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SYNTHESIS OF IVABRADINE VIA CYCLISATION OF AN ACETAL INTERMEDIATE
专利权人:
LES LABORATOIRES SERVIER
发明人:
PEGLION, JEAN-LOUIS,DESSINGES, AIMEE
申请号:
NZ59813812
公开号:
NZ598138A
申请日:
2012.02.09
申请国别(地区):
NZ
年份:
2012
代理人:
摘要:
Disclosed is a process for the synthesis of ivabradine of formula (I): characterised in that a compound of formula (VI) wherein R1 and R2, which are the same or different, represent linear or branched alkoxy groups or together with the carbon atom carrying them form a 1,3-dioxane, 1,3-dioxolane or 1,3-dioxepane ring, is subjected to a reductive amination reaction with the compound of formula (VII), in the presence of a reducing agent, in an organic solvent, a mixture of organic solvents or a mixture of organic solvent(s) and water, to yield the compound of formula (VIII) (such as the compound N-{ [(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl} -N-(2,2-dimethoxyethyl)-N-methylpropane-1,3-diamine) which is subjected to a condensation reaction with the compound of formula (IX), in the presence of a base in an organic solvent, to yield the compound of formula (X) (such as N-{ 3-[{ [(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl} -(methyl)amino]propyl} -N-(2,2-dimethoxyethyl)-2-(3,4-dimethoxyphenyl)acetamide) which is subjected to a cyclisation reaction in an acid medium to yield the compound of formula (V), which is subjected to a hydrogenation reaction to yield ivabradine of formula (I), which may optionally be converted into addition salts thereof with a pharmaceutically acceptable acid selected from hydrochloric acid, hydrobromic acid, sulphuric 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 5 acid, oxalic acid, methanesulphonic acid, benzenesulphonic acid and camphoric acid, and into hydrates thereof.
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