反应详情

温度

89 °C

To the solution containing 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.22 kg, 4.8 mol) from the previous step was added 3-chloro-6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazine (1.17 kg, 4.4 mol). K3PO4-3H2O (2.34 kg, 8.8 mol) was dissolved in water (5 L) then added to the above solution. The mixture was purged with nitrogen 3 times. Pd(PPh3)4 (500 g, 0.42 mol) was added under nitrogen, and the reaction mixture was heated to reflux at 89° C. for 16 hours. After 16 hours, HPLC showed that the reaction was complete. After cooling to room temperature, the mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. CH2Cl2 (10 L×3) and 10% K2CO3 solution (15 L) were added to the above residue. The organic layers were separated and combined, followed by washing with water twice (10 L×2) and concentration under reduced pressure to give yellow oil. MTBE (10 L) was used to dissolve the yellow oil. Petroleum ether (4 L) was added slowly with stirring. A few dark solids precipitated and were removed by filtration. The filtrate was concentrated under reduced pressure and dissolved in CH2Cl2 (20 L). 2N HCl (5 L) was added slowly and a large amount of precipitate formed. After stirring for another 1 hour, the solid was collected by filtration and washed with EtOAc (2 L). The solid was dried in vacuo at 50° C. to give 5-chloro-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol hydrochloride (0.9 kg, 2.2 mol). MS m/z 362.0 [M+H]+; 1H-NMR: (DMSO-d6, 400 MHz) δ 9.26 (d, J=11.6 Hz, 1H), 8.49 (d, J=12 Hz, 1H), 8.38 (d, J=9.6 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.44 (d, J=9.6 Hz, 1H), 7.07 (d, J=2 Hz, 1H), 7.02 (dd, Ja=2 Hz, Jb=8.4 Hz, 1H), 5.73 (m, 1H), 2.31 (dd, Ja=4 Hz, Jb=13.2 Hz, 2H), 1.84 (dd, Ja=11.6 Hz, Jb=2 Hz, 2H), 1.51 (s, 6H), 1.49 (s, 6H).

1. additionthen added to the above solution
2. customThe mixture was purged with nitrogen 3 times
3. temperaturethe reaction mixture was heated
4. temperatureAfter cooling to room temperature
5. filtrationthe mixture was filtered through a pad of celite
6. concentrationthe filtrate was concentrated under reduced pressure
7. additionCH2Cl2 (10 L×3) and 10% K2CO3 solution (15 L) were added to the above residue
8. customThe organic layers were separated
9. washby washing with water twice (10 L×2) and concentration under reduced pressure
10. customto give yellow oil
11. dissolutionto dissolve the yellow oil
12. customA few dark solids precipitated
13. customwere removed by filtration
14. concentrationThe filtrate was concentrated under reduced pressure
15. dissolutiondissolved in CH2Cl2 (20 L)
16. addition2N HCl (5 L) was added slowly
17. customa large amount of precipitate formed
18. stirringAfter stirring for another 1 hour
19. filtrationthe solid was collected by filtration
20. washwashed with EtOAc (2 L)
21. customThe solid was dried in vacuo at 50° C.