An Effective Additive for Introducing the Triazole Unit of Ensitrelvir: Combination of LiCl and Et3N to Easily Generate Lithium Triazinolate

Abstract

An efficient and robust method was developed to introduce the triazole unit of Ensitrelvir, a COVID-19 therapeutic agent. One of the key steps is introducing the triazole unit in the triazinone with Cs2CO3 and KI in a heterogeneous system. Detailed reaction screening revealed that addition of LiCl allowed the reaction to proceed quantitatively in the presence of inexpensive Et3N, and the selectivity of the N-alkylation was greatly improved. The key to promoting the reaction is the mild formation of the lithium triazinolate accompanied by precipitation of Et3N∙HCl (the only insoluble matter in this reaction). Dissolving all the substrates and reagents should contribute to further improvement of the process robustness.