反应详情

温度

30 °C

A dried round bottom flask was charged with 2-(2,4-difluorophenyl)-3-iodo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (1.50 g, 4.17 mmol, Example #C.1.1) and THF (20 mL) under an atmosphere of nitrogen to give a brown suspension. The reaction mixture was cooled to about 30° C. and then i-PrMgCl (2.0 M in THF, 2.5 mL, 5.0 mmol) was added dropwise. The reaction mixture was stirred at about −25° C. for about 15 min. In a separate dry flask, zinc chloride (0.70 g, 5.1 mmol) was dissolved in THF (20 mL). The zinc chloride solution was added dropwise to the heteroaryl Grignard solution and formed a brown suspension. The reaction mixture was stirred for about 30 min. In a separate flask, a mixture 6-iodo-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (1.14 g, 3.96 mmol; Preparation #H.1) and DMF (20 mL) was heated until all of the solids were in solution and then cooled down to about 30° C. To the DMF solution, Pd(Ph3P)4 (Strem, 0.19 g, 0.164 mmol) was added. This solution was poured into the zincate suspension and the mixture was immediately heated to about 80° C. in an oil bath. After heating at about 80° C. for about 3 h, the mixture was cooled to ambient temperature. The reaction was concentrated in vacuo and the residue was partitioned between in DCM (50 mL) and 1N HCl (100 mL). The layers were separated and the aqueous layer was washed with additional DCM (50 mL) and basified with solid Na2CO3. Upon basification, a yellow precipitate formed that was collected by vacuum filtration. The crude material was purified by silica gel chromatography using DCM/MeOH/NH4OH 990/9/1 to give a glass-like solid that was triturated and washed with Et2O to give the title compound (0.111 g, 7%): LC/MS (Table 1, Method a) Rt=2.75 min; MS m/z: 395.5 (M+H)+.

1. customto give a brown suspension
2. customIn a separate dry flask
3. customformed a brown suspension
4. stirringThe reaction mixture was stirred for about 30 min
5. temperaturecooled down to about 30° C
6. temperaturethe mixture was immediately heated to about 80° C. in an oil bath
7. temperatureAfter heating at about 80° C. for about 3 h
8. temperaturethe mixture was cooled to ambient temperature
9. concentrationThe reaction was concentrated in vacuo
10. customthe residue was partitioned between in DCM (50 mL) and 1N HCl (100 mL)
11. customThe layers were separated
12. washthe aqueous layer was washed with additional DCM (50 mL)
13. customUpon basification, a yellow precipitate formed
14. filtrationthat was collected by vacuum filtration
15. customThe crude material was purified by silica gel chromatography
16. customto give a glass-like solid
17. customthat was triturated
18. washwashed with Et2O