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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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Pyronaridine 371
Cl
N
Cl
O
3
C
Cl
Cl
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Discussion. The C10 chloride of 7,10- dichloro- 2- methoxybenzo[b][1,5]naphthyridine is displaced by 4- amino- 2,6- bis(pyr
rolidin-
1- ylmethyl)phenol in the final step.
N
N
OH
OH
N
HN
N
N
10
7
5
N
OCH
3
2
Cl
H2N
N
OCH
3
7,10- Dichloro- 2- methoxybenzo[b][1,5]naphthyridine is formed from the benzo[b][1,5]naphthyridine- 10(5H)- one. The benzo[b]
[1,5]naphthyridine-
arylamino-2- methoxypyridine is formed by copper- catalyzed displacement of chloride from 2,4- dichlorobenzoic acid by
55-
amino- 2- methoxypyridine (Ullmann–Goldberg Reaction). 5- Amino- 2- methoxypyridine is formed by reduction of the nitro-
pyridine. 2-
Methoxy- 5- nitropyridine is formed by chloride displacement from 2- chloro- 5- nitropyridine by methanol.
10(5H)- one is formed by intramolecular acylation at C6 of the 5- arylamino- 2- methoxypyridine. The
N
N
O
l
N
NH
OCH
OH
3
OCH
3
Cl
O
OH
Cl
Cl
NH
2
N
OCH
3
N
H
NO
N
OCH
N
2
3
N
CH3OH
NO
Cl
OCH
2
P372
H
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4- Amino- 2,6- bis(pyrrolidin- 1- ylmethyl)phenol is formed by reduction of the 4- nitrophenol. The pyrrolidin- 1- ylmethyl
substituents are introduced by the reaction of 4-
nitrophenol with paraformaldehyde and pyrrolidine (Mannich Reaction).
O
N
OH
N
2
N
N
O
2
N
OH
N
H H
N
O
2
N
H
OH
Extended Discussion
The Mannich Reaction is the final step in an alternative route to pyronaridine. List pros and cons for the two routes and
select one route as the preferred route.
O
O
CH
O
F
R
O
CH
F
O
CH
O
F
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Raltegravir
Anti- infective Medicines/Antiviral Medicines/Antiretrovirals/Integrase Inhibitors
CH
N
N
3
O
3
N
H
N
N
OH
H
N
373
When one component of a target
molecule is more expensive than the
others, the preferred process often
has that more expensive component
introduced late in the synthesis.
CH3CH
3
Discussion. The hydroxyl group at C5 of the pyrimidine is released in the final step by hydrolysis of the pivalate ester. An
amide is formed by the reaction of the amine with 5- methyl- 1,3,4- oxadiazole- 2- carbonyl chloride. The amine is released by
cleavage of the benzyl carbamate. The 5- hydroxyl group is protected as a pivalate ester.
CH
N
N
3
O
O
N
N
3
O
3
H
N
CH3CH
CH
3
H
N
CH3CH
N
N
3
O
N
N
3
OH
H
N
O
O C(CH3)
O
H
N
3
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
R374
CH
O C(CH3)
O
O
O
O
O
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O
3
CH
H2N
CH3CH
3
N
N
3
N
N
3
Cl
O
O
O
H
N
O
O C(CH3)
F
3
O
CH
3
O
F
N
PhCH2O
H
N
H
N
N
O
CH3CH
3
O
O
CH
3
OH
F
O
N
CH
PhCH2O
H
N
CH3CH
H
N
N
3
CH
3
3
CH
Cl
3
Methylation of the 5,6- dihydroxypyrimidine- 4- carboxamide with trimethylsulfoxonium iodide is selective for N1. The
pyrimidine- 4- carboxamide is formed by the reaction of the methyl ester with 4- fluorobenzylamine.
CH
CH
3
N
O
O
H
N
CH3CH
HN
H
N
CH3CH
HN
H
N
CH3CH
N
3
O
N
3
O
N
3
PhCH2O
O
I
S
CH
3
CH
3
PhCH2O
3
PhCH2O
OH
O
OH
O
OH
H
N
H
N
OCH
F
F
F
H2N
3
Raltegravir 375
Ph
OCH
3
N
CH
N
N
3
O
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The 5,6- dihydroxypyrimidine- 4- carboxylate is formed by the addition of the amidoxime to dimethyl acetylenedicarboxylate followed by rearrangement of the adduct on heating. The amidoxime is formed from the nitrile. The amine is protected
as the benzyl carbamate. 2- Amino- 2- methylpropanenitrile is formed from acetone, cyanide, and ammonia (Strecker
Synthesis
).
PhCH2O
O
CH3O
CH2O
O
HN
H
N
N
CH3CH
O O
3
O
OCH
3
OH
N
H
O
N
CH3CH
NH
2
3
OH
OCH
PhCH2O
3
O
PhCH2O
H
N
CH3CH
CN
3
OCH
O
O
O
3
N
H
O
N
CH3CH
NH
2
3
O
PhCH
O Cl
2
3
CH3CH
CNH2N
CH
NaCN
O
CH
3
3
5- Methyl- 1,3,4- oxadiazole- 2- carbonyl chloride is formed from the carboxylate salt. The carboxylate salt is formed by
hydrolysis of the ester. The 1,3,4- oxadiazole ring is assembled in one step from 5- methyl- 1H- tetrazole and ethyl oxalyl
chloride (ethyl chlorooxoacetate).
OK
CH
3
N
OCH2CH
O
O
O
O
OCH2CH
3
Cl
N
3
O
Cl
CH
3
N
O
O
N
N
CH
3
N
N
H
Extended Discussion
Draw the structures for the retrosynthetic analysis for one alternative route to ethyl 5- methyl- 1,3,4- oxadiazole- 2- carboxylate.
Would this key intermediate be less expensive if produced by the alternative route? List assumptions used to answer the
question.
R376
O
CH
3
NO
NO
CH
O
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Ranitidine
Gastrointestinal Medicines/Antiulcer Medicines
2
CH
3
N
3
S
N
H
CH
N
H
A β- nitroenamine is often formed by displacement of a leaving group from the β-
carbon of
a nitroalkene by an amine.
Discussion. The S- alkylcysteamine displaces methanethiol (methyl mercaptan) from N- methyl- 1- (methylthio)-
2- nitroethenamine in the final step. The S- alkylcysteamine is formed from the furfuryl alcohol and cysteamine.
5- (Dimethylaminomethyl)furfuryl alcohol is formed by the reaction of furfuryl alcohol with dimethylamine and formaldehyde (Mannich Reaction). Cysteamine is formed by hydrolysis of 2- thiazoline- 2- thiol. (Poisonous hydrogen sulfide is a
byproduct of this hydrolysis. Draw the structures of one alternative route to cysteamine from thiazoline- 2- thiol which does
not produce hydrogen sulfide as a byproduct.)
2
CH
3
N
H
CH
CH
3
N
3
S
N
H
O
CH
3
N
3
O
CH
3
CH
N
3
NO
2
CH
3
CH3S
N
H
N
OH
NH
2
(CH3)2NH
HS
O
H H
cysteamine
NH
2
SH
S
OH
S
O
N- Methyl- 1- (methylthio)- 2- nitroethenamine is formed by the addition of nitromethane to methyl isothiocyanate followed
CH
NO
CH
3
CH
CH
OH
O
CH
CH
CH
O
CH
3
3
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by S- methylation.
2
CH3NO
2
CH
H
OCH
3
3
CH3NCS
3
S N
NO
H
2
CH
KS N
3
O
CH3OS
O
Extended Discussion
Draw the structures of a retrosynthetic analysis of one alternative route to N- methyl- 1- (methylthio)- 2- nitroethenamine. List
the pros and cons for both routes to this intermediate and select one route as the preferred route.
Retinoic Acid (All- trans)
377Retinoic Acid (All- trans)
Antineoplastics and Immunosuppressives/Cytotoxic and Adjuvant Medicines
CH
3
3
3
3
An alkene is often formed by the reaction of an aldehyde or ketone with a phosphorus ylid (Wittig
Reaction).
CH
Discussion. The carboxylic acid of all- trans retinoic acid (Tretinoin) is released by ester hydrolysis in the final step. The
C11-C12 double bond is formed from a phosphonium salt and an aldehyde (Wittig Reaction). (What is the E/Z ratio of
the C11-C12 bond in the product mixture?) The phosphonium salt is formed by the reaction of vinyl- β- ionol with triphe-
nylphosphine. (Draw the structures of four diene diastereomers formed in this reaction.) Vinyl- β- ionol is formed by the
addition of vinylmagnesium bromide to β- ionone (Grignard Reaction). Vinylmagnesium bromide is formed from vinyl
bromide.
3
3
CH
CH
CH
3
11
3
3
CH
3
3
3
12
CH
3
OH
O
CH
OCH
R378
CH
3
CH
β
H
O
O
OH
CH
CH
CH
3
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CH3CH
3
3
X
PPh
3
H
CH
O
3
OCH
CH
3
CH
CH
3
3
3
OH
CH
3
PPh
3
BrMg Br
CH3CH
3
O
O
CH
3
vinyl- β -ionol
CH
3
-ionone
Methyl (E)- 3- methyl- 4- oxo- 2- butenoate, the aldehyde for the Wittig reaction, is formed by condensation of methyl glyoxalate and propanal. (What is the E/Z ratio in the product mixture?)
CH
CH
O
3
H
OCH
3
3
H
OCH
3
O
O
Retinol (Vitamin A1)
Vitamins and Minerals
CH
3
3
CH
3
3
Discussion. In the final step of the retinol synthesis associated with Hoffmann- La Roche and now DSM, the alcohol is
released by hydrolysis of the acetate ester. The all- (E) conjugated double bond system forms by dehydration of secondary
alcohol at C10 of the side chain. The acetate ester is formed by acetylation of the C15 primary alcohol. The C11-C12 alkene
is formed by hydrogenation of an alkyne using Lindlar catalyst. The secondary alcohol at C10 is formed by addition of the
alkynylmagnesium halide to the aldehyde 2- methyl- 4- (2,6,6- trimethyl- 1- cyclohexen- 1- yl)- 2- butenal (Grignard Reaction).
An alkene is often formed by dehydration of an alcohol.
The dehydration is facilitated when the alkene formed
is stabilized by conjugation. If the alkene can form (E) -
and (Z)-
diastereomers, both are formed in the dehydration. The more stable alkene is the major product when
the diastereomers can interconvert under dehydration
conditions.
379Retinol (Vitamin A1)
CH
CH
CH
3
CH
gX
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CH3CH
CH3CH
CH3CH
CH
CH
3
11
10
3
3
10
12
3
CH
3
3
CH
3
3
CH
3
15
OH
3
O
O
CH
3
O
OH
CH
3
CH
CH
3
3
3
CH
3
O CH
3
OO
CH
3
OH
CH
3
CH
3
3
CH
CH
3
CH
3
OH
3
O CH
CH3CH
3
CH
3
XMg
OM
CH
3
3
H
OH
O
CH
OH
CH
3
The alkynylmagnesium halide is formed by reaction of (Z)- 3- methylpent- 2- en- 4- yn- 1- ol with ethylmagnesium bromide.
Ethylmagnesium bromide is formed from bromoethane. (Z)- 3- Methylpent- 2- en- 4- yn- 1- ol is formed by rearrangement of
3- methylpent- 1- en- 4- yn- 3- ol. This tertiary alcohol is formed by addition of a metal acetylide to methyl vinyl ketone.
2- Methyl- 4- (2,6,6- trimethyl- 1- cyclohexen- 1- yl)- 2- butenal is formed from β- ionone in two steps. Addition of ethyl chloro-
acetate to the ketone forms the glycidic acid ester (Darzens Reaction). The aldehyde is formed by hydrolysis of the ester
followed by decarboxylation.
R380
CH
β
CH
Br
CH
H
3
O
(E)-4-acetoxy-2-methyl-2-butenal
HO
O
2
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3
Mg
CH3CH
OMgBr
3
CH
3
CH3CH
Extended Discussion
CH
3
O
CH3CH
H
3
-ionone
CH
2
3
MgBr
3
3
O
H
OCH2CH
CH
3
3
HO
CH
3
HC CH
OH
Br
CH3CH
2
CH
3
OCH2CH
CH
O
O
3
CH3CH
O
CH
3
Cl
3
O
The alternative BASF route to retinol utilizes the same Wittig reagent that is used to produce retinoic acid. The aldehyde
partner required for the Wittig reaction leading to retinol is (E)- 4- acetoxy- 2- methyl- 2- butenal. Draw the structures of a
retrosynthetic analysis of one route to this aldehyde. Include the structures of the retrosynthetic analysis of any organic
starting material(s) from petrochemical or biochemical raw materials.
3
O CH
O
Ribavirin
Anti- infective Medicines/Antiviral Medicines/Other Antivirals
Anti- infective Medicines/Antiviral Medicines/Antihepatitis Medicines/Medicines for Hepatitis C/Other Antivirals
A nucleoside analog 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 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 the r
conditions.
NH
N
N
N
O
eaction
OH OH
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