反应详情

To a 30-L reactor was charged 3,6-dichloropyridazine (1 kg, 6.7 mol), 2,2,6,6-tetramethylpiperidin-4-ol (1.05 kg, 6.7 mol) and THF (5 L). The mixture was stirred and cooled to −5° C. tBuOK (1.13 kg, 10.1 mol) dissolved in THF (10 L) was added slowly to the reactor while keeping the temperature at −5-0° C. The reaction mixture became deep brown during addition. After the addition was complete, the mixture was stirred for 1 hour at −5-0° C., after which time HPLC analysis showed that the reaction was complete. Ice water (1:1, 10 kg) was added slowly to quench the reaction. The mixture was concentrated under reduced pressure to remove most of the THF. The residue was extracted with EtOAc twice (10 L+5 L). The combined organic layer was washed with water (10 L×3), then concentrated under reduced pressure to give a black residue. Petroleum ether (25 L) was added to this residue while stirring. The dark solid that formed was removed by filtration. The pale yellow filtrate was concentrated under reduced pressure to give a yellow solid, which was dried at 50° C. in vacuo to give 3-chloro-6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazine (1.3 kg, 4.8 mol), and was used in the next step without further purification. MS m/z 270.1 [M+H]; 1H-NMR: (CDCl3, 400 MHz) δ 7.36 (d, J=9.2 Hz, 1H), 6.90 (d, J=9.2 Hz, 1H), 5.74 (m, 1H), 2.20 (dd, Ja=4 Hz, Jb=12.4 Hz, 2H), 1.30 (m, 14H).

1. additionwas added slowly to the reactor
2. customat −5-0° C
3. additionThe reaction mixture became deep brown during addition
4. additionAfter the addition
5. stirringthe mixture was stirred for 1 hour at −5-0° C.
6. customto quench
7. customthe reaction
8. concentrationThe mixture was concentrated under reduced pressure
9. customto remove most of the THF
10. extractionThe residue was extracted with EtOAc twice (10 L+5 L)
11. washThe combined organic layer was washed with water (10 L×3)
12. concentrationconcentrated under reduced pressure
13. customto give a black residue
14. stirringwhile stirring
15. customThe dark solid that formed
16. customwas removed by filtration
17. concentrationThe pale yellow filtrate was concentrated under reduced pressure
18. customto give a yellow solid, which
19. customwas dried at 50° C. in vacuo