A mixture of 2-chloro-5-fluoro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine hydrochloride (6.68 g, 20.68 mmol, 1 equiv), 4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)benzenamine (6.80 g, 31.02 mmol, 1.5 equiv), and PTSA monohydrate (3.15 g, 16.54 mmol, 0.8 equiv) in IPA (200 mL) were heated to 70° C. for 4 days. LCMS indicated 2-4% of the cleaved tetrazole product and 7-9% unreacted 2-chloro-5-fluoro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine. After cooling the reaction mixture to ambient temperature, 3-amino benzoic acid (8.51 g, 62.04 mmol, 3 equiv) was added and heated to 70° C. for overnight to scavenge the unreacted pyrimidine. After cooling to ambient temperature, the crude mixture was concentrated to dryness. The residue was taken in ice-cold water and EtOAc then adjusted to ca. pH 12-14 with 1N NaOH (300 mL). The aqueous and organic layers were partitioned, and the organic layer washed with 1N NaOH (2×300 mL). The aqueous layer was extracted with EtOAc (1×150 mL). The combined organic extracts were dried (Na2SO4), filtered, and the solvent removed under vacuum. The crude product was purified by flash chromatography and eluted with DCM:2M NH3/MeOH=100:0 to 96:4 using 1% 2M NH3/MeOH increments to provide the desired product which was triturated with EtOAc/hexane to give the title compound (5.16 g, 53%) as a solid.
