反应详情

To a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid (39.3 g, 100.0 mmol) in dry tetrahydrofuran (500 mL, 0.2 M), under nitrogen atmosphere, was added (R)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (14.7 g, 100.0 mmol), followed by N-methylmorpholine (27.5 mL, 0.25 mole). The orange-colored solution was cooled with an ice-water bath. Diphenylphosphinic chloride (22.9 mL, 0.12 mole) was added dropwise. Some solid formed. The mixture was warmed to ambient temperature and stirred for 18 hrs. Water was added to quench the reaction and the tetrahydrofuran was evaporated in vacuo. The remaining oil was dissolved in ethyl acetate (500 mL), washed with a mixture of saturated brine and saturated sodium bicarbonate (1:1) two times. The ethyl acetate was removed and the crude oily solid was purified by flash chromatography (silica gel, hexane-acetone/2:1) to give N-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide as an off-white solid after drying in a vacuum oven at 40° C. for 20 hrs: 41.7 g (79.8%), m.p. 124–125° C. The impure fractions were combined and purified by a second column chromatography using the same condition to give a 2nd batch of 6.4 g (12.3%), mp 124–125° C., total yield 48.1 g (92.1%). 1H NMR (d6-DMSO): δ 11.9 (s, br, 1H), 8.7 (s, br, 1H), 7.6 (d, 1H, J=10.99 Hz), 7.4 (m, 2H), 7.2 (m, 1H), 6.7 (m, 1H), 4.2 (m, 1H), 4.0 (t, 1H, J1=8.3 Hz, J2=6.8 Hz), 3.8 (m, 2H), 3.7 (m, 1H), 1.3 (s, 3H), 1.2 (s, 3H); 19F NMR (d6-DMSO): δ−128.0, −133.1, −144.3; MS: 523 (M++1).

1. temperatureThe orange-colored solution was cooled with an ice-water bath
2. customSome solid formed
3. customto quench
4. customthe reaction
5. customthe tetrahydrofuran was evaporated in vacuo
6. dissolutionThe remaining oil was dissolved in ethyl acetate (500 mL)
7. washwashed with a mixture of saturated brine and saturated sodium bicarbonate (1:1) two times
8. customThe ethyl acetate was removed
9. customthe crude oily solid was purified by flash chromatography (silica gel, hexane-acetone/2:1)