Palladium-Catalyzed C–O Coupling of a Sterically Hindered Secondary Alcohol with an Aryl Bromide and Significant Purity Upgrade in the API Step

The final two steps used to prepare greater than 1 kg of a compound evaluated as a treatment for type 2 diabetes are reported. The application of a palladium-catalyzed C–O coupling presented significant challenges due to the nature of the reactants, impurities produced, and noncrystalline coupling intermediate. Process development was able to address these limitations and enable production of kilogram quantities of the active pharmaceutical ingredient (API) in greater efficiency than a Mitsunobu reaction for formation of the key bond. The development of a sequence that telescopes the coupling with the subsequent ester hydrolysis to yield the API and the workup and final product crystallization necessary to produce high-quality drug substance without the need of column chromatography are discussed.