Development of an Optimized Synthetic Process for Onradivir Featuring a “One-Pot” Miyaura–Suzuki Coupling Reaction

Influenza A virus (IAV) is a highly contagious pathogen responsible for significant global morbidity and mortality, with an estimated 1 billion infections annually. Onradivir, a next-generation PB2 inhibitor derived from Pimodivir, shows superior activity against drug-resistant IAV variants but faces manufacturing challenges. We report a scalable 7-step synthesis featuring two key innovations: (1) a silver-catalyzed radical cyclopropylation (89.5% conversion) replacing hazardous Grignard reagents; (2) a streamlined one-pot Miyaura–Suzuki coupling achieving 66% yield for intermediate 8. The route eliminates column chromatography through strategic recrystallizations, reduces Pd catalyst loading, and employs cost-effective ethyl acetate solvent. Process optimizations at 15 g scale demonstrate a consistent 5.8% yield for the API (representing a 7-fold improvement over the original method), with all intermediates either crystallized or telescoped to minimize purification losses. The developed methodology facilitates the commercial development of Onradivir and provides a general platform for the synthesis of structurally complex PB2 inhibitors.