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.