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 in the medicinal synthetic stage, the overall yield of the longest linear sequence (six steps) was improved by approximately 7-fold. Furthermore, nine out of the twelve isolated intermediates were crystallized directly from each reaction mixture without any extractive work-up (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 following abbreviations (or combinations thereof) were used to denote 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. The analytical result coincided with that described in the literature.…”

“…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.…”

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

“…We believe the development of this practical process for manufacturing of 1 contributes to re-establishing the safety and security of society and addressing the COVID-19 pandemic. 39 …”

“…In addition, the present practical process settled all the issues that made large-scale synthesis difficult, i.e., removal of corrosive acid by evaporation and the generation of noxious odors from thiol derivatives. We believe the development of this practical process for manufacturing of 1 contributes to re-establishing the safety and security of society and addressing the COVID-19 pandemic …”

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

“…113 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 proles in vivo for once-daily oral dosing, which makes it an universal broad-spectrum antiviral clinical candidate for treating COVID-19. [113][114][115] Fig. 11 Structure of noncovalent Mpro inhibitors based on ML300 scaffold.…”