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

Abstract

We describe the development of the practical manufacturing of Ensitrelvir, which was discovered as a SARS-CoV-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.

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

“…The analytical result coincided with that described in the literature. 3) 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (3a) The analytical result coincided with that described in the literature. Using DBU: Triazinone 2 (6.00 g, 16.5 mmol), triazole 3a (3.60 g, 21.4 mmol), LiCl (0.94 g, 22.2 mmol), DMA (36.0 mL) and DBU (6.13 g, 40.3 mmol) were mixed.…”

“…The analytical result coincided with that described in the literature. 3) 3-benzyl-6-(m-tolyloxy)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione (4b); Typical Procedure…”

“…b Previous condition: Cs 2 CO 3 , KI. 3 c Assay yield/HPLC in the reaction mixture. d Amount used: 3.0 equiv.…”

“…In our previous work, 1 was synthesized by convergent coupling of indazole, 1,3,5-triazinone (2) and 1,2,4-triazole (3a) prepared by a scalable synthetic method (longest linear steps: 6 steps; total yield: 35%) (Scheme 1). 3) Considering the need for large supplies of 1 led us to try to further improve the synthesis method.…”

Main and papain-like proteases as prospective targets for pharmacological treatment of coronavirus SARS-CoV-2

“…The compound S-217622 exhibited high antiviral activity in vitro against all currently outbreaking SARS-CoV-2 variants, including Delta and Omicron, and showed favorable pharmacokinetic profiles in vivo for once-daily oral dosing, which makes it an universal broad-spectrum antiviral clinical candidate for treating COVID-19. 113–115…”