Initial Process Development and Scale-Up of the Synthesis of a Triple Reuptake Inhibitor ALB 109780

Early process development toward a triple reuptake inhibitor is described. Three different routes were evaluated; one of them was optimized and scaled up to generate 470 g of API as this route minimized the formation of undesired side products. The selected route featured Eaton’s reagent-mediated cyclization of a phenyl acetamide, copper-mediated Buchwald–Hartwig coupling to install a morpholine moiety, and palladium-catalyzed α-arylation of a dihydroisoquinolinone to construct the core structure.