| 摘要 |
<p>#CMT# #/CMT# Preparation of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (I), comprises (a) transforming (3,4-dimethoxyphenyl)acetic acid (IV) into an amide compound (V), and (b) subjecting (V) to a cyclization reaction in an acidic condition to give (I), after isolating. #CMT# : #/CMT# Preparation of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (I), comprises (a) transforming (3,4-dimethoxyphenyl)acetic acid (IV) into an amide compound of formula (V), and (b) subjecting (V) to a cyclization reaction in an acidic condition to give (I), after isolating. Either R 1, R 21-6C alkoxy; or CR 1R 21,3-dioxane, 1,3-dioxolane or 1,3-dioxepane. An independent claim is included for a preparation of ivabradine and its salts, comprising transforming (IV) into (I), then transforming (I) into ivabradine and optionally converting ivabradine into its addition salt using 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 their hydrates. #CMT#[Image]#/CMT# #CMT#ACTIVITY : #/CMT# Cardiant; Vasotropic; Antianginal; Antiarrhythmic. #CMT#MECHANISM OF ACTION : #/CMT# None given. #CMT#USE : #/CMT# (I) is useful for preparing ivabradine (claimed), which is useful in the treatment or prevention of myocardial ischemia such as angina pectoris, myocardial infarction, associated rhythm disturbances and condition involving rhythm disturbances, preferably supraventricular rhythm disturbances and heart failure. No biological data given. #CMT#ADVANTAGE : #/CMT# The process provides (I) in an industrial scale, with a yield of above 92% and a chemical purity of 99.5%. #CMT#ORGANIC CHEMISTRY : #/CMT# Preferred Process: The step (a) comprises: either preliminary transformation of (IV) to a 3,4-dimethoxyphenyl compound of formula (VI) in the presence of an organic solvent, and subjecting (VI) to a condensation reaction with an amine compound of formula (H 2N-CH 2-CH(R 1)-R 2) (VII) in the presence of base and an organic solvent to give (V); or reacting (IV) with (VII) in the presence of a coupling agent and an organic solvent to give (V). In the process, (V) and (VI) are not isolated. The transformation of (IV) to (VI) is carried out at 20-40[deg] C. The transformation of (VI) to (VII) is carried out at 0-40[deg] C. X : halo or OCOR 3; and R 31-6C alkyl, phenyl, benzyl or imidazolyl. Preferred Components: (VI) is (3,4-dimethoxy-phenyl)-acetyl chloride. The solvent used for the transformation of (IV) to (VI) and (VI) to (VII) is dichloromethane. The reagent used for transformation of (IV) to (VI) is thionyl chloride. The amount of thionyl chloride used in the transformation reaction of (IV) to (VI) is 1-1.3 moles per mole of (IV). The amount of (VII) used in the reaction with (VI) is 1-1.2 moles per mole of (VI). The amount of base used in the reaction of (VI) with (VII) is 1-1.3 moles per mole of (VI). The base used in the reaction of (VI) with (VII) is pyridine, 4-dimethylaminopyridine or a tertiary amine, preferably triethylamine. The amount of acid used in cyclization of (V) is 5-15 moles per mole of (V). The cyclization of (V) is carried out at 0-40[deg] C. The acid used for cyclization of (V) is concentrated sulfuric acid. The amount of concentrated sulfuric acid used in cyclization of (V) is 1.5-3 ml/g of (IV). #CMT#[Image]#/CMT# #CMT#EXAMPLE : #/CMT# (3,4-Dimethoxyphenyl)acetic acid (135 g) and dichloromethane (270 ml) were charged into a reactor and heated to reflux, then thionyl chloride (90 g) was added dropwise. The mixture was stirred at reflux for 3 hours to give a solution (A) containing (3,4-dimethoxy-phenyl)-acetyl chloride. Dichloromethane (225 ml), 2,2-dimethoxyethylamine (44.15 g) and triethylamine (44.35 g) were charged into a reactor and then cooled to 10[deg] C, then the solution (A) (237.4 g) was added dropwise, by maintaining the temperature to 10[deg] C. The mixture was stirred for 2 hours at 15[deg] C to give a solution (A1) containing N-(2,2-dimethoxyethyl)-2-(3,4-dimethoxyphenyl)acetamide. (A1) was added into a reactor and cooled to 10[deg] C, then 36N sulfuric acid (150 ml) was added, by maintaining the temperature at below 20[deg] C. The mixture was stirred at 15-20[deg] C for 10 hours and worked up to give 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (yield of 92.9% and purity of greater than 99.5%).</p> |
