Reaction Steps
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 4-fluorophenylacetic acid (0.37 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 and 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. The organic 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 N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(4-fluoro-phenyl)-acetamide as a white solid (0.64 g, 65%): mp, 214-216° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.0 min (99%); 1H NMR (DMSO-d6): δ 2.03-2.08 (m, 1H), 2.51-2.63 (m, 2H), 2.86-2.91 (m, 1H), 3.53 (s, 2H), 4.72 (d, J=6.0 Hz, 2H), 5.12-5.18 (dd, J=5, 12 Hz, 1H), 7.10-7.16 (m, 2H), 7.29-7.34 (m, 2H), 7.62-7.65 (m, 1H), 7.78-7.81 (m, 2H), 8.67 (t, J=5.9 Hz, 1H), 11.14 (s, 1H). 13C NMR (DMSO-d6) δ: 21.95, 30.90, 37.83, 41.17, 48.82, 114.77, 115.05, 121.89, 127.12, 130.81, 130.92, 131.51, 132.24, 132.28, 133.19, 134.67, 139.09, 159.42, 162.62, 166.90, 167.42, 169.78, 170.51, 172.73. Anal Calcd for C22H18FN3O5: C, 62.41; H, 4.29; N, 9.92; F, 4.49. Found: C, 62.05; H, 4.18; N, 9.85; F, 4.48.
