Synthesis of Nirmatrelvir: Design and Optimization of an Efficient Telescoped Amidation–Dehydration Sequence

Development of a scalable route for the synthesis of nirmatrelvir, the novel SARS-CoV-2 3C-like protease inhibitor discovered in 2020 by Pfizer scientists, was initiated shortly thereafter to supply material for the first clinical studies. This route was optimized for commercial manufacture of nirmatrelvir in high yield and acceptable quality with consideration of efficiency and sustainability. Herein, we report the evolution of final steps (3–5) used to synthesize nirmatrelvir (steps 3–5), from the manufacture of the initial regulatory lot to the design and implementation of the final commercial process.