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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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Primaquine 351
CH3O
CH3O
CH
2
O
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HN
CH
N
HN
NH
2
3
CH
N
O
N
3
O
CH3O
NH
N
O
2
CH
3
O
N
O
8- Amino- 6- methoxyquinoline is formed from the 8- nitroquinoline. 6- Methoxy- 8- nitroquinoline is formed from
methoxy- 2- nitroaniline and glycerol (Skraup–Doebner–von Miller Synthesis).
4-
O
3
CH3O
CH3O
OH
OH
NH
N
NO
N
2
NO
NH
2
2
OH
N- (4- Oxopentyl)phthalimide is formed from 5- chloro- 2- pentanone by chloride displacement. (The chloride displacement by phthalimide and subsequent cleavage of the phthalimide to release the primary amine is an example of the
Gabriel Synthesis.) 5- Chloro- 2- pentanone is formed from α- acetyl- γ- butyrolactone.
O
O
CH
N
3
O
HN
O
O
O
O
CH
Cl
3
CH
3
O
P352
O
CH
H
CH
O
CH
CH
OCH2PhO
OH
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Extended Discussion
Draw the structures of the retrosynthetic analysis of an alternative route to primaquine from 8- amino 6- methoxyquinoline. Include the structures of the retrosynthetic analysis of any organic starting material(s) from petrochemical or biochemical raw materials. List pros and cons for the two routes and select one route as the preferred route.
Procarbazine
Antineoplastics and Immunosuppressives/Cytotoxic and Adjuvant Medicines
3
N
H
3
N
N
H
CH
3
In 1- methylhydrazine, N1 is more nucleophilic than N2.
Discussion. Both nitrogen atoms of the hydrazine are released by cleavage of carbamate protecting groups in the final
step. The amide is formed from the acid chloride and isopropylamine. The acid chloride is formed from the carboxylic acid.
The carboxylic acid is formed by hydrolysis of the methyl ester.
H
N
3
N
H
PhCH2O O
CH
N
3
N
OCH2PhO
3
N
H
O
Cl
H2N
PhCH2O O
CH
3
CH
CH
3
CH
3
N
N
OCH2PhO
PhCH2O O
CH
3
3
N
N
OCH2PhO
O
CH
3
N
H
CH
O
3
PhCH2O O
CH
3
O
OCH
3
N
N
Progesterone 353
O
CH
Br
O
CH
O
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The key C–N bond is formed by bromide displacement by the methylhydrazine dicarboxylate. Methyl
4-
bromomethylbenzoate is formed by bromination of methyl p- toluate. Dibenzyl 1- methylhydrazine- 1,2- dicarboxylate is
formed from methylhydrazine and benzyl chloroformate.
PhCH2O O
3
N
N
OCH2PhO
OCH
3
O
OCH
3
PhCH2O O
NH
3
N
OCH2PhO
CH
CH
3
CH
PhCH2O Cl
O
OCH
3
NH
3
2
N
H
O
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to procarbazine. List pros and cons for both
routes and select one route as the preferred route.
Progesterone
Hormones, Other Endocrine Medicines and Contraceptives/Contraceptives/Intravaginal Contraceptives
CH
3
H
H H
CH
3
3
H
A single- enantiomer molecule with multiple chiral carbons is often
formed by the modification of a natural product which has most or all of
the chiral carbons already in place.
P354
CH
CH
O
CH
16-dehydropregnenolone acetate
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Discussion. Progesterone is manufactured in three steps from 16- dehydropregnenolone acetate and in six steps from diosgenin. Diosgenin is a phytosteroid sapogenin isolated from the tubers of Discorea wild yam.
In the final step, progesterone is formed from pregnenolone by oxidation of the secondary alcohol at C3 and migration
of the double bond. Pregnenolone is formed by hydrolysis of pregnenolone acetate. Pregnenolone acetate is formed by
hydrogenation of 16- dehydropregnenolone acetate.
3
3
O
CH
3
H
CH
O
H
3
H H
CH
CH
3
H H
HO
3
O
CH
3
CH
3
H
H
CH
3
O
CH
3
H
CH
O
3
O
H
3
H H
CH
CH
H
3
O
H
3
O
H
The 16- alkene of 16- dehydropregnenolone acetate is formed from diosone by β- elimination. Diosone is formed by oxidation of the 20(22)diosgenin with acetic anhydride. The three-
alkene of pseudodiosgenin- 3,26- diacetate. Pseudodiosgenin 3,26- diacetate is formed by the reaction of
step synthesis of 16- dehydropregnenolone acetate from diosgenin by acetyla-
tion, oxidation, and elimination is known as the Marker Degradation.
CH
CH
CH
CH
CH
3
diosgenin
HO
CH
3
stigmasterol
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355Progesterone
3
O
3
CH
H
3
O
H
3
O
H
CH
3
O
CH
3
O
CH
O
3
O
CH
O
O
3
H
3
H
H
diosone
CH
H
CH
3
H
3
O
CH
3
CH
O
O
CH
O
3
CH
3
O
3
O
H
H
H
pseudodiosgenin-3,26-diacetate
21
CH
HO
3
H
CH
3
20
11
CH
1
2
3
4
5
H
3
9
H H
6
17
16
H
26
O
CH
22
O
CH
3
3
O
O
O
CH
3
Extended Discussion
Draw structures of the retrosynthetic analysis of an alternative route to progesterone from stigmasterol. List the pros and
cons for both routes.
CH
3
H
H H
CH
CH
3
3
H
CH
3
CH
3
P356
H
H
H
3
Cl
Cl
2
OHCH
CH
CH
3
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Proguanil
Anti- infective Medicines/Antiprotozoal Medicines/Antimalarial Medicines/For Prophylaxis
NH
NH
CH
3
A biguanide is formed by addition of an amine to a
cyanoguanidine.
N
N
N
CH
Discussion. The biguanide of proguanil is formed from 4- chloroaniline, isopropylamine, and dicyanamide. Dicyanamide
is available as the sodium salt.
CH
3
Cl
NH
N
H
NH
N
H
C
CH
3
N
H
CH
3
NN
C
N
H
C
N
Na
NH
N
H
N
H
NN
C
Cl
N
C
H2N CH
3
NH
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to proguanil from the same starting materials.
List the pros and cons for both routes. Is one route preferred?
Propofol
Anesthetics, Preoperative Medicines, and Medical Gases/Injectable Medicines
3
3
3
Every target molecule in this workbook must meet high purity specifications. When
the starting materials are inexpensive and the route is just one or two steps, the
CH
target molecule purification procedure is often a major contributor to the cost of
the drug.
Propranolol 357
CH
CH
OHO O OH
3
CH
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Discussion. Disconnection of the isopropyl substituents suggests phenol and propene or isopropanol are the starting
materials. Catalysts for the alkylation reaction include mineral acids and acidic zeolites. The search for the catalyst and
reaction conditions that result in both high phenol conversion and high propofol selectivity continues to this day. Since
propofol is a liquid (melting point 18
uct mixture into high-
purity propofol is an important contributor to the manufacturing cost.
°C) with a high boiling point (242 °C), the procedure for conversion of the crude prod-
OHCH
3
3
CH
3
CH
3
OH
CH2=CHCH
3
In an alternative route, the final step is the decarboxylation of the 4- hydroxy- 3,5- diisopropylbenzoic acid.
OHCH
3
3
CH
3
CH
3
CH
3
OHCH
3
CH
3
CH
3
OH
CH2=CHCH
3
Extended Discussion
Each target molecule has a list of known impurities. Draw the structures for propofol impurities A through P from the
European Pharmacopeia. Identify seven of these impurities which are most likely to be easily separated from propofol by
distillation.
Propranolol
Antimigraine Medicines/For Prophylaxis
O N
OH
3
H
CH
A β- amino alcohol is often formed by ring- opening of
an epoxide by an amine.
P358
CH
H
S
O
3
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Discussion. Propranolol is a 1 : 1mixture of the (R)- and (S)- enantiomers. The (S)- enantiomer is active. The β- amino alco-
hol is formed by ringformed by chloride displacement from epichlorohydrin by 1-
opening of the epoxide of glycidyl 1- naphthyl ether by isopropylamine. Glycidyl 1- naphthyl ether is
naphthol (Williamson Ether Synthesis).
CH
3
O
OH
N
H
CH
3
H2N
O
3
CH
3
O
Cl
O
OH
Extended Discussion
Review the Safety Data Sheet for epichlorohydrin. List the precautions to take before, during, and after the reaction of
epichlorohydrin with 1-
naphthol.
Propylthiouracil
Hormones, Other Endocrine Medicines and Contraceptives/Thyroid Hormones, and Antithyroid Medicines
A thiouracil is often formed by the reaction of a β- ketoester with thiourea.
HN
N
CH
Discussion. The ring is formed by condensation of thiourea with ethyl 3- oxohexanoate. Ethyl 3- oxohexanoate is formed
O
OO
2
HO
O
3
HO
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by the reaction of the acyl Meldrum’s acid with ethanol. Meldrum’s acid is acylated with butanoyl chloride.
HN
359Prostaglandin E1
CH
O
3CH2
NH
2
S NH
O
O CH
S
CH3CH2OH
3
N
H
CH
OO
O O
O CH
CH
3
CH
3
CH
3
O O
Meldrum'sAcid
Cl
3
O CH
CH
3
3
3
Extended Discussion
Draw the structures of a retrosynthetic analysis of an alternative route to ethyl 3- oxohexanoate. 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 as the preferred route.
Prostaglandin E
Specific Medicines for Neonatal Care/Medicines Administered to the Neonate
O
1
Prostaglandin analogs with the cyclopentanone core of
OH
prostaglandin E are often formed by conjugate addition
of an alkenylcuprate reagent to a cyclopent-2-en-1one. A 4-alkoxy or 4-trialkylsiloxy group on the α-face
of the cyclopent-2-en-1-one directs the conjugate
addition at C3 to the β-face.
CH
P360
O
O
P
3
3
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Discussion. Prostaglandin E1 (alprostadil) is formed in just three steps from (R)- norprostol. (R)- Norprostol is formed in
seven steps from suberic acid (1,8-
The C11 and C15 alcohols and the carboxylic acid are all released in the final step. (List the protecting groups P
used in this route to prostaglandin E1. Select one option for P
joining C3 of the ring and the side chain is formed by conjugate addition of an alkenylcuprate to the cyclopentof an alcohol-
protected (R)- norprostol. The alcohol of (R)- norprostol is protected. (R)- Norprostol is formed by enzyme-
octanedioic acid).
1
1
and one option for P2 to use in the analysis.) The C–C bond
and P2
2- en- 1- one
mediated hydrolysis of the racemic acetate ester. The racemic acetate ester is formed by the reaction of a mixture of norprostol and the isomeric 5separated from the (S)-
substituted 4- hydroxycyclopent- 2- en- 1- one with acetic anhydride. (R)- Norprostol is then
acetate and the (S)- acetate is racemized and recycled.
O
9
11
HO
O
O
1
Cu
O
O
CH
O
15
HO
2
OP
3
OH
1
CH
3
O
OCH
3
CH
3
O
OCH
3
P1O
HO
HO
O
P2O
O
(R)-norprostol
O
OH
O
O
norprostol
CH
OCH
3
CH
3
O
OCH
3
O
OCH
3
O
OCH
3
O
O
CH
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