Buchwald-Hartwig amination

A mixture of the product of (6-chloro-2-[(2,3-difluorobenzyl)thio]-N-{(1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl}pyrimidin-4-amine) (1.1 g, 25 mmol), azetidine-1-sulfonamide (0.51 g, 3.8 mmol), palladium(II)tris(dibenzylideneacetone) dipalladium (0) (0.15 g), XPhos (0.15 g) and cesium carbonate (1.2 g, 20 mmol) in dry dioxane (15 mL) was heated in a microwave in an open vessel at 100°C/300W max for 12 minutes with stirring. The mixture was allowed to cool to room temperature, acetic acid (2.4 mL) was added and the solvent removed in vacuo. The residues were partitioned between water and ethyl acetate, and the organic fraction was separated, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo to give a red gum (1.7 g). The product was purified twice by chromatography (SiO2, EtOAc :isohexane 1 : 1 then EtOAc :isohexane 4:6) to give the product as a colourless foam (1.0 g, 75%).

 

Patent reference: WO2010007427 (Astrazeneca)

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