Ivabradine hydrochloride, S-16260-2 (R-isomer), S-16257-2, S-16257, Procoralan
盐酸伊伐布雷定 伊伐雷定 Chemical Name: (+)-3-[3-[N-[4,5-Dimethoxybenzocyclobutan-1(S)-ylmethyl]-N-methylamino]propyl]-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one hydrochloride
CAS No. 148849-67-6, 155974-00-8 (free base), 148870-80-8 (racemate)
项目整合开发状态: Phase III
项目研究机构: Servier (Originator)
合成路线:Reduction of 4,5-dimethoxybenzocyclobutane-1-carbonitrile (I) with BH3 in THF gives 4,5-dimethoxybenzocyclobutan-1-ylmethylamine (II),which is treated with ethyl chloroformate (III) and triethylamine in dichloromethane to yield carbamate (IV).Reduction of carbamate (IV) by means of LiAlH4 in THF provides racemic N-(4,5-dimethoxybenzocyclobutan-1-yl)-N-methylamine (V),which is submitted to optical resolution with camphorsulfonic acid (CSA) to afford the desired (S)-enantiomer (VI).Reaction of the known 3-(3-chloropropyl)-7,8-dimethoxy-2,3-dihydro-1H-3-benzazepin-2-one (VII) with NaI in acetone yields the corresponding 3-iodopropyl derivative (VIII),which is condensed with the chiral amine (VI) by means of K2CO3 in acetone to afford adduct (IX).Finally,this compound is hydrogenated with H2 over Pd(OH)2 in AcOH.
📌 参考资料/链接：
参考文献标题:Benzocyclobutyl- or indanyl-alkyl-amino-alkyl substd.3-benzazepin-2-ones useful in the treatment of cardiovascular diseases
文献作者:Peglion,J.-L.; Vian,J.; Vilaine,J.-P.; Villeneuve,N.; Janiak,P.; Bidouard,J.-P.(ADIR et Cie.)
参考来源:EP 0534859; FR 2681862; JP 1993213890; US 5296482
📄 详细内容
合成路线:Reduction of 4,5-dimethoxybenzocyclobutane-1-carbonitrile (I) with BH3 in THF gives 4,5-dimethoxybenzocyclobutan-1-ylmethylamine (II),which is treated with ethyl chloroformate (III) and triethylamine in dichloromethane to yield carbamate (IV).Reduction of carbamate (IV) by means of LiAlH4 in THF provides racemic N-(4,5-dimethoxybenzocyclobutan-1-yl)-N-methylamine (V),which is submitted to optical resolution with camphorsulfonic acid (CSA) to afford the desired (S)-enantiomer (VI).Reaction of the known 3-(3-chloropropyl)-7,8-dimethoxy-2,3-dihydro-1H-3-benzazepin-2-one (VII) with NaI in acetone yields the corresponding 3-iodopropyl derivative (VIII),which is condensed with the chiral amine (VI) by means of K2CO3 in acetone to afford adduct (IX).Finally,this compound is hydrogenated with H2 over Pd(OH)2 in AcOH.
参考文献标题:Ivabradine Hydrochloride
文献作者:Sorbera,L.A.; Castar,J.
参考来源:Drugs Fut 2003,28(7),652
产品链接: CAS No. 148849-67-6›› 产品链接: CAS No.155974-00-8››