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

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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.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.