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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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Fluoxetine 181
RouteA
CF
3
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Discussion. Manufacturers with the process equipment and expertise to work with electrophilic fluorinating agents
produce 5-
fluorouracil by fluorination of uracil or fluorination of cytosine followed by hydrolysis of the amino group. List
the options for starting material (uracil or cytosine), fluorinating agent, solvent, reaction temperature, reaction time, and
the yield of 5-
fluorouracil associated with each option.
HN
N
O
N
H
uracil
NH
N
H
NH
N
N
H
cytosine
2
2
F
O
RouteB
O
HN
O
O
HN
N
H
O
N
H
F
O
F
O
Extended Discussion
Draw the structures of a retrosynthetic analysis of one alternative route to 5- fluorouracil from sodium fluoroacetate. Include the
structures of the retrosynthetic analysis of sodium fluoroacetate and any other organic starting material(s) from petrochemical
or biochemical raw materials.
Fluoxetine
Medicines for Pain and Palliative Care/Medicines for Other Common Symptoms in Palliative Care
Medicines for Mental and Behavioral Disorders/Medicines Used in Mood Disorders/Medicines Used in Depressive Disorders
The trifluoromethyl group is often formed from a trichloromethyl group by
halogen exchange (Halex Reaction).
O
NHCH
3
Discussion. Fluoxetine is a 1 : 1mixture of (R)- and (S)- enantiomers. The ether is formed in the final step by displacement
of chloride from 4- chlorobenzotrifluoride by 3- methylamino- 1- phenyl- 1- propanol. (List all the options for the base, solvent, catalyst, reaction temperature, and time. Which reaction conditions are preferred?) The alcohol and the amine are
released by carbonate and carbamate hydrolysis. The carbonate and carbamate are formed by reaction of 3- dimethylamin
o- 1- phenyl- 1- propanol with ethyl chloroformate. The secondary alcohol is formed by reduction of the ketone. 3- Dimethyl
amino- 1- phenyl- 1- propanone is formed from acetophenone, formaldehyde, and dimethylamine (Mannich Reaction).
F182
S
CF
OH
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CF
3
O
NHCH
3
O
O
O
OCH2CH
N
O
N
CH
3
CH
3
OCH2CH
CH
3
3
3
OH
OH
O
CH
Cl
3
NHCH
CH
N
CH
3
O
H H
CF
3
3
3
(CH3)2NH
Extended Discussion
Draw the structures for the retrosynthetic analysis of one alternative route to 3- methylamino- 1- phenyl- 1- propanol. 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 to this intermediate.
Fluphenazine
Medicines for Mental and Behavioral Disorders/Medicines Used in Psychotic Disorders
Nucleophilic aromatic substitution is often facilitated
by an electronCN) on an ortho or para ring carbon. No electron-
3
N
withdrawing group is required when the displacement
results in the formation of a five- or six- membered ring.
N
Leaving groups for a nucleophilic aromatic substitution
include fluorine, chlorine, and nitro.
N
Discussion. A tertiary amine is formed in the final step by displacement of chloride by 2- (1- piperazinyl)ethanol. Another
tertiary amine is formed by the displacement of bromide in 1- bromo- 3- chloropropane by 2- trifluoromethyl- 10H- phenoth
iazine. 2- (1- Piperazinyl)ethanol is formed by ring- opening of ethylene oxide with piperazine.
withdrawing group (NO
, SO2R, COOR,
2
S
CF
CF
S
S
CF
CF
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Fluphenazine 183
9
10
3
1
N
N
N
OH
S
3
N
CF
3
S
N
H
ClBr
Cl
HN
N
HN
O
NH
OH
2- Trifluoromethyl- 10H- phenothiazine is formed by intramolecular displacement of a nitro group by a formamide followed
by amide hydrolysis under the ringthioether is formed by chloride displacement by the thiol. The thiol, 2from 4-
chloro- 3- nitrobenzotrifluoride by displacement of chloride by sodium sulfide followed by reduction of the nitro group
Chloro- 3- nitrobenzotrifluoride is formed by nitration of 4- chlorobenzotrifluoride.
.4-
formation conditions. The formamide is formed from the amine and formic acid. The
amino- 4- (trifluoromethyl) benzenethiol, is formed
CF
3
N
H
CF
3
S
S
N
O H
Cl
O2N
NO
3
NH
2
CF
3
NH
NO
2
2
SH
O
HO
NH
2
Cl
S
O2N
CF
CF
H OH
3
3
Cl
S
3
NO
2
CF
3
NO
2
CF
3
F184
OH
H
2
O OH
O OH
H
Cl
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Extended Discussion
Draw the structures of the retrosynthetic analysis of an alternative route to 2- trifluoromethyl- 10H- phenothiazine from
chloro- 4- nitrobenzotrifluoride. Draw the structures for the retrosynthetic analysis for 3- chloro- 4- nitrobenzotrifluori
3de from petrochemical or biochemical raw materials. List the pros and cons for both routes to 2-
trifluoromethyl- 10H-
phenothiazine and select one route as the preferred route.
Folic Acid
Medicines Affecting the Blood/Antianaemia Medicines
amino- 4- hydroxypteridine is often
O
O
HN
N
N
N
N
N
H
N
H
O
A 2formed by
– 6α-
hydroxy aldehyde or ketone.
condensation of 2,4,5- tetra amino
hydroxypyrimidine with an α- halo or
Discussion. Folic acid has one chiral carbon with the (S)- configuration. The chiral carbon is delivered in the starting
material L-glutamic acid. Folic acid is assembled in a single step from three components: 2,4,5- triamino- 6- hydroxypyrimidine,
N-
(4- aminobenzoyl)- - glutamic acid, and 1,1,3- trichloroacetone. 1,1,3- Trichloroacetone is formed by chlorination of
acetone.
O
O
H2N
N
N
N
H
O OH
O
N
H
O
Cl
Cl
HN
H2N
O
HN
N
2
N
NH
NH
N
2
2
N
H
OH
O
OH
O
CH
O
CH
3
3
2,4,5- Triamino- 6- hydroxypyrimidine is formed by reduction of the 5- nitrosopyrimidine. The Nitrosopyrimidine is
formed by nitrosation of 2,4- diamino- 6- hydroxypyrim-idine.
Fomepizole 185
H
2
H
O OH
OH
O OH
L- glutamic acid
N
H
CH
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HN
O
NO
N
NH
2
H2N
HN
O
N
NH
O
NH
NH
2
2
H2N
HN
N
2
N
N- (4- Aminobenzoyl)- - glutamic acid is formed by reduction of N- (4- nitrobenzoyl)- - glutamic acid. The amide is formed
from 4-
nitrobenzoyl chloride and - glutamic acid. - Glutamic acid is produced by fermentation.
O
N
H
N
2
O2N
OH
O
O
Cl
O2N
OH
O
NH
2
O
OH
N
H
O
O
Extended Discussion
List the many challenges associated with manufacturing of high- purity 1,1,3- trichloroacetone. Other reagents have been
used in a three- component condensation with 2,4,5- triamino- 6- hydroxypyrimidine and N- (4- aminobenzoyl)- - glutamic
acid to produce folic acid. Draw structures for three of these reagents.
Fomepizole
Antidotes and Other Substances Used in Poisonings/Specific
3
A pyrazole is often formed from hydrazine and a 1,3equivalent.
N
Discussion. Disconnections suggest fomepizole is formed from hydrazine and methylmalonaldehyde. The stable diacetal,
tetraethoxy- 2- methylpropane, serves as a functional equivalent of the unstable dialdehyde. 1,1,3,3- Tetraethoxy- 2- m
1,1,3,3ethylpropane is formed from 1- ethoxy- 1- propene and triethyl orthoformate. 1- Ethoxy- 1- propene is formed from
1,1- diethoxypropane by the elimination of ethanol.
dicarbonyl compound or its functional
F186
CH
OCH2CH
3
HO
OH
O
3
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3
3
N
N
H
CH
CH3CH2O
3
OCH2CH
OCH2CH
3
HC(OCH2CH3)
3
3
CH
OCH2CH
CH
3
OCH2CH
3
3
OCH2CH
3
Extended Discussion
Alternative routes to fomepizole proceed via 4- methyl- 4,5- dihydropyrazole, 4- methylpyrazole- 3,5- dicarboxylic acid,
4-
methylpyrazole- 3- carboxylic acid, and 3,5- diamino- 4- methylpyrazole. Draw a retrosynthetic scheme for one of these alternative routes. Include the structures of the retrosynthetic analysis of any organic starting material(s) from petrochemical or
biochemical raw materials. Compare the two routes and select one route as the preferred route.
Formoterol
Medicines Acting on the Respiratory Tract/Antiasthmatic and Medicines for Chronic Obstructive Pulmonary Disease
H
N
CH
3
OH
NHH
H
N
OCH
3
A β- amino alcohol with a primary
β-
C is often formed by ring- opening
of an epoxide by an amine.
O
HO
Discussion. Formoterol is a 1 : 1mixture of the (R,R)- and (S,S)- enantiomers.
All four stereoisomers have been evaluated for bronchodilation activity. The potency order is: R,R > R,S = S,R > S,S. The
(R,R)- enantiomer is 1000 times more potent than the (S,S)- enantiomer.
The phenol and the secondary amine are released in the final step by hydrogenolysis of the benzyl ether and benzyl
amine. The (R,R)- and (S,S)- enantiomers of dibenzylformoterol are separated from the (R,S)- and (S,R)- enantiomers of
dibenzylformoterol by crystallization of the fumarate salts.
NHH
CH
3
OCH
HO
OH
Bn
O
OH
Bn
3
R,Sand S,R
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Formoterol 187
H
N
CH
3
NHH
R,Rand S,S
OCH
3
O
OH
Bn
HO
O
N
OH
O
CH
Bn
3
OCH
3
O
NHH
O
R,Rand S,S
OH
N
CH
BnO
NHH
R,Rand S,S
3
OCH
3
R,Sand S,R
The amide is formed by acylation of the aniline with the mixed anhydride from formic acid and acetic anhydride.
The aniline is formed by reduction of the nitroaromatic.
N
CH
Bn
N
Bn
N
CH
CH
3
3
3
OCH
OCH
OCH
3
3
CH
H OH
O
3
BnO
O
CH
BnO
3
BnO
O
O
NHH
O
NH
NO
R,Rand S,S
R,Sand S,R
OH
2
2
R,Rand S, S
R,Sand S,R
OH
R,Rand S,S
The alcohol is formed by reduction of the ketone. The tertiary amine is formed bromide displacement from the αbromoketone by the secondary amine.
F188
OH
Bn
Bn
2
3
O
3
2
O
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N
CH
BnO
NO
2
R,Rand S,S
3
OCH
3
R,Sand S,R
O
Bn
N
CH
HN
Bn
3
CH
3
OCH
3
OCH
BnO
NO
2
O
Br
O
NO
The α- bromoketone is formed by bromination of the ketone. The benzyl ether is formed by chloride displacement from
benzyl chloride by the phenol (
hydroxyacetophenone.
4′-
Williamson Ether Synthesis). 4′- Hydroxy- 3′- nitroacetophenone is formed by nitration of
Br
CH
O
Cl
NO
O
2
O
CH
3
NO
2
O
CH
3
HO
NO
HO
Fosfomycin 189
3
CH
O
H H
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The secondary amine is formed by reductive amination from 4- methoxyphenylacetone and benzylamine.
4-
Methoxyphenylacetone is formed from 4- methoxyphenylacetic acid and acetic anhydride.
H
N
CH
3
O
CH
3
OCH
O
O CH
3
O
3
OH
NH
O
2
CH
3
OCH
3
OCH
Extended Discussion
Arformoterol is the pure (R,R)- enantiomer. Draw the structures of the retrosynthetic analysis of one arformoterol process
which has the β-
amino alcohol formed by ring- opening of an epoxide by an amine.
Fosfomycin
Anti- infective Medicines/Antibacterials/Other Antibacterials
OH
3
P
O
OH
In a molecule with two adjacent chiral carbons, one chiral carbon is often used to direct the
formation of the second.
Discussion. Two routes to fosfomycin, (1R,2S)- 1,2- epoxypropylphosphonic acid, will be presented. Route A utilizes a
resolution. Route B is an asymmetric synthesis.
In Route A, fosfomycin is separated from the 1
: 1mixture of (1R,2S)- and (1S,2R)- enantiomers by resolution in the final
step. The 1 : 1mixture of enantiomeric epoxides is formed by epoxidation of cis- propenylphosphonic acid. The phosphonic
acid is formed from di- tert- butyl cis- propenylphosphonate by acid- catalyzed cleavage of the esters. Di- tert- butyl cis-
propenylphosphonate is formed by hydrogenation of di- tert- butyl propadienylphosphonate. The propadienylphosphonate
is formed by the rearrangement of di- tert- butyl 2- propynyl phosphite. The phosphite is formed in situ from propargyl alco-
hol and di- tert- butyl phosphorochloridite. Di- tert- butyl phosphorochloridite is formed in situ from tert- butyl alcohol and
phosphorus trichloride.
F190
H H
CH
O
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H H
3
O
H
CH
3
O
H
P
O P
OH
OH
CH
3
O
O
H H
CH
3
H
C
C
H
3
3
CH
CH
3
CH
CH
CH
CH
3
H H
CH
3
O
H
CH
3
3
3
3
3
OH
P
OH
O
O
O
O
CH
CH
O
P
OH
O
Ph CH
CH3CH
H
O
P
O
CH3CH
CH
3
3
OPOClCH
3
NH
CH
CH
OH
3
3
3
3
3
3
CH
3
CH
P
O
P
O
H
C
P
O
OH
OH
NH
Ph CH
OH
OH
CH3CH
CH
O
O
CH
CH3CH
CH
3
CH
HO CH
2
3
3
3
3
3
3
3
In Route B, the epoxide is formed in the final step by displacement of para- toluenesulfonate on C1 by the hydroxyl group
on C2. The phosphonic acid is formed by hydrolysis of the dimethyl phosphonate. The para-
toluenesulfonate is formed
from the 1,2- diol. The C2 hydroxyl group is released by transesterification of the acetate ester. The C1 hydroxyl group is
formed by reduction of the carbonyl group of the acyl phosphonate. [What is the highest ratio of the major (1S,2S)- and
minor (1R,2S)- diastereomers formed in this reduction? What reaction conditions are associated with the highest ratio?]
The acyl phosphonate is formed from the acid chloride and dimethylphosphite (Michaelis–Arbuzov Reaction). The acid
chloride is formed from the carboxylic acid. (S)-
2- Acetoxypropionic acid is formed from (S)- lactic acid and acetic acid. (S)-
Lactic acid is manufactured by chemical synthesis and by fermentation.
H H
CH
3
O
H
CH
3
OH
H
CH
3
O
CH
3
OH
O
P
O
H
P
O
Cl
OH
OH
ArSO2Cl
OCH
3
OCH
3
O
P
H
OCH
OCH
SO2Ar
OH
O
H
OCH
OCH
3
3
P
O
O
H H
CH
3
OSO2Ar
P
O
OH
OH
OHOH
CH
H
3
H H
OCH
CH
3
O
O
P
O
CH
3
3
3
O
H
OCH
3
3
OH
CH
3
O
O
CH
3
CH
H
CH
3
O
O
CH
3
OCH
OCH
3
3
P
O
O
H
OH
3
OH
CH
O
OH
3
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