Process for the preparation of a substituted perhydroisoindole

摘要

The industrial preparation of a substituted perhydroisoindole of formula (I) or a pharmaceutically acceptable salt thereof comprises: a) reacting dimethyl succinate with benzaldehyde in a methanolic medium to produce the diacid of formula (II); b) the diacid (II) is heated in an aprotic medium in the presence of acetic anhydride to produce the anhydride of formula (III); c) the anhydride (III) is reacted with perhydroisoindole of formula (IV) in an aprotic solvent to produce the compound of formula (V); d) compound (V) is subjected to catalytic hydrogenation using as asymmetric hydrogenation catalyst the complex rhodium/(2S, 4S)-N-butoxycarbonyl-4-diphenylphosphino-2-diphenylphosphino-methylpyrrolidine or Rh/(S,S) BPPM in methanolic or methylene chloride medium followed by conversion to a salt in the presence of an amine A to produce a compound of formula (VI); e) compound (VI) in a basic medium in the presence of a mineral salt yields an addition salt of the compound of formula (I) which is converted optionally into the corresponding acid or f) compound (VI) in an acidic medium yields the compound of formula (I) which is converted optionally into a pharmaceutically acceptable addition salt.