Reaction Steps
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 3-chloro-phenylacetic acid (0.41 g, 2.4 mmol) were added. The reaction was then added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol) and was stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo, and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was 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: 30% EtOAc in CH2Cl2 for 10 min, then increase to 60% EtOAc in CH2Cl2 over 20 min) to afford 2-(3-chloro-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide as a white solid (0.73 g, 76%): mp, 185-187° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.2 min. (99%); 1H NMR (DMSO-d6): δ 2.03-2.08 (m, 1H), 2.52-2.63 (m, 2H), 2.86-2.91 (m, 1H), 3.56 (s, 2H), 4.73 (d, J=6.0 Hz, 2H), 5.12-5.18 (dd, J=5, 13 Hz, 1H), 7.23-7.82 (m, 7H), 8.70 (t, J=6 Hz, 1H), 11.13 (s, 1H). 13C NMR (DMSO-d6) δ: 21.95, 30.90, 37.87, 41.53, 48.83, 121.93, 126.40, 127.15, 127.82, 128.94, 130.04, 131.52, 132.74, 133.25, 134.66, 138.54, 139.01, 166.88, 167.41, 169.77, 170.03, 172.73. Anal Calcd for C22H18ClN3O5: C, 60.08; H, 4.12; N, 9.55; Cl, 8.06. Found: C, 59.92; H, 3.85; N, 9.55; Cl, 8.37.
