Development of a Manufacturing Process toward the Convergent Synthesis of the COVID-19 Antiviral Ensitrelvir

We describe the development of the practical manufacturing of Ensitrelvir, which was discovered as a SARSCoV-2 antiviral candidate. Scalable synthetic methods of indazole, 1,2,4-triazole and 1,3,5-triazinone structures were established, and convergent couplings of these fragments enabled the development of a concise and efficient scale-up process to Ensitrelvir. In this process, introducing a meta-cresolyl moiety successfully enhanced the stability of intermediates. Compared to the initial route at the early research and development stage, the overall yield of the longest linear sequence (6 steps) was improved by approximately 7-fold. Furthermore, 9 out of the 12 isolated intermediates were crystallized directly from each reaction mixture without any extractive workup (direct isolation). This led to an efficient and environmentally friendly manufacturing process that minimizes waste of organic solvents, reagents, and processing time. This practical process for manufacturing Ensitrelvir should contribute to protection against COVID-19.

Automated summary

We describe the development of a practical manufacturing process for Ensitrelvir, a discovered SARSCoV-2 antiviral candidate. Scalable synthetic methods of indazole, 1,2,4-triazole, and 1,3,5-triazinone structures were established, enabling a concise and efficient scale-up process. The introduction of a meta-cresolyl moiety successfully enhanced intermediate stability, resulting in approximately 7-fold improvement in overall yield. Furthermore, direct isolation of intermediates from reaction mixtures minimized waste and led to an environmentally friendly manufacturing process.