Reaction Steps
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, 2.7 mmol) in THF (30 mL) was cooled to 5° C. 4-Methoxyphenyl isocyanate (0.4 g, 2.7 mmol) was added, and 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 one hour then filtered. The solid was slurried with hot methanol (20 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(4-methoxy-phenyl)-urea (0.8 g, 93%) as a white solid: mp 320-322° C.; 1H NMR (DMSO-d6) δ 2.00-2.04 (m, 1H), 2.36-2.64 (m, 2H), 2.86-3.00 (m, 1H), 3.68 (s, 3H, OCH3), 4.35-4.57 (m, 4H, 2CH2), 5.12-5.19 (dd, J=4.6 and 13.0 Hz, 1H, CH), 6.61 (t, J=5.5 Hz, 1H, NH), 6.83 (d, J=8.9 Hz, 2H, Ar), 7.27 (d, J=8.9 Hz, 2H, Ar), 7.47-7.64 (m, 3H, Ar), 8.40 (s, 1H, NH), 11.03 (s, 1H); 13C NMR (DMSO-d6) δ 22.58, 31.18, 46.20, 51.58, 55.11, 113.86, 119.70, 121.49, 128.27, 130.34, 131.62, 133.36, 135.76, 139.88, 154.08, 155.47, 168.10, 171.00, 172.84; Anal. calcd. for C22H22N4O5: C, 62.55; H, 5.25; N, 13.26. Found: C, 62.61; H, 4.95; N, 13.59.
