Development of Practical Manufacturing Process of Ensitrelvir‚ a SARS–CoV–2 3CL Protease Inhibitor for Oral Treating COVID–19

Ensitrelvir, SARS–CoV–2 3CL protease inhibitor, has been discovered for the treatment of the coronavirus disease 2019 (COVID–19). Ensitrelvir is structurally composed from three main units, which are indazole unit, triazole unit and triazinone unit. Synthetic strategies where these three units are employed at latter steps in the synthesis made it possible to construct a highly productive convergent route. In addition, the lean manufacturing process was also established through process optimization based on SELECT perspectives. These achievements contributed for the rapid commercial manufacturing of Ensitrelvir with less than one year. In this report, we describe R&D activities for route scouting and process optimization. In addition, a few trouble shootings which occurred during the manufacturing are also introduced. Lastly, additional study for further investigations to improve productivity and flexibility are briefly explained. © 2025 Society of Synthetic Organic Chemistry. All rights reserved.