Research on the Synthesis Process of the Key Intermediate T18 in Nirmatrelvir

Abstract

The development of antiviral drugs against COVID-19 has attracted significant interest in recent years. Paxlovid, developed by Pfizer, is an orally administered small molecule drug for the treatment of COVID-19. It has attracted widespread attention due to its outstanding clinical performance. Nirmatrelvir, as the active ingredient of Paxlovid, has a huge market demand. Therefore, the development of a mild, efficient, and industrially feasible synthesis method for Nirmatrelvir is meaningful.
 This study investigates the synthesis process of the key amide intermediate T18 in Nirmatrelvir. Various amide synthesis methods were attempted, and it was determined that the best result can be achieved by using HOPO as a catalyst and using EDCI as condensing agent. Based on this, detailed optimization of reaction parameters was carried out to further reduce the amount of HOPO and eliminate the use of ethyl acetate, methyl tert-butyl ether, brine and magnesium sulfate. Additionally, the post-treatment process was simplified, and a crystallization process more suitable for industrial production requirements was developed. These findings provide important technical support for the industrial production of Nirmatrelvir.