Process for the preparation of 2-(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline

摘要

Industrially applicable process for preparing 2-(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide, and salts thereof.

主权项

1. A process for preparing 2-(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide, or a pharmaceutically acceptable salt thereof, or a solvate or hydrate of a pharmaceutically acceptable salt comprising:
a) reductively aminating 1,2,3,4-tetrahydroisoquinoline, or a salt thereof, with cyclohexanecarboxaldehyde to give 2-cyclohexylmethyl-1,2,3,4-tetrahydroisoquinoline, or a salt thereof; b) reacting 2-cyclohexylmethyl-1,2,3,4-tetrahydroisoquinoline, or a salt thereof, with excess chlorosulfonic acid to give 2-cyclohexylmethyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride HX salt, and optionally recrystallizing the 2-cyclohexylmethyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride HX salt; c) coupling 2-cyclohexylmethyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride HX salt with (−)-2-(2-aminoethyl)-1-methylpyrrolidine to form 2-(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; d) optionally reacting 2-(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide with a stoichiometric amount or an excess of a salt-forming acid in a solvent to form a salt or a hydrate or solvate thereof; and e) optionally recrystallizing the product of step d).