Route Optimization of the Noncovalent Modulator of Hemoglobin PF-07059013 for Treatment of Sickle Cell Disease through a Palladium-Mediated C–O Coupling, Part II: Pilot Plant Scale Manufacture

Abstract

Herein, we report the optimization of the first process chemistry route for pilot-plant-scale manufacture of PF-07059013 (1), a noncovalent modulator of hemoglobin for the treatment of sickle cell disease. Five areas of improvement are discussed in detail, namely, an alternative synthetic sequence to install the pyridone functionality before benzylic ether formation, a shorter and safer route to quinoline fragment 9, a tosyl-swap strategy to avoid isolation of a thermally unstable tosylate intermediate, Pd-catalyzed C–O coupling with low catalyst loading and efficient Pd removal, and improved final isolation of the API freebase. The new route was executed in our pilot plant facility to deliver 76 kg of API.