Synthesis of Nirmatrelvir: Development of an Efficient, Scalable Process to Generate the Western Fragment

Abstract

Nirmatrelvir (1), a novel and specific inhibitor of the SARS-CoV-2 3C-like protease, was developed by Pfizer scientists in mid 2020. Efforts to develop a scalable process to manufacture nirmatrelvir were undertaken with a great sense of urgency, as there were no effective treatments available for the worldwide patient population at that time. We used a convergent approach to generate this molecule. The first two steps used to generate the western fragment of nirmatrelvir from l-tert-leucine, ethyl trifluoroacetate, and a [3.1.0] bicyclic proline derivative are described here. This is the first of a series of four papers describing the commercial process of the development of nirmatrelvir.