An Environmentally Responsible Synthesis of the SARS-CoV-2 Mpro Inhibitor Nirmatrelvir (PF‑07321332), the Active Ingredient in Paxlovid

A convergent route to the antiviral drug nirmatrelvir is described, arriving at the targeted drug in 45% overall yield with no loss of stereointegrity. Critical amide bond-forming steps utilize green technology that avoids traditional peptide coupling reagents. Likewise, dehydration of a primary amide to the corresponding nitrile is performed under environmentally benign conditions in water that avoids use of the Burgess reagent. Comparisons with the original literature procedures described highlight the decrease in environmental footprint associated with this approach.