反应详情

温度

90 °C

A mixture of 4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (14.7 g, 44.6 mmol), 2-methyl-6-(methylsulfonyl)pyridin-3-amine (8.20 g, 44.0 mmol), palladium acetate (0.50 g, 2.23 mmol), 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (1.65 ml, 4.64 mmol), and sodium 2-methylpropan-2-olate (6.50 g, 67.6 mmol) in dioxane (300 mL) were stirred at 90° C. for 1 h and then at 60° C. overnight. The reaction mixture was cooled and filtered. The solid was washed with ethyl acetate. The filtrate was concentrated and the residue was purified by silica gel column chromatography using hexane/ethyl acetate (1:2). The fractions containing only the product were collected, and concentrated to give the title compound (4.6 g, 22%) that was crystallized from ethyl acetate/hexane as a white solid. The fractions containing the product contaminated with impurities were concentrated and the residue was further purified by recrystallization from ethanol to give the title compound (2.5 g, 12%) as a white solid. The two combined to give 7.1 g of the title compound in 34% yield. Exact mass calculated for C21H29N5O6S: 479.2. Found: LCMS m/z=480.4 (M+H+); 1H NMR (400 MHz, CDCl3) δ 1.27 (d, J=6.3 Hz, 6H), 1.80-1.85 (m, 2H), 2.02-2.07 (m, 2H), 2.66 (s, 3H), 3.19 (s, 3H), 3.38-3.45 (m, 2H), 3.78-3.83 (m, 2H), 4.01 (s, 3H), 4.91-4.97 (m, 1H), 5.38-5.42 (m, 1H), 7.30 (s, 1H), 7.97 (d, J=8.6 Hz, 1H), 8.20 (s, 1H), 9.01-9.04 (d, J=8.6 Hz, 1H).

1. customat 60° C.
2. customovernight
3. temperatureThe reaction mixture was cooled
4. filtrationfiltered
5. washThe solid was washed with ethyl acetate
6. concentrationThe filtrate was concentrated
7. customthe residue was purified by silica gel column chromatography
8. additionThe fractions containing only the product
9. customwere collected
10. concentrationconcentrated