Process for the synthesis of ivabradine and its pharmaceutically acceptable acid addition salts

摘要

Preparing 3-{3-[(3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-trien-7-ylmethyl)-methyl-amino]-propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one (VIII) comprises: reacting 3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile (II) and 7,8-dimethoxy-3-(3-methylamino-propyl)-1,3,4,5-tetrahydro-benzo[d]azepin-2-one (IX) in the presence of lanthanide in a solvent to obtain N-[3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-propyl]-3,4-dimethoxy-N-methyl-bicyclo[4.2.0]octa-1(6),2,4-triene-7-carboxamidine (X); and transforming (X) by the action of a hydride donor. Preparing 3-{3-[(3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-trien-7-ylmethyl)-methyl-amino]-propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one (VIII) or its racemic form or optically active form comprises: reacting 3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile (II) and 7,8-dimethoxy-3-(3-methylamino-propyl)-1,3,4,5-tetrahydro-benzo[d]azepin-2-one (IX) in the presence of transition metal or lanthanide in a solvent to obtain N-[3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-propyl]-3,4-dimethoxy-N-methyl-bicyclo[4.2.0]octa-1(6),2,4-triene-7-carboxamidine (X); and transforming (X) by the action of a hydride donor. An independent claim is included for N-[3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-propyl]-3,4-dimethoxy-N-methyl-bicyclo[4.2.0]octa-1(6),2,4-triene-7-carboxamidine (X). ACTIVITY : Cardiant; Vasotropic; Antianginal; Antiarrhythmic. MECHANISM OF ACTION : None given.