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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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Ceftazidime 81
OHO
H
O
H
2
O
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Ceftazidime
Anti- Infective Medicines/Antibacterials/Beta- Lactam Medicines
Many cephalosporin antibiotics are semisynthetic. When
CH
CH
3
3
OH
O
N
H
N
H
S
S
N
O
N
N
O
N
2
Discussion. Hydrolysis of a tert- butyl ester releases the side chain carboxylic acid in the final step. The side chain amide
is formed from the amine (7-
PyCA) and a thioester.
the cephalosporin target has a substituted methyl or an
alkene substituent at position 3, it is often formed from
cephalosporin C.
S
H2N
S
H2N
CH
3
CH
3
O
N
S
N
N
O
O
S
CH
CH
N
CH
CH
N
OC(CH3)
S
3
3
O
N
O
3
3
O
N
O
3
N
H
N
O
O
H
N
O
OH
H
N
OC(CH3)
H
N
H2N
S
N
OHO
3
S
N
OHO
H
S
N
O
OHO
7-PyCA
N
C82
cephalosporin C
(C
2HCl
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The amine and carboxylic acid of 7- PyCA are released by cleavage of N-Si and O-Si bonds. The pyridinium salt is formed
by displacement of iodide by pyridine. The iodide is introduced by displacement of the allylic acetate in a derivative produced by N and O-
silylation of 7- aminocephalosporanic acid (7- ACA). 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
H3)3SiHN
3
H
S
N
O
H
S
N
OHO
7-ACA
O CH
O
N
OSi(CH3)
3
O CH
O
(CH3)3SiNHSi(CH3)
3
I
3
3
H
S
N
O
OHO
7-PyCA
H
S
N
O
O
O
HO
NH
OSi(CH3)
2
N
N
I
3
H
N
O
O
(CH3)3SiHN
O
H2N
O
H
S
7
N
4
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 O- alkyloxime is formed by O- alkylation of the oxime with tert- butyl α- bromoisobutyrate.
The thiazole ring of is formed by reaction of the α–bromoketone with thiourea (Hantzsch Thiazole Synthesis). The αbromoketone is formed by bromination of the ketone. The oxime is formed by nitrosation of ethyl acetoacetate.
Ceftazidime 83
OO
OO
OO
O
O
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S
H2N
H2N
CH
CH
3
3
O
OC(CH3)
3
N
S
N
CH
CH
3
3
OC(CH3)
3
O
N
OH
S
N
O
S
N
O
H2N
N
3
S
S
Br
CH3CH
S
O
3
OC(C H3)
3
N
O
CH
3
CH
3
O
N
S
N
O
OC(CH3)
OCH2CH
3
OH
N
3
S
N
O
S
OCH2CH
H2N
NH
2
H2N S
OH
N
OCH3CH
CH
3
3
OH
N
OCH2CH
CH
3
3
OCH2CH
3
Br
Extended Discussion
Ceftazidime and cefixime both have a carboxylic acid on the amide side chain. In the ceftazidime retrosynthetic analysis,
the carboxylic acid precursor is a tert- butyl ester. In the cefixime retrosynthetic analysis, the carboxylic acid precursor is a
methyl ester. Why are different esters used?
C84
OCH
H
H
O
O
OCH
H
7-ACA
OH
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Ceftriaxone
Anti- Infective Medicines/Antibacterials/Beta- Lactam Medicines
N
3
H
N
H
S
Many cephalosporin antibiotics are
semisynthetic. When the cephalosporin
target has a substituted methyl or an
alkene substituent at position 3, it is
S
N
N
2
O
N
OHO
CH
SO
3
N
N
N
often formed from cephalosporin C.
Discussion. The side chain amide is formed in the final step from an amine (7- ACT) and a thioester. The side chain
thioether of 77-
ACA is formed by enzyme- mediated hydrolysis of the side chain amide of cephalosporin C. Cephalosporin C is produced
ACT is formed by displacement of the allylic acetate of 7- aminocephalosporanic acid (7- ACA) by the thiol.
by the fungus A. chrysogenum.
N
S
N
H2N
OCH
N
S
N
N
2
3
S
O
3
H
N
O
N
S
H2N
O
H
S
N
OHO
H2N
O
H
S
N
OHO
SO
CH
3
H
N
O CH
N
N
N
H
S
OHO
O
7-ACT
3
CH
O
O
S
3
HS
CH
N
N
N
H
N
3
O
O
N
N
O
Ceftriaxone 85
3
cephalosporin C
HO
O
OCH
O
CH
O O
O
O
O
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H
S
7
1
N
3
O CH
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 by O-
alkylation of the oxime. The oxime is formed by nitrosation of ethyl acetoacetate.
S
H2N
N
H2N
N
3
S
O
N
S
S
N
H2N
OCH
O
3
OCH2CH
3
NH
2
N
S
N
H2N S
N
Br
OCH
O
N
S
3
OH
O
N
S
OCH
S
3
S
N
OCH2CH
3
O
O
N
3
CH
OCH2CH
The thiol 1,2,4- triazineone ring is formed by the reaction of 1-methylhydrazine-1-carbothioamide with dimethyl oxalate.
1-Methylhydrazine-1-carbothioamide is formed by the reaction of methylhydrazine with potassium thiocyanate.
O
CH3OS
OH
3
3
CH
3
N
OCH2CH
OCH
3
O
3
CH
3
OCH2CH
3
C86
CH
O
HO
Cl
Cl
Cl
Cl
O
HO
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OCH3O
HS
N
N
N
3
O
OH
CH
S
3
NH
2
O
NH
CH3O
2
N
CH
KSCN
3
H
N
NH
2
Extended Discussion
The thiazole ring is formed in the final step in several alternative routes to ceftriaxone. Draw the structures for a retrosynthetic analysis for one of these alternative routes. List the pros and cons for both routes and select one route as the preferred route.
Chlorambucil
Antineoplastics and Immunosuppressives/Cytotoxic and Adjuvant Medicines
A β- chloroethylamine is a very reactive alkylating agent.
A β-
chloroethylamine is often formed from a β–amino
N
alcohol in the final step of the synthesis.
Discussion. The bis- (2- chloroethyl)amine is formed from the bis- (2- hydroxyethyl)amine in the final step. The carboxylic
acid is formed by hydrolysis of the methyl ester during the aqueous workup of the final step. The bisamine is formed by ring-
opening of ethylene oxide by the amine. The methylene directly attached to the ring is formed by
(2- hydroxyethyl)
reduction of the ketone. Under the ketone reduction conditions, the aniline is released from the acetanilide and the ester
is formed from the carboxylic acid. The aryl ketone is formed by the reaction of acetanilide with succinic anhydride
(Friedel–Crafts Acylation).
N
O
HO
H2N
O
HO
N
CH3O
O
CH3O
Chloramphenicol 87
HO
CH
O
OH
O
Cl
OH
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O
3
HN
CH3OH
O
O
CH
O
3
HN
O
O
O
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to chlorambucil from benzene. List the pros and
cons for both routes and select one route as the preferred route.
Chloramphenicol
Anti- Infective Medicines/Antibacterials/Other Antibacterials
When a target molecule has two adjacent chiral carbons, one chiral carbon
is often used to direct the formation of the other.
Cl
N
2
HN
Discussion. Chloramphenicol has been manufactured by fermentation and by at least 3 unique synthetic routes published
more than 50
years ago. These synthetic routes rely on a resolution of an intermediate to separate one enantiomer from a
racemic mixture.
In one preferred route utilizing a resolution, the amide is formed in the final step from the amine and methyl dichloroacetate.
The amine, (R,R)be resolved is released by hydrolysis of the acetamide. The 2-
2- amino- 1- (4- nitrophenyl)- 1,3- propanediol, is separated from the (S,S)- enantiomer by resolution. The amine to
acetamido- 1,3- propanediol is formed by reduction of the
2- acetamido- 3- hydroxyketone (Meerwein–Pondorf–Verley Reduction). Four stereoisomeric products are formed in this reduc-
tion. The (R,R)- and (S,S)- enantiomer pair crystallizes from the mixture. 2- Acetamido- 3- hydroxy- 1- (4- nitrophenyl)- 1- propanone is
formed by the reaction of 2- acetamido- 4′- nitroacetophenone with formaldehyde (Aldol Reaction). The acetamide is formed from
the amine and acetic anhydride. The amine is formed by bromide displacement from 2- bromo- 4′- nitroacetophenone by hexamethylenetetramine (Delepine Reaction). The α- bromoketone is formed by bromination of 4′- nitroacetophenone.
C88
OH
OH
O
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O2N
O2N
O2N
OH
OH
Cl
HN
O2N
(R,R)
OH
HN
O2N
NH
Cl
O
OHOH
2
(R,R) and (S,S) (R,R) and (S,S)
HN
OH
O
O
O2N
HN O
O
NH
2
OH
CH
3
H H
Cl
CH3O
Cl
O
O
O
CH
3
O
O
CH
3
O
Br
CH
3
NH
N
2
O
CH
3
O
2
O2N
O
CH
3
(CH2)6N
4
O2N
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to chloramphenicol which does not utilize a resolution of an intermediate. 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.
Chlorhexidine 89
Cl
Cl
Cl
N
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Chlorhexidine
Disinfectants and Antiseptics/Antiseptics
NH NH
H
N
A biguanide is formed by addition of an amine to a cyanoguanidine.
Discussion. The functional group on the left and right of symmetrical chlorhexidine is called a biguanide. The biguanide is
formed by addition of 4-
hexanediamine) to dicyanamide. Dicyanamide is formed in situ from sodium dicyanamide.
(1,6-
H
N
NH NH
H
N
N
H
N
H
N
H
chloroaniline to the nitrile of a cyanoguanidine. The cyanoguanidine is formed by addition an amine
H
N
Cl
Cl
H2N
NH NH
NH
2
Extended Discussion
NH NH
H
N
H
N
H
N
C
N
NH
H
N
NH
H
N
C
N
2
N
H
C
N
N
H
N
H
NH
N
H
C
Na
N
N
H
N
C
C
N
Draw the structures of the retrosynthetic analysis of an alternative route to chlorhexidine from the same starting materials.
List the pros and cons for both routes. Is one route preferred?
C90
NCl
CH
3
Cl
CH
NCl
3
Cl
Cl
OH
O
OH
O
Cl
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Chloroquine
Anti- Infective Medicines/Antiprotozoal Medicines/Antimalarial Medicines/For Curative Treatment
Anti-
Infective Medicines/Antiprotozoal Medicines/Antimalarial Medicines/For Prophylaxis
Medicines for Diseases of Joints/Disease-
Modifying Agents Used in Rheumatoid Disorders
HN
CH
3
3
N
CH
A nitrogen substituent at C2 or C4 on a quinoline ring is often
introduced by displacement of chloride.
Discussion. Chloroquine is a 1 : 1mixture of the (R)- and (S)- enantiomers. Chloride at C4 of 4,7- dichloroquinoline is dis-
1,N1
placed by N
- diethyl- 1,4- pentanediamine (novoldiamine) in the final step.
3
N
CH
3
Cl
H2N
CH
3
novoldiamine
HN
CH
3
N
CH
3
N
CH
4,7- Dichloroquinoline is formed from 7- chloro- 4- hydroxyquinoline (7- chloroquinolin- 4- one). 7- Chloroquinolin- 4- one is
formed by thermolysis/decarboxylation of the quinolonesis. The quinoline ring is formed by ortho-
ylenemalonate with 3example of the Gould-
chloroaniline. The four- step sequence from 3- chloroaniline to 7- chloro- 4- hydroxyquinoline is an
Jacobs Reaction.
N
CH3CH2O
O
N
H
O
OCH2CH
acylation of the aniline. The enamine is formed by reaction of ethyl ethoxymeth-
O
3
3- carboxylic acid. The carboxylic acid is formed by ester hydroly-
O
NH
NCl
OCH2CH
Cl
CH3CH2O
3
Cl
NH
N
H
O
2
O
OCH2CH
OCH2CH
Cl
3
3
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