ARTICLE pubs.acs.org/OPRD
Use of an Iridium-Catalyzed Redox-Neutral Alcohol-Amine Coupling on Kilogram Scale for the Synthesis of a GlyT1 Inhibitor Martin A. Berliner,*,† Stephane P. A. Dubant,‡ Teresa Makowski,† Karl Ng,† Barbara Sitter,† Carrie Wager,† and Yinsheng Zhang† †
Chemical Research and Development, Pharmaceutical Sciences, Pfizer Global Research and Development, Groton Laboratories, 558 Eastern Point Rd, Groton, Connecticut 06340, United States ‡ Chemical Research and Development, Pharmaceutical Sciences, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom
bS Supporting Information ABSTRACT: A recent development for the efficient and environmentally friendly synthesis of aliphatic amines is the transitionmetal-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 g 2000) while retaining reasonable reaction times (98% purity, with
