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 4-(trifluoromethyl)phenylacetic acid (0.6 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). After stirring at room temperature overnight, the reaction mixture was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) then washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 4:6) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(4-trifluoromethyl-phenyl)-acetamide (0.7 g, 71%) as a white solid: mp 144-146° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=5.58 min. (97%); 1H NMR (DMSO-d6) δ 2.03-2.08 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.91 (m, 1H), 3.66 (s, 2H), 4.74 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 7.50-7.82 (m, 7H), 8.75 (t, J=5.8 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.94, 30.90, 37.89, 41.75, 48.83, 121.93, 124.95 (125.01, 125.05, 125.10), 122.56 (126.16), 126.96 (127.15, 127.38), 129.94, 131.52, 133.26, 134.69, 138.95, 140.95, 166.88, 167.41, 169.78, 169.87, 172.73; Anal. Calcd. for C23H18N3O5F3: C, 58.35; H, 3.83; N, 8.88; F, 12.04. Found: C, 58.19; H, 3.53; N, 8.73; F, 12.07.
