To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and phenylisocyanate (0.36 g, 3.30 mmol) in THF (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 18 h then cooled to rt. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), water (100 mL), dried (MgSO4) and then concentrated. The product was dried in vacuo to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-phenyl-urea as a white solid (0.77 g, 63% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.38 min (99.57%); mp: 288-290° C.; 1H NMR (DMSO-d6) δ 1.99-2.07 (m, 1H, CHH), 2.44-2.62 (m, 2H, CHH, CHH), 2.82-2.96 (m, 3H, CHH, CH2), 4.47 (d, J=5.9 Hz, 2H, CH2), 5.15 (dd, J=5.3, 12.5 Hz, 1H, CH), 6.82-6.93 (m, 2H, Ar), 7.22 (t, J=7.6 Hz, 2H, Ar), 7.40 (d, J=8.0 Hz, 2H, Ar), 7.78-7.91 (m, 3H, Ar, NH), 8.72 (s, 1H, NH), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.01, 30.93, 42.62, 48.99, 117.83, 121.26, 121.69, 123.48, 128.64, 129.67, 131.60, 133.21, 140.27, 148.79, 155.28, 167.03, 167.20, 169.83, 172.74; LCMS: MH=407; Anal Calcd for C21H18N4O5+0.2H2O: C, 61.52; H, 4.52; N, 13.66. Found: C, 61.33; H, 4.36; N, 13.46.
