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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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Tazobactam 421
O
O
N
O
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Extended Discussion
Draw the structures of the retrosynthetic analysis of an alternative route to tamoxifen. 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. Is one route preferred?
Tazobactam
Anti- infective Medicines/Beta- Lactam Medicines
H
N
formed by oxidation of the sulfide. A C─N bond is formed by
of one side product of this reaction.) The 2β(Draw the structure of the benzothiazolereaction mixture?) The alkene and disulfide are both formed by the reaction of the 1β-
-bromine is removed by reduction. The benzhydryl ester is formed by O- alkylation of the carboxylic acid. The 1β-
A 6α
O
S
CH
OH
3
N
N
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.
chloride displacement by 1,2,3- triazole. (Draw the structure
chloromethylpenam is formed by the reaction of an alkene and disulfide.
containing byproduct of this reaction. How is this byproduct separated from the
sulfoxide with 2- mercaptobenzothiazole.
sulfoxide is formed by oxidation of the sulfide. The amino group of 6- aminopenicillanic acid (6- APA) is replaced by bromide via the diazonium salt. 6-
Aminopenicillanic acid is formed by enzyme- mediated hydrolysis of the side chain amide
of penicillin G. Penicillin G (benzylpenicillin) is produced by the fungus Penicillium chrysogenum.
T422
penicillin G
O
2
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O
H
6
N
O
O
S
CH
1
2
3
N
N
N
O
OH
O
H
S
CH
3
N
N
O
OCH(Ph)
N
N
O
2
O
N
N
O
S
O
OCH( Ph)
CH
3
N
N
N
2
H
N
O
H
S
CH
3
Cl
N
OCH( Ph)
2
N
N
N
H
O
HS
CH
3
CH
3
OCH(Ph)
S
Br
O
H
S
CH
3
N
CH
3
O
2
O
O
CH(Ph)
S
H
S
S
N
O
H
S
N
O
CH
3
O
OCH( Ph)
2
O
O
Br
O
H
S
CH
3
N
CH
OH
3
N
NH
Br
O
2
O
Ph Ph
H
S
CH
3
N
CH
3
H2N
H
S
CH
3
N
CH
3
O
OH
O
O
OH
6-AP A
H
N
O
H
S
CH
3
N
CH
3
O
OH
O
1,2,3- Triazole is released by hydrogenolysis of 1- benzyl- 1,2,3- triazole. 1- Benzyl- 1,2,3- triazole is formed by
[3 + 2]- cycloaddition of benzyl azide and acetylene. Benzyl azide is formed from benzyl chloride.
Tenofovir Disoproxil 423
NH
3
CH
CH
3
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N
N
N
H
N
N
N
HC CH
N
3
Cl
Extended Discussion
Draw the structures of the retrosynthetic analysis of an alternative route to tazobactam that does not use 1,2,3- triazole. List
the pros and cons for both routes. Is one route preferred?
Tenofovir Disoproxil
Anti- infective Medicines/Antiviral Medicines/Antiretrovirals/Nucleoside or Nucleotide Reverse Transcriptase Inhibitors
Anti-
infective Medicines/Antiviral Medicines/Antihepatitis Medicines/Medicines for Hepatitis B/Nucleoside or Nucleotide
Reverse Transcriptase Inhibitors
2
A nucleotide analog is often formed from the nucleoside
analog (the phosphate is often introduced last). A nucleo-
N
N
side analog is often formed by displacement of a leaving
group on the sugar by N9 of adenine.
3
O
CH
3
O
CH
3
O
Discussion. The phosphonate diester is formed by dialkylation of the phosphonic acid with chloromethyl isopropyl carbon-
O
O
O
O
O
N
P
O
N
H
O
CH
ate. The phosphonic acid is formed by dealkylation of the diethyl phosphonate. The ether C─O bond is formed by displacement of para- toluenesulfonate (tosylate) by the (R)- alcohol (Williamson Ether Synthesis). The (R)- alcohol is formed by
the ring- opening of (R)- propylene carbonate with adenine. The tosylate is formed from diethyl hydroxymethylphosphonate
and para- toluenesulfonyl chloride.
T424
NH
NH
CH
CH
3
CH
3
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CH
CH
CH
CH
2
N
3
N
O
O
3
O
O
3
O
P
O
O
O
O
3
NH
2
N
N
N
N
H
N
N
H
CH
O
3
HO
P
CH
3
NH
2
N
N
H
HO
CH
N
N
3
CH
O O
O
3
N
Cl
NH
2
N
adenine
N
N
H
2
N
N
N
N
H
CH
O
3
OHO
O
O
O
CH
3
H
3CH2
3CH2
O
O
P
O
O
CH
3
CH3CH2O
O
O
S
O
Ar
CH3CH2O
P
CH3CH2O
O
CH3CH2O
Extended Discussion
Draw the structures of a retrosynthetic analysis of one route to (R)- propylene carbonate.
Terbinafine
Dermatological Medicines (Topical)/Antifungal Medicines
3
CH
N
CH
3
CH
A sp2C─spC bond is often formed by a transition metal-
catalyzed coupling of an aryl or vinyl halide (X=Cl, Br, I) with
a terminal alkyne. The (E/Z)- stereochemistry of the vinyl halide is usually retained in the product.
ArSO2Cl
OH
P
O
Testosterone 425
O
OH
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Discussion. The sp2C⏤spC bond is formed in the final step by coupling of the vinyl chloride with 3,3- dimethyl- 1- butyne
(Sonogashira Coupling). The tertiary amine is formed by displacement of the allylic chloride of 1,3a secondary amine. The secondary amine, N1-
chloromethylnaphthalene by methylamine. (Terbinafine is the trans- alkene. 1,3- Dichloropropene is manufactured as a
mixture of cis-
and trans- alkenes. At what point(s) in the process are the cis- and trans- diastereomers separated? Provide
methyl- 1- naphthylmethylamine, is formed by chloride displacement from
dichloropropene by
details for the separation process(es).)
CH
3
CH
CH
N
CH
CH
3
CH
3
3
CH
3
3
CH
N
3
Cl
CH
3
3
NH
ClCl
Cl
CH3NH
2
Extended Discussion
Draw the structures of the retrosynthetic analysis of an alternative route to terbinafine where the C-C bond is not formed
by a transition metal-
catalyzed coupling. 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.
Testosterone
Hormones, Other Endocrine Medicines and Contraceptives/Androgens
CH
CH
3
H
3
H
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. A steroid 4- ene- 3- one is often formed from the
5- ene- 3- ol by oxidation of the alcohol and double bond migration into conjugation with the ketone.
T426
O
OH
O
O
dehydroepiandrosterone acetate
CH
CH
3
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Discussion. Testosterone is manufactured in three steps from androst- 4- ene- 3,17- dione and four steps from a phytosterol.
In the final step, the 4migration. The 17βandrost-
4- ene- 3,17- dione with triethyl orthoformate. Androst- 4- ene- 3,17- dione is formed by microbial oxidation/side
ene- 3- one is released from the 3- ethoxy- 3,5- diene by hydrolysis of the enol ether and double bond
alcohol is formed by reduction of the C17 ketone. The 3- ethoxy- 3,5- diene is formed by reaction of
chain degradation of phytosterols (plant sterols) including stigmasterol.
CH
CH
H
3
H
H
CH
CH
HC(OCH2CH3)
H
3
H
3
H
Extended Discussion
3
CH3CH2O
O
3
HO
CH
OH
CH
3
H
3
H
H
CH
3
H
CH
3
H
H
CH3CH2O
CH
CH
3
CH
3
H
H
3
17
CH
CH
3
CH
3
3
H H
3
5
4
6
stig masterol
Diosgenin is a phytosteroid sapogenin isolated from the tubers of Discorea wild yam. Draw structures of the retrosynthetic analysis of an alternative route to testosterone from diosgenin via dehydroepiandrosterone acetate.
CH
3
O
O
CH
3
CH
H
3
CH
H
3
O
H
3
O
H
HO
H H
H
CH
3
diosgenin
H
O
Tetracaine
H
O
CH
CH
3
O
CH
H
HO
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Ophthalmological Preparations/Local Anesthetics
427Tetracaine
3
N
3
O
N
CH
A secondary amine is often formed by reductive amination from a primary amine and an aldehyde or
ketone.
Discussion. Tetracaine is formed by transesterification from the ethyl ester and 2- dimethylaminoethanol. The ethyl ester
is formed from the carboxylic acid (Fischer Esterification). 4tion from 4-
aminobenzoic acid and butanal.
3
CH
CH
3
3
CH
N
N
3
O
CH3CH2O
OH
N
H
O
(Butylamino)benzoic acid is formed by reductive amina-
CH
3
N
H
CH
3
O
CH3CH2OH
N
CH
3
HO
O
O
NH
H
2
CH
3
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to ethyl 4- (butylamino)benzoate. List the pros
and cons for both routes to ethyl 4-
(butylamino)benzoate. Is one route preferred?
T428
OH
O
CH
CH
2
OO
OH
CH
CH
2
tetracycline
CH
CH
8
9
NH
CH
OH
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Tetracycline
Opthalmological Preparations/Anti- infective Agents
CH
3
OH
3
H H
OH
3
N
Many tetracyclines are semisynthetic, they are formed by modification
of the C and/or D rings of a tetracycline natural product (tetracycline,
OH
NH
chlorotetracycline, oxytetracycline) or a tetracycline produced by a
mutant strain of S. aureofaciens (6-
emethyltetracycline, 7-
bromotetracycline).
demethyltetracycline, 7- chloro- 6- d
Discussion. Tetracycline is manufactured by fermentation or by hydrogenolysis of the chlorine of chlorotetracycline.
OH
CH
3
6
H H
5
7
10 11 12
OH O OH
3
OH
3
N
4
OH
3
ABCD
2
NH
1
O
2
O
Cl
OH
CH
OH
3
O
H H
3
OH
OH
chlorotetracyclin
3
N
OH
NH
OO
Thiamine
Vitamins and Minerals
2
N
3
N
CH
Cl
N
3
S
Discussion. Highly crystalline thiothiamine is oxidized to thiamine in the final step. The reaction of the dithiocarbamate
with aqueous acid forms the 3H- thiazole- 2- thione and releases the side chain alcohol by acetate ester hydrolysis (Hantzsch
Thiazole Synthesis). A dithiocarbamate salt formed in situ from 4- amino- 5- aminomethyl- 2- methylpyrimidine (Grewe
diamine) and carbon disulfide displaces chloride from an α- chloroketone to form the dithiocarbamate.
A thiazole is often formed by condensation of a thiourea or thioamide
with an α–haloketone.
Thiamine 429
CH
NH
CH
3
3
NH
CH
H
NC
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NH
2
Cl
N
3
N
CH
N
3
S
CH
3
OH
NH
2
N
S
N
H
S
O
O
3
N
CH
3
O CH
3
N
N
CH
2
CH
3
thiothiamine
NH
N
3
N
Grewe diamine
Cl
S
N
S
OH
2
NH
2
CS
2
O
O
O CH
CH
The side chain amine of Grewe diamine is released by hydrolysis of the formamide. The pyrimidine ring is formed from
acetamidine and the 3-
anilinoacrylonitrile.
2
NH
2
O
O
NC
N
3
N
Grewe diamine
NH
2
CH
NH
N
H
Cl
N
3
N
N
H
H
NH
CH
3
NH
2
The 3- anilinoacrylonitrile is formed from α–formyl- β- formylaminopropionitrile sodium salt and 2- chloroaniline. α–
Formyl- β- formylaminopropionitrile sodium salt is formed from 3- aminopropanenitrile, methyl formate, and carbon mon-
oxide. 3- Aminopropanenitrile is formed from acrylonitrile.
NH
O
NC
N
H
H
ONa
Cl
NH
2
O
O
CO
N
H
H
Cl
H OC H
NC
NH
3
NC
2
T430
O
3
CH
CH
2
CH
CH
CH
3
CH
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The alpha-chloroketone, 5- acetoxy- 3- chloro- 2- pentanone, is formed from 2- acetyl- 2- chlorobutyrolactone and acetic
anhydride by hydrolysis, decarboxylation, and acetylation. The α-
chlorolactone is formed by chlorination of α- acetyl- γ-
butyrolactone.
CH
O
Cl
3
O
O CH
3
CH
3
Cl
O
CH
O
O
O
CH
3
O
O
O
CH
O
3
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to thiamine from Grewe diamine. List the pros
and cons for both routes. Is one route preferred?
Tigecycline
Anti- infective Medicines/Antibacterials/Other Antibacterials
3
O
H
CH
N
N
H
3
3
N
OH
3
H H
O OH
3
OH
3
N
OH
NH
O
O
Many tetracyclines are semisynthetic, they are formed by modification of the C and/or D rings of a tetracycline natural
product (tetracycline, chlorotetracycline, oxytetracycline) or a tetracycline produced by a mutantstrain of Streptomyces
aureofaciens (6- demethyltetracycline, 7- chloro- 6- demethyltetracycline, 7- bromotetracycline).
Discussion. Tigecycline is manufactured from 7- chloro- 6- demethyltetracycline. The amide of the side chain at position 9
is formed from the acid chloride and 9- aminominocycline in the final step.9- Aminominocycline is formed by reduction of
the 9- nitrominocycline. 9- Nitrominocycline is formed by nitration of minocycline.
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