反应详情

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+).

1. temperatureunder reflux
2. stirringmixture was stirred
3. temperatureunder reflux for another hour
4. waitat room temperature for 3 days
5. concentrationThe mixture was concentrated
6. extractionresidue was extracted with brine and AcOEt
7. dry with materialOrganic phases were dried over MgSO4
8. filtrationfiltered
9. concentrationconcentrated
10. customThe residue was purified by column chromatography (hexane/AcOEt 2:1→1:1)