To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.70 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.82 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 3-difluoromethoxy benzoic acid (0.45 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol). After stirring at room temperature overnight, the reaction mixture was concentrated in vacuo, and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was then washed with water (2×30 mL) and brine (30 mL), and dried over MgSO4. Solvent was removed in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 0% MeOH in CH2Cl2 to 5% MeOH in 10 min then stay at this ratio for 15 min) to afford 3-difluoromethoxy-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-benzamide as a white solid (0.64 g, 65%): mp, 164-166° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.6 min (99%); 1H NMR (DMSO-d6): δ 2.04-2.09 (m, 1H), 2.53-2.64 (m, 2H), 2.85-2.93 (m, 1H), 4.92 (d, J=6.0 Hz, 2H), 5.14-5.20 (dd, J=5, 12 Hz, 1H), 6.97-7.86 (m, 8H), 8.97 (t, J=6.0 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.95, 30.91, 38.29, 48.86, 113.18, 116.60, 119.08, 120.02, 121.91, 125.34, 127.12, 128.74, 129.58, 131.48, 131.54, 113.18, 116.60, 119.08, 120.02, 121.91, 125.34, 127.12, 127.74, 128.58, 131.48, 131.54, 132.96, 134.64, 138.89, 147.66, 165.60, 166.94, 167.51, 169.81, 172.73. Anal Calcd for C22H17F2N3O6: C, 57.77; H, 3.75; N, 9.19; F, 8.31. Found: C, 57.62; H, 3.60; N, 8.99; F, 8.32.
