H
2
O
CH
H
H
O
H H
3
3
3
O
CH
CH
3
O
CH
PhNHCH
3
3
3
CH
3
3
O
CH
O
CH
3
3
H
O
CH
H
H
CH
3
3
O
CH
3
HO
17α
-acetoxypregnenolone
HC(OCH2CH3)
3
CH
3
O
17αα-acetoxyprogesterone
O
CH
H
H
H
The secondary alcohol at C3 of 17α- acetoxypregnenolone is formed by hydrolysis of the acetate. The 3,17- diacetate is
formed by reaction of the 3,17- diol with acetic anhydride. A β- bromine at C16 is removed by hydrogenolysis. The bromohydrin is formed by ring- opening of the 16α,17- epoxide. The 16α,17- epoxide is formed from the 16- alkene. The 3β- alcohol
is formed by hydrolysis of the acetate ester of 16- dehydropregnenolone acetate under the epoxidation conditions.
Medroxyprogesterone Acetate 267
CH
O
CH
O
HO
16-dehydropregnenolone acetate
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CH
HO
O O
3
O CH
CH
3
H
CH
CH
3
CH
3
O
H
3
CH
O
CH
3
3
CH
3
H
3
O
CH
O
3
O
H
3
O
CH
H
O
CH
O
CH
3
3
OH
CH
3
CH
3
3
OH
H
H
O
CH
CH
3
3
O
H
H
HO
O
CH
3
H
3
CH
CH
3
H
3
H
H
Br
CH
H
3
H
H
HO
O
CH
CH
H
3
CH
3
3
H
HO
H
CH
3
O
H
H
The 16- alkene of 16- dehydropregnenolone acetate is formed from diosone by β- elimination. Diosone is formed by oxida-
O
tion 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.
M268
CH
CH
CH
CH
3
diosgenin
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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
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
HO
3
H
CH
3
20
11
CH
1
2
3
4
5
H
3
9
H H
6
17
16
H
26
O
CH
22
3
O
CH
O
3
O
O
CH
3
Extended Discussion
Draw the structures of the retrosynthetic analysis of an alternative route to medroxyprogesterone acetate that does not use
a Mannich Reaction to introduce the methyl group at C6. List the pros and cons for both routes.
Mefloquine
3
3
3
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Anti- infective Medicines/Antiprotozoal Medicines/Antimalarial Medicines/For Prophylaxis
Mefloquine 269
HN
HN
A fluorine-
containing substituent on a heterocycle is
often delivered in a starting material used to construct
CF
HO
H
N
CF
3
CF
HO
the heterocycle.
H
N
CF
3
Discussion. Mefloquine is a 1 : 1mixture of (11S,12R)- and (11R,12S)- enantiomers. The final step is a hydrogenation to
form the secondary alcohol from the ketone and the piperidine from the pyridine. The ketone is formed from the cyanohydrin. The cyanohydrin is formed by α4-
chloroquinoline by 2- (2- pyridin- 2- yl)acetonitrile. 2- (2- Pyridin- 2- yl)acetonitrile is formed from 2- (chloromethyl)pyridine
oxidation of the nitrile. The nitrile is formed by displacement of chloride from the
hydrochloride.
HO
11
HN
12
HO
H
HN
N
O
H
CF
N
3
CF
3
CF
N
N
3
CF
3
CF
N
3
CF
3
N
NC
HO
NC
Cl
N
CN
N
KCN
Cl
CF
N
3
CF
3
CF
N
3
CF
3
N
CF
3
CF
The 4- chloroquinoline is formed from the 4- hydroxyquinoline. The quinoline ring is formed by condensation of ethyl
4,4,4,- trifluoroacetoacetate with 2- trifluoromethylaniline (Conrad–Limpach Synthesis). Ethyl 4,4,4,- trifluoroacetoacetate
is formed from ethyl trifluoroacetate and ethyl acetate (mixed Claisen Condensation). Ethyl trifluoroacetate is formed
from trifluoroacetic acid and ethanol (Fischer Esterification).
M270
Cl
OH
3
3
3
Cl
3
Cl
3
I I
OH
HO
iotroxic acid
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CF
N
3
CF
3
CF
N
3
O
CH3CH2O
O
CF
3
CF
3
CF
NH
2
3
O
CH
3
CF
OCH2CH
O
OCH2CH
3
3
CH3CH2OH
CF
O
OH
3
The synthesis of 2- trifluoromethylaniline from α,α,α- trifluorotoluene is accomplished in three steps: chlorination, nitration, and nitro group reduction/reductive dehalogenation.
CF
NH
2
CF
NO
2
CF
CF
Extended Discussion
Draw the structures of the retrosynthetic analysis of an alternative route to mefloquin which forms the C11 alcohol by ringopening of an epoxide. Include the structures of the retrosynthetic analysis of any organic starting material(s) from petrochemical or biochemical raw materials. List the pros and cons for both routes.
Meglumine Iotroxate
Diagnostic Agents/Radiocontrast Media
OH
OH
NHCH
3
OH
I
H
O
N
O
O
O
OH
HO
meglumine
O
I
H
N
O
O
I I
Amides are ubiquitous in drug structures. Amide formation from an amine and acid chloride, anhydride, ester, or carboxylic acid is often very efficient.
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