2-(Di-tert-butylphosphino)biphenyl → 4-[6-(6-Bromo-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester

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Reaction Steps

A mixture of 4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (3.3 g, 10.0 mmol), 6-bromo-2-methyl-pyridin-3-ylamine (1.88 g, 10.0 mmol), palladium acetate (118 mg, 0.53 mmol), 2-(di-t-butylphosphino) biphenyl (157 mg, 0.53 mmol) and LiN(TMS)2 (1M in THF, 15 mL, 15 mmol) in 75 mL of dioxane was stirred under reflux. After 4.5 h, more palladium acetate (111 mg, 0.50 mmol) was added and mixture was stirred under reflux for another hour and then at room temperature for 3 days. The mixture was concentrated and residue was extracted with brine and AcOEt. Organic phases were dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (hexane/AcOEt 2:1→1:1) to give 4-[6-(6-bromo-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester as a solid (2.09 g, 44%). 1HNMR (CDCl3, 400 MHz) a 1.27-1.28 (d, 6H), 1.84-1.87 (m, 2H), 2.02-2.08 (m, 2H), 2.58 (s, 3H), 3.40-3.47 (m, 2H), 3.73 (s, 3H), 3.77-3.82 (m, 2H), 4.93-4.97 (m, 1H), 5.41-5.43 (m, 1H), 7.44-7.46 (m, 1H), 7.91-7.93 (m, 1H), 8.24 (s, 1H), 8.70 (s br, 1H). Exact mass calculated for C20H26BrN5O4 479.12. found 482.0 (MH+).

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