Early Development of Ibuzatrelvir: Navigating Polymorph and Crystallization Challenges in a Protecting Group-Free Direct Amidation and Amidation-Dehydration Sequence

Abstract Ibuzatrelvir is an orally bioavailable, next-generation clinical candidate developed for the treatment of COVID-19 infections. It was identified during the pandemic, prior to the approval of PAXLOVID, and displays a more favorable pharmacokinetic profile than nirmatrelvir. Consequently, the initial development of ibuzatrelvir proceeded under highly accelerated timelines. This report details the optimization of the end-stage synthesis sequence and its advancement throughout the initial clinical production campaigns. The study highlights an efficient protecting group-free amidation of tert-leucine and describes a complex isolation process following a telescoped amidation-dehydration cascade leading to ibuzatrelvir with a 30% increase in yield. The finalized synthetic route was successfully scaled up, enabling the manufacture of several hundred kilograms to support clinical research initiatives.