反应详情

温度

90 °C

To the DMF solution (20 ml) of 1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethylamine (0.80 g, 2.7 mmol) was added Et3N (1.6 ml, 12 mmol) followed by 2-bromomethyl-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (1.0 g, 3.2 mmol). The mixture was heated at 90° C. for 12 hours then cooled to room temperature. The mixture was extracted with EtOAc (50 ml) and water (50 ml). The organic layer was washed with water (50 ml) and brine (50 ml), dried over Na2SO4 and concentrated in vacuo. The resulted oil was purified by silica gel chromatography to give cyclopropanecarboxylic acid {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.35 g, 30%): mp 115–117° C.; 1H NMR (CDCl3) δ 0.83–0.92 (m, 2H, c-CH2), 1.09–1.13 (m, 2H, c-CH2), 1.45 (t, J=7.0 Hz, 3H, CH3), 1.66–1.70(m, 1H, c-CH), 2.98(s, 3H, SO2CH3), 3.64(dd, J=3.8, 14 Hz, 1H, CH2), 4.10 (q, J=6.8 Hz, 2H, OCH2), 4.33 (dd, J=10, 14 Hz, 1H, CH2), 4.37 (dd, J=5, 50 Hz, 2H, CH2N), 5.69–5.74 (m, 1H, NCH), 6.57 (t, JH-F=75 Hz, 1H, CF2H), 6.94–7.04 (m, 3H, Ar), 7.18 (d, J=7.5 Hz, 1H, Ar), 7.47 (t, J=7.5 Hz, 1H, Ar), 8.45 (d, J=8.5 Hz, 1H, Ar), 10.42 (s, 1H, NH); 13C NMR (CDCl3) δ 9.06, 15.3, 16.9, 42.4, 49.0, 52.5, 56.3, 65.6, 112.4, 113.9, 116.6, 117.5, 117.6, 118.7, 119.9, 120.7, 123.8, 134.5, 136.5, 138.9, 141.1, 141.9, 151,9, 170.9, 173.4; Anal Calcd for C24H26F2N2O6S: C, 56.68; H, 5.15; N, 5.51. Found: C, 56.72; H, 5.15; N, 5.38.

1. temperaturethen cooled to room temperature
2. extractionThe mixture was extracted with EtOAc (50 ml) and water (50 ml)
3. washThe organic layer was washed with water (50 ml) and brine (50 ml)
4. dry with materialdried over Na2SO4
5. concentrationconcentrated in vacuo
6. customThe resulted oil was purified by silica gel chromatography