反应详情

温度

80 °C

A suspension of trans-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.227 mmol) in ethylene glycol dimethyl ether (8 mL) was treated with N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (0.097 g, 0.238 mmol), tetrakis(triphenylphosphine)palladium (0.016 g, 0.014 mmol), and a solution of sodium carbonate (0.057 g, 0.538 mmol) in water (4 mL). The reaction mixture was stirred for 21.5 h at 80° C. The precipitate was filtered, and the organic layer was evaporated under reduced pressure. Dichloromethane (15 mL) was added and the layers were partitioned. The aqueous layer was extracted with dichloromethane (200 mL). The combined organic layers were dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a 10% methanol in dichloromethane to 50% methanol in dichloromethane step gradient on Sq 16× ISCO CombiFlash. The column afforded 0.083 g (68%) of trans-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide. 1H NMR (d6-DMSO) δ 9.4316 (s, 1H), 8.2427 (s, 1H), 8.1207-8.1003 (d, 1H, J=8.16 Hz), 7.7173-7.6974 (d, 1H, J=7.96 Hz), 7.5979-7.5769 (d, 1H, J=8.4 Hz), 7.3507-7.2758 (m, 4H), 7.1695-7.1321 (t, 1H), 4.6893-4.6324 (m, 1H), 4.0400 (s, 3H), 3.9571 (s, 3H), 2.5 (m, 3H), 2.4055-2.3279 (m, 5H), 2.1606 (s, 3H), 2.1094-1.9367 (m, 6H), 1.5214-1.4624 (m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium Acetate in Water to 95% Acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.12 min (100%), M+ 594.3.

1. filtrationThe precipitate was filtered
2. customthe organic layer was evaporated under reduced pressure
3. additionDichloromethane (15 mL) was added
4. customthe layers were partitioned
5. extractionThe aqueous layer was extracted with dichloromethane (200 mL)
6. dry with materialThe combined organic layers were dried over magnesium sulfate
7. filtrationfiltered
8. customevaporated under reduced pressure
9. customThe crude material was purified by flash chromatography on silica gel using a 10% methanol in dichloromethane to 50% methanol in dichloromethane step gradient on Sq 16× ISCO CombiFlash