Optimized Kilogram-Scale Synthesis and Impurity Identification of SHEN26 (ATV014) for Treating COVID-19

SHEN26, a 5′-cyclohexane-carboxylate prodrug of the nucleoside analog GS-441524, is a potent RdRp inhibitor currently undergoing phase III clinical trials for coronavirus disease 2019 (COVID-19) treatment. To meet clinical demands and future market supply, it is essential to develop preparation methods suitable for industrial manufacture. In this study, we provide a 3-step industrial synthesis method for SHEN26 with chromatography-free postreaction treatments. 10-kg-scale synthesis was achieved with a total of 57% yield. Impurities in the synthesis process of SHEN26 were also identified and analyzed. The purity of GMP-graded active pharmaceutical ingredient (API) reached 98.9% (<1.1% impurity), demonstrating the viability of this synthetic route for large-scale manufacture of SHEN26.