反应详情

温度

25 °C

To a suspension of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (100 g, 170 mmol) in DCM (1 L) was added TFA (80 mL, 1077 mmol) dropwise. The mixture was stirred at 25° C. for 2 h. The mixture was then concentrated. To the residue was added H2O (500 mL) dropwise and then neutralized with saturated Na2CO3 solution to adjust pH=7.5. The precipitate was filtered, washed with H2O (350 mL×3) and dried in vacuo. To the solid was added PE/EA (3:1, v/v, 300 mL) and stirred for 0.5 h. The solid was filtered and washed with PE/EA (3:1, v/v, 100 mL×2). The solid was redissolved in DCM/MeOH (20:1, v/v, 1.5 L) and then concentrated in vacuo to a minimal amount of solvent (about 150 mL). The solid was filtered, washed with CH3CN (50 mL×2) and dried in vacuo. The residual solid was added to EtOH (2.5 L) and heated to 80° C. After the solid was dissolved completely, the mixture was concentrated in vacuo to give a white solid of 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (61.4 g, 131 mmol, 77% yield): 1H NMR (400 MHz, CD3OD) δ 7.40-7.30 (m, 2H), 7.25-7.18 (m, 2H), 6.88 (s, 1H), 5.98 (s, 1H), 4.11 (q, J=7.2 Hz, 2H), 3.81 (s, 2H), 1.56 (s, 6H), 1.37 (t, J=7.2 Hz, 3H); ES-LCMS m/z: 468 (M+H).

1. concentrationThe mixture was then concentrated
2. additionTo the residue was added H2O (500 mL) dropwise
3. filtrationThe precipitate was filtered
4. washwashed with H2O (350 mL×3)
5. customdried in vacuo
6. additionTo the solid was added PE/EA (3:1, v/v, 300 mL)
7. stirringstirred for 0.5 h
8. filtrationThe solid was filtered
9. washwashed with PE/EA (3:1, v/v, 100 mL×2)
10. dissolutionThe solid was redissolved in DCM/MeOH (20:1, v/v, 1.5 L)
11. concentrationconcentrated in vacuo to a minimal amount of solvent (about 150 mL)
12. filtrationThe solid was filtered
13. washwashed with CH3CN (50 mL×2)
14. customdried in vacuo
15. additionThe residual solid was added to EtOH (2.5 L)
16. temperatureheated to 80° C
17. dissolutionAfter the solid was dissolved completely
18. concentrationthe mixture was concentrated in vacuo