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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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Itraconazole 221
Cl
Cl
Cl
Cl
3
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Cl
O
O
O
SO2CH
3
Cl
O
O
OH
H
N
CH3SO2Cl
Ph
O
O
N
OH
glycerol
Cl
O
CH
N
N
N
enant iom er pair (2R ,4S) (2S,4R )
Cl
O
O
N
N
N
enant iom er pair (2R ,4S) (2S,4R )
Cl
O
O
Br
O
OH
O
Ph Cl
Ph
O
Cl
enant iom er pair (2R ,4S) (2S,4R )
Cl
enant iom er pair (2R ,4S) (2S,4R )
Cl
O
CH
O
3
Cl
N
N
N
O
O
Br
N
HO OH
OH
Cl
The phenol for the final step is released by cleavage of the methyl ether. The triazolone is alkylated with 2- bromobutane.
The triazolone is formed from the semicarbazide and formamidine. The semicarbazide is formed from the phenyl carbamate. The phenyl carbamate is formed from the aniline and phenyl chloroformate. The aniline is formed by reduction of
the nitroaromatic.
I222
CH
CH
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HO
CH3O
3
CH3O
O
3
CH
3
N
N N
N
N
CH
O
3
CH
3
N
N N
N
N
O
CH
O
N N
N N
N
O
NH
N
NHNH
Br
2
NH
3
CH
3
NH
H
NH
2
O
OPh
CH3O
N N
NH
O
CH3O
CH3O
N N
N N
NH
NO
2
Cl
2
OPh
There are many potential routes to 1- (4- methoxyphenyl)- 4- (4- nitrophenyl)piperazine. In one analysis, a C-N bond is
formed by nucleophilic displacement of chloride from 1- chloro- 4- nitrobenzene by 1- (4- methoxyphenyl)piperazine. There
are also many potential routes to 1- (4- methoxyphenyl)piperazine. In one analysis, 1- (4- methoxyphenyl)piperazine is
formed from para- anisidine and bis(2- chloroethyl)amine hydrochloride. Bis(2- chloroethyl)amine hydrochloride could be
considered the starting material or could be formed from diethanolamine and carried directly into the piperazine
formation.
Ivermectin 223
CH
Cl
HO
HO
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CH3O
O
3
CH3O
N N NO
N NH
NH
2
Cl
Cl
NH
HO
2
NO
2
NH
The same starting materials are used in an alternative route to 1- (4- methoxyphenyl)- 4- (4- nitrophenyl)piperazine.
CH3O
N N
NO
2
CH3O
NH
Cl
2
N NO
Cl
HO
2
N NO
2
HO
HO
NH
Cl NO
2
Extended Discussion
Draw the structures of a retrosynthetic analysis of one alternative route to itraconazole from 2′,4′- dichloroacetophenone.
Estimate the overall yield of itraconazole from 2′,4′- dichloroacetophenone for both routes.
Ivermectin
Anti- infective Medicines/Antifilarials
I224
CH
OCH
OH
CH
R
CH
OCH
CH
R
CH
CH
OH
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HO
3
CH3O
3
O O
iverme ct in B
iverme ct in B
CH
1a
1b
O O
O
CH
3
3
R=CH3CH
R=CH
3
3
O
O
OH
2
O
H
O
CH
3
3
H
CH
3
A single- enantiomer molecule with multiple chiral carbons is often formed by modification of a natural product which
has most or all of the chiral carbons already in place.
Discussion. Ivermectin, a mixture of B1a and B1b forms (at least 80% B1a and not more than 20% B1b), is semisynthetic.
Ivermectin is formed by selective hydrogenation of the C22-C23 double bond of a mixture of avermectins B
(Wilkinson’s catalyst). Avermectins B
and B1b are produced by the soil bacterium Streptomyces avermitilis.
1a
and B1b
1a
HO
CH
HO
3
CH3O
O O
1'
1"
3
O O
CH
3
O
CH
3
14
11
10
3
15
23
22
O
O
O
1
3
H
CH
3
9
OH
ivermectin B
ivermectin B
R=CH3CH
1a
R=CH
1b
2
3
8
3
4
O
CH
3
H
OH
OCH
3
CH3O
CH
3
O O
CH
3
R
O
O
CH
CH
3
3
O
3
O O
O
H
CH
3
OH
aavermectinB
vermectinB
R=CH3CH
1a
R=CH
1b
2
3
O
CH
3
H
Extended Discussion
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Draw the structures of three known ivermectin impurities. Is the impurity traced back to an impurity in the starting material or was the impurity formed from avermectin B
or avermectin B1b in the hydrogenation step?
1a
225Ivermectin
226
3
O
Cl
Cl
O
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K
Ketamine
Anesthetics, Preoperative Medicines, and Medical Gases/Injectable Medicines
NHCH
An α-
aminoketone is often formed from an α- bromoketone by displacement of bromide
by an amine. The reaction is efficient when the α-
carbon is primary.
Discussion. Ketamine is a 1 : 1mixture of (R)- and (S)- enantiomers. Ketamine is formed by reaction of the α- bromoketone
formed from 2The ketone is formed by the addition of cyclopentylmagnesium bromide to 2-
chlorophenyl cyclopentyl ketone with methylamine. The α- bromoketone is formed by bromination of the ketone.
chlorobenzonitrile (Grignard Reaction).
Cyclopentylmagnesium bromide is formed from bromocyclopentane.
Cl
NHCH
3
O
MgBr
Cl
CN
OH
Br
NCH
3
Cl
Br
CH3NH
O
2
Cl
Extended Discussion
(S)- Ketamine nasal spray is being evaluated for patients with treatment- resistant depression. Provide details for the synthesis of (S)- ketamine by separation of (R)- and (S)- ketamine and racemization and recycle of (R)- ketamine.
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
HO
HO
OH
OH
HO
HOCH
OH
OH
lactose
L
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Lactulose
Medicines for Pain and Palliative Care/Medicines for Other Common Symptoms in Palliative Care
HOCH
OH
CH2OH
O
2
O
HO
CH
2
O
Alcohol adds to an aldehyde or ketone to form a
hemiacetal. The addition is reversible: a hemiacetal is
in equilibrium with the alcohol and the aldehyde or
ketone.
227
Discussion. Lactulose (4- O- β- -galactopyranosyl- - fructose) is formed from lactose (4- O- β- -galactopyranosyl- - glucose)
(Lobry de Bruyn–Alberda van Ekenstein Reaction). Lactose for manufacture of lactulose is obtained from bovine
CH2OH
ction.
HO
OH
OH
O
HO
O
OH
OH
O
OH
whey, a byproduct of cheese produ
2
O
HO
OH
CH2OH
O
O
HO
Extended Discussion
The transformation of lactose into lactulose results in a mixture containing lactulose and smaller amounts of residual lactose,
galactose, glucose, tagatose, and epilactose. Draw the structures for tagatose and epilactose. How are tagatose and epilactose
formed?
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
L228
NH
O
HO
NH
NH
CH
CH
3
3
CH
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Lamivudine
Anti- infective Medicines/Antiviral Medicines/Antiretrovirals/Nucleoside–Nucleotide Reverse Transcriptase Inhibitors
Anti-
infective Medicines/Antiviral Medicines/Antiretrovirals/Integrase Inhibitors
2
A chiral auxiliary can be used to control the
stereochemical outcome of a reaction which forms a
N
O
N
S
nearby chiral carbon. A chiral auxiliary strategy for
formation of a chiral carbon is cost-
effective when the
auxiliary is inexpensive and when the auxiliary can be
recovered after the chiral carbon is formed.
Discussion. The primary alcohol of lamivudine is formed by reduction of the ()- menthyl ester in the final step. (How is
menthol separated from lamivudine?) The bond joining the rings is formed by nucleophilic displacement of an acetate leav-
()ing group by N1 of cytosine (Silyl–Hilbert–Johnson Reaction). (The (2R,5R)-
product and the (2R,5S)- diastereomer side
product are both formed. What is the highest ratio of product to side product? What reaction conditions are associated with the
highest ratio of product to side product?) The acetate is formed from the alcohol. The (5R)-
hydroxy- 1,3- oxathiolane- (2R)carboxylate is formed by the condensation of (1R)- ()- menthyl glyoxalate hydrate with 1,4- dithiane- 2,5- diol. Both the (2R,5R)alcohol and (2R,5R)- acetate are crystallized from a mixture of stereoisomers.
HO
2
N
O
N
S
CH
O
(–)-menthol
3
CH
3
OH
3
CH
3
CH
3
CH
O
O
O
3
S
2
N
N
O
CH
3
O
O
CH
CH
3
3
O
O
CH
3
S
OH
O
OH
NH
2
CH
N
O
O
O
HO
N
H
cytosine
CH
3
CH
S
S
OH
3
O
CH
3
3
CH
O
O O
3
S
O
O CH
OH
3
Lamotrigine 229
CH
CH
CH
3
H
2
Cl
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(1R)- ()- Menthyl glyoxalate hydrate is formed by ozololysis of ()- dimenthyl fumarate. The fumarate diester is formed
from fumaric acid and ()-
menthol. ()- Menthol is produced by synthesis or by isolation from corn mint oil.
3
O
OH
O
OH
CH
CH
3
3
CH
3
3
3
CH
CH
3
CH
O
O
O
O
3
CH
3
O
OH
OH
HO
O
CH
3
CH
3
(-)-menthol
Extended Discussion
Draw the structures of the retrosynthetic analysis of an alternative route to lamivudine using N4- acetylcytosine in place of
cytosine. List the pros and cons for both routes and select one route as the preferred route.
Lamotrigine
Anticonvulsants/Antiepileptics
NH
2
N
N
N
N
Cl
Discussion. The 1,2,4- triazine ring is formed from the amidinohydrazone in the final step. The amidinohydrazone is formed
by addition of aminoguanidine to 2,3- dichlorobenzoyl cyanide. The benzoyl cyanide is formed from the benzoyl chloride and
copper cyanide. 2,3- Dichlorobenzoyl chloride is formed by hydrolysis of 2,3- dichlorobenzotrichloride. The benzotrichloride
is formed by chlorination of 2,3- dichlorotoluene. 2,3- Dichlorotoluene is formed by chlorination of 2- chlorotoluene. (What is
the composition of the mixture produced in the chlorination of 2- chlorotoluene? How is 2,3- dichlorotoluene separated from
the mixture?)
The synthesis of a 1,2,3-
trisubstituted benzene by electrophilic aromatic substitution is often inefficient because
substitution at a para position typically predominates
over substitution at an ortho position. A 1,2,3-trisubstituted benzene is often formed early in a synthesis when
materials are less expensive and the mixture of regioisomers formed is more easily separated.
L230
Cl
Cl
Cl
HO
HO
O
CH
PPB=4-phenylbenzoyl
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NH
2
NC
2
N
N
Cl
O
Cl CH
Cl
Cl
Cl
Cl
3
H2N
N
N
H2N
NH
Cl
Cl
N
NC
NH
2
N
H
Cl
O
Cl
Cl NH
H2N
CuCN
Cl
Cl
CH
3
Cl
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to 2,3- dichlorobenzoyl chloride.
Latanoprost
Opthalmological Preparations/Miotics and Antiglaucoma Medicines
3
O
HO
CH
3
PPBO
PPB-Coreylactone
Prostaglandins are often constructed from a Corey Lactone. Oxidation of the primary alcohol forms an aldehyde which is
used to introduce the lower side chain. Reduction of the lactone then forms another aldehyde which is used to introduce
the upper side chain.
O
O
OH
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