反应详情

温度

0 °C

Ethyl acetoacetate (2.55 mL, 20.0 mmol) was dissolved in CHCl3 (5 mL) and then the solution was cooled to 0° C. Bromine (1.03 mL, 20.0 mmol) in CHCl3 (6 mL) was added dropwise and then the reaction was stirred at 0° C. for 2 h. The reaction was warmed to rt and stirred for 16 h. The headspace of the reaction vessel was purged with air to remove HBr, and then the reaction was stirred an additional 2 h open to air. The reaction was washed with ice-cold water (20 mL) and then the aqueous layer was extracted with DCM (10 mL). The combined organic layers were washed with brine and then dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The residue was placed in a 100 mL round bottom flask equipped with a stir bar and then dry DMF (10 mL) was added. 5-Bromo-3-chloro-6-aminopyridazine (2.08 g, 10.0 mmol) was added and then the reaction was stirred at rt for 4 d. The reaction was poured into water (50 mL) and then the mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), and then dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude product was chromatographed on an 80 g SiO2 pre-packed column eluting with 0-20% EtOAc/DCM to afford the title compound 28a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.05 (s, 1H), 7.35 (s, 1H), 4.22 (q, J=7.2 Hz, 2H), 3.95 (s, 2H), 1.30 (t, J=7.1 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C10H9BrClN3O2: 318.0 (M+H). Found: 318.0.

1. temperatureThe reaction was warmed to rt
2. stirringstirred for 16 h
3. customThe headspace of the reaction vessel was purged with air
4. customto remove HBr
5. stirringthe reaction was stirred an additional 2 h open to air
6. washThe reaction was washed with ice-cold water (20 mL)
7. extractionthe aqueous layer was extracted with DCM (10 mL)
8. washThe combined organic layers were washed with brine
9. dry with materialdried over MgSO4
10. filtrationfiltered
11. customThe solvent was removed under reduced pressure
12. customThe residue was placed in a 100 mL round bottom flask
13. customequipped with a stir bar
14. additiondry DMF (10 mL) was added
15. stirringthe reaction was stirred at rt for 4 d
16. extractionthe mixture was extracted with EtOAc (3×30 mL)
17. washThe combined organic extracts were washed with water (50 mL) and brine (50 mL)
18. dry with materialdried over MgSO4
19. filtrationfiltered
20. customThe solvent was removed under reduced pressure
21. customThe crude product was chromatographed on an 80 g SiO2 pre-packed column
22. washeluting with 0-20% EtOAc/DCM