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. Do, Kevin J. Doyle, Jonathan Fifer, Kaitlyn C. Gray, Alan M. Happe, Mark A. Hardink, Aran K. Hubbell, Chintelle James, Hrushikesh P. Khadamkar, Javier Magano, Emma L. McInturff, Jason G. Mustakis · Organic Process Research & Development · 2023
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.