反应详情

A mixture of N-(5-bromo-2-morpholinophenyl)-7-fluoro-2-(2-fluorophenyl)-3-methylquinolin-4-amine (50 mg, 98 μmol), morpholine (0.017 mL, 196 μmol), tris(dibenzylideneacetone)dipalladium(0) (6.3 mg, 6.9 μmol), X-Phos (7.0 mg, 15 μmol) and sodium tert-butoxide (19 mg, 196 μmol) in toluene (4.00 mL, 37552 μmol) was degassed by evacuation-back fill 3× then heated to reflux in an oil bath for 90 min, after which time LC-MS indicated only desired product predominated. The reaction was equilibrated to rt, concd under reduced pressure and the concentrate partitioned between 25 mL each DCM and water. The organic separation was stirred over anhydrous magnesium sulfate, filtered and the filtrate concd under reduced pressure to afford a yellow-brown solid. The product was isolated by reversed phase HPLC on Phenomenex™ C18 column, eluting with MeCN/water+0.1% TFA. 1H NMR (400 MHz, chloroform-d) δ ppm 7.83 (1H, dd, J=9.2, 6.1 Hz), 7.70 (1H, dd, J=10.0, 2.5 Hz), 7.52 (1H, td, J=7.4, 2.0 Hz), 7.33-7.45 (1H, m, J=7.9, 7.9, 5.4, 2.0 Hz), 7.15-7.30 (3H, m), 7.06-7.15 (1H, m), 7.03 (1H, d, J=8.6 Hz), 6.36 (1H, dd, J=8.6, 2.7 Hz), 5.96 (1H, d, J=2.0 Hz), 3.83 (4H, t, J=4.5 Hz), 3.58-3.75 (4H, m), 2.97 (4H, d, J=2.7 Hz), 2.75-2.92 (4H, m), 2.11 (3H, d, J=2.3 Hz). Mass Spectrum (ESI) m/e=517.2 (M+1).

1. customwas degassed by evacuation-back fill 3×
2. temperaturethen heated
3. temperatureto reflux in an oil bath for 90 min
4. customwas equilibrated to rt
5. customconcd under reduced pressure and the concentrate partitioned between 25 mL each DCM and water
6. customThe organic separation
7. filtrationfiltered
8. customthe filtrate concd under reduced pressure to afford a yellow-brown solid
9. customThe product was isolated by reversed phase HPLC on Phenomenex™ C18 column
10. washeluting with MeCN/water+0.1% TFA