Reaction Steps
3-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 then concentrated. The residue was stirred with 1N HCl (30 mL) for 1 hour and filtered. The solid was slurried with hot methanol (15 mL) to give 1-(3-chloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.8 g, 91%): mp 250-252° C.; 1H NMR (DMSO-d6) δ 2.00-2.05 (m, 1H), 2.37-2.65 (m, 2H), 2.86-2.98 (m, 1H), 4.37 (d, J=5.3 Hz, 2H, CH2), 4.44 (d, J=17.2 Hz, 1H), 4.51 (d, J=17.3 Hz, 1H), 5.11-5.18 (dd, J=4.9 and 13.1 Hz, 1H, CH), 6.82 (t, J=5.4 Hz, 1H, NH), 6.92-6.95 (m, 1H, Ar), 7.18-7.27 (m, 2H, Ar), 7.48-7.65 (m, 4H, Ar), 8.84 (s, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.57, 31.18, 39.68, 46.20, 51.59, 116.15, 117.13, 120.78, 121.57, 128.30, 130.21, 130.35, 131.64, 133.06, 135.37, 139.90, 141.86, 154.99, 168.07, 171.00, 172.82; Anal. calcd. for C21H19N4O4Cl: C, 59.09; H, 4.49; N, 13.13; Cl, 8.31. Found: C, 59.06; H, 4.39; N, 13.24; Cl, 7.95.
