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 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*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.

A Survey of the Borrowing Hydrogen Approach to the Synthesis of some Pharmaceutically Relevant Intermediates

“…The impressive application of this technology by Pfizer in the synthesis of PF-03463275 notwithstanding, 8 it appears that the demands of complex, polar polyfunctional intermediates common to pharmaceutical targets do still impose some limitations on the broad applicability of the chemistry. Nevertheless, we have found significant encouragement from some key examples that this technology has the potential to deliver improved processes for pharmaceutical manufacture.…”

“…7 Furthermore, a Pfizer research team have recently described the optimisation and scale-up of an iridium-catalysed alkylation of a benzylic amine with a primary alcohol. 8 This work identified an advantage in carrying out the reaction in pressure equipment to allow for heating above the azeotrope temperature of toluene/water, providing a higher and more consistent yield, and allowing catalyst loadings to be reduced to <0.05 mol% iridium.…”

Iron catalysed direct alkylation of amines with alcohols

“…N-alkylated benzyl amines are particularly important targets, as these moieties are present in a variety of drug molecules, for example, a glycine transporter type 1 inhibitor, which has shown potential in the treatment of schizophrenia 29 (Fig. 6b).…”

“…6a), a dopamine antagonist used in the treatment of Parkinson's disease 11,31 . The application of iron-based homogeneous catalyst in the preparation of pharmaceutically active molecules is highly desired, given the limited allowed ppm levels of noble metal catalysts in the final products 29 . Taking advantage of the previously established reactivity of benzyl alcohol and piperidine in our system (Fig.…”

Insight into O2‐Promoted Base‐Catalyzed N‐Alkylation of Amines with Alcohols

“…Indeed, numerous other homogeneous catalysts such as those that contain palladium, [6] rhodium, [7] copper, [8] iron, [9] platinum, [10] and osmium [11] have also been developed, and several protocols are already utilized in the pharmaceutical industry. [12] The mechanism of these transition-metal-catalyzed N-alkylation reactions proceeds through a dehydrogenation/imination/ hydrogenation sequence. In addition, Lewis acid [13] and heterogeneous catalysts [14] have also been intensively studied and implemented in valuable applications.…”