| 摘要 |
Preparing ivabradine (I) comprises: reductive amination of aldehyde compound (VI) with N'-[[(8S)-3,4-dimethoxy-8-bicyclo[4.2.0]octa-1(6),2,4-trienyl]methyl]-N'-methyl-propane-1,3-diamine (VII) in the presence of reducing agent to give (bicyclo[4.2.0]octatrienylmethyl)-propane-diamine compound (VIII); condensing (VIII) with (3,4-dimethoxy-phenyl)-acetyl chloride (IX) to give substituted phenyl-acetamide compound (X); cyclizing (X); and hydrogenating 3-{3-[((S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-trien-7-ylmethyl)-methyl-amino]-propyl}-7,8-dimethoxy-1,3-dihydro-benzo[d]azepin-2-one (V). Preparing ivabradine (I) comprises: reductive amination reaction of aldehyde compound of formula (R2-CHR1-C(=O)-H) (VI) with N'-[[(8S)-3,4-dimethoxy-8-bicyclo[4.2.0]octa-1(6),2,4-trienyl]methyl]-N'-methyl-propane-1,3-diamine (VII) in the presence of a reducing agent, or organic solvent and its mixture or a mixture of organic solvent and water, to give (dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-trien-7-ylmethyl)-methyl-propane-1,3-diamine compound of formula (VIII); condensing (VIII) with (3,4-dimethoxy-phenyl)-acetyl chloride (IX) in the presence of a base in an organic solvent, to give a substituted phenyl-acetamide compound of formula (X); cyclizing (X) in an acid medium to give 3-{3-[((S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-trien-7-ylmethyl)-methyl-amino]-propyl}-7,8-dimethoxy-1,3-dihydro-benzo[d]azepin-2-one (V); and hydrogenating (V) to give ivabradine (I), which is optionally converted into its addition salts with an acid comprising hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid and camphoric acid, and their hydrates. Either R1, R2 : 1-6C alkoxy groups; or CR1R2 : 1,3-dioxane, 1,3-dioxolane or 1,3-dioxepane. Independent claims are included for: (1) (dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-trien-7-ylmethyl)-methyl-propane-1,3-diamine compound (VIII); and (2) a substituted phenyl-acetamide compound (X). [Image] ACTIVITY : Cardiant; Antianginal; Antiarrhythmic. MECHANISM OF ACTION : None given. |
