Use of an Iridium-Catalyzed Redox-Neutral Alcohol-Amine Coupling on Kilogram Scale for the Synthesis of a GlyT1 Inhibitor

Abstract

A recent development for the efficient and environmentally friendly synthesis of aliphatic amines is the transition-metal-catalyzed redox-neutral coupling of an alcohol and an amine, generally referred to as a “borrowing hydrogen” reaction. In this work, we describe the first kilogram-scale application of this technology in the synthesis of PF-03463275, a GlyT1 inhibitor developed for the treatment of schizophrenia. Using (Cp*IrCl2)2 the reaction has been optimized to achieve catalyst loadings lower than 0.05 mol % iridium (S/C ≥ 2000) while retaining reasonable reaction times (<24 h). Water and a tertiary amine are essential for high catalytic activity, resulting in dramatically increased reaction rates compared to existing literature protocols. Methods for iridium removal are also described.