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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5429_Библиотеки_им_академика_М_И_Перельмана
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Atracurium Besylate 31
CH3O
CH
CH
CH
N
CH3O
CH
CH
CH3O
O
O
Br
O
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O
3
O
3
O
3
(R)-tetrahydropapaverine
O
3
O
3
CH3O
CH3O
HN
NH
CH3O
CH3O
CH3O
CH3O
O
CH3O
NH
CH3O
CH3O
NH
CH3O
CH3O
CH3O
2
OH
O
The acrylate is formed by elimination of hydrogen bromide. The diester is formed from 1,5- pentanediol and
bromopropanoic acid (Fischer Esterification).
3-
O
Br
Br OH
O
O
HO
O
O
O
OH
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to cisatracurium besylate. List the pros and cons
for both routes. Is one route preferred?
A32
N
CH
CH
CH
O
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Atropine
Anesthetics, Preoperative Medicines and Medical Gases/Preoperative Medication and Sedation for Short- Term Procedures
Antidotes and Other Substances Used in Poisonings/Specific
Ophthalmological Preparations/Mydriatics
3
O
O
OH
A rigid bicyclic structure is often used to direct the formation of a new
chiral carbon.
Discussion. Atropine, a 1 : 1mixture of the tropane alkaloids (R)- hyoscyamine and (S)- hyoscyamine, is usually produced
by extraction from the plants Atropa belladonna, Datura stramonium, or Duboisis myoporoides.
Atropine can also be synthesized from tropic acid and tropinone. In the final step of the synthesis, the primary alcohol is
released by acetate ester hydrolysis. The tropic acid ester is formed from the acid chloride and the alcohol, 3-
tropanol
(tropine).
3
N
3
O
O
OH
CH
N
3
O
O
O
O
8
1
N
CH
3
tropine
3
Cl
OH
O
In a one- pot procedure, the acetate ester is formed from acetyl chloride and the primary alcohol of tropic acid then the
CH
3
O
acid chloride is then formed from the carboxylic acid. Tropic acid is formed by hydrolysis of the ethyl ester. The
α- hydroxymethyl ester is formed by reduction of the α- formyl ester. The α- formyl ester is formed from ethyl phenylacetate and
ethyl formate (mixed Claisen Condensation).
Atropine 33
CH
3
O
CH
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Cl
3CH2
O
OH
CH
3
O
O
O
O
CH
3
O
HO
OH
CH3CH2O
O
O
O
CH
3
HO
CH3CH2O
O
Cl
O
tropic acid
O
H OCH2CH
O
OH
3
The axial alcohol of tropine is formed by reduction of the ketone. Tropinone is efficiently assembled in a single step
from methylamine, 2,5-
Acetonedicarboxlic acid is formed by oxidative decarboxylation of citric acid. Citric acid is produced by
1,3-
dimethoxytetrahydrofuran, and 1,3- acetonedicarboxylic acid (Robinson–Schopf Reaction).
fermentation.
CH
3
3NH2
N
OH
tropine tropinone
OCH
3
O
OCH
CH
O
N
3
OH
O
O OH
O O
CH
N
3
HO
HO
citric acid
COOH
COOH
COOH
O
HO
Extended Discussion
The yield in the first one- pot synthesis of tropinone, described by Robinson in 1917, was just 17%. After a century of process
development, the yield for the one- pot synthesis is now 90%! List the references for the available procedures, the process
modification(s) made, and the tropinone yield. Which process modification had the greatest impact on the yield?
A34
N
NO
NO
O
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Azathioprine
Antineoplastics and Immunosuppressives/Immunosuppressive Medicines
Medicines for Diseases of Joints/Disease-
Modifying Agents Used in Rheumatoid Disorders
N
2
An aromatic thioether is often formed by displacement of chloride or bromide by
a thiol.
CH
N
3
S
H
N
N
N
Discussion. The thioether is formed in the final step by displacement of chloride from 5- chloro- 1- methyl- 4- nitroimidazole
by 6-
mercaptopurine. 5- Chloro- 1- methyl- 4- nitroimidazole is formed by nitration of 5- chloro- 1- methylimidazole.
Chloro- 1- methylimidazole is formed from N,N′- dimethyloxamide (Wallach Imidazole Synthesis). The oxamide is formed
5from diethyl oxalate and methylamine. 6-
N
N
CH
3
2
S
H
N
N
N
N
Mercaptopurine is formed from hypoxanthine.
SH
H
N
N
N
N
O
HN
N
hypoxanthine
H
N
N
NO
2
N
Cl
3
N
CH
Extended Discussion
Draw the structures of a retrosynthetic analysis of one alternative route to the thioether by nucleophilic aromatic substitution of chloride from 6- chloropurine. Compare the two routes and select one route as the preferred route.
CH3NH
OCH2CH
2
3
N
N
CH
Cl
CH3NH
3
O
NHCH
3
CH3CH2O
O
O
Azithromycin
2
3
CH
CH
CH
2
O
erythromycin A
CH
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Anti- Infective Medicines/Antibacterials/Other Antibacterials
Ophthalmological Medicines/Anti-
Infective Agents
Azithromycin 35
3
OH
CH
3
HO
O
O
OCH
O
N(CH3)
O
3
CH
CH
3
OH
Macrolide antibiotics are produced by fermentation or
are semisynthetic. The process for manufacture of a
semisynthetic macrolide antibiotic often begins with
conversion of the C9ketone of erythromycin A to the
oxime.
3
HO
3
CH3CH
HO
3
N
CH
3
O
2
O
CH
3
CH
Discussion. Azithromycin is semisynthetic. Azithromycin is formed from the essential medicine erythromycin A which is
produced by fermentation.
HO
HO
3
CH3CH
CH
3
N
11
12
O
2
O
azithromycin
9a
CH
9
CH
CH
CH3CH
HO
3
2
CH
3
11
12
CH
O
O
CH
3
OH
CH
6
3
3
3
HO
O
O
OCH
O
CH
O
CH
3
3
OH
3
N(CH3)
CH
2
3
9
OH
3
CH
CH
3
OH
CH
6
3
3
HO
O
O
OCH
O
CH
O
CH
3
3
3
OH
N(CH3)
CH
3
The tertiary amine of azithromycin is formed in the final step by methylation of the secondary amine with formaldehyde
and formic acid (Eschweiler–Clarke Reaction). The secondary amine (9- deoxo- 9a- aza- homoerythromycin) is formed by
reduction of an iminoether. The 6,9- iminoether (the iminoether involving the hydroxyl group at C6 and carbon at C9) is
formed by rearrangement of an (E)- O- arylsulfonyl oxime (Beckmann Rearrangement). The (E)- O- arylsulfonyloxime is
formed from the (E)- oxime and an arylsulfonyl chloride (List the arylsulfonyl chlorides and (O)- arylsulfonyloxime yields).
(E)- Erythromycin A oxime is formed from erythromycin A. (How is (E)- erythromycin A oxime separated from
erythromycin A oxime?)
(Z)-
A36
(E)-erythromycin Aoxime
3
CH
OH
CH
3
(Z)-erythromycin A oxime
HO
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O
HO
CH
CH
3
HO
HO
3
HO
3
CH
CH
CH
3
3
3
N
CH
3
azit hromycin
9a
N
9
O
OH
6,9-iminoether
OH
N
OH
6
CH
CH
CH
3
3
OH
CH
3
CH
3
ArSO2Cl
OH
CH
3
3
H H
CH
HO
3
HO
CH
CH
HO
3
HO
3
CH
CH
11
CH
HN
10
9
8
9a
CH
3
3
OH
CH
6
O
N
3
SO2Ar
CH
3
OH
OH
CH
3
O
3
10
11
9
OH
CH
3
8
OH
CH
6
3
erythromyc in A
Extended Discussion
(Z)- Erythromycin A oxime can be prepared from (E)- erythromycin A oxime. Draw structures for the products formed as
(Z)-
erythromycin A oxime is carried through the same sequence used to convert (E)- erythromycin A oxime to
azithromycin.
N
CH
3
HO
3
OH
(E)-erythromycin A oxime
CH
3
OH
CH
3
CH
HO
3
CH
3
N
OH
CH
3
OH
CH
Aztreonam
O
H
O
OH
O
H
O
OH
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Anti- Infective Medicines/Antibacterials/β- Lactam Medicines
Aztreonam 37
enantiomer molecule with multiple chiral carbons is often
CH
CH
A single-
3
3
OH
formed by modification of a natural product which has most or all of
the chiral carbons already in place.
O
N
H
N
S
N
O
O
N
2
CH
3
O
N
S
Discussion. In the final step, the carboxylic acid of aztreonam is released by hydrolysis of the tert- butyl ester. The amide bond
near the center of the molecule is formed by reaction of the amine of the ammonium sulfamate zwitterion with a thioester.
CH
CH
3
3
OH
O
N
H
N
S
N
N
2
O
O
CH
3
O
N
S
S
OH
O
H2N
CH
CH
3
3
OC(C H3)
3
O
N
H
N
N
O
O
CH
3
O
N
S
O
S
H2N
The amine of the ammonium sulfamate zwitterion is released by cleavage of the protecting group. The β- lactam ring is
formed by displacement of the secondary methanesulfonate by the N- acylsulfamate nitrogen. The N- acyl sulfamate is
formed from the amide. The methanesulfonate is formed from the alcohol. The amine of - threonine amide is protected
(List the protecting groups. Select one protecting group to use in the analysis). - Threonine amide is formed from threonine methyl ester. - Threonine methyl ester hydrochloride is formed from - threonine (Fischer Esterification). Threonine is produced by fermentation.
O
CH
CH
3
3
O
OC(CH3)
3
H3N
CH
3
N
S
H
N
O
N
O
S
O
N
S
O
O
A38
H
OSO2CH
L-threonine
Na
H
O
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3
N
3
CH
3
P1HN
CH
3
P1HN
CH
3
H
O
N
O
S
O
O
O
N
SO
3
Na
O
SO
3
N
H
P1HN
H3N
SO2CH
CH
3
3
O
H
O
NH
2
OH
Cl
CH
3
H
O
OCH
3
1
P
H2N
CH3SO2Cl
H
N
O
O
OH
NH
OH
OH
OH
CH
3
H2N
H
2
CH
3
O
NH
CH
3
H
2
H
CH3OH
The thioester is formed from the carboxylic acid and 2,2′- dithiobis(benzothiazole). The carboxylic acid is formed by
hydrolysis of the ethyl ester. The O-
bromoisobutyrate. The thiazole ring is formed by reaction of an α- bromoketone with thiourea (Hantzsch Thiazole
αSynthesis). The α-
bromoketone is formed by bromination of the ketone. The oxime is formed by nitrosation of ethyl
alkyloxime is formed by O- alkylation of the oxime with tert- butyl
acetoacetate.
CH
3
CH
3
O
N
S
N
N
2
O
O
S
OC(CH3)
N
S
CH
3
CH
3
N
3
OC(CH3)
3
O
OH
S
N
O
H2N
N
N
S
S
S
S
H
O
OO
OO
OO
S
O
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H2N
NH
2
H2N S
Br
Aztreonam 39
CH
3
CH
3
O
N
N
O
OC(CH3)
OCH2CH
3
OH
3
S
N
Br
OCH2CH
3
CH3CH
N
O
O
3
OC(C H3)
3
H2N
OH
N
OCH3CH
CH
3
3
OH
N
OCH2CH
CH
3
3
OCH2CH
3
Extended Discussion
Draw the structures of the retrosynthetic analysis of an alternative route to the ammonium sulfamate zwitterion. 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 to the ammonium sulfamate zwitterion as the preferred route.
N
3
O
CH
3
O
N
S
O
40
O
3
O
O
O
2
3
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B
Beclomethasone Dipropionate
Medicines Acting on the Respiratory Tract/Antiasthmatic and Medicines for Chronic Obstructive Pulmonary Disease
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 16β- methyl and 17αhydroxy substituents is often formed by ring- opening of
a 16α,17-
epoxide with a methylmagnesium halide.
HO
CH
O
3
O
O
CH2CH
O
CH2CH
3
CH
3
H
Cl H
CH
3
Discussion. Beclomethasone dipropionate is manufactured in 3 steps from beclomethasone, 12 steps from 16βmethylpregnane- 3β,17α,21- triol 21- acetate, 19 steps from 16- dehydropregnenolone acetate, and 22 steps from diosgenin.
Diosgenin is a phytosteroid sapogenin isolated from the tubers of Dioscorea wild yam.
Beclomethasone 17α,21- dipropionate is formed from the 17α- propionate and propanoic anhydride. The 17α-
propionate is formed via the 17α,21- orthoester. The 17α,21- orthoester is formed by reaction of beclomethasone and trimethyl orthopropionate (1,1,1-
HO
CH
3
Cl H
trimethoxypropane).
O
CH
3
H
O
CH2CH
O
O
CH2CH
CH
3
3
3
O
HO
CH
3
Cl H
O
CH
3
H
OH
O
O
O
CH
3
O
CH2CH
3
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
CH3CH
O
CH2CH
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