反应详情

4-Cyanobutylzinc bromide solution (3.0 equiv., 0.50 mol, 1.0 L) was charged into an argon gas purged 5000 mL 3 neck round bottom flask. Argon(g) purge for 5 minutes followed by the addition of 1117 (1.0 equiv., 0.167 mol, 55.3 g) and NiCl2(dppp) (0.15 equiv., 0.0251 mol, 13.6 g) under a blanket of argon(g). The reaction usually goes to completion after 4 hours (TLC: 1:1 hexanes-ethyl acetate). EtOAc (15 vol., 832 mL) added to deep red solution. Water (15 vol., 832 mL) was added, thick slurry formed. 1N HCl added until slurry breaks to pale blue layer (˜6 vol., 333 mL). Transferred to separatory funnel and organic layer was washed with 1N HCl (2×500 mL), dried (MgSO4) and concentrated by rotary evaporation (bath≦30° C.) to a solid reddish oil. Oil dissolved in dichloromethane (15 vol., 832 mL), silica gel (100 g) was slurried into red solution, this was concentrated by rotary evaporation (bath≦30° C.) to a solid reddish powder. Loaded onto a bed of silica gel (5 cm×11 cm), flushed with 25% hexanes in ethyl acetate (3 L), combined organics concentrated by rotary evaporation (bath≦30° C.). Dried under high vacuum to a constant weight to afford N-(6-(4-cyanobutyl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide 1118: yield of 58.2 g (92%). 1H NMR (300 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.28 (d, J=9.2 Hz, 1H), 7.65 (d, J=9.2 Hz, 1H), 7.52-7.27 (m, 4H), 3.89 (s, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.56 (t, J=7.0 Hz, 2H), 1.80 (m, 2H), 1.61 (m, 2H).

1. custompurged 5000 mL 3 neck round bottom flask
2. customArgon(g) purge for 5 minutes
3. customThe reaction
4. customthick slurry formed
5. washTransferred to separatory funnel and organic layer was washed with 1N HCl (2×500 mL)
6. dry with materialdried (MgSO4)
7. concentrationconcentrated by rotary evaporation (bath≦30° C.) to a solid reddish oil
8. dissolutionOil dissolved in dichloromethane (15 vol., 832 mL)
9. concentrationthis was concentrated by rotary evaporation (bath≦30° C.) to a solid reddish powder
10. customflushed with 25% hexanes in ethyl acetate (3 L)
11. concentrationcombined organics concentrated by rotary evaporation (bath≦30° C.)
12. customDried under high vacuum to a constant weight