Reaction Steps
Triethylamine (0.6 g, 5.9 mmol) was added slowly 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 dimethylcarbamoyl chloride (0.3 g, 3.2 mmol) in THF (100 mL). The mixture was stirred at room temperature overnight. Another portion of dimethylcarbamoyl chloride (0.3 g) and 1,8-diazabicyclo[5,4,0]-undec-7-ene (0.6 g) was added and stirred for another day. The mixture was concentrated, and the residue was stirred with 1N HCl (15 mL). The mixture was filtered, and the solid was slurried with hot methanol (10 mL) to give 3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1,1-dimethyl-urea (0.3 g, 46%) as a white solid: mp 169-171° C.; 1H NMR (DMSO-d6) δ 1.99-2.04 (m, 1H), 2.32-2.64 (m, 2H), 2.80 (s, 6H, 2CH3), 2.85-3.00 (m, 1H), 4.27 (d, J=5.6 Hz, 2H, CH2), 4.40 (d, J=17.3 Hz, 1H), 4.47 (d, J=17.3 Hz, 1H), 5.10-5.17 (dd, J=5.0 and 13.2 Hz, 1H, CH), 6.94 (t, J=5.6 Hz, 1H, NH), 7.44-7.64 (m, 3H, Ar), 11.02 (s, 1H); 13C NMR (DMSO-d6) δ 22.58, 31.18, 35.88, 46.20, 51.55, 121.20, 128.08, 130.38, 131.39, 136.35, 139.77, 158.08, 168.15, 171.00, 172.83; Anal. calcd. for C17H20N4O4: C, 59.29; H, 5.85; N, 16.27. Found: C, 59.05; H, 5.91; N, 15.92.
