Published: August 13, 2011 r2011 American Chemical Society 1052 dx.doi.org/10.1021/op200174k | Org. Process Res. Dev. 2011, 15, 1052–1062 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,* ,† St  ephane 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 b S Supporting Information 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*IrCl 2 ) 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 (<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. ’ INTRODUCTION The construction of carbonÀnitrogen bonds is central to the preparation of bioactive organic molecules. Significant chemical literature is associated with heterocycle synthesis and amine acylation, and more recent and substantial efforts have resulted in development of efficient methods for the transition-metal- catalyzed construction of arylÀnitrogen bonds. 1 In contrast, the transition-metal-catalyzed synthesis of aliphatic CÀN bonds has received comparatively less attention. 2 These reactions typically proceed via a series of discrete steps involving sequential de- hydrogenation of the alcohol (to form a carbonyl compound) followed by imine formation and subsequent reduction (Figure 1). As a result of the action of the catalyst as a hydride shuttle be- tween starting material and product, these processes are typically described in the literature as “borrowing hydrogen” or “hydrogen autotransfer” reactions to reflect the redox-neutral nature of the overall process. From a process development perspective, application of this chemistry offers several potential advantages over existing tech- niques (e.g., direct alkylation, reductive amination). In addition to a significant improvement in atom economy (water is the only byproduct of the reaction), the redox-neutral process features operational simplicity and reduced environmental impact through solvent and waste stream reduction. In this report, we describe the optimization and kilogram-scale application of an iridium- catalyzed redox-neutral coupling of an alcohol and a substituted benzylamine as applied to the synthesis of PF-03463275 (1), a glycine transporter type 1 (GlyT1) inhibitor that has potential as a therapy for schizophrenia. 3 The seven-step medicinal chemistry synthesis of PF- 03463275 is shown in Scheme 1. 3a The synthesis starts from exo-N-benzyl-3-azabicyclo[3.1.0]hexane-6-methanol (2), 4 which is converted to the N-Boc alcohol 4 via amino alcohol 3. Swern oxidation of 4 provides aldehyde 5, which is utilized without purification in a reductive amination with 3-fluoro-4-chloroben- zylamine (6) to generate secondary amine 7. Installation of the amide in 9 is accomplished by coupling with N-methylimidazole- 4-carboxylic acid (8) under typical conditions. After column chromatography, the Boc group in 9 is removed with hydrogen chloride to generate pyrrolidine 10. In the final step, the N-methyl group on the pyrrolidine is introduced using a reductive amina- tion with formaldehyde. Following cleanup by silica gel chroma- tography, 1 is rendered crystalline by a reslurry in ethyl acetate. Interestingly, all bond-forming steps in the synthesis of 1 from 2, 6, and 8 generate new carbonÀnitrogen bonds, and no carbonÀ carbon bonds are formed. 5 The primary drivers for the development of a new route for the synthesis of 1 focused on operational issues. Most intermediates (3, 4, 5, 7, and 9) are oils, and their salts, while solids, proved to be hygroscopic and unsuitable for handling and storage. We also sought to avoid formaldehyde use in the final step while eliminating the need for protecting groups. We were mindful of the potential difficulties engendered by the presence of unprotected amines in the API and precursors. In practice, this latter concern proved to be the major driver for the selection of chemistry during process development, as many common transformations uti- lize exogenous amine bases that must be removed during work- up. Given this constraint, a step-reordered route to 1 was designed to address many of the existing concerns in the discovery synthesis while incorporating our desired changes (Scheme 2). 6 This modified route is shorter and employs formaldehyde earlier in the process in a telescoped debenzyla- tion/reductive amination reaction to eliminate the need for Received: June 28, 2011