EV71 3C蛋白酶抑制剂NK-1.8k的合成与优化

Synthesis and synthetic process optimization of the enterovirus 713C protease inhibitor NK-1.8k

目的对EV71 3C蛋白酶抑制剂NK-1.8k的合成工艺进行探究及优化。方法以N-Boc-L-谷氨酸二甲酯为起始原料,依次经过取代、还原胺化、脱保护、酰胺缩合、水解,还原等反应得到目标化合物NK-1.8k。在原合成路线基础上,在合成重要中间体5时改串线式为并线式,总合成路线由七步变为六步,并优化了一些后处理方式。结果中间体及目标化合物的结构经MS、1H NMR确证,反应总收率较原路线的10.7%提高至13.3%。结论本文所确立的NK-1.8k的合成路线合理可行,使用的原料廉价易得,操作简单,大多数反应条件温和可控,后处理简便,中间体易分离纯化,步骤较短,收率较高。该方法可为NK-1.8k以及类似产物的进一步合成研究提供有价值的参考。

Objective To synthesize the enterovirus 713 C protease inhibitor NK-1.8 k and optimize the synthetic process.MethodsWith N-Boc-L-glutamic acid dimethyl ester as the starting material,the target compound NK-1.8 k was synthesized via the substitution,reductive amination,deprotection,amide condensation,hydrolysis,and reduction reactions.Compared with the original synthetic route,the tandem string type in the important intermediate 5 synthesis was changed to parallel type,thereby the total synthetic reactions were condensed from seven steps to six steps,and some post-processing methods were also optimized.ResultsThe structures of intermediates and the target compound were confirmed by MS and1 H NMR data,and the total yield of the target compound synthesis was increased to 13.3%from 10.7%of the original route.ConclusionThe synthetic route established in this article for NK-1.8 k is reasonable and feasible,the raw materials used are cheap and easily available,the operation is simple,most of the reaction conditions are mild and controllable,the post-processing is simple,the intermediates are easy to separate and purify,the steps are short,and the yield is high.This method provides a valuable reference for the further synthesis of NK-1.8 k and similar products.