Development of a Scalable Amidation-Dehydration Telescope Process for the Synthesis of Ibuzatrelvir

Abstract Ibuzatrelvir is a second-generation, orally administered inhibitor of the SARS-CoV-2 Mpro that has enhanced metabolic stability compared to nirmatrelvir. Although early manufacturing campaigns enabled rapid large-scale supply, the final amidation–dehydration sequence faced significant challenges in robustness, impurity control, and downstream processing. In this report, we detail a streamlined telescoped process comprising a robust and efficient 2-chloro-1-methylpyridinium p-toluenesulfonate (CMPT)-mediated amidation followed by a clean trifluoroacetic anhydride (TFAA)-driven dehydration to overcome existing limitations. Process refinements in distillation, solvent exchange, and crystallization delivered a reproducible, sustainable route that was demonstrated at multikilogram scale. The optimized process afforded ibuzatrelvir in high yield, purity, and potency while markedly reducing process mass intensity (PMI) and cycle time, establishing an efficient and industrially viable approach for long-term manufacturing.