艾沙拉唑的合成和分子力场模拟研究

Study on the Synthesis Properties of Esaprazole

研究了艾沙拉唑(Ⅱ)的合成和分子力场。以环己胺和氯乙酰氯为原料合成了N-环己基-2-氯乙酰胺(Ⅰ)。再以Ⅰ与哌嗪为原料合成了Ⅱ。采用三因素三水平的正交法对Ⅰ的合成条件进行了优化,发现合成Ⅰ的最优条件为:n环己胺∶n氯乙酰氯∶nNaOH=1∶1.5∶3,反应温度为15℃;最优条件下平行实验的RSD=0.42%。采用重结晶法进行了Ⅱ的纯化,与已有文献相比,易于工业化。利用软件FieldTemplatre2.2.0和FieldAlign2.1进行了Ⅱ的分子力场计算,发现其与苯并咪唑类质子泵抑制剂与靶体作用的分子力场接近,显示出Ⅱ具有质子泵抑制活性的潜力。

N-cyclohexyl-2-chloroacetamide was prepared from cyclohexylamine and chloroacetylchloride. Esaprazole is prepared from N-cyclohexyl-2-claloroacetamide and piperazine. They are characterized by IR spectra and 1H-NMR spectra. The orthogonal optimization method of three factors and three levels is designed and used to optimize the synthesis route of N-cyclohexyl-2-chloroacetamide. It is found that the optimal materials mol-ratio ： n cyclohexylamine ： n chloroacetylchloride ： nNaOH=1 ： 1. 5 ： 3, and the optimal temperature is at 15℃. Under the optimal conditions, N-cyclohexyl-2-chloroacetamide is prepared three times with the high average yield 93% and the RSD=0. 42%, which prove that the synthesis route is stable. Esaprazole is purified by re-crystallization method, which is much easy to industry than the literature method vacuum distillation. The molecular force field of omeprazole, pantoprazole and rabeprazole is counted by FieldTemplater2.2.0, which is used as a model to count the molecular force field of esaprazole by FieldAlign2. 1.1. It is found that it is similar between the molecular force field of esaprazole and benzimidazoles, which shows that the bio-activities of esaprazole and benzimidazoles is similar.