Ensitrelvir is a 3CLpro inhibitor developed by SHIONOGI & CO., Ltd. of Japan for the treatment of COVID-19 and was approved for marketing in Japan on November 1, 2022. Various research results show that compared with Pfizer's Paxlovid and Merck's molnupiravir, Ensitrelvir is currently the most effective, safest and longest-lasting drug in the world! The synthesis of ensitrevir can be divided into four segments, and the docking of these four segments. Among them, the challenging segments are the triazole and indole segments due to the issue of methylation selectivity. In this study, DFT theory was primarily employed to investigate the activation energy of 1-methyl-1,2,4-triazole-3-carboxylic acid methyl ester and its positional isomers under different solvent conditions. Through experimental screening, selective methylation of 1H-1,2,4-triazole-3-carboxylic acid methyl ester was achieved. Subsequently, single crystals of the main product were cultivated, and calculations of electron density, nuclear magnetic resonance vibrations, etc., were performed for the three products to study the differences in the properties of various methylation products. Further structural confirmation of the three compounds was carried out using HMBC two-dimensional spectra.
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