Reaction Steps
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and 3,5-difluorobenzoyl chloride (0.59 g, 2.8 mmol). This mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was then quenched with MeOH (1 mL) and washed with H2O (40 mL), 1N HCl (40 mL) and brine (40 mL). The organic layer was dried over MgSO4 and concentrated in vacuo, and the resulting mixture was stirred with acetone (10 mL). The resulting suspension was filtered, and the solid was washed with acetone and dried in vacuum oven to afford 3,5-dichloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-benzamide as a white solid (0.8 g, 76%): mp, 250-252° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 50/50 (CH3CN/H2O): tR=4.3 min (96%); 1H NMR (DMSO-d6): δ 2.05-2.11 (m, 1H), 2.53-2.64 (m, 2H), 2.85-2.93 (m, 1H), 4.95 (d, J=5.7 Hz, 2H), 5.15-5.21 (dd, J=5, 12 Hz, 1H), 7.76-7.94 (m, 6H), 9.37 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.97, 30.92, 38.54, 48.86, 121.99, 126.20, 127.21, 130.82, 131.52, 133.27, 134.32, 134.83, 137.11, 138.54, 163.94, 166.92, 167.47, 169.81, 172.74. Anal Calcd for C21H15Cl2N3O5: C, 54.80; H, 3.28; N, 9.13; Cl, 15.41. Found: C, 54.93; H, 2.96; N, 9.01; Cl, 15.62.
