Reaction Steps
Cyclopropanecarboxylic acid {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide was prepared by the procedure of example 8 from 3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.8 g, 1.7 mmol), CDI (0.41 g, 2.5 mmol) and hydroxylamine hydrochloride (0.23 g, 3.6 mmol) in THF (30 ml) to give cyclopropanecarboxylic acid {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.60 g, 80% yield): mp 116-118° C.; 1H NMR (CDCl3): δ 0.82 (m, 2H, c-CH2), 1.02 (m, 2H, c-CH2), 1.36 (t, J=6.8 Hz, 3H, OCH2CH3), 1.58 (m, 1H, c-CH), 2.86 (dd, J=5, 15 Hz, 1H, CH2), 3.15 (dd, J=10, 15 Hz, 1H, CH2), 3.30 (broad, 1H, NHOH), 4.01 (q, J=7.0 Hz, 2H, OCH2CH3), 4.02 (d, J=17.5 Hz, 1H, CH2N), 4.34 (d, J=17.5 Hz, 1H, CH2N), 5.42 (broad, 1H, NH2), 5.71 (m, 1H, CHN), 6.07 (broad, 1H, NHOH), 6.53 (t, JH-F=75 Hz, 1H, CF2H), 6.88 (m, 3H, Ar), 7.07 (d, J=7.5 Hz, 1H, Ar), 7.30 (t, J=7.5 Hz, 1H, Ar), 8.28 (d, J=8 Hz, 1H, Ar), 10.35 (s, 1H, NHCO). 13C NMR (CDCl3): δ 8.27, 8.39, 14.5, 16.0, 35.4, 47.3, 52.4, 64.8, 111.8, 113.3, 115.9, 116.9, 117.0, 118.9, 120.0, 122.6, 133.3, 136.6, 137.6, 140.0, 141.5, 150.8, 167.5, 169.7, 172.8; Anal. Calcd. for C24H25F2N3O6+0.34H2O: C, 58.16; H, 5.22; N, 8.48; Found: C, 58.25; H, 5.37; N, 8.58, 1.25H2O
