反应详情

A stirred solution of 2-iodoaniline (32.6 g, 149 mmol) and 4-fluorophenylboronic acid (20.8 g, 149 mmol) in tetrahydrofuran (1.5 L) was treated under nitrogen with [1,1 ′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (2.20 g, 2.69 mmol) and a 5 N sodium hydroxide solution (60 mL). The reaction mixture was heated at reflux for twelve hours, cooled to room temperature, and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (250 mL) and extracted with a saturated, aqueous, sodium chloride solution (100 mL). The aqueous phase was further extracted with ethyl acetate (2×50 mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to a brown oil. The brown oil was filtered through a short column of silica gel, and eluted with a mixture of ethyl acetate-hexane (1:4). After evaporation of the solvent in vacuo, a solution of the crude 4′-fluoro-biphenyl-2-ylamine in dichloromethane (75 mL) was treated with pyridine (27.7 mL, 343 mmol), acetic anhydride (15.5 mL, 164 mmol), and 4-(N,N-dimethylamino)pyridine (0.55 g, 4.5 mmol). After stirring for twelve hours at room temperature, the reaction was quenched with a saturated, aqueous, ammonium. chloride solution (250 mL). The separated aqueous phase was extracted with dichloromethane (3×75 mL), and the combined organic phase washed sequentially with a 0.1 N hydrochloric acid solution (2×50 mL), and a saturated, aqueous, sodium bicarbonate solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a second brown oil. After toluene was added and removed in vacuo (3×), the resulting brown solid was crystallized from ethyl acetate-hexane to yield a first crop of the desired product (19.0 g). The mother liquor was concentrated and purified by flash column chromatography on silica gel, eluting with ethyl acetate-hexane (1:4), to obtain a second crop (5.0 g). The combined crops afforded the title compound as a homogeneous, colorless, crystalline, solid (24.0 g, 70%). m.p. 123-124° C.; MS [(+ESI), m/z]: 230 [M+H]+;

1. temperatureThe reaction mixture was heated
2. temperatureat reflux for twelve hours
3. customthe solvent removed in vacuo
4. dissolutionThe residue was dissolved in ethyl acetate (250 mL)
5. extractionextracted with a saturated, aqueous, sodium chloride solution (100 mL)
6. extractionThe aqueous phase was further extracted with ethyl acetate (2×50 mL)
7. dry with materialThe combined organic phase was dried over anhydrous magnesium sulfate
8. filtrationfiltered
9. concentrationconcentrated in vacuo to a brown oil
10. filtrationThe brown oil was filtered through a short column of silica gel
11. washeluted with a mixture of ethyl acetate-hexane (1:4)
12. customAfter evaporation of the solvent in vacuo
13. customthe reaction was quenched with a saturated, aqueous, ammonium
14. extractionThe separated aqueous phase was extracted with dichloromethane (3×75 mL)
15. washthe combined organic phase washed sequentially with a 0.1 N hydrochloric acid solution (2×50 mL)
16. dry with materialThe organic phase was dried over anhydrous sodium sulfate
17. filtrationfiltered
18. concentrationconcentrated in vacuo to a second brown oil
19. additionAfter toluene was added
20. customremoved in vacuo (3×)
21. customthe resulting brown solid was crystallized from ethyl acetate-hexane