Suppression of a Palladium-Mediated Homocoupling in a Suzuki Cross-Coupling Reaction. Development of an Impurity Control Strategy Supporting Synthesis of LY451395

Described herein is the development of a control strategy resulting in exclusion of a persistent impurity ( 6 ) formed by a palladium (II)-mediated homocoupling of boronic acid ( 3 ) during a Suzuki cross-coupling reaction. Nearly complete suppression of the undesired homocoupling reaction was achieved through two process modifications. Thus, addition of a mild reducing agent, potassium formate, and use of a facile nitrogen subsurface sparge prior to introduction of the catalyst resulted in nearly complete exclusion of homocoupling dimer 6 . These modifications apparently minimized the concentration of free Pd(II) in the reaction mixture without causing significant reduction of the oxidative addition product. In addition, use of palladium black as a heterogeneous coupling catalyst rendered the palladium control strategy trivial. Thus, the catalyst was separated from the product solution through use a clarifying filtration, resulting in near quantitative separation of palladium from LY 451395 ( 5 ). These conditions were successfully executed in three campaigns using 3-, 5-, 12-, and 22-L glassware.