A short synthesis of cisapride: A gastrointestinal stimulant derived from cis-4-amino-3-methoxypiperidine

Article abstract of DOI:10.1016/S0040-4039(01)01098-X

Cisapride was synthesized in seven steps from piperidin-4-one by using a diastereoselective reduction of an α-oximino ether with the complex BH₃·THF.

Full text of DOI:10.1016/S0040-4039(01)01098-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5713–5715
A short synthesis of cisapride: a gastrointestinal stimulant
derived from cis-4-amino-3-methoxypiperidine
Janine Cossy,a,* Jose L. Molinaa and Jean-Roger Desmursb
aLaboratoire de Chimie Organique associe´ au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
bRhodia, 190 Avenue Thiers, 69457 Lyon Cedex 06, France
Received 5 April 2001; accepted 15 June 2001
Abstract—Cisapride was synthesized in seven steps from piperidin-4-one by using a diastereoselective reduction of an a-oximino
ether with the complex BH3·THF. © 2001 Elsevier Science Ltd. All rights reserved.
Metoclopramide is used clinically as a stimulant of
upper gastrointestinal motility and as an antiemetic.1
The gastric prokinetic action of metoclopramide is
ascribed to stimulation of the gut motility by an
increase in acetylcholine release from the cholinergic
nerves of the gut.2 Acetylcholine release is due to either
blockade of the serotonin (5-HT3)3 receptors4–6 or acti-
vation of particular 5-HT-like receptors which have not
yet been characterized in enteric nervous systems.7 This
mechanism of action, however, remains to be deter-
mined. On the other hand, metoclopramide has a
dopamine D2 receptor antagonistic property, which is
not related to its gastric prokinetic activity.8,9 Blockade
of dopamine D2 receptors in metaclopramide is
reported to reduce several unfavorable effects such as
central nervous system depression and extrapyramidal
syndrome in man,10,11 which limits its clinical use.
Recently, several benzamide compounds such as diazo-
pride 2,12 BRL-24924 313–15 and cisapride 4,16,17 show-
ing potent gastric prokinetic action and reduced
dopamine D2 receptor antagonistic activity, were
derived from a modification of the side chain of meto-
clopramide (Scheme 1).
Cisapride has been previously synthesized from pipe-
ridin-4-one in 13 steps18 or 11 steps.17 A shorter synthe-
sis has been reported in nine steps with an overall yield
of 3%.19 Here, we report a more efficient synthesis of
cisapride from piperidin-4-one in seven steps with an
overall yield of 4.5%.
Scheme 1. Benzamide compounds with potent gastric prokinetic action.
Keywords: cisapride; piperidin-4-one; oximino ether; reduction; borane.
* Corresponding author. Fax: 33 1 40 79 44 29; e-mail: janine.cossy@espci.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01098-X

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J. Cossy et al. / Tetrahedron Letters 42 (2001) 5713–5715
Scheme 2. Synthesis of cisapride.
Piperidin-4-one hydrochloride 5 was transformed into
amide 6 by treatment with carboxylic acid 12 in the
presence of pivaloyl chloride and triethylamine in
refluxing toluene for 16 h (yield 61%). The introduction
of the methoxy group at the C-3 position of the pipe-
ridine was achieved in two steps. The first step involved
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with BH3·THF.

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