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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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Nilotinib 311
O
O
O
O
OH
CH
O
CH
3
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N
N
2
N
2
O
O
N
CH
3
H
O2N
O
O
S
O
O
CH
H2N
N
O
CH
3
CH
3
O
3
O
O
S
O
CH
O
S
3
O
2- Methyl- 1,4- oxathiane- 4,4- dioxide is formed by oxidation of 2- methyl- 1,4- oxathiane. The 1,4- oxathiane is formed from
the diol. The diol is formed by ring-
O
O
S
3
CH
opening of propylene oxide with 2- mercaptoethanol.
CH
OH
S
3
CH
3
O
S
3
OH
O
SH
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to 4- amino- 3- methylthiomorpholine- 1,1- diox
ide. List the pros and cons for both routes to this intermediate and select one route as the preferred route.
Nilotinib
Antineoplastics and Immunosuppressives/Cytotoxic and Adjuvant Medicines
3
CH
3
N
N
N
CF
Initial disconnection of a bond near the center of a large molecule is often associated with the most convergent synthesis.
Amides are often efficiently formed by reaction of an amine with an acid chloride, anhydride, ester, or carboxylic acid.
H
N
O
N
H
N
N
Discussion. Nilotinib is rapidly assembled from three components of comparable complexity. The amide C-N bond is
formed from the ethyl ester.
N312
CH
CH
3
CH
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3
CH
3
N
N
N
H
N
N
H
N
O
N
CF
NH
3
2
CH3CH2O
CH
N
H
3
N
N
3
N
N
O
N
CF
The pyrimidine ring of the ester is formed from a guanidine and a β- amino- α,β- unsaturated ketone (Pinner Pyrimidine
Synthesis). The β-
dimethyl acetal. The guanidine is formed from the amine and cyanamide. Ethyl 3reduction of ethyl 4-
amino- α,β- unsaturated ketone is formed by the reaction of 3- acetylpyridine with dimethylformamide
amino- 4- methylbenzoate is formed by
methyl- 3- nitrobenzoate. Ethyl 4- methyl- 3- nitrobenzoate is formed by nitration of ethyl para- toluate.
3CH2
CH
N(CH3)
2
CH
3
N
O
O
HN
CH
3
NH
NH
N
N
H
N
2
CH
3
H2NCN
NH
2
O
CH
N
3
NO
2
CH3O
O
CH
3
CH
CH
3
N
OCH
3
3
N
3
CH3CH2O
O
OCH2CH
O
3
O OCH2CH
3
O OCH2CH
3
The amine for the final step is formed by displacement of bromide by 4- methylimidazole. [A side product is also
formed in this reaction. Draw the structure of the side product. List the options for the reaction conditions (catalyst
system, solvent, temperature, time) and the ratio of product to side product and the yield associated with each option.]
3- Bromo- 5- (trifluoromethyl)aniline is formed by reduction of 3- bromo- 5- nitrobenzotrifluoride. 3- Bromo- 5 nitrobenzotrifluoride is formed by bromination of 3- nitrobenzotrifluoride.
Nitrofurantoin 313
CH
3
3
3
O
O
O
O
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CH
3
3
N
N
NH
2
Br
CF
3
N
CF
NH
NH
Br NO
2
NO
2
CF
2
CF
Nitrofurantoin
Anti- infective Medicines/Antibacterials/Other Antibacterials
A semicarbazone is often formed by condensation of an
N
2
O
N
N
NH
Discussion. Nitrofurantoin is formed by condensation of the aldehyde and 1- aminohydantoin in the final step. [Is the (Z)isomer also formed in this condensation? If so, how is it separated from nitrofurantoin?] The aldehyde is released by in situ
hydrolysis of 51-
aminohydantoin can be in situ or can be a separate step. Which is preferred?) The hydantoin ring is formed from acetone
nitro- 2- furaldehyde diacetate. 1- Aminohydantoin is released by hydrolysis. (The hydrolysis to form
semicarbazone and ethyl chloroacetate. Acetone semicarbazone is formed from acetone and semicarbazide.
aldehyde or ketone with a semicarbazide.
CH
3
O
O
O2N
H
O2N
O
O
N
2
O
N
N
O
NH
O
H2N
N
CH
O
3
NH
O
CH
O
O
CH
3
O
N
N
3
O
NH
O
1-aminohydantoin
CH
O
N
3
CH
NH
3
O
NH
Cl
2
OCH2CH
3
CH
O
3
CH
H2N
3
O
N
NH
H
2
N314
O
1-aminohydantoin semicarbazinoacetic acid
O
O
norethisterone norethisterone enanate
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Extended Discussion
1- Aminohydantoin is formed in situ from semicarbazinoacetic acid. Draw the structures of a retrosynthetic analysis of
semicarbazinoacetic acid. List the pros and cons for both routes and to nitrofurantoin and select one route as the preferred
route.
CH
O2N
H
O2N
N
2
O
N
N
O
O
NH
H2N
O
O
N
O
O
NH
H2N
O
CH
3
N
O
NH
2
O
3
O
O
O
OH
O
NorethisteroneandNorethisteroneEnanate
Hormones, Other Endocrine Medicines, and Contraceptives/Contraceptives/Oral Hormonal Contraceptives
Hormones, Other Endocrine Medicines, and Contraceptives/Contraceptives/Injectable Hormonal Contraceptives
CH
3
H H
H
O
CH
H
O
3
A single-
OH
CH
3
H
H
H
H
enantiomer molecule with multiple chiral carbons is often formed by modification of a natural product which
hasmostorallofthechiralcarbonsalreadyinplace.AsteroidmissingtheC19methylgroup(a19-nor-steroid)isoften
formed by Birch Reduction of a steroid with an aromatic A- ring.
Discussion. Norethisterone is manufactured in seven steps from estrone and in 10 steps from β- sitosterol. Norethisterone
enanate is manufactured in 2 steps from norethisterone.
315
OH
OH
CH
estrone
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The 4- ene- 3- one of norethisterone (norethindrone) is formed from the 3- ethoxy- 3,5- diene by hydrolysis of the enol ether
followed by double bond migration. The tertiary alcohol at C17 is formed by addition of a metal acetylide to the C17ketone.
ethoxy- 3,5- diene is formed by reaction of estr- 4- ene- 3,17- dione with triethyl orthoformate. The 4- ene- 3- one is
The 3formed from the 3is formed by oxidation of the secondary alcohol. The 3formed in the reduction of estrone methyl ether (Birch Reduction). Estrone methyl ether is formed by Oestrone (Williamson Ether Synthesis). (List the methylating agents used for this O-
methoxy- 2,5- diene by hydrolysis of the enol ether followed by double bond migration. The ketone at C17
methoxy- 2,5- diene and the secondary alcohol at C17 are both
methylation of
methylation. List the reaction condi-
tions and yield of estrone methyl ether for each methylating agent.)
3CH2
CH
3
H H
H
O
H H
H
O
H
H
CH3CH2O
O
CH
3
HC CH
H
O
O
CH
3
H
H
HC(OCH2CH3)
H H
H
H H
H
3
H
CH
3
H
O
CH
3
H
OH
CH
3
H
H
CH3O
CH
3
O
Estrone is formed by A- ring aromatization from androsta- 1,4- diene- 3,17- dione 17- ethylene glycol ketal (acetal). The
acetal is formed from androsta- 1,4- diene- 3,17- dione (boldione) and ethylene glycol. Androsta- 1,4- diene- 3,17- dione is
formed by microbial oxidation/side chain degradation of phytosterols (plant sterols) including β- sitosterol.
CH3O
O
CH
3
H
H
H
CH3X
HO
H
H
CH
H
O
3
N316
HO
3
β
CH
O
norethisterone
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O
CH
3
H
H
H
CH
3
H
O
CH
3
O
H
H
O
CH
3
CH
3
O
CH
3
OH
HO
CH
O
H
3
H
H
HO
19
CH
1
2
3
4
5
18
CH
20
3
H
H
3
H
6
17
H
-sitosterol
CH
CH
3
A diester is formed by reaction of norethisterone with heptanoic anhydride (enanthic anhydride). Hydrolysis of the enol
ester and double bond migration releases norethisterone enanate.
O
CH
3
CH
O
3
H H
H
H
O
OH
CH
3
3
CH
O
3
H H
H
H
O
CH
O
3
H H
H
H
CH
3
O
O O
O
CH
3
Extended Discussion
Draw the structures of the retrosynthetic analysis of an alternative route to norethisterone from estrone methyl ether that
does not have the 3- ethoxy- 3,5- diene as an intermediate.
CH
3
O
OH
O
3
O
O
3
3
3
O
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Ofloxacin
Ophthalmological Preparations/Anti- infective Agents
F
N
N
O
N
CH
Nucleophilic aromatic substitution is often facilitated
by an electron-
withdrawing group (NO
, SO2R, COOR,
2
CN) on an ortho or para ring carbon. No electronwithdrawing group is required when the displacement
results in the formation of a five-
or six- membered ring.
Leaving groups for nucleophilic aromatic substitution
include fluorine, chlorine, and nitro.
317
Discussion. Ofloxacin is a 1 : 1mixture of the (R)- and (S)- enantiomers. Fluoride at C7 of the quinolone ring is displaced
methylpiperazine in the final step. The carboxylic acid is released by ester hydrolysis.
by 1-
CH
F
N
N
CH
3
F
F
NH
N
O
O
O
N
CH
3
N
CH
O
F
OH
F
OH
3
O
N
O
O
OCH2CH
CH
A ring and the C-O bond at quinolone position 8 are formed by intramolecular displacement of fluoride by the alcohol.
The quinolone ring is formed by intramolecular displacement of fluoride by the amine. An enamine is formed by displacement of ethanol from the enol ether by 2- amino- 1- propanol (- alaninol) followed by elimination of ethanol. (Draw the
structures of the retrosynthetic analysis of one alternative route to 2- amino- 1- propanol.)
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
O318
F
F
OH
F
O
O
F
F
O
O
F
O
O
F
F
F
F
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O
OCH2CH
N
O
F
CH
3
O
F
O
NH
OCH2CH
CH
3
F
3
F
F
F
3
F
N
OH
O
F OCH2CH
F
CH
3
O
O
OCH2CH
OCH2CH
3
3
3
NH
2
CH
3
OH
The enol ether is formed by reaction of the β- ketoester with triethyl orthoformate. The β- ketoester is formed from
tetrafluorobenzoyl chloride. In one preferred approach, diethyl malonate is the reaction partner. (The four- step
2,3,4,5conversion of the 2-
fluorobenzoyl chloride to the quinolone is known as the Grohe–Heitzer Sequence.) The acid chloride
is formed from the carboxylic acid.
OCH2CH
F OCH2CH
F
O
CH3CH2O
Cl
F
Extended Discussion
Draw the structures of the retrosynthetic analysis of 1,2,3- trifluoro- 4- nitrobenzene from petrochemical or biochemical
3
3
O O
F
F
OCH2CH
OCH2CH
F
HC(O CH2CH3)
F
O
3
F
F
F
3
2
OH
raw materials. Draw the structures of the retrosynthetic analysis of one alternative route to ofloxacin from
1,2,3- trifluoro- 4- nitrobenzene. List the pros and cons for the two routes to ofloxacin.
Ombitasvir
CH
3
CH
H
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Anti- infective Medicines/Antiviral Medicines/Antihepatitis Medicines/Medicines for Hepatitis C/Other Antivirals
Ombitasvir 319
CH
CH
OCH
3
HN
3
N
3
O
O
H
N
O
CH
3
CH
3
3
N
CH3O
H
N
O
O
H
N
CH
3
CH
3
N
When a target molecule has an axis of
symmetry, a preferred route often has
O
intermediates which also have an axis
of symmetry.
Discussion. The proline amides are formed in the final step by reaction of the 2,5- bis(4- aminophenyl)pyrrolidine with the
carboxylic acid of the Moc-
CH
3
HN
CH
3
N
dipeptide N- (methoxycarbonyl)- - valyl- - proline (Moc- val- pro- OH).
OC
H
3
CH
O
O
H
N
O
3
3
CH
3
CH3O
H
N
O
O
H
N
CH
CH
N
N
O
3
CH
CH
3
3
CH
3
CH
O
3
H
N
O
O
CH
CH
3
3
N
N
2
N
NH
2
HO
O
The (2S,5S)- bis(4- aminophenyl)pyrrolidine is formed by reduction of the (2S,5S)- bis(4- nitrophenyl)pyrrolidine. The
(2S,5S)- bis(4- nitrophenyl)pyrrolidine is formed by the reaction of 4- tert- butylaniline with the (1R,4R)- dimethanesulfonate.
The (1R,4R)- dimethanesulfonate is formed from the (1R,4R)- diol. The (1R,4R)- diol is formed by reduction of the 1,4- dione.
1,4- bis(4- Nitrophenyl)- 1,4- butanedione is formed from 2- bromo- 4′- nitroacetophenone and 4′- nitroacetophenone.
O320
H
CH
2
CH
Br
CH
OBn
CH3O
N
3
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CH
N
2
3
CH
3
3
NH
2
N
CH3SO
2
OO
SO2CH
3
O2N NO
OHOH
O2N NO
O O
O2N NO
O2N
H2N
2
CH3OSOCH
2
2
O2N
CH
3
CH
3
3
NO
N
CH
3
CH
3
CH
3
O
3
O
O
NO
2
CH
3
O
The carboxylic acid of the Moc- dipeptide is released by hydrogenolysis of the benzyl ester (Moc- val- pro- OBn). The Mocdipeptide amide is formed by reaction of the carboxylic acid of Moc- - valine (Moc- val- OH) and the amine of - proline
benzyl ester (H-
pro- OBn).
O
3
H
N
O
O
CH
CH
3
3
N
HO
O
CH3O
O
BnO
H
N
O
N
O
CH
CH
CH3O
3
3
H
N
O
O
Moc-L-valine
OH
CH
CH
3
3
O
N
H
Omeprazole
Gastrointestinal Medicines/Antiulcer Medicines
O
N
N
H
CH
3
S
OCH
3
A thioether is often formed by displacement of a leaving group by a thiol.
CH
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