Organic Process Research & Development 2010, 14, 918–920
An Improved Process for the Synthesis of 5-Bromo-3-(1-methylpiperidin-4-yl)-
1H-indole: A Key Intermediate in the Synthesis of Naratriptan Hydrochloride
†
,†
‡
‡
Nellisara D. Shashikumar, Ganga Naika Krishnamurthy,* Sundara Raj Rao K, Kanakamajalu Shridhara,
§
‡
Halehatti S. Bhojya Naik, and Kuppuswamy Nagarajan
Department of Chemistry, Sahyadri Science College (Autonomous), Shimoga-577203, Karnataka, India, Alkem Laboratories
Ltd., Bangalore-560058, Karnataka, India, and Department of Industrial Chemistry, KuVempu UniVersity,
Shimoga-577451, Karnataka, India
ably give bis derivatives. Silane reduction8 is preferred
to the above-mentioned methods, as it gives 4 without
the formation of intermediate 3.
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Abstract:
An improved process has been developed for the synthesis of
5-bromo-3-(1-methylpiperidin-4-yl)-1H-indole, a key intermediate
of naratriptan hydrochloride, which is used as a drug for migraine.
A novel one-pot synthetic procedure using triethyl silane was
developed for scale-up.
Results and Discussion
Synthesis of 5-bromo-3-(1-methylpiperidin-4-ly)-1H-indole
(
4) (Scheme 2) involves condensation of 1 and 2, in the presence
4,5
of KOH and ethanol as solvent at reflux temperature, followed
by reduction of 3. During our optimization experiments, we
found that the purification of unreacted 3 from 4 is difficult,
leads to low yield, and also produces many impurities in the
final product 4. To obtain 4 in good yield, without impurity 3
Introduction
Naratriptan is an important drug for the treatment of acute
1
attack of migraine, exhibiting high affinity for 5-HT1D
2
,3
receptor. It acquires the majority of market as migraine
drugs. In the literature, many processes are described for
(
less than 0.05%), sodium borohydride reduction was optimized
by varying different parameters (Table 1). Better results were
obtained with sodium borohydride and acetic acid at a temper-
ature range of 40-45 °C (entry 2, Table 1). Other advantages
of the use of sodium borohydride are lower cost and easy
handling.
4
-7
the synthesis of naratriptan.
An important route for the
synthesis of naratriptan is shown in Scheme 1 and the
interesting key intermediate in the synthesis is 5-bromo-3-
(
1-methylpiperidin-4-yl)-1H-indole (4). Preparation of 4
involves the condensation of N-methylpiperidone 2 with
-bromoindole (1) under basic conditions to give (3), which
on catalytic hydrogenation gives 4. Reduction of 3 may be
A novel route has been developed for the synthesis of 4 by
5
12
using silane for reductive alkylation (Scheme 3). The author
noted that very strong acid and very weak acids are not active
in reductive alkylation, in our experiments, we found that strong
acid can be used (Table 2) with triethylsilane for reductive
alkylation, but weak acids fail to give the desired product. The
reductive alkylation process has the advantage of less reaction
time (30 min to 3 h) and also reduces the isolation of
intermediate 3. The optimized process gives good yield and
purity in shorter time (entry 5, Table 2).
1
3-16
done by using NaBH
4
/AcOH,
which overcomes the
difficulties of handling catalytic hydrogenation.
In general, alkylation on the C3 of indole includes use
of alkyl halides under basic conditions, which suffers from
low efficiency and regioselectivity (C3 to N1). Aldehydes
and ketones can be used as alkylating agents; under basic
conditions they give alkenes, which require reduction, an
additional step. However, in acidic conditions they invari-
*
Author to whom correspondence may be sent. E-mail:
Conclusion
gkmnaik_sahyadri@yahoo.co.in.
We have developed a scaleable process for the synthesis
of 5-bromo-3-(1-methylpiperidin-4-ly)-1H-indole (4) by
†
Sahyadri Science College (Autonomous).
Alkem Laboratories Ltd.
Kuvempu University.
‡
§
(
(
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Vol. 14, No. 4, 2010 / Organic Process Research & Development
10.1021/op100018r 2010 American Chemical Society
Published on Web 05/25/2010