反应详情

温度

0 °C

ZnCl2 (5. 17 g, 38.0 mmol) was weighed into a flask, which was then flame dried and flushed with N2. Anhydrous THF (20 ml) was then added at 0° C., followed by 2.5 M nBuLi (15.2 ml, 38.0 mmol). The reaction mixture was stirred at 0° C. for 15 min, after which 2-fluoro-4-iodoaniline (3.00 g, 12.7 mmol) in anhydrous THF (10 ml) and Pd(PPh3)4 (0.74 g, 0.64 mmol) were added sequentially. The mixture was allowed to warm to RT and stirred for a further 6 h. The mixture was poured into ice/Et2O, the organic layer separated and the aqueous layer further extracted with Et2O. The combined organic fractions were washed with sat. NaHCO3, dried (Na2SO4) and concentrated under reduced pressure. The resulting solid was removed from the mixture by filtration and the filtrate purified by flash chromatography on silica (12.5% EtOAc/Hexane as eluant) to give the desired product (30%, 3.7 mmol). 1H NMR [400 MHz, CDCl3]δ 6.80 (dd, J=12.1, 1.8 Hz, 1 H), 6.76-6.65 (m, 2 H), 3.65 (br s, 2 H), 2.49 (t, J=7.7 Hz, 2 H), 1.57-1.49 (m, 2 H), 1.32 (sextet, J=7.3 Hz, 2 H), 0.91 (t, J=7.3 Hz, 3 H). LCMS (ACPI+) 168 (100%). Step B: Preparation of 2-(4-butyl-2-fluoroanilino)-3,4-difluorobenzoic acid

1. temperaturewhich was then flame
2. customdried
3. customflushed with N2
4. additionAnhydrous THF (20 ml) was then added at 0° C.
5. temperatureto warm to RT
6. stirringstirred for a further 6 h
7. customthe organic layer separated
8. extractionthe aqueous layer further extracted with Et2O
9. washThe combined organic fractions were washed with sat. NaHCO3
10. dry with materialdried (Na2SO4)
11. concentrationconcentrated under reduced pressure
12. customThe resulting solid was removed from the mixture by filtration
13. customthe filtrate purified by flash chromatography on silica (12.5% EtOAc/Hexane as eluant)