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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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Permethrin
CH3CH
C
O
CH3CH
Cl
Cl
Cl
Cl
O
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Dermatologic Medicines (Topical)/Scabicides and Pediculicides
Permethrin 341
3
Cl
A cyclopropanecarboxylate is often formed from a γ-
halocarboxylate (X=Cl, Br).
l
O
O
Discussion. Permethrin is manufactured as a mixture of four stereoisomers. (Draw the structures of the four stereoisomers.)
phenoxybenzyl ester is formed in the final step by transesterification from the methyl ester. The cyclopropanecarboxylate
The 3is formed by chloride displacement from the γ-
ester by transesterification. (What is the ratio of the cisof 1,1,1ethyl-
trichloro- 4- methyl- 3- penten- 2- ol with triethyl orthoacetate (Johnson–Claisen Rearrangement). 1,1,1- Trichloro- 4- m
3- penten- 2- ol is formed by isomerization of 1,1,1- trichloro- 4- methyl- 4- penten- 2- ol. 1,1,1- Trichloro- 4- methyl- 4- penten- 2-
chlorohexenoate. During this reaction, the methyl ester is formed from the ethyl
and trans- products?) The γ- chlorohexenoate is formed by the reaction
ol is formed from chloral and isobutylene (Prins Reaction).
3
Cl
O
Cl
O
CH3CH
Cl
Cl Cl
CH
Cl
OH
3
CH
CH
3
O
3
OCH
3
HO
O
O
Cl
Cl
OCH2CH
3
CH
3
Cl
CH3C(OCH2CH3)
3
O
OH
CH
3
3
CH3OH
Cl
Cl
H
Cl
CH
3
CH
3
P342
HO
3
H
O
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3- Phenoxybenzyl alcohol is formed by reduction of the aldehyde or by hydrolysis of the benzyl chloride. The aldehyde is
formed by the oxidation of 3-
Phenoxytoluene is formed by chloride displacement from chlorobenzene by meta- cresol (Ullmann- type Reaction).
3-
phenoxytoluene. The benzyl chloride is formed by radical chlorination of 3- phenoxytoluene.
H
O
O
Cl
3
OCH
O
or
O
OHCH
Cl
Extended Discussion
Draw the structures of the retrosynthetic analysis of an alternative route to permethrin that uses carbon tetrachloride or
bromotrichloromethane as a starting material. List the pros and cons for both routes and select one route as the preferred
route.
Phenobarbital
Anticonvulsants/Antiepileptics
O
HN
N
CH2CH
O
3
A pyrimidine- 4,6- dione is often formed by the reaction of a malonate diester with an
amidine, thiourea, or urea.
Phenytoin 343
O
O
O
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Discussion. The pyrimidine ring is assembled by the reaction of diethyl 2- ethyl- 2- phenylmalonate with urea. The
2,2-
disubstituted malonate is formed by alkylation of the 2- phenylmalonate. Diethyl 2- phenylmalonate is formed from
ethyl phenylacetate and diethyl carbonate or diethyl oxalate (mixed Claisen Condensation).
O
HN
N
H
CH3CH2O OCH2CH
O
CH2CH
O
3
O
NH
3
CH3CH2O
2
NH
2
CH3CH2O
CH3CH2O
O
CH2CH
3
O
O
CH3CH2O
CH3CH2O
O
O
CH3CH2Br
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to phenobarbital from diethyl malonate or ethyl
cyanoacetate.
Phenytoin
Anticonvulsants/Antiepileptics
HN
O
NH
When a target molecule is readily accessible from inexpensive starting materials by
more than one route, reaction and workup procedures and equipment requirements
become key factors in the selection of a preferred route.
Discussion. Phenytoin is formed in a single step from benzil and urea (Blitz Synthesis).
HN
O
NH
O
O
O
H2N NH
2
P344
O
3
3
O
CH2CH
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Phenytoin is also formed in a single step from benzophenone, potassium cyanide, and ammonium carbonate (Bucherer–
Bergs Reaction).
HN
O
NH
O
KCN
(NH4)2CO
3
Extended Discussion
List the pros and cons for both routes to phenytoin and select one route as the preferred route.
Piperacillin
Anti- infective Medicines/Antibacterials/Beta- lactam Medicines
3
N
N
O
O
Penicillins are produced by fermentation or are semisynthetic. A
semisynthetic penicillin is often formed by acylation of the amine of
6- aminopenicillanic acid (6- APA). 6- APA is produced from penicillin
G (benzylpenicillin) by enzyme-
mediated hydrolysis of the side-
chain amide.
O
NH
H
N
O
H
S
CH
N
O
CH
OH
Discussion. Piperacillin is formed in a single step from another essential medicine, ampicillin. The urea is formed in the
O
CH2CH
3
3
O
O
Cl
Cl
H
6-aminopenicillanic acid(6-APA)
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final step by acylation of the ampicillin amine by a carbamoyl chloride.
345Piperacillin
3
N
N
O
NH
O
O
H
N
O
H
S
CH
3
N
CH
3
O
OH
O
CH2CH
N
N
Cl
3
O
O
NH
2
H
N
O
H
S
CH
N
CH
O
ampicillin
OH
The carbamoyl chloride is formed from 1- ethylpiperazine- 2,3- dione and phosgene. The piperazine- 2,3- dione is formed
from N-
ethylethylenediamine and diethyl oxalate.
CH2CH
3
N
O
CH2CH
N
3
O
CH2CH
NH
3
O
OCH2CH
3
N
O
O
N
H
O
NH
2
O OCH2CH
3
Cl
Extended Discussion
Draw the structures of the retrosynthetic analysis of an alternative and more convergent route to piperacillin from
6- aminopenicillanic acid (6- APA). List the pros and cons for both routes.
H2N
O
S
CH
3
N
O
CH
OH
3
P346
N N
Cl Cl
NCl
NCl
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Piperaquine
Anti- infective Medicines/Antiprotozoal Medicines/Antimalarial Medicines/For Curative Treatment
N N
N N
A nitrogen substituent on C2 or C4 of a quinoline ring is
often introduced by displacement of chloride by nucleophilic aromatic substitution. The substitution is facilitated by the ring nitrogen and can be further facilitated
by an electron- withdrawing group (NO
, SO2R, COOR,
2
CN) on C3 of the ring.
Discussion. The symmetry of piperaquine suggests disconnections back to 1,3- dibromopropane and 7- chloro- 4- (piperazin- 1- yl)
quinoline. The 4-
(piperazin- 1- yl)quinoline is formed by displacement of chloride from 4,7- dichloroquinoline by
piperazine.
N N
N N
N N
Cl Cl
H
N
Br Br
N
H
N
Cl
N
H
Praziquantel 347
Cl
Cl
Cl
O
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4,7- Dichloroquinoline is formed from 7- chloro- 4- hydroxyquinoline (7- chloroquinolin- 4- one). The quinolin- 4- one is
formed by thermolysis/decarboxylation of the quinolin-
4- one- 3- carboxylic acid. The carboxylic acid is formed by ester
hydrolysis. The quinoline ring is formed by acylation of the aromatic ring with loss of ethanol. The enamine is formed by
displacement of ethanol from the enol ether of ethyl ethoxymethylenemalonate by 3from 3-
chloroaniline to 7- chloro- 4- hydroxyquinoline is an example of the Gould–Jacobs Reaction.)
chloroaniline. (The four- step sequence
N
O
Cl
N
H
O
Extended Discussion
CH3CH2O
OCH2CH
OH
NCl
O
3
O
OCH2CH
NH
Cl
CH3CH2O
3
Cl
O
NH
O
N
H
2
O
O
OCH2CH
OCH2CH
OH
3
3
Draw the structures for two impurities often found in crude 7- chloro- 4- (piperazin- 1- yl)quinoline. List the details (equivalents of piperazine, solvent, temperature, time, workup procedure, yield, and purity/impurities) for the procedures used to
produce 7- chloro- 4- (piperazin- 1- yl)quinoline. Select one procedure as the preferred procedure.
Praziquantel
Anti- infective Medicines/Intestinal Anthelminthics
Anti- infective Medicines/Antichistosomal and Other Antitrematode Medicines
Amides are ubiquitous in drug structures. Amide formation from an
N
N
O
amine and acid chloride, anhydride, ester, or carboxylic acid is often very
efficient.
P348
O
O
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Discussion. Praziquantel is produced as a 1 : 1mixture of the (R)- and (S)- enantiomers. [Only the (R)- enantiomer is active.
There is considerable interest in a cost-
competitive route to the (R)- enantiomer.]
There are two routes to praziquantel. In Route A, the cyclohexanecarboxamide is formed in the final step from the amine
and cyclohexanecarbonyl chloride. The amine, 2,3,6,7-
tetrahydro- 1H- pyrazino[2,1- a]isoquinolin- 4(11bH)- one, is released by
hydrolysis of the benzamide. The piperazine ring is formed by chloride displacement by the benzamide. The chloroacetamide
is formed from chloroacetyl chloride and the secondary amine. In a single step, the primary amine is formed by hydrogenation
of the nitrile, the secondary amine is released by benzoyl migration to the primary amine, and the 3,4dihydroisoquinoline is reduced. The 1,2-
dihydroisoquinoline is assembled from isoquinoline, benzoyl chloride, and potas-
double bond in the
sium cyanide (Reissert Reaction). Isoquinoline is isolated from coal tar.
N
N
O
O
N
N
O
NH
O
Cl
H
N
Cl
N
NH
O
N
H
N
O
N
CN
Cl
O
Cl
O
O
Cl
KCN
In Route B, the cyclohexanecarboxamide is also formed in the final step from the amine and cyclohexanecarbonyl chloride. The amine, 2,3,6,7- tetrahydro- 1H- pyrazino[2,1- a]isoquinolin- 4(11bH)- one, is formed from 2- (2,2- dimethoxyethylam
ino)- N- phenethylacetamide (Pictet–Spengler Reaction). The 2- aminoacetamide is formed by chloride displacement
from the 2- chloroacetamide by aminoacetaldehyde dimethyl acetal. 2- Chloro- N- phenethylacetamide is formed from chlo-
roacetyl chloride and phenethylamine. Aminoacetaldehyde dimethyl acetal is formed from chloroacetaldehyde dimethyl
acetal.
O
N
Prednisolone 349
O
O
O
H
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O
CH3O
N
N
O
O
NH
OC
N
H
2
H
3
O
N
H
NH
H
OC
3
CH3O
Cl
CH3O
N
Cl
OC
NH
H
Cl
O
O
NH
3
Cl
2
Cl
Extended Discussion
Draw the structures of the components used to form praziquantel by a multicomponent Ugi Reaction.
Prednisolone
Antiallergics and Medicines Used in Anaphylaxis
Antineoplastics and Immunosuppressives/Hormones and Antihormones
Opthalmological Preparations/Anti- inflammatory Agents
A single- enantiomer molecule with multiple chiral carbons is often
CH
HO
CH
3
H
3
H
H
OH
O
formed by the modification of a natural product which has most or all
of the chiral carbons already in place. A steroid 1,4- diene- 3- one is
often formed by microbial dehydrogenation of the 4- ene- 3- one.
P350
O
O
O
OH
hydrocortisone
CH3O
3
2
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Discussion. Prednisolone is manufactured by microbial dehydrogenation of another essential medicine, hydrocortisone.
HO
CH
CH
3
H
3
H
H
OH
OH
HO
CH
3
H
O
CH
3
OH
H
H
Extended Discussion
List the alternative chemical methods used to convert hydrocortisone acetate to prednisolone acetate. List the pros and cons
for these methods.
Primaquine
Anti- infective Medicines/Antiprotozoal Medicines/Antimalarial Medicines/For Curative Treatment
A secondary amine is often formed by reductive amination from an aldehyde or ketone and a primary amine.
N
HN
NH
CH
Discussion. Primaquine is a mixture of (R)- and (S)-enantiomers. The primary amine of primaquine is released by cleavage of the phthalimide. The secondary amine is formed by reductive amination of N- (4- oxopentyl)phthalimide with
8- amino- 6- methoxyquinoline.
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