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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5434_Библиотеки_им_академика_М_И_Перельмана
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(c)
(d)
3. (a)
(a′)
202 9 Solutions to the exercises
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(b′)
(c′)
(d′)
4. (a) D-N(CH
3
)C(CH
3
)
3
is a hard analog of D-N(CH
3
)
2
.
(b) D-COOCH
3
is a soft analog of D-CH
3
.
(c) D-COOC(CH
3
)
3
is a soft analog of D-COOC
2
H
5
.
t-Bu
+
cation is stable, and degradation of the ester occurs at physiological pH.
(d) D-C
6
H
4
-pCF
3
is a hard analog of D-C
6
H
5
.
(e) D-CH
2
CONHR is a hard analog of D-CH
2
COOR because the former is more dif-
ficult to hydrolyze.
(f) D-COOCH
2
N
+
R
3
is a soft analog of D-COO(CH
2
)
2
N
+
R
3
because the former is an
unstable acyloxymethyltrimethylammonium derivative
9.5 Exercises to Chapter 7 203
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5. (a)
It has been transformed into a soft analog because its hydrolytic metabolism
is facilitated in the modified drug.
(b)
The second drug is a soft analog of aryloxypropanolamine (with an ester
group easy to hydrolyze).
(c)
The second drug is a soft analog: it is an active metabolite of phenylbutazone.
(d)
Hard analog: the first drug is transformed into a carbamate more resistant to
hydrolysis.
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(e)
Hard analog: by introduction of a steric hindrance in the proximity of the
ester group that hinders its hydrolysis.
6.
9.6 Exercises to Chapter 8
(a) (RS)-Fluoxetine
Fluoxetine (Prozac
®
, see Chapter 4 of Volume 2 of this series) was marketed for
the first time in 1986. Although it has been on the market for 37 years, it remains
one of the most prescribed antidepressant drugs.
9.6 Exercises to Chapter 8 205
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The disconnection process begins with the cleavage of the C–O bond. The cleavage
of the C–Obondleadstop-trifluoromethylphenol 9.1 and the functionalized amine
9.2, the precursor of which is the amino alcohol 9.3. The increase in the oxidation
state of the hydroxyl function generates β-aminoketone 9.4, whose disconnection
process, based on a Mannich reaction, leads to acetophenone, formaldehyde, and
methylamine (Scheme 9.1). Fluoxetine prepared according to the synthesis de-
scribed in Scheme 9.2 is obtained in racemic form.
Scheme 9.1: Retrosynthetic analysis of fluoxetine.
Scheme 9.2: Synthesis of racemic fluoxetine.
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(b) Nifedipine
Nifedipine is a calcium channel blocker of the 1,4-dihydropyridine type, used in med-
icine for the relief of angina pectoris,aswellasforarterialhypertension(seeChap-
ter 10 of Volume 2 of this series). Scheme 9.3 outlines the retrosynthesis of nifedipine.
1,4-Dihydropyr idines are obtained from Hantzsch synthesis, i.e. they should be
formed from 1 mol of aldehyde, 2 mol of 1,3-diCO compound, and 1 mol of ammo-
nia. The necessary β-ketoester to react with o-nitrobenzaldehyde (Scheme 9.4) is
prepared previously by the Claisen condensation of ethyl acetate.
Scheme 9.3: Retrosynthesis of nifedipine.
Scheme 9.4: Synthesis of nifedipine.
9.6 Exercises to Chapter 8 207
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(i) Trimethoprim
Trimethoprim is a bacteriostatic antibiotic derived from a trimethoxybenzylpyrimi-
dine and almost exclusively used in the treatment of urinary tract infections (see
Chapter 12 of Volume 2 of this series). Its retrosynthesis is shown in Scheme 9.5:
Synthesis begins with an aldol condensation of the benzaldehyde derivative with 3-
ethoxypropionitrile. The ethoxy group in an allylic position can be displaced by a
nucleophile. An amino group of guanidine is the nucleophile in this displacement
process, while the second amino group is added to the cyano group. Proton 1,3-
rearrangement gives rise to the drug shown in Scheme 9.6.
(ii) Methotrexate (MTX)
MTX (see Chapter 13 of Volume 2 of this series) is an antimetabolite that has anti-
proliferative and immunosuppressive activity by competitively inhibiting the en-
zyme dihydrofolate reductase. This is a key enzyme in the metabolism of folic
acid that regulates the amount of intracellular folate available for the synthesis of
proteins and nucleic acids. It prevents the formation of tetrahydrofolat e neces-
sary for the synthesis of nucleic acids. Its retrosynthesis is shown in Scheme 9.7.
Scheme 9.5: Retrosynthesis of trimethoprim.
Scheme 9.6: Synthesis of trimethoprim.
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The route begins with formation of the pyrimidine base by condensation between
guanidine and malononitrile, followed by the introduction of the new amino
Scheme 9.7: Retrosynthesis of methotrexate.
Scheme 9.8: Synthesis of methotrexate.
9.6 Exercises to Chapter 8 209
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group by diazo coupling and subsequent reduction. The next step builds up the
molecule in a single-step one-pot synthesis (Scheme 9.8).
(iii) Sumatriptan
Sumatriptan (see Chapter 4 of Volume 2 of this series) is a medicine that belongs
to the group of triptans and is used for the treatment of migraine. Its retrosynthe-
sis is shown in Scheme 9.9.
Synthesis of sum atriptan is shown in Scheme 9.10. Sumatriptan was the first seroto-
nergic agonist introduced in therapeutics in 1991 by Glaxo. For its synthesis, the 4-
substituted aniline by an N-methylsulfamoylmethyl group is the starting material. An-
iline nitrogen is converted into diazonium salt with nitrous acid. Its reduction with
tin(II) chloride yields the corresponding arylhydr azine, which is condens ed with 3-
cyanopropionaldehyde diethyl acetal to give the hydrazine, which undergoes a Fisher
rearrangement to give indole 9.5. Finally, the reduction of the nitrile t o primary
amine and i ts treatment with an excess of formaldehyde and sodium borohydride
leads to N,N-dimethyl derivative (sumatriptan).
Scheme 9.9: Retrosynthesis of sumatriptan.
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Scheme 9.10: Synthesis of sumatriptan.
9.6 Exercises to Chapter 8 211
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