PROCESS FOR SYNTHESIS OF IVABRADINE, ALPHA-CRYSTALLINE FORM OF IVABRADINE HYDROCHLORIDE, PHARMACEUTICAL COMPOSITIONS COMPRISING IT AND USES THEREOF

摘要

Method for synthesis of ivabradine (I; (3-{3-[{[(7S)-3,4-dimethoxybicyclo[4,2,0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino]propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one) or its acid addition salts. Method for synthesis of ivabradine (I; (3-{3-[{[(7S)-3,4-dimethoxybicyclo[4,2,0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino]propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one) or its acid addition salts with HX comprises: (A) catalytic hydrogenation of acetal (V) at 40-80[deg]C to form the corresponding tetrahydro compound (VI); (B) reacting (VI) with the benzocyclobutane derivative (VII), in presence of hydrogen and a catalyst at 40-100[deg]C to give, after filtering off catalyst and isolation, the HX salt of (I), optionally treated with base to give free (I). R 1 and R 21-6C linear or branched alkoxy or together complete a 1,3-dioxan or 1,3-dioxolan ring; HX : hydrochloric, hydrobromic, sulfuric, phosphoric, (trifluoro)acetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulfonic, benzenesulfonic or camphoric acids Independent claims are also included for the following: (1) compounds (VI); and (2) compounds (V) where R 1 and R 2 are together 1,3-dioxan or 1,3-dioxolan ring. [Image] ACTIVITY : Cardiant; Antianginal; Antiarrhythmic. No details of tests for these activities are given. MECHANISM OF ACTION : None given.