Development of a Large-Scale Copper(I)/TEMPO-Catalyzed Aerobic Alcohol Oxidation for the Synthesis of LSD1 Inhibitor GSK2879552

Abstract

An improved process to an aldehyde en route to an LSD1 inhibitor was developed using an aerobic oxidation with a CuI and TEMPO (2,2,6,6-tetramethylpiperdine 1-oxyl) catalyst system. In this report, kinetic information is utilized to understand the generation a of number of key byproducts that affect catalyst performance and aldehyde yield. Insight into factors affecting the formation of these byproducts is presented. This CuI/TEMPO catalyst facilitates rapid conversion of the starting aliphatic alcohol in 1–2 h with apparent zero-order kinetics unprecedented for this substrate class with this catalyst system. Process optimization of catalyst components and reaction solvent led to the successful 400 g scale-up of this oxidation with bubbling air in a batch reactor.