| 摘要 |
Preparing ivabradine (I) comprises: subjecting N-{3-[((S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-trien-7-ylmethyl )-methyl-amino]-propyl}-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-2-oxo-acet amide (VI) to the action of a thiol in an organic solvent to form N-{3-[(dimethoxy-bicyclo[4.2.0]octa-trienylmethyl)-methyl-amino]-prop yl}-N-[2-(dimethoxy-phenyl)-ethyl]-hydroxy-acetamide compound (VII); cyclization reaction of (VII) to yield tetrahydro-benzo[d]azepin-2-one compound (VIII); reduction reaction of (VIII) to yield ivabradine (I). Preparing ivabradine (I) comprises: subjecting N-{3-[((S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-trien-7-ylmethyl )-methyl-amino]-propyl}-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-2-oxo-acet amide (VI) to the action of a thiol in an organic solvent to form N-{3-[(dimethoxy-bicyclo[4.2.0]octa-trienylmethyl)-methyl-amino]-prop yl}-N-[2-(dimethoxy-phenyl)-ethyl]-hydroxy-acetamide compound of formula (VII); cyclization reaction of (VII) to yield tetrahydro-benzo[d]azepin-2-one compound of formula (VIII); reduction reaction of (VIII) to yield ivabradine (I), which can 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. R : alkyl (optionally perfluorinated), aryl group, or benzyl group (all optionally substituted) or CH 2CO 2C 2H 5group. Independent claims are included for: (1) N-{3-[((S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-trien-7-ylm ethyl)-methyl-amino]-propyl}-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-2-oxo -acetamide (VI); (2) N-{3-[(dimethoxy-bicyclo[4.2.0]octa-trienylmethyl)-methyl-amino] -propyl}-N-[2-(dimethoxy-phenyl)-ethyl]-hydroxy-acetamide compound (VII); and (3) tetrahydro-benzo[d]azepin-2-one compound (VIII). [Image] - ACTIVITY : Cardiant; Vasotropic; Antianginal; Antiarrhythmic. - MECHANISM OF ACTION : None given.
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