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 acetonitrile (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-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 3,5-difluorophenylacetic acid (0.4 g, 2.4 mmol) were added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight. The resulting suspension was filtered, and the solid was reslurried in hot acetone (15 mL) to afford 2-(3,5-difluoro-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide (0.5 g, 56%) as a white solid: mp, 238-240° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.63 min. (97%); 1H NMR (DMSO-d6) δ 2.02-2.07 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.60 (s, 2H), 4.73 (d, J=5.8 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 6.89-7.14 (m, 3H), 7.65-7.84 (m, 3H), 8.70 (t, J=5.8 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.94, 30.90, 37.91, 41.41, 48.83, 101.62 (101.95, 102.30), 112.18 (112.28, 112.41, 112.51), 121.95, 127.16, 131.52, 133.29, 134.68, 138.91, 140.24 (140.37, 140.50), 160.39 (160.57, 163.64, 163.82), 166.88, 167.41, 169.53, 169.77, 172.72; Anal. Calcd. for C22H17N3O5F2: C, 59.87; H, 3.88; N, 9.52; F, 8.61. Found: C, 59.66; H, 3.83; N, 9.77; F, 8.47.
