反应详情

温度

100 °C

4-fluoro-5-iodopyridin-2-amine (intermediate 22, 240 g, 1 mol), zinc cyanide (125 g, 1.05 mol), zinc (13 g, 0.2 mol), Pd2(dba)3 (25 g, 25 mmol) and dppf (55 g, 0.1 mol) in DMA (800 ml) were degassed and charged into the round bottom flask under nitrogen. The mixture was stirred at 100° C. for 3 h. The reaction mixture was diluted with 5% NaHCO3 (2 l), extracted with EtOAc (4×600 ml). The combined organic layers were washed with 5% NaOH (1 l), dried over Na2SO4, concentrated to 700 ml. The resulting organic phase was eluted through silica gel column with EtOAc (1.7 l). The combined organic filtrate was washed with 2 M HCl (3×800 ml). The pH of the aqueous phase was adjusted to 10 with saturated NaHCO3. The aqueous phase was extracted whit DCM (3×500 ml). The combined DCM was dried over Na2SO4 and concentrated. The residue was further purified by column chromatography (eluted with pentane: EtOAc 10:1 to 3:2) followed by recrystallization from pentane/EtOAc 3/1 to give the title compound as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, 1H), 7.40 (s, 2H), 6.34 (d, 1H).

1. additioncharged into the round bottom flask under nitrogen
2. extractionextracted with EtOAc (4×600 ml)
3. washThe combined organic layers were washed with 5% NaOH (1 l)
4. dry with materialdried over Na2SO4
5. concentrationconcentrated to 700 ml
6. washThe resulting organic phase was eluted through silica gel column with EtOAc (1.7 l)
7. washThe combined organic filtrate was washed with 2 M HCl (3×800 ml)
8. extractionThe aqueous phase was extracted whit DCM (3×500 ml)
9. dry with materialThe combined DCM was dried over Na2SO4
10. concentrationconcentrated
11. customThe residue was further purified by column chromatography (eluted with pentane: EtOAc 10:1 to 3:2)
12. customfollowed by recrystallization from pentane/EtOAc 3/1