Isopropyl 4-[(6-chloro-5-methoxypyrimidin-4-yl)oxy]piperidine-1-carboxylate → 4-[5-Methoxy-6-(2-methyl-6-[1,2,4]triazol-1-yl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic Acid Isopropyl Ester

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Sodium tert-butoxide (8.28 mL, 67.61 mmol) was added portionwise to a mixture of 2-methyl-6-(1H-1,2,4-triazol-1-yl)pyridin-3-amine (4.94 g, 28.17 mmol) isopropyl 4-(6-chloro-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate (9.29 g, 28.17 mmol) and in dioxane (136 mL) at 18°C over a period of 1 minute under nitrogen. The mixture was degassed by subjecting to vacuum then nitrogen atmosphere (six times). Palladium(II) acetate (0.063 g, 0.28 mmol) and 2,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo{3.3.3}undecane (0.200 mL, 0.56 mmol) was added and the mixture degassed again. The resulting suspension was stirred at 90 °C for 3 hours. Palladium(II) acetate (0.126 g, 0.56 mmol) and 2,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo{3.3.3}undecane (0.400 mL, 1.12 mmol) was added and the reaction stirred at 90 °C for 5 hours. The reaction mixture was diluted with water (100 mL) then extracted with EtOAc (300 mL), and washed with saturated brine (100 mL). The aqueous was extracted with EtOAc ( 100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography (330g column), elution gradient 0 to 10% EtOH in DCM (rising quickly to 5% then more slowly to 10%). Pure fractions were evaporated to dryness to afford impure isopropyl 4-(5-methoxy-6-(2-methyl-6-(1H-1,2,4-triazol-1-yl)pyridin-3-ylamino)pyrimidin-4-yloxy)piperidine-1-carboxylate, EN02029-80-P, as a yellow solid. The chromatography was repeated to give a slightly purer sample, EN02029-80-P2. This was triturated with Et2O (40 mL) to give a mobile solid which was filtered off and washed with Et2O (2 x 10 mL) then hexane (2 x 10 mL) to give a pale yellow solid, EN02029-80-solid 1. Analysis of this compound showed good purity so this mobile pale yellow solid was handed in as EN02029-80-01.

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