4-(6-Chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester → 4-[6-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic Acid Isopropyl Ester

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Sodium tert-butoxide (9.83 mL, 80.31 mmol) was added portionwise to isopropyl 4-(6-chloro-5-methylpyrimidin-4-yloxy)piperidine-1-carboxylate (10.50 g, 33.46 mmol) and 2-methyl-6-(methylsulfonyl)pyridin-3-amine (5.92 g, 31.79 mmol) in dioxane (160 mL) at 18ºC over a period of 1 minute under nitrogen. The reaction was degassed with vacuum / nitrogen (6 times) and 2,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo{3.3.3}undecane (0.238 mL, 0.67 mmol) and Palladium(II) acetate (0.075 g, 0.33 mmol) was added and the suspension was stirred at 90 °C for a further 2 hours. More 2,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo{3.3.3}undecane (0.238 mL, 0.67 mmol) and Palladium(II) acetate (0.075 g, 0.33 mmol) was added and the suspension was stirred at 90 °C for a further another 2 hours before being allowed to cool and stirred at room temperature overnight. The reaction was worked up with water (50 mL) and diluted with EtOAc (400 mL), and washed sequentially with water (100 mL) and saturated brine (50 mL). The organic layer was 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 50% EtOAc in DCM (rising quickly to 20% then more slowly to 50%). The impure fractions were collected and combined and purified again in exactly the same way. Pure fractions were evaporated to dryness to afford isopropyl 4-(5-methyl-6-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)pyrimidin-4-yloxy)piperidine-1-carboxylate, EN02029-72-solid-1, as a yellow solid. This solid was recrystallised from MeOH (~ 50 mL) and the resultant solid filtered off and washed with cold MeOH (2 x 5 mL), Et2O (2 x 5 mL) then isohexane (2 x 5 mL). The solid, EN02029-72-solid-2 was combined with the product from EN02029-67-01 and the whole sample was named EN02029-72-01 (8.39 g) and submitted to the collection.

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