Synthesis of Nirmatrelvir: Development of an Efficient, Scalable Process to Generate the Western Fragment
Russell F. Algera, Christophe Allais, Aaron F. Baldwin, Husein Becirovic, Paul Bowles, Adam R. Brown, Jamie M. Buske, Hugh J. Clarke, Nga M., Kevin Doyle, Jonathan Fifer, Kaitlyn Gray, Alan M. Happe, Mark Hardink, Aran K. Hubbell, Chintelle James, Hrushikesh P. Khadamkar, Javier Magano, Emma L. McInturff, Jason Mustakis, Gizem Ozbuyukkaya, Jared L. Piper, D.W. Place, John A. Ragan, Blake Rauschenberger, Giselle P. Reyes, Rawan Shehadeh, Corey L. Stanchina, Michael Stanley, R. Matthew Weekly, Ethan Weinstein, Gerald A. Weisenburger, Ethan Wood, Hatice G. Yayla, Shu Yu
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.