多韦替尼乳酸盐的合成研究
发布时间：2018-11-23 17:57
【摘要】：随着癌症患者的逐渐增加，各种抗癌药物相继问世进行临床研究，多韦替尼现阶段正进行临床研究。 多韦替尼属于苯并咪唑喹啉酮的一种衍生物，根据研究和科学实验，证明这种药物对于肝癌晚期患者具有明显的治疗效果。 本文通过查阅相关文献，总结多韦替尼乳酸盐的合成路线的优缺点，最终选择以5-氯-2-硝基苯胺和N-甲基哌嗪回流反应,可以得到5-(4-甲基哌嗪基-1-基)-2-硝基苯胺,然后由5-(4-甲基哌嗪基-1-基)-2-硝基苯胺经过催化加氢还原硝基可以形成4-(4-甲基哌嗪基-1-基)邻苯二胺,再与β-乙氧基-β-亚胺基丙酸乙酯盐酸盐在酸性条件下回流成环,得到6-（4-甲基哌嗪）-1-氢-苯并咪唑-2-乙酸乙酯,接下来6-（4-甲基哌嗪）-1-氢-苯并咪唑-2-乙酸乙酯与2-氨基-6-氟苯腈在碱性条件下环合得多韦替尼，最后多韦替尼与乳酸成盐得到对位替尼乳酸盐。该方法避免了氨基易氧化的缺点，简化了操作步骤。 通过对各步反应条件的优化，最终我们选择了5-氯-2-硝基苯胺与N-甲基哌嗪的摩尔比为1：3，，不需要溶剂；在乙醇做溶剂在75℃下用钯碳加氢还原，在2-氨基-6-氟苯腈制备过程中选择温度为90℃，最后用六甲基二硅基氨基锂作为碱，成盐用乙醇作为溶剂，在整个过程中反应产率提高了，产物更加容易处理。整个合成路线最终的产率达到44.5%。 对合成过程的中间体进行了熔点、红外、高效液相、核磁等相关的分析和结构表征。根据实验结果表明得到的产物图谱与目标产物相符合，最终合成的化合物达到了预期要求，其性能指标、结构与目标需求一致。 可以预测以5-氯-2-硝基苯胺为初始原料合成多韦替尼乳酸盐的路线是切实可行的。
[Abstract]:With the increasing number of cancer patients, various anticancer drugs have been published to carry out clinical research. Dovetinib is a derivative of benzimidazole quinolinone, which has been proved to be effective in the treatment of advanced liver cancer. In this paper, the advantages and disadvantages of the synthesis route of dovetinib lactate were summarized, and the reflux reaction of 5-chloro-2-nitroaniline and N-methylpiperazine was selected. 5- (4-methylpiperazino-1-yl) -2-nitroaniline was obtained. Then 4- (4-methylpiperazinyl-1-yl) -2-nitroaniline was hydrogenated to form 4- (4-methylpiperazinyl-1-yl) o-phenylenediamine by catalytic hydrogenation of nitroaniline. Ethyl 6- (4-methylpiperazine) -1-hydrobenzimidazole-2-acetate was obtained by refluxing with ethyl 尾 -ethoxy- 尾 -iminolpropionate under acidic conditions. Then 6- (4-methylpiperazine) -1-hydrobenzimidazole-2-acetate ethyl ester and 2-amino-6-fluorobenzonitrile were cyclized to obtain dovetinib under alkaline conditions. Finally, dovetinib was salted with lactic acid to obtain paratinib lactate. This method avoids the disadvantage that amino is easy to oxidize and simplifies the operation steps. By optimizing the reaction conditions, the molar ratio of 5-chloro-2-nitroaniline to N-methylpiperazine is 1: 3, and no solvent is needed. In the solvent of ethanol, palladium carbon was hydrogenated at 75 鈩
本文编号：2352308
[Abstract]:With the increasing number of cancer patients, various anticancer drugs have been published to carry out clinical research. Dovetinib is a derivative of benzimidazole quinolinone, which has been proved to be effective in the treatment of advanced liver cancer. In this paper, the advantages and disadvantages of the synthesis route of dovetinib lactate were summarized, and the reflux reaction of 5-chloro-2-nitroaniline and N-methylpiperazine was selected. 5- (4-methylpiperazino-1-yl) -2-nitroaniline was obtained. Then 4- (4-methylpiperazinyl-1-yl) -2-nitroaniline was hydrogenated to form 4- (4-methylpiperazinyl-1-yl) o-phenylenediamine by catalytic hydrogenation of nitroaniline. Ethyl 6- (4-methylpiperazine) -1-hydrobenzimidazole-2-acetate was obtained by refluxing with ethyl 尾 -ethoxy- 尾 -iminolpropionate under acidic conditions. Then 6- (4-methylpiperazine) -1-hydrobenzimidazole-2-acetate ethyl ester and 2-amino-6-fluorobenzonitrile were cyclized to obtain dovetinib under alkaline conditions. Finally, dovetinib was salted with lactic acid to obtain paratinib lactate. This method avoids the disadvantage that amino is easy to oxidize and simplifies the operation steps. By optimizing the reaction conditions, the molar ratio of 5-chloro-2-nitroaniline to N-methylpiperazine is 1: 3, and no solvent is needed. In the solvent of ethanol, palladium carbon was hydrogenated at 75 鈩
本文编号：2352308
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