反应详情

温度

19 °C

A 1000 mL three-neck flask fitted with internal temperature probe and addition funnel was flushed with Ar(g). Under positive Argon pressure 4-cyanobutylzinc bromide (0.5M in THF, 500 mL, 250 mmol) was charged into the addition funnel then added to the reaction vessel at room temperature. Solid N-(6-chloropyridazin-3-yl)-2-phenylacetamide (20.6 g, 83.3 mmol) was added to the stirred solution at RT under Ar(g) flow, followed by the addition of NiCl2(dppp) (4.52 g, 8.33 mmol). The resulting mixture was stirred at 19° C. for 240 minutes and then quenched with ethanol (120 mL). Water (380 mL) added to the stirred red solution, giving a thick precipitate. Ethyl acetate (760 mL) added and stirred well for 30 minutes. The solids were removed by filtration through a pad of celite. The mother liquor was then transferred to a separatory funnel and the organic layer was washed with H2O (380 mL), 0.5% ethylenediaminetetraacetic acid solution (380 mL) and again with H2O (380 mL). The organic layer was concentrated by rotoevaporation. Resulting red oil was redissolved in EtOAc (200 mL) and 1M HCl (380 mL) was added to the well stirred flask. After 30 minutes the mixture was transferred to separatory funnel and the aqueous layer collected. The organic layer was extracted with 1M HCl (2×380 mL). The aqueous layer's pH was then adjusted to ˜7 using 7.5% sodium bicarbonate solution and the pale yellow precipitate was collected by suction filtration, rinsed with water (200 mL) and diethyl ether (2×200 mL). The solid was dried overnight under high vacuum to afford N-(6-(4-cyanobutyl)pyridazin-3-yl)-2-phenylacetamide (1023, 14.76 g). 1H NMR (300 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.23 (d, J=9.036 Hz, 1H), 7.59 (d, J=9.246 Hz, 1H), 7.32 (m, 5H), 3.79 (s, 2H), 2.90 (t, J=7.357 Hz, 2H), 2.56 (t, J=7.038 Hz, 2H), 1.79 (t, J=7.311 Hz, 2H), 1.63 (t, J=7.01 Hz, 2H)

1. customA 1000 mL three-neck flask fitted with internal temperature probe and addition funnel
2. customwas flushed with Ar(g)
3. additionthen added to the reaction vessel at room temperature
4. customquenched with ethanol (120 mL)
5. additionWater (380 mL) added to the stirred red solution
6. customgiving a thick precipitate
7. stirringstirred well for 30 minutes
8. customThe solids were removed by filtration through a pad of celite
9. customThe mother liquor was then transferred to a separatory funnel
10. washthe organic layer was washed with H2O (380 mL), 0.5% ethylenediaminetetraacetic acid solution (380 mL) and again with H2O (380 mL)
11. concentrationThe organic layer was concentrated by rotoevaporation
12. customResulting red oil
13. stirringstirred flask
14. waitAfter 30 minutes the mixture was transferred to separatory funnel
15. customthe aqueous layer collected
16. extractionThe organic layer was extracted with 1M HCl (2×380 mL)
17. filtrationthe pale yellow precipitate was collected by suction filtration
18. washrinsed with water (200 mL) and diethyl ether (2×200 mL)
19. customThe solid was dried overnight under high vacuum