Novel synthetic process for (2E) -3- (3,4-dimethoxyphenyl) prop-2-enenitrile and its application in the synthesis of ivabradine and its addition salts with pharmaceutically acceptable acids
Process (P1) for synthesizing (2E)-3-(3,4-dimethoxyphenyl)prop-2-enenitrile (I), comprises subjecting 4-bromo-1,2-dimethoxybenzene (II) to a coupling reaction with acrylonitrile in the presence of a palladium catalyst, a ligand, a base and a phase transfer agent in an organic solvent to yield (I). Process (P1) for synthesizing (2E)-3-(3,4-dimethoxyphenyl)prop-2-enenitrile of formula (I), comprises subjecting 4-bromo-1,2-dimethoxybenzene of formula (II) to a coupling reaction with acrylonitrile in the presence of a palladium catalyst, a ligand, a base and a phase transfer agent in an organic solvent to yield (I). An independent claim is also included for a process (P2) for synthesizing ivabradine, or its salts and hydrates, comprising: converting (II) into (I) according to the process (P1)； subsequently converting (I) into 3-(3,4-dimethoxyphenyl)propanenitrile (III) by a reduction reaction； converting (III) into 3-(2-bromo-4,5-dimethoxyphenyl)propanenitrile (IV) by a bromination reaction； and subsequently converting (IV) into ivabradine, which may be 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 or camphoric acid), and into its hydrates. [Image].
