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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5671_Библиотеки_им_академика_М_И_Перельмана
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Budesonide 61
O
O
prednisolone
3
3
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The 9(11)- ene of the tetraene is formed by elimination of the C11β mesylate which is formed in situ. The 16- alkene is
formed by elimination of the 17αreaction of the 17α-
acetate with acetic anhydride. The 17α- acetate is formed from prednisolone 17α,21- ethyl orthoacetate.
acetate of prednisolone 17α,21- diacetate. Prednisolone 17α,21- diacetate is formed by
The orthoester is formed from prednisolone and triethyl orthoacetate.
CH
O
CH
3
O CH
3
SO2CH
3
O
H
3
H
CH
3
H
O
CH
3
H
H
O
O
CH
O
HO
CH
O
CH
3
H
3
O
O
CH
3
HO
CH
3
O
CH
3
O
H
O
O
CH
CH
3
O
H
O
H
O
H
H
O
CH
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to the key tetraene intermediate.
O
O
3
O
CH
3
HO
CH
3
H
O
CH
3
OH
OH
H
H
O
B62
O
3
O
21-acetoxypregna-1,4,9(11),16-tetraene-3,20-dione
3
3
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O
O CH
CH
CH
3
H
3
H
Bupivacaine
Anesthetics, Preoperative Medicines, and Medical Gases/Local Anesthetics
CH
3
H
N
N
O
CH
CH
A piperidine is often formed by catalytic hydrogenation of a pyridine.
Palladium, platinum, rhodium, ruthenium, and nickel catalysts have
all been used. The hydrogenation is often run under acidic conditions to prevent catalyst deactivation by the piperidine product.
Discussion. Bupivacaine is a 1 : 1mixture of enantiomers. Levobupivacaine, the (S)- enantiomer, is also manufactured for clinical
use. The tertiary amine of bupivacaine is formed in the final step by NThe amide is formed from 2,6-
dimethylaniline (2,6- xylidene) and the acid chloride. Pipecolic acid chloride hydrochloride is
formed from pipecolic acid. Pipecolic acid is formed by catalytic hydrogenation of 2-
CH
3
CH
H
N
O
CH
3
3
NH
CH
N
CH
3
Cl
2
O
N
HCl
H
3
HO
CH
3
N
H
O
alkylation of the secondary amine with 1- bromobutane.
picolinic acid.
H
N
CH
O
3
Br
HO
N
H
CH
3
N
O
Extended Discussion
Draw the structures of the retrosynthetic analyses for three alternative routes to bupivacaine from the same starting materials (2,6- dimethylaniline, picolinic acid, 1- bromobutane) using the same transformations (catalytic hydrogenation, amide
C─N bond formation, N- alkylation) in a different order.
O
3
3
CH
C
O
O
NH
3
CH
OH
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Caffeine
Specific Medicines for Neonatal Care/Medicines Administered to the Neonate
63
CH
3
N
O
N
N
N
A urea, thiourea, or amidine often provides the carbon at position 2 of a pyrimidine.
CH
Discussion. Caffeine is formed by methylation of theophylline. (List the methylating reagents and caffeine yield associated with each reagent.) Theophylline is formed by dehydration of 5,6-
formamide is formed by reaction of the 5,6- diamine with formic acid. The amine at position 5 results from reduction of
5the oxime. The oxime is formed by nitrosation of 6condensation of cyanoacetic acid with N,N′-
CH
3
CH
3
N
N
O
3
N
CH
O
N
N
3
H
N
CH
H
O
3
N
dimethylurea.
HO H
amino- 1,3- dimethyluracil. 6- Amino- 1,3- dimethyluracil is formed by
CH
NH
3
O
O
2
N
N
CH
the ophylline
H
N
N
3
CH
3
diamino- 1,3- dimethyluracil 5- formamide. The
CH3X
O
N
N
N
CH
3
CH
3
N
O
O
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
NH
O
2
O
N
CH
NH
O
2
N
CH
CH
NH
2
3
O
3
N
H
N
H
CH
3
O
HO
N
CH
O
3
CN
C64
H
O
O
O
1,3,5-triazine
O
H
H
H
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Extended Discussion
In one alternative route, theophylline is formed by the reaction of 5,6- diamino- 1,3- dimethyluracil with 1,3,5- triazine. Is
this alternative route preferred?
N
N
N
Calcium Folinate/Folinic Acid
Antineoplastics and Immunosuppressives/Cytotoxic and Adjuvant Medicines
Oxidative instability of a intermediate presents a sig-
H
O
N
N
2
N
H
O
N
N
H
N
H
HO
NH
OH
Discussion. Folinic acid (5- formyl- 5,6,7,8- tetrahydrofolic acid, leucovorin) is manufactured from another essential medicine,
folic acid, as a 1
tetrahydrofolic acid in the final step. (10- Formyl- 5,6,7,8,- tetrahydrofolic acid also forms in the hydrolysis. What are preferred
8conditions for formation of folinic acid?) 5,10and in situ dehydration of 10-
: 1mixture of two diastereomers [(6S,S) and (6R,S)]. Folinic acid is formed by hydrolysis of 5,10- methenyl- 5,6,7,
Methenyl- 5,6,7,8- tetrahydrofolic acid is formed by reduction of 10- formylfolic acid
formyl- 5,6,7,8,- tetrahydrofolic acid. 10- Formylfolic acid is formed from folic acid and formic acid.
nificant challenge when the intermediate is isolated. A
folinic acid synthesis avoiding the isolation of
5,6,7,8-
tetrahydrofolic acid and/or 10- formyl- 5,6,7,8-
tetrahydrofolic acid is preferred.
H O
O
N
H2N
N
2
N
H
O
N
N
N
N
H
H
N
Cl
N
NH
O
N
H
HO
N
HO
O
O
O
NH
HO
OH
O
Capecitabine 65
H
O
O
H
folicacid
O
OH OH
CH
3
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2
H2N
2
O
H
N
N
N
N
N
H
O
N
N
H
O
N
N
H
5
6
7
8
N
H
N
N
H OH
N
N
O H
O H
O
10
N
HO
O
N
HO
O
N
H
HO
O
NH
O
OH
O
NH
OH
O
NH
O
OH
Extended Discussion
The (6S,S)- diastereomer, levoleucovorin, is the biochemical cofactor associated with the desired pharmacological activity.
Draw the structures of a retrosynthetic scheme or draw a flow diagram for one route to levoleucovorin.
Capecitabine
Antineoplastics and Immunosuppressives/Cytotoxic and Adjuvant Medicines
A nucleoside is often formed by displacement of a leaving group on the sugar
HN
N
O
N
3
O
O
F
CH
by nitrogen of the heterocycle. The displacement usually results in a mixture
of two products, with the heterocycle on the top face (β) or the bottom face
(α) of the sugar. Factors which influence the β- product to α- product ratio
include the heterocycle, the sugar, the leaving group, and the reaction
conditions.
C66
O
3
3
O
3
3
3
O
O
OO
3
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Discussion. The hydroxyl groups are released by ester hydrolysis in the final step. The carbamate is formed from pentyl
chloroformate and the amine. The nucleoside CN bond is formed by displacement of the C1 acetate of
1,2,3-
triacetyl- 5- deoxyribose by N1 of the essential medicine flucytosine (5- fluorocytosine) (silyl–Hilbert–Johnson
Reaction). (What is the highest reported yield of the β–anomer? What reaction conditions are associated with the highest
yield? How are the α– and β-
HN O
N
anomers separated?)
F
CH
O
3
CH
HN O
F
N
CH
CH
CH
O
3
O
OH OH
N
O
3
O
O O
N
NH
N
2
CH
O
CH
CH
CH
O O
3
3
O
Cl
O
O
F
N
3
O
O
CH
3
O
NH
2
F
CH
3
O CH
3
N
O
O
O
O
CH
O O
3
O
CH
N
H
flucytosine
1,2,3- Triacetyl- 5- deoxy- - ribose is formed by reaction of 5- deoxy- - ribose with acetic anhydride. The three hydroxyl
groups of 5-
deoxy- - ribose are released by acetal hydrolysis. The methyl group at C5 is formed by reduction of
a p- toluenesulfonate ester. The p- toluenesulfonate ester is formed by reaction of p- toluenesulfonyl chloride with the C5
alcohol of methyl 2,3- O- isopropylidene- - ribofuranoside. Methyl 2,3- O- isopropylidene- - ribofuranoside is formed from
- ribofuranose, acetone, and methanol. - Ribofuranose is produced by fermentation.
CH
CH
3
O
3
O
O CH
O
CH
O
OO
3
CH
3
O CH
CH
3
O
OH OH
3
OH
CH
CH3CH
OCH
3
O
3
Carbamazepine 67
Ar
2
10 11
2
2
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SO
O
2
CH3CH
OCH
O
OO
3
3
ArSO2Cl
HO
OO
CH3CH
HO
OCH
O
3
D-ribofuranose
3
CH
O
OH OH
O
3
CH3OH
OH
CH
3
Carbamazepine
Anticonvulsants/Antiepileptics
Medicines for Mental and Behavioral Disorders/Medicines Used in Mood Disorders/Medicines Used in Bipolar Disorders
Diphenylamine and ammonia are formed by the reaction of two molecules of aniline
under strongly acidic conditions at elevated temperature.
N
O
NH
Discussion. Carbamazepine is formed by the reaction of 5H- dibenzo[b,f]azepine with potassium cyanate. 5H- Dibenzo
[b,f]azepine is formed from 10,11ibenzyl.) The azepine ring is formed by cyclization of 1,21,2-
bis(2- nitrophenyl)ethane. 1,2- bis(2- Nitrophenyl)ethane is formed by dimerization of 2- nitrotoluene.
5
N
O
NH
NH
2
2
dihydro- 5H- dibenzo[b,f]azepine. (These compounds are often called iminostilbene and iminod-
bis(2- aminophenyl)ethane. The diamine is formed by reduction of
NH
N
H
KOCN
2
NO
NO
2
N
H
CH
3
NO
C68
NH
3
OHO
NH
3
penicillin G
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Extended Discussion
List the reagent(s) used in one alternative route from 5H- dibenzo[b,f]azepine to carbamazepine. List the pros and cons for
both routes. Is one route preferred?
Cefalexin
Anti- Infective Medicines/Antibacterials/Beta- Lactam Medicines
2
H
N
H
S
Many cephalosporin antibiotics are semisynthetic. When the cephalosporin target has a methyl substituent at position 3, the core structure is often formed from penicillin G (benzylpenicillin).
O
O
N
CH
Discussion. The side chain amide is formed by the enzyme- mediated acylation of 7- aminodeacetox ycephalosporanic
acid (7tion of the side chain phenacetyl amide. Ring expansion from the five-
ADCA) with - α- phenylglycine methyl ester. The amine of 7- ADCA is released by enzyme- mediated deacyla-
membered ring of penicillin G to the sixmembered ring of phenacetyl 7- ADCA is also mediated by an enzyme. Penicillin G is produced by the fungus Penicillium
chrysogenum.
2
H
N
O
O
H
1
S
7
N
3
CH
3
NH
2
O
OCH
H2N
3
O
H
S
N
CH
H
N
O
O
PhCH
2
- α- Phenylglycine methyl ester is produced by resolution. - α- Phenylglycine methyl ester is formed from the carbox-
ylic acid and methanol (Fischer Esterification).
CH
CH
OH
OHO
3
3
OHO
H
S
N
CH
3
OHO
PhCH
2
H
N
O
O
H
N
7-ADCA
S
O
Cefazolin 69
H
N
3
H
3
N
3
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NH
2
OCH
3
O
NH
2
OCH
3
O
CH3OH
NH
2
OH
O
Extended Discussion
Draw the structures of a retrosynthetic analysis for an alternative nonenzyme route to phenacetyl 7- ADCA from penicillin
G. List the byproducts associated with each reagent used in the alternative route.
Cefazolin
Anti- Infective Medicines/Antibacterials/Beta- Lactam Medicines
H
N
N
N
N
O
O
S
N
O
OH
S
N
S
CH
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.
N
Discussion. The side chain amide of cefazolin is formed in the final step from an amine and a mixed anhydride formed
from 1H7-
aminocephalosporanic acid (7- ACA) by a thiol. 7- ACA is formed by enzyme- mediated hydrolysis of the side chain amide
tetrazole- 1- acetic acid. The side chain thioether is formed by displacement of the allylic acetate of
of cephalosporin C. Cephalosporin C is produced by the fungus Acremonium chrysogenum.
H
N
N
N
N
N
7
O
O
H2N
O
C(CH3)
3
N
O
N
N
O
O
1
S
N
3
S
N
N
S
OHO
CH
H
S
N
S
N
N
S
OHO
CH
C70
OHO
H
3
HO
HS
3
N
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H2N
S
N
N
O CH
3
N
O
7-ACA
O
HS
S
OHO
CH
O
H
S
N
O CH
3
NH
H
N
2
O
O
O
cephalosporin C
The mixed anhydride is formed from the carboxylic acid and pivaloyl chloride. 1H- Tetrazole- 1- acetic acid is formed in a
single step from glycine, triethyl orthoformate, and azidotrimethylsilane. Azidotrimethylsilane is formed from chlorotrimethylsilane and sodium azide.
HC(OCH2CH3)
3
N
N
N
N
O
O
O
C(CH3)
N
N
N
3
O
Cl C(CH3)
O
OH
3
(CH3)3SiN
H2N
3
O
glycine
(CH3)3SiC l
OH
The thiol, 2- mercapto- 5- methyl- 1,3,4- thiadiazole is assembled in a single step from thioacetamide, hydrazine, and carbon
disulfide.
N
N
CH
S
3
CS
NH
2
2
S
CH
Extended Discussion
Draw the structures of a retrosynthetic analysis of one alternative route to 1H- tetrazole- 1- acetic acid. List and discuss the
reactivity hazards(s) associated with both routes to 1H- tetrazole- 1- acetic acid.
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