Route Optimization of the Non-covalent Modulator of Hemoglobin PF-07059013 for the Treatment of Sickle Cell Disease, Part I: From Discovery Synthesis to First Kilogram-Scale Manufacture

The scalable route to PF-07059013 (3), a non-covalent modulator of hemoglobin for the treatment of sickle cell disease, is discussed. Optimization of the discovery route is presented, examining bond connections, late-stage Buchwald–Hartwig C–O coupling, and palladium content reduction strategies. The first process chemistry route to deliver 11 kg of the final API is also discussed.