Reaction Steps
4-Chlorophenyl isocyanate (0.4 g, 2.7 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and triethylamine (0.3 g, 2.9 mmol) in THF (30 mL) at 5-10° C. After stirring at 5° C. for 10 minutes, the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (1 mL) and concentrated. The residue was stirred with 1NHCl (30 mL) for 30 minutes. The mixture was filtered, and the solid was slurried with hot acetone (10 mL) to give 1-(4-chloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.7 g, 73%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.00-2.04 (m, 1H), 2.33-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.36-4.58 (m, 4H, 2CH2), 5.11-5.18 (dd, J=5.0 and 12.5 Hz, 1H, CH), 6.77 (t, J=5.0 Hz, 1H, NH), 7.27 (d, J=10.0 Hz, 2H, Ar), 7.40 (d, J=10 Hz, 2H, Ar), 7.47-7.64 (m, 3H, Ar), 8.77 (s, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.57, 31.18, 39.68, 45.19, 51.58, 119.29, 121.56, 124.66, 128.30, 128.44, 130.35, 131.64, 135.46, 139.31, 139.92, 155.08, 168.07, 171.00, 172.84; Anal. calcd. for C21H19N4O4Cl: C, 59.09; H, 4.49; N, 13.13; Cl, 8.31. Found: C, 58.85; H, 4.35; N, 12.97; Cl, 8.19.
