反应详情

温度

60 °C

A mixture of hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole (1.0 eq), N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (710 mg, 1.8 mmol, 0.95 eq), K2CO3 (524 mg, 3.8 mmol, 2.0 eq) and KI (16 mg, 0.095 mmol, 0.05 eq) in DMF (12 mL) was heated at 60° C. for 3 h and cooled to room temperature. The reaction mixture was quenched with water (10 mL) and diluted with EtOAc (20 mL). The organic phase was separated from the mixture, and the water phase was extracted with EtOAc (20 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (20:1 (v/v) CH2Cl2/CH3OH) to give the crude product, which was recrystallized from CH2Cl2/PE to afford the title compound as a grayish-white solid (230 mg, 25.00%), HPLC: 99.11%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 489.9 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.09 (2H, m), 2.74 (4H, m), 2.99 (2H, dd, J=3.3, 10.4 Hz), 3.56 (2H, m), 3.80 (2H, m), 3.99 (3H, s), 4.12 (2H, t, J=3.5 Hz), 4.22 (2H, t, J=6.8 Hz), 7.14 (1H, t, J=8.8 Hz), 7.23 (1H, s), 7.29 (1H, d, J=15.8 Hz), 7.60 (1H, m), 7.89 (1H, dd, J=2.5, 6.5 Hz), 8.63 (1H, s) ppm.

1. temperaturecooled to room temperature
2. customThe reaction mixture was quenched with water (10 mL)
3. additiondiluted with EtOAc (20 mL)
4. customThe organic phase was separated from the mixture
5. extractionthe water phase was extracted with EtOAc (20 mL×3)
6. dry with materialThe combined organic phases were dried over anhydrous Na2SO4
7. concentrationconcentrated in vacuo
8. customThe residue was purified by a silica gel column chromatography (20:1 (v/v) CH2Cl2/CH3OH)
9. customto give the crude product, which
10. customwas recrystallized from CH2Cl2/PE