A Sustainable Synthesis of the SARS-CoV-2 Mpro Inhibitor Nirmatrelvir, the Active Ingredient in Paxlovid

A 7-step, 3-pot synthesis of the antiviral drug nirmatrelvir is described, arriving at the targeted drug in 70% overall yield. Critical amide bond-forming steps utilize new green technology that completely avoids traditional peptide coupling reagents, as well as epimerization of stereocenters. Likewise, dehydration of a primary amide to the corresponding nitrile is performed and avoids use of the Burgess reagent and chlorinated solvents. Direct comparisons with the original literature procedures highlight both the anticipated decrease in cost and environmental footprint associated with this route, potentially expanding the availability of this important drug worldwide.