反应详情

温度

-72 °C

n-BuLi (1.3 ml, 2.09 mmol) is stirred in THF (4 ml), under N2, and cooled to −72° C. 1,4-dimethyl-1H-pyrazole (170 mg, 2.04 mmol, in THF, 1 ml) is added slowly, stirred for 5 min. then allowed to warm to ambient temp. and stirred for 45 min. The mixture is cooled to −72° C. and a zinc chloride solution (4.3 ml, 2.14 mmol, 0.5 M in toluene) added, warmed to ambient temp. and treated with 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine and PdCl2(dppf)-CH2Cl2 complex (Aldrich, 40 mg, 0.05 mmol). The mixture is heated to 65° C. overnight, cooled to ambient temp., added to water and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by chromatography using a hexane-ethyl acetate gradient (100% hexane to 50% ethyl acetate in hexane) to elute the product. The title compound is obtained (0.7% yield). ES-MS (m/z): calc'd for C18H25N5: 311.4; found 312.2 (M+H)+. 1H NMR (400 mHz, CDCl3): δ 7.51 (s, 1H), 6.75 (s, 1H), 3.72 (s, 3H), 3.33 (m, 1H), 2.53 (s, 3H), 2.43 (s, 3H), 2.00 (s, 3H), 1.87 (m, 4H), 0.92 (m, 6H).

1. temperatureto warm to ambient temp.
2. stirringstirred for 45 min
3. temperatureThe mixture is cooled to −72° C.
4. temperaturewarmed to ambient temp.
5. temperatureThe mixture is heated to 65° C. overnight
6. temperaturecooled to ambient temp.
7. extractionextracted twice with EtOAc
8. washThe combined organic extracts were washed with brine
9. dry with materialdried over Na2SO4
10. filtrationfiltered
11. concentrationconcentrated
12. customThe crude product is purified by chromatography
13. washto elute the product