冠状病毒3Cpro蛋白酶抑制剂GC376的合成研究

Synthesis of coronavirus 3Cpro protease inhibitor GC376

GC376是一种广谱性冠状病毒3Cpro蛋白酶抑制剂。本文以N-Boc-L-谷氨酸二甲酯作为起始原料,经氰化、环化、去Boc、酰胺化、还原、氧化、磺酸盐化合成了GC376,中间体及目标化合物的结构经~1H NMR表征。设计了两条合成路线,路线2较路线1减少了两步反应,提高了反应收率。采用单因素法,考察了还原剂种类,底物的浓度和还原剂PtO的载样量对关键中间体3的合成条件的影响,将3的合成收率由文献报道的58%提高到83%;HOAt作为缩合剂,使中间体5的收率由文献报道的72%提高到82%。本文对于GC376的合成研究具有重要的实际应用价值。

GC376 is a broad-spectrum coronavirus 3 Cpro protease inhibitor.In this paper,GC376 was synthesized from N-Boc-L-glutamic dimethyl ester by cyanidation,cyclization,de-Boc,amidation,reduction,oxidation and sulfonation,and the structures of the intermediate and the target compound were characterized by~1H NMR.This paper designed two synthesis routes which route 2 reduced two reaction steps and improved the reaction yield than route 1.The single factor method was used to investigate the effects of the type of reducing agent,the concentration of the substrate and the loading amount of reducing agent PtOon the synthesis conditions of the key intermediate 3.The synthesis yield of 3 was increased from 58%reported in the literature to 83%.As a condensation agent,HOAt increased the yield of intermediate 5 from 72%to 82%.This paper had important practical application value for the synthesis research of GC376.