Reaction Steps
To the stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) and 3-fluoro-4-trifluoromethylbenzoyl chloride (0.6 g, 2.8 mmol) in dry methylene chloride (60 mL), was added diisopropylethylamine (0.7 g, 5.4 mmol). After stirring at room temperature overnight, the reaction mixture was quenched with methanol (1 mL) and washed with water (2×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: CH3OH: CH2Cl2 3:97) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-fluoro-4-trifluoromethyl-benzamide (0.6 g, 53%) as a white solid: mp 165-167° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=8.20 min. (99%); 1H NMR (DMSO-d6) δ 2.06-2.12 (m, 1H), 2.53-2.65 (m, 2H), 2.87-2.93 (m, 1H), 4.98 (d, J=5.7 Hz, 2H), 5.15-5.21 (dd, J=5.3 and 12.5 Hz, 1H), 7.76-7.84 (m, 3H), 7.95-8.01 (m, 3H), 9.45 (t, J=5.7 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 21.97, 30.92, 38.54, 48.87, 115.88 (116.17), 118.56 (118.72, 119.00, 119.16), 122.30, 123.94 (123.98), 120.52 (124.13), 127.25, 127.74 (127.80), 131.55, 133.24, 134.83, 138.51, 140.42 (140.52), 157.04 (160.38), 164.19, 166.91, 167.48, 169.81, 172.74; Anal. Calcd. for C22H15N3O5F4: C, 55.35; H, 3.17; N, 8.80; F, 15.92. Found: C, 55.00; H, 2.95; N, 8.80; F, 15.92.
