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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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Iohexol 211
OH
CH
OH
H
OH
OH
O
O
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Discussion. Iohexol has three chiral carbons. Iohexol is a mixture of stereoisomers produced from achiral starting materials. The acetanilide is N-
alkylated by reaction with 3- chloro- 1,2- propanediol in the final step. The acetanilide is formed by
acetylation of the aniline with acetic anhydride. (The esters also formed are hydrolyzed.)
aminoisophthalic diamide is iodinated at C2, C4, and C6. The 5- aminoisophthalic diamide is formed by reduction
The 5of the 5and 3-
nitroisophthalic diamide. The 5- nitroisophthalic diamide is formed from the diester, dimethyl 5- nitroisophthalate,
amino- 1,2- propanediol.
H
O
N
OH
II
H
N
O
OH
H
N
N
I
OCH
3
OH
OH
OH
Cl
HO
OH
H
HO
N
II
I
O
OH
O
HN
O
3
H2N
OH
OH
OH
H
CH
N
II
H
N
I
O
O
3
O
O
CH
OH
OH
3
O
OH
O
H
N
OH
O
H
N
OH
N
2
I
H
N
O
N
2
II
OH
H
N
OH
H
N
OH
H2N
O
O
OH
OH
H2N
OH
OH
O OCH
3
OH
H
N
O
OH
O2N
OCH
3
I212
CH
CH
CH
CH
CH
CH
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Extended Discussion
Draw a flow diagram for the workup procedure for separation of iohexol from the by- products and side products formed in
the final step.
Ipratropium Bromide
Medicines Acting on the Respiratory Tract/Antiasthmatic and Medicines for Chronic Obstructive Pulmonary Disease
3
3
3
Br
N
O
OH
A reaction on or near a rigid bicyclic structure is often highly
O
stereoselective.
Discussion. Ipratropium bromide is a 1 : 1 mixture of the (R)- and (S)- enantiomers. The primary alcohol is released by
acetate ester hydrolysis in the final step. The quaternary ammonium bromide is formed by reaction of the tertiary amine
with bromomethane. The ester is formed from the acid chloride and the alcohol, N- isopropylnortropine.
CH
3
N
3
3
Br
OH
O
CH
CH
3
CH
3
O
CH
3
Br
N
3
O
O
3
CH
N
3
CH3Br
O
O
CH
3
O
CH
3
CH
8
1
N
3
O
3
O
CH
3
OH
O
O
N-isopropyln ortropine
Cl
O
O
Ipratropium Bromide 213
O
citric acid
CH
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The acid chloride is formed from the carboxylic acid. The acetate ester is formed by the reaction of tropic acid with acetyl
chloride. Tropic acid is formed by hydrolysis of the ester. Ethyl 3-
hydroxy- 2- phenylacrylate. The 3- hydroxyacrylate is formed by condensation of ethyl phenylacetate with ethyl for-
ethyl 3-
hydroxy- 2- phenylpropanoate is formed by reduction of
mate (mixed Claisen Condensation).
CH
HO
O
Cl
3
OH
O
O
Cl
O
CH
3
O
O
CH
3
O
HO
O
tropic acid
O
3CH2
OH
O
CH3CH2O
OH
H OCH2CH
3
CH3CH2O
O
O
O
N- Isopropylnortropine is formed by stereoselective reduction of the ketone. N- Isopropylnortropinone is efficiently assembled
in a single step from isopropylamine, 2,5Reaction). 1,3-
Acetonedicarboxlic acid is formed by oxidation of citric acid. Citric acid is produced by fermentation.
dimethoxytetrahydrofuran, and 1,3- acetonedicarboxylic acid (Robinson–Schopf
CH
CH
CH
CH
3
CH
N
3
OH
3
CH
N
3
O
N-isopropyln ortropine
NH
CH3O
2
O
CH3O
OH O OH
O
HO
O
O
OH
HO
3
3
O OH
I214
O
CH2CH
O
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Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to N- isopropylnortropine. 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 the two routes to N-
isopropylnortropine and select one route as the preferred route.
Irinotecan
Antineoplastics and Immunosuppressives/Cytotoxic and Adjuvant Medicines
3
O
N
N
N
CH3CH
N
O
2
OOH
Semisynthesis of a target molecule from a natural product
is often based on known reactions or reaction conditions
which are uniquely selective when applied to the natural
product.
Discussion. Irinotecan is most often manufactured from camptothecin by alkylation at C7 and oxidation at C10. Two
routes have the C7 alkylation before the C10 oxidation. In Route A, the carbamate is formed by acylation of
7- ethyl- 10- hydroxycamptothecin using the carbamoyl chloride. 7- Ethyl- 10- hydroxycamptothecin is formed from
ethylcamptothecin- 1- oxide by photochemical rearrangement. The N- oxide is formed by oxidation of 7- ethylcamptothecin.
77-
Ethylcamptothecin is formed from camptothecin and propanal under Fenton’s Reagent conditions. Camptothecin is an
alkaloid first isolated from the deciduous tree Camptotheca acuminata.
Irinotecan 215
CH2CH
O
O
camptothecin
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3
O
O
O
N
N
N
O
CH3CH
N
CH2CH
3
HO
Cl
O
N
N
N
CH3CH
2
OH
O
O
N
2
OH
O
CH2CH
3
O
N
N
O
CH3CH
2
O
OOH
O
CH2CH
3
O
N
N
CH3CH
10
H
2
7
O
N
N
O
CH3CH
2
OH
O
CH3CH
2
OH
O
In Route B, the carbamate is again formed by acylation of 7- ethyl- 10- hydroxycamptothecin using the carbamoyl chloride.
7- Ethyl- 10- hydroxycamptothecin is formed by oxidation of 7- ethyl- 1,2,6,7- tetrahydrocamptothecin. The 1,2,6,7-
tetrahydrocamptothecin (a mixture of three diastereomers) is formed by hydrogenation of 7- ethylcamptothecin.
7- Ethylcamptothecin is formed from camptothecin and propanal under Fenton’s Reagent conditions.
I216
CH2CH
O
O
camp toth ecin
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3
O
O
O
N
N
N
O
CH3CH
N
CH2CH
3
HO
Cl
N
N
N
CH3CH
2
OH
O
O
O
2
OH
O
CH2CH
3
O
N
N
H
O
CH3CH
2
OOH
N
CH2CH
3
O
CH3CH
10
N
N
O
H
2
7
6
O
N
2
N
1
O
CH3CH
2
OH
O
CH3CH
2
OH
O
The carbamoyl chloride is formed by reaction of 4- piperidinopiperidine (1,4′- bipiperidine) with phosgene. The secondary amine of
4- piperidinopiperidine is released by hydrogenolysis of the benzyl group of 1- benzyl- 4- piperidinopiperidine. 1- Benzyl 4- piperidinopiperidine is formed from 1- benzyl- 4- piperidinone and piperidine by reductive amination.
Isoflurane 217
O
F
Cl
F
F
F
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O
Ph
Cl
N
N
Cl
Cl
H
N
N
Ph
N
N
N
O
H
N
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route (Route C) to irinotecan from camptothecin
which has the C10 hydroxylation before the C7 alkylation. List the pros and cons for the three routes. (Include the solubility
data for each step.)
Isoflurane
Anesthetics, Preoperative Medicines and Medical Gases/General Anesthetics and Oxygen/Inhalational Medicines
F
O
An alkyl fluoride is often formed by the displacement of chloride by fluoride.
Discussion. Isoflurane is a 1 : 1mixture of the (R)- and (S)- enantiomers. The α- chloro ether is formed in the final step by
chlorination. (The α,αused?) The difluoromethyl ether is formed by chloride displacement from the dichloromethyl ether (Swarts Reaction).
The dichloromethyl ether is formed by chlorination of the methyl ether. (How selective is this chlorination?) The methyl
ether is formed from 2,2,2from 2- chloro- 1,1,1- trifluoroethane by chloride displacement. 2- Chloro- 1,1,1- trifluoroethane (also known as HCFC- 133a)
is formed from trichloroethylene.
dichloro ether side product is also converted to isoflurane by reduction. What reducing agents are
trifluoroethanol and dimethyl sulfate (Williamson Ether Synthesis). The alcohol is formed
I218
N
O
H
2
O
H
N
F
Cl
F
F
F
Cl
F
F
O
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Cl
F
F
F
O
Cl
Cl Cl
Cl
O
F
O
F
CH
F
3
F
F
F
F
F
F
O
CH3OS
OH
OCH
O
F
F
F
F
HCFC-133 a
3
Extended Discussion
Draw the structures of the retrosynthetic analysis of an alternative route to isoflurane from trichloroethylene and chlorodifluoromethane (HCFC-
22). List the pros and cons for both routes.
Isoniazid
Anti- infective Medicines/Antibacterials/Antituberculosis Medicines
Anti-
infective Medicines/Antiviral Medicines/Antiretrovirals/Medicines for Prevention of HIV- Related Opportunistic Infections
N
NH
A pyridine with one carbon substituent is often formed from the methylpyridine (picoline).
Discussion. Isoniazid is formed in a single step by reaction of 4- pyridinecarbonitrile (isonicotinonitrile) with hydrazine
hydrate.
N
NH
2
N
CN
Extended Discussion
Draw the structures of the retrosynthetic analysis of an alternative route to isoniazid from citric acid. List the pros and cons
for both routes and select one route as the preferred route.
Isosorbide Dinitrate
2
O2N
Cl
N
CH
3
O
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Cardiovascular Medicines/Antianginal Medicines
O
H
O
Itraconazole 219
O
H
O
NO
An alkyl nitrate ester is often formed from the alcohol and nitric acid. The alkyl
nitrate ester functional group is an explosophore.
Discussion. Isosorbide dinitrate is formed by the reaction of isosorbide with nitric acid. [NOTE: The isosorbide dinitrate
safety data sheet (SDS) indicates an extreme risk of explosion by fire, friction, or other sources of ignition.]
N
2
O
H
O
O
H
O
NO
2
HO
O
isosorbide
H
O
H
OH
Extended Discussion
Isosorbide mononitrate is also manufactured on metric ton scale. Draw the structures of a retrosynthetic analysis of one
route to isosorbide mononitrate.
Itraconazole
Anti- infective Medicines/Antifungal Medicines
O
Cl
O
O
N
N
O N
enantiomer pair A: (2R,4S,R) (2S,4R,S)
enantiomer pair B: (2R,4S,S) (2S,4R,R)
N N
An aldehyde or ketone reacts with an alcohol or diol to form an acetal. The reaction is catalyzed by acid and is especially
favorable when it results in formation of a five- or six- membered ring (1,3- dioxolane or 1,3- dioxane).
3
CH
N
N
I220
CH
3
Cl
enan tiomer pair:(2R,4S) (2S,4R)
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Discussion. Itraconazole is manufactured as 1 : 1mixture of two enantiomer pairs. In all four stereoisomers, the dichlorophenyl
substituent at C2 and the aryloxymethyl substituent at C4 on the dioxolane ring are trans. The ether C-O bond is formed in the
final step by displacement of a methanesulfonate by the phenol (Williamson Ether Synthesis).
O
Cl
O
Cl
Cl
O
N
N
N
O
O
N
N
N
O N N
enan tiomer pair A: (2R,4S,R)(2S,4R,S)
enan tiomer pair B: (2R,4S,S)(2S,4R,R)
OMs
HO
N N
enan tiomer pair:R S
N
O
N
N
N
3
CH
N
N
CH
3
CH
3
The methanesulfonate is formed from the alcohol. The alcohol is released by hydrolysis of the benzoate ester. The C-N
bond to 1,2,4-
triazole is formed by a bromide displacement. (Draw the structure of a side product of the bromide displacement.) The alcohol is protected as a benzoate ester, and the enantiomer pair (2R,4S) and (2S,4R) is crystallized from the
mixture. The 2formed from glycerol and 2′,4′-
bromomethyl- 1,3- dioxolane is formed by bromination of the 2- methyl- 1,3- dioxolane. The 1,3- dioxolane is
dichloroacetophenone.
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