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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5429_Библиотеки_им_академика_М_И_Перельмана
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Extended Discussion
Cl
2
OHO
Cl
OHO
OHO
OHO
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List the pros and cons for both routes to fosfomycin. Is one route preferred?
Furosemide
Cardiovascular Medicines/Medicines Used in Heart Failure
Diuretics
191Furosemide
O O
S
NH
O
N
H
When the target molecule has a benzene ring with multiple substituents, it is
likely that one or more of the substituents will be introduced by electrophilic
aromatic substitution. Activating/deactivating and directing effects of substituents often determine the order of introduction of ring substituents in the
preferred synthesis.
Discussion. Chloride is displaced by furfurylamine in the final step. (Why is this displacement selective for one of the two
chlorides?) The sulfonamide is formed by reaction of the sulfonyl chloride with ammonia. The sulfonyl chloride is formed
by chlorosulfonylation of 2,4-
O
N
H
dichlorobenzoic acid.
O O
S
NH
OHO
Cl
O O
S
NH
2
O
Cl
2
O O
S
NH
Cl
2
Cl
Cl
Extended Discussion
What is the highest yield reported for the chloride displacement by furfurylamine? by any primary amine? What is the
best yield reported for the analogous fluoride displacement by furfurylamine? Draw the structures of the retrosynthetic
analysis of 4- chloro- 2- fluoro- 5- sulfamoylbenzoic acid. Include the structures of the retrosynthetic analysis of any organic
starting material(s) from petrochemical or biochemical raw materials.
Cl
Cl
192
FOH
HO
NH
HO
FOBz
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G
Gemcitabine
Antineoplastics and Immunosuppressives/Cytotoxic and Adjuvant Medicines
2
A nucleoside is often formed by displacement of a leaving group on the sugar by nitrogen
of the heterocycle. The displacement usually results in a mixture of two products, with the
N
heterocycle on the top face (β) or the bottom face (α) of the sugar. Factors which influence
the β- product to α- product ratio include the heterocycle, the sugar, the leaving group, and
O
N
F
O
the reaction conditions.
Discussion. Gemcitabine is crystallized from the mixture of β- anomer and α- anomer. The mixture of anomers is formed
in the final step by release of the alcohols by ammonolysis of the benzoate esters. A mixture of the β- anomer (major) and
α- anomer (minor) is formed in the displacement of the α- methanesulfonate at C1 by N1 of cytosine. (What is the highest
reported β to α ratio? What reaction conditions are associated with the highest ratio?)
NH
2
NH
2
N
O
N
F
O
BzO
O
NH
2
N
N
F
O
BzO
O
N
cytosine
F
O
N
H
FOH
The α- methanesulfonate is crystallized from a mixture of the α- and β- anomers. The methanesulfonate is formed from
the alcohol. The alcohol is formed by reduction of the lactone.
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
FOBz
OMs
193Gemcitabine
BzO
O
BzO
O
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O
F
OSO2CH
FOBz
BzO
3
BzO
F
O
O
SO2CH
3
FOBz
F
O
FOBz
CH3SO2Cl
OH
BzO
F
O
FOBz
The lactone with the correct (R,R )- configuration is crystallized from a mixture of the (R,R)- and (S,R)- diastereomers.
The alcohols at sugar C4 and C5 are released by hydrolysis of the acetonide. The C4 alcohol forms the lactone. The C5
alcohol is then protected as thebenzoate ester. An alcohol is formed as a mixture of (R,R)the addition of an organozinc(II) bromide to -
glyceraldehyde acetonide (Reformatsky Reaction). The alcohol is then
and (R,S)- diastereomers by
protected as the benzoate ester. [What is the highest (R,R) to (S,R) ratio reported for the mixture of diastereomers? What
reaction conditions are associated with the highest ratio?] The organozinc(II) bromide is formed from ethyl
bromodifluoroacetate.
O
O
5
F
O
4
3
O
1
2
FOBz
Bz
BzO
F
O
O
F
HO
BzO
Ph Cl
F
O
F
O
O
3
3
O
O
Ph Cl
3
F F
OCH2CH
OH
F
Br
O
F
OCH2CH
O
3
3
CH
CH
CH
CH
O
3
3
O
O
3
3
O
Bz
O
F F
H
O
OCH2CH
F
BrZn
3
F
O
CH
CH
OCH2CH
Extended Discussion
Draw the structures of a retrosynthetic analysis of one alternative route to gemcitabine based on fluorination of a carbohydrate derivative.
G194
CH
3
H
CH
3
3
H
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Gliclazide
Hormones, Other Endocrine Medicines, and Contraceptives/Insulins and Other Medicines Used for Diabetes
An N-
arylsulfonylsemicarbazide is often formed by dis-
O O
S
O
N
H
N
N
H
H
Discussion. In the final step, gliclazide is formed by displacement of ammonia from 4- toluenesulfonylurea by thehydrazine. 4-
Toluenesulfonylurea is formed from 4- toluenesulfonyl chloride and urea.
placement of ammonia from an Nhydrazine.
arylsulfonylurea by a
O
N
H
H
H
N
N
H
CH
H
O
O
S
Cl
H2N
O
NH
2
O O
S
CH
O O
S
3
N
H2N
O
N
H
NH
2
The hydrazine is formed by reduction of the nitrosamine. The nitrosamine is formed by nitrosation of cis- 3azabicyclo[3.3.0]octane. The secondary amine of cis- 3- azabicyclo[3.3.0]octane is formed by reduction of the imide. (List
the methods for the imide reduction. Which method is associated with the highest yield?) The imide is formed by ringopening of the anhydride with ammonia followed by ring- closure and dehydration. The anhydride is formed from crude
1,2- cyclopentanedicarboxylic acid (mixture of cis- and trans- diastereomers). The crude dicarboxylic acid is formed from
ethyl 3- bromo- 2- oxocyclohexanecarboxylate (Favorskii Rearrangement). The α- bromoketone is formed by bromination of ethyl 2-
oxocyclohexanecarboxylate. Ethyl 2- oxocyclohexanecarboxylate is formed from cyclohexanone and diethyl
carbonate (mixed Claisen Condensation).
Glutaral 195
H
H
Br
H
HO
H
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H
H2NN
O
HN
O
H
H
H
O
OCH2CH
ON N
H
O
H
O
H
O
O
3
O
OCH2CH
3
OO
HN
H
O
HO
HO
O
O
CH3CH2O OCH2CH
3
Extended Discussion
Draw the structures of the retrosynthetic analysis of onealternative route to 1,2- cyclopentanedicarboxylic acid. Include the
structures of the retrosynthetic analysis of anyorganic 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.
Glutaral
Disinfectants and Antiseptics/Disinfectant
H
O O
An aldehyde is often formed by oxidation of an alcohol or alkene. The reaction and workup conditions must be selected
O OH
to minimize over- oxidation to the carboxylic acid or Aldol Condensation of the aldehyde.
Discussion. Glutaral forms a hydrate in aqueous solution. The hydrate is in equilibrium 3,4- dihydro- 2H- pyran- 2- ol.
Glutaral hydrate is manufactured by oxidation of cyclopentene or by hydrolysis 3,4- dihydro- 2- methoxy- 2H- pyran.
H
O O
or
O OH
OCH3O
OHH
O
OHH
OHO
G196
NO
NO
2
O2N
O
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Glyceryl Trinitrate
Cardiovascular Medicines/Antianginal Medicines
2
O
An alkyl nitrate ester is often formed from the alcohol and nitric acid. The alkyl
nitrate ester functional group is an explosophore.
O
O
Discussion. Glyceryl trinitrate (glycerol trinitrate or nitroglycerin) is formed by the reaction of glycerol with nitric acid.
(NOTE: Nitroglycerin may explode when subjected to heat, shock, or flame.)
NO
2
O
O
N
2
O
NO
HO
2
OH
OH
glycerol
Extended Discussion
Draw the structures and list the names of the functional groups in organic molecules which are explosophores.
CI
F
H
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Haloperidol
Medicines for Pain and Palliative Care/Medicines for Common Symptoms in Palliative Care
Medicines for Mental and Behavioral Disorders/Medicines Used in Psychotic Disorders
Tertiary amines are ubiquitous in drug structures. A tertiary
amine is often formed by alkylation of a secondary amine. The
alkylation is most efficient when the amine is used in excess,
O
N
OH
and the carbon with the leaving group (Cl, Br, I, OTs, OMs) is primary or benzylic.
197
Discussion. The ketone is released by hydrolysis of the acetal in the final step. The tertiary amine is formed by nucleophilic
substitution of chloride by the piperidine. The piperidine is formed by N- debenzylation of the 1- benzylpiperidine. The acetal is
formed from the ketone and ethylene glycol. The ketone is formed from fluorobenzene and 4- chlorobutanoyl chloride (Friedel–
Crafts Acylation).
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
H198
Cl
F
F
Ph
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O
N
F
Cl
Cl
HO
OH
OH
O
OO
N
F
OO
Cl
OH
Cl
OH
N
H
O
Cl
Cl
OH
N
Ph
Cl
F
The 1- benzylpiperidin- 4- ol is formed by addition of 4- chlorophenylmagnesium bromide to 1- benzyl- 4- piperidinone (Grignard
Reaction
). The 4- chlorophenylmagnesium bromide is formed from 1- bromo- 4- chlorobenzene.
MgBr
CH
OH
N
2
Cl
O
N
CH2Ph
Cl
Br
Cl
Extended Discussion
4- Chloro- 4′- fluorobutyrophenone can also be formed by the reaction of a Grignard reagent with a nitrile. Draw the structures
of the retrosynthetic analysis of this alternative route. 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 to 4- chloro- 4′- fluoro
butyrophenone. Is one route preferred?
Halothane
F
F
Cl
Br
F
HCFC-133a
NH
2
NH
H
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Anesthetics, Preoperative Medicines and Medical Gases/General Anesthetics and Oxygen/Inhalational Medicines
199Hydralazine
F
An alkyl fluoride is often formed by the displacement of chloride by fluoride.
Discussion. Halothane is a 1 : 1 mixture of the (R)- and (S)- enantiomers. Halothane is formed by bromination of
2- chloro- 1,1,1- trifluoroethane. (How can the side product 1,1- dibromo- 1- chloro- 2,2,2- trifluoroethane be converted to halothane?)
2- Chloro- 1,1,1- trifluoroethane (also known as HCFC- 133a) is formed from trichloroethylene and hydrogen fluoride.
F
F
Cl
Br
F
F
F
Cl
Cl Cl
Cl
Extended Discussion
Draw the structures of the retrosynthetic analysis of a route to (S)- halothane which does not rely on separation of enantiomers by chiral gas chromatography.
Hydralazine
Cardiovascular Medicines/Antihypertensive Medicines
HN
N
N
A nitrogen substituent on C1 or C4 of a phthalazine ring is often introduced by displacement
of chloride.
Discussion. Hydralazine is formed from 1- chlorophthalazine by chloride displacement by hydrazine. 1- Chlorophthalazine is formed
from 1(2H)- phthalazinone (phthalazone). Phthalazone is formed by the reaction of phthalaldehydic acid with hydrazine.
HN
2
N
N
Cl
N
N
O
NH
N
O
OH
O
Extended Discussion
Describe the alternative process for formation of 1- chlorophthalazine in a single step from α,α,α,α′,α ′-
pentachloro- ortho- xylene.
H200
NH
H
O O
H
O O
H
O O
O O
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and
Draw the structure of a dimer impurity that might form in the final chloride displacement step. Provide details of the
procedure for the final step that ensure a low level of this dimer impurity in the isolated hydralazine.
Hydrochlorothiazide
Cardiovascular Medicines/Medicines Used in Heart Failure
Diuretics
Cl
N
When the target molecule has a benzene ring with multiple substituents, it is
likely that one or more of the substituents will be introduced by electrophilic
N
2
S
S
aromatic substitution. Activating/deactivating and directing effects of substituents often determine the order of introduction of ring substituents in the preferred synthetic sequence.
Discussion. The thiadiazine ring of hydrochlorothiazide (HCTZ) is formed in the final step by bridging the aniline and
sulfonamide by reaction with formaldehyde. The disulfonamide is formed by reaction of the disulfonyl chloride with
ammonia. The disulfonyl chloride is formed by the reaction of 3- chloroaniline with chlorosulfonic acid at elevated temperature. (Since 3- chloroaniline is manufactured from benzene, all substituents on the ring are introduced by electrophilic
aromatic substitution.)
O
H H
2
N
2
O O
Cl
Cl
S
HCTZ
Cl
S
H
N
S
O O
NH
S
Cl
NH
2
Cl
Cl
H2N
S
O O
NH
2
NH
S
O O
2
NH
Extended Discussion
Draw the structure of the dimeric impurity (HCTZ- CH2- HCTZ) formed in the final step. Describe how the workup procedure is designed to reduce the amount of this impurity in the isolated HCTZ.
Hydrocortisone
Antiallergics and Medicines Used in Anaphylaxis
Antineoplastics and Immunosuppressives/Hormones and Antihormones
Dermatological Medicines (Topical)/Anti- inflammatory and Antipruritic Medicines
Gastrointestinal Medicines/Anti- inflammatory Medicines
Hormones, Other Endocrine Medicines and Contraceptives/Adrenal Hormones and Synthetic Substitutes
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