Synthesis process, and crystalline form of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1h)-yl]propoxy}benzamide hydrochloride and its free base as well as the pharmaceutical compositions containing them

摘要

Synthesizing 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide hydrochloride (I), comprises reacting 2-methoxy-1-[2-(2-methoxy-acetyl)-cyclopentyl]-ethanone (II) with an ammonia to form tetrahydro-cyclopenta[c]pyrrole-1,3-dione (III), reducing (III) to yield octahydro-cyclopenta[c]pyrrole (IV), which is subsequently subjected to: either a coupling reaction with a benzamide compound (V); or a reductive amination with a benzamide compound (VI) to give free base of (I), which is soaked in hydrochloric acid to form (I) i.e isolated in the form of a solid. Synthesizing 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide hydrochloride (I), comprises reacting 2-methoxy-1-[2-(2-methoxy-acetyl)-cyclopentyl]-ethanone (II) with an ammonia, where the reaction mixture is then subjected to pyrolysis, at a temperature of greater than 100[deg] C to form tetrahydro-cyclopenta[c]pyrrole-1,3-dione (III), reducing (III) to yield (3aR,6aS)-octahydro-cyclopenta[c]pyrrole (IV), which latter compound is subsequently subjected: either to a coupling reaction, under basic conditions in a polar medium, with a benzamide compound of formula (V); or to a reductive amination with a benzamide compound of formula (VI) to give free base of (I), which is soaked in hydrochloric acid to form (I) i.e. isolated in the form of a solid. Y1 : -CH 2-Hal or -CH 2-OSO 2-R; Hal : halo; R : 1-6C alkyl or -C 6H 4-CH 3; either R1a, R2a : 1-6C alkyl; or R1aR2a : -(CH 2) n-; and n : 2-3, where one of R1a and R2a is H and the other is 1-6C alkyl. Independent claims are included for: (1) a crystalline form-I of (I) having an X-ray diffraction pattern on powder having diffraction lines as given in the specification; and (2) a composition comprising (I) in combination with one or more inert vehicles. [Image] ACTIVITY : Nootropic; Dermatological; Neuroprotective; Antiparkinsonian; Cerebroprotective; Antialcoholic; Vasotropic; Tranquilizer; Anorectic; Analgesic. MECHANISM OF ACTION : None given.