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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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H
OCH
3
Cefepime
OHO
OCH
H
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Anti- Infective Medicines/Antibacterials/Beta- Lactam Medicines
Cefepime 71
N
S
N
N
2
3
H
N
O
O
H
S
N
N
CH
3
Many cephalosporin antibiotics are semisynthetic. When
the cephalosporin target has a substituted methyl substituent or an alkene at position 3, it is often formed from
cephalosporin C.
Discussion. The side chain amide is formed in the final step from the amine and a thioester. The amine and carboxylic acid
are released by cleavage of N─Si and O─Si bonds. The quaternary ammonium salt is formed by displacement of iodide by
methylpyrrolidine. Iodide displaces the allylic acetate in a silylated derivative of 7- aminoce pha losporanic acid (7- ACA).
N7-
ACA is formed by enzyme- mediated hydrolysis of the side chain amide of cephalosporin C. Cephalosporin C is produced
by the fungus Acremonium chrysogenum.
N
S
N
H2N
3
H
N
O
O
H
S
N
N
CH
3
OCH
N
3
S
N
H2N
H
S
S
OHO
N
O
S
N
O
N
2
N
CH
3
OHO
(CH3)3SiH N
O
H
S
N
O
OSi(CH3)
N
CH
3
(CH3)3SiHN
O
H
S
N
O
OSi(CH3)
3
N
I
CH
3
C72
cephalosporin C
H
(C
OCH
OCH
CH
O
O
O
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H3)3SiH N
O
HO
H
S
N
O CH
3
O
O
OSi(CH3)
3
O
H
N
NH
2
O
H2N
S
N
(CH3)3SiNHSi(CH3)
O CH
3
3
O
O
OHO
7-ACA
H
S
7
1
N
3
O CH
3
O
O
OHO
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 thiazole ring is formed by reaction of an α–bromoketone with thiourea (Hantzsch
Thiazole Synthesis). The α- bromoketone is formed by bromination of the ketone. The O- methyloxime is formed
by O-
alkylation of the oxime. The oxime is formed by nitrosation of ethyl acetoacetate.
H2N
S
N
S
H2N
N
N
3
S
O
N
S
S
N
N
H2N
3
OH
O
N
N
S
S
S
S
OCH
N
3
OCH2CH
N
O
3
S
H2N NH
Br
2
O
OCH
3
N
OCH2CH
3
O
O
O
CH
3
N
CH3OSOCH
OH
O
3
3
O O
OCH2CH
O
3
CH
3
OCH2CH
3
CH
3
OCH2CH
3
Cefixime 73
OHO
H
O
O
H
7-AVCA
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Extended Discussion
Draw the structures of a retrosynthetic analysis of one alternative route which utilizes a different protection–deprotection strategy in the conversion of 7routes and select one route as the
ACA to the amine used in the final acylation step. List pros and cons for both
preferred route.
Cefixime
Anti- Infective Medicines/Antibacterials/Beta- Lactam Medicines
O
N
H
N
N
2
S
N
O
O
OH
H
S
N
Many cephalosporin antibiotics are semisynthetic. When
the cephalosporin target has a substituted methyl or an
alkene substituent at position 3, it is often formed from
cephalosporin C.
Discussion. The side chain carboxylic acid is released in the final step by ester hydrolysis. The side chain amide is formed
from the amine, 7-
amino- 3- vinylcephem- 4- carboxylic acid (7- AVCA), and a thioester.
O
H2N
N
H
N
S
N
O
OH
H
S
N
O
H2N
N
N
2
S
O
O
N
H
N
S
O
O
N
S
O
N
O
OCH
3
N
S
O
OCH
H
N
H2N
OHO
3
S
OHO
H
S
N
O
OHO
C74
H
H
H
P
3
cephalosporin C
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7-
AVCA is formed from 7- aminocephalosporanic acid (7- ACA) in an eight- step linear sequence. Four steps in the
sequence are protections or deprotections. The protecting groups are not specified in the analysis since there are two manufacturing routes which use the same sequence. The carboxylic acid is released by cleavage of protecting group P
amine is released by cleavage of a protecting group P
. The vinyl group is formed from the phosphonium salt and formal-
1
. The
2
dehyde (Wittig Reaction). The phosphonium salt is formed by leaving group (I, Br, Cl) displacement by triphenylphosphine. The halide is formed from the alcohol. The carboxylic acid is protected. The amine is protected. The alcohol is
formed from 7-
aminocephalosporanic acid (7- ACA) by hydrolysis of the ester. 7- ACA is formed by enzyme- mediated
hydrolysis of the side chain amide of cephalosporin C. Cephalosporin C is produced by the fungus A. chrysogenum.
H2N
O
P1N
O
N
1
O
N
7-AVCA
H
N
O
H
N
S
OHO
S
OP
2
S
OH N
OHO
P1N
H2N
H2N
O
H
N
O
O
H
O
S
N
O
S
S
OP
H H
OP
2
OHO
2
O
PPh
OH
3
H2N
O
P1N
P1N
O
H
N
S
N
O
S
OP
2
PPh
X=Cl,Br,I
OP
2
O
O
3
X
CH
O
H
N
O
S
OHO
HO
The thioester is formed from the carboxylic acid and 2,2′- dithiobis(benzothiazole). The thiazole ring is formed by reaction of an α–bromoketone with thiourea (Hantzsch Thiazole Synthesis). The α- bromoketone is formed from the ketone
and the carboxylic acid is formed by hydrolysis of the tert- butyl ester. The O- alkyloxime is formed by reaction of the oxime
with methyl chloroacetate. The oxime is formed by nitrosation of tert- butyl acetoacetate.
O
2
7-ACA
H
N
ONH
O
H
S
7
1
N
3
O
OHO
CH
3
O
Cefotaxime 75
O
O
O
O
O
OHO
3
OCH
H
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H2N
H2N
CH
O
O
N
N
S
OCH
N
3
N
H2N
S
S
O
S
N
O
N
OCH
3
OH
O
N
S
S
S
S
O
O
S
O
N
OC(CH3)
OCH
3
3
NH
O
2
N
OH
OCH
3
CH
3
Br
O
OH
N
3
OC(CH3)
O
O
O
O
Cl
OCH
3
3
CH
3
OC(CH3)
3
Extended Discussion
Identify the protecting groups P1 and P2 used in both routes to 7- amino- 3- vinylcephem- 4- carboxylic acid (7- AVCA). List the
pros and cons for both routes. Is one route preferred?
Cefotaxime
Anti- Infective Medicines/Antibacterials/Beta- Lactam Medicines
N
3
H
S
N
O CH
S
H
N
N
O
O
N
2
O
Many cephalosporin antibiotics are semisynthetic.
When the cephalosporin target has a substituted
methyl or an alkene substituent at position 3, it is
often formed from cephalosporin C.
C76
OCH
3
H
cephalosporin C
OCH
H
OCH
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Discussion. The side chain amide is formed in the final step from 7- aminocephalosporanic acid (7- ACA) and a thioester.
7-
ACA is formed by enzyme- mediated hydrolysis of the side chain amide of cephalosporin C. Cephalosporin C is produced
by the fungus A. chrysogenum.
N
3
H
N
H
S
S
N
O
N
O CH
3
O
H2N
O
OHO
OCH
N
S
N
N
2
3
S
O
N
S
O
H2N
H
S
N
O CH
O
OHO
7-ACA
O
H
S
7
1
N
3
O CH
3
HO
NH
H
N
2
O
O
O
OHO
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 thiazole ring is formed by reaction of an α–bromoketone with thiourea (Hantzsch
Thiazole Synthesis). The α- bromoketone is formed by bromination of the ketone. The O- methyloxime is formed
alkylation of the oxime. The oxime is formed by nitrosation of ethyl acetoacetate.
by O-
N
S
N
N
2
O
3
3
N
S
N
S
S
H2N
N
OH
O
N
N
S
S
S
S
Ceftaroline 77
OCH
CH
O
O
HO
HO
CH
3
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N
3
OCH2CH
S
N
O
3
S
H2N NH
Br
2
O
OCH
3
N
OCH2CH
3
O
H2N
O
O
N
3
O O
O
CH
3
OCH2CH
3
CH
3
O
OH
N
CH3OSOCH
OCH2CH
3
O
CH
3
3
OCH2CH
3
Extended Discussion
There are many alternative active esters which react with 7- ACA to form cefotaxime. Select one of these alternative
active esters.
1) Draw the structures of the reagent(s) used to prepare the active ester. Draw the structures of the retrosynthetic analysis
of each reagent from petrochemical or biochemical raw materials.
2) What is the yield of active ester?
3)
What is the yield of cefotaxime using this active ester?
What byproduct(s) form in the amide formation?
4)
Ceftaroline
Anti- Infective Medicines/Antibacterials/Beta- Lactam Medicines
N
N
S
O
Discussion. The side chain amide is formed in the final step from an amine and an acid chloride. The dichlorophosporamide is hydrolyzed in the workup of the final step. The carboxylic acid at cepham C4 is released from the diphenylmethyl
(benzhydryl) ester. The amine is released by cleavage of the side chain phenacetyl amide. The pyridine is alkylated by reaction with iodomethane. The thioether at cepham C3 is formed by displacement of methanesulfonate by the thiol.
N
NHP
OCH2CH
H
N
O
N
3
H
S
N
O
N
S
S
OO
Many cephalosporin antibiotics are semisynthetic. An oxygen or sulfur substituent at the 3-
position of a cephalosporin
is often formed from a 3- exomethylene substituent. The
cephalosporin with a 3- exomethylene substituent is often
formed from penicillin G (benzylpenicillin).
C78
CH
2
Ph
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3
N
HO
HO
OCH2CH
N
N
S
O
N
O
NHP
OCH2CH
3
3
H
H
N
7
O
1
S
N
N
3
S
4
OO
S
CH
3
N
2HCl
N
H
S
N
N
S
S
OHO
CH
3
I
N
Cl
N
Cl
H2N
S
O
N
NHP
O
O
Cl
CH
3
N
Cl
H2N
H
S
N
N
O
S
S
PhCH
2
H
N
O
O
H
S
N
N
S
S
N
O
OCHPh
2
O
OCHPh
2
N
CH3I
N
HS
OSO2CH
S
3
CH
H
2
N
O
O
H
S
N
N
S
O
OCHPh
S
2
PhCH
2
H
N
O
O
H
S
N
O
OCHPh
The methanesulfonate is formed by reaction of the enol with methanesulfonyl chloride. The sulfide is formed by reduction of the sulfoxide. The enol is formed by ozonolysis of the cephem C3 exomethylene substituent. The cephem with the
3- exomethylene substituent is formed by reaction of a sulfinyl chloride with an alkene. The sulfinyl chloride and alkene are
both formed by ring- opening of the penam sulfoxide. The penam sulfoxide is formed by oxidation of the penam sulfide.
The benzhydryl ester is formed by O- alkylation of the carboxylic acid of penicillin G. Penicillin G is produced by the fungus
P. chrysogenum.
Ceftaroline 79
H
Ph
H
Ph
penicillin G
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CH
PhCH
CH
H
2
N
S
PhCH
2
H
N
S
CH3SO2Cl
O
O
N
SO2CH
O
O
OCHPh
2
O
3
O
O
H
2
N
O
O
H
S
PhCH
2
N
OH
O
OCHPh
2
H
N
O
O
O
H
2
N
O
O
H
Cl
S
PhCH
2
H
N
N
CH
3
O
OCHPh
2
O
O
N
OH
O
OCHPh
2
O
H
S
N
O
S
OCHPh
CH
CH
OCHPh
2
3
3
2
O
H
N
O
PhCH
H
2
N
O
H
PhCH
S
CH
3
N
CH
3
2
O
H
N
O
O
O
O
CHPh
2
H
S
CH
3
N
CH
3
OH
O
Ph2CHCl
The acid chloride is formed by reaction of the carboxylic acid with phosphorus trichloride. The dichlorophosphoramide
is also formed. The carboxylic acid is formed by hydrolysis of the nitrile. The 1,2,4- thiadiazole ring is formed by reaction of
an amidine with potassium thiocyanate. The amidine is formed from a nitrile. (The desired diastereomer is the major product.) The C─O bond is formed by O- alkylation of the oxime. The oxime is formed by nitrosation of malononitrile.
C80
OCH2CH
Cl
3
2
HS
2
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O
P
KSCN
Cl
S
NH
HN
3
N
OCH2CH
OH
O
NC
3
N
S
N
H2N
CH3CH2Br
OH
N
CN
Cl
3
N
S
N
H2N
CH2CH
3
O
N
N
N
N
NH
O
OCH2CH
N
CN
NC
OCH2CH
N
CN
CNNC CN
4- (4- Pyridinyl)thiazole- 2- thiol is formed by the reaction of ammonium dithiocarbamate with the α–bromoketone.
Ammonium dithiocarbamate is formed from carbon disulfide. The α–bromoketone is formed by bromination of the ketone,
4- acetylpyridine.
N
N
N
CS
CH
3
N
S
Extended Discussion
O
NH
Br
S S
4
NH
O
2
Draw the structures of a retrosynthetic analysis of a more convergent alternative route where methylation of the pyridine
nitrogen is accomplished before formation of the thioether. List the pros and cons for both routes. Is one route preferred?
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