【作者】 张静；

【导师】 宋健；

【作者基本信息】 天津大学 ， 药物化学， 2003， 硕士

【摘要】 西尼地平(Cilnidipine)是由日本Fujirebio公司研制的一种新型的亲酯性很强的1,4-二氢吡啶类钙离子拮抗剂。本文以双乙烯酮,乙二醇单甲醚,3-羟基丙腈和肉桂醇为原料合成了西尼地平。并对其拆分进行了探索性研究。反应的重要中间产物及最终目标化合物均采用核磁共振及质谱确定了结构。首先以双乙烯酮为原料分别与乙二醇单甲醚,3-羟基丙腈进行酯化反应、氨化反应,然后与肉桂醇进行环缩和反应以及水解反应合成西尼地平。以间硝基苯甲醛计,总收率为50.0%。在该路线中,双乙烯酮酯化反应的最佳反应条件为:反应温度为80~85℃;双乙烯酮与乙二醇单甲醚的摩尔比为1:1;反应时间为2.5~3h;催化剂为三乙胺。氨化反应的最佳反应温度为5~10℃。对于环合反应的研究表明比较好的加料顺序是先将间硝基苯甲醛加入反应体系,加热至80℃回流进行反应7h,在常温搅拌10h后再将3-氨基-2-丁烯酸甲氧基乙酯加入反应体系回流条件下进行环合反应。水解反应的最佳反应条件为:适宜的溶剂为丙酮;NaOH与1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸-2-甲氧乙酯-5-乙烯基氰酯(5)的摩尔比为1.68:1。拆分试剂选用辛可尼丁,拆分出具有手性的辛可尼丁盐。最终产物西尼地平通过核磁共振及质谱进行了结构鉴定。更多还原

【Abstract】 Cilnidipine is a new 1,4-dihydropyridine calcium channel blocker developed by Fujirebio Pharma. In this paper, Cilnidipine was prepared by acylation, ammonization, cyclization, esterification and hydrolysis from diketene, 2-methoxyethanol, 3-Hydroxy-propionitril and cinnamyl alcohol. The intermediates and final products were characterized by NMR and MS.Route: Cilnidipine was synthesized by acylation, ammonization, cyclization, esterification and hydrolysis from diketene, 2-methoxy- ethanol, 3-Hydroxy-propionitril and cinnamyl alcohol. The overall yield of Cilnidipine based on m-Nitrobenzaldehyde was 50.0%.The optimum conditions of acylation was as follows:reaction temperature was 80~85℃. The mole ratio of diketene and 2-methoxy- ethanol was 1:1; reaction time was 2.5~3h and the optimum catalyts was triethylamine. The optimum conditions of ammonization: reaction temperature was 5~10℃. The experimental results showed that the best order of adding reactants was as follows:m-nitrobenzaldehyde and isopropyl alcohol were added to reaction system and stirred at 80℃ for 7h, then stirred at room temperature for 10h. At last amino ester was added to reaction system. The optimum conditions of hydrolysis:the optimum solvent was acetone and the mole ratio of NaOH and the compound (5) was 1.68:1. The Optical iomer of Cinchonidine salt was prepared. The final product was characterized by NMR and MS.更多还原