反应详情

温度

90 °C

A 50 mL round bottomed flask was charged with 1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethane-1,2-dione (0.300 g, 0.908 mmol, Preparation #M.1), hydroxylamine hydrochloride (0.631 g, 9.08 mmol) and EtOH (5 mL). The resulting mixture was treated with pyridine (3.67 mL, 45.4 mmol) and was then heated to about 90° C. for about 7 h. The mixture was cooled to ambient temperature, diluted with EtOAc (10 mL), washed with 1N HCl (10 mL) and water (10 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to afford a yellow residue. To the residue was added triphenylphosphine (0.328 g, 1.25 mmol) and toluene (5 mL). The mixture was cooled to about 0° C. and DIAD (0.243 mL, 1.25 mmol) was added to give a solution which was heated to about reflux for about 1 h. The solution was cooled to ambient temperature, diluted with EtOAc (10 mL) and washed with saturated aqueous NaHCO3 (10 mL). The organics were separated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by flash chromatography on silica gel with MeOH/DCM (0-5% gradient) followed by RP-HPLC (Table 1, Method n) to afford the title compound (0.056 g, 20%) as a yellow solid. LC/MS (Table 1, Method g) Rt=2.83 min; MS m/z 343 (M+H)+.

1. temperatureThe mixture was cooled to ambient temperature
2. washwashed with 1N HCl (10 mL) and water (10 mL)
3. customThe organics were separated
4. dry with materialdried over MgSO4
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. customto afford a yellow residue
8. temperatureThe mixture was cooled to about 0° C.
9. customto give a solution which
10. temperaturewas heated
11. temperatureto about reflux for about 1 h
12. temperatureThe solution was cooled to ambient temperature
13. washwashed with saturated aqueous NaHCO3 (10 mL)
14. customThe organics were separated
15. dry with materialdried over MgSO4
16. filtrationfiltered
17. concentrationconcentrated to dryness
18. customThe residue was purified by flash chromatography on silica gel with MeOH/DCM (0-5% gradient)