To a solution of 3-chloro-4-(trifluoromethyl)aniline (0.60 g, 3.07 mmol), pyridine (0.24 g, 3.07 mmol), and DIEA (1.10 ml, 6.14 mmol) in acetonitrile (5 mL) was added phosgene (1.54 mL, 2.91 mmol, 20% in toluene) via syringe at 0° C. After 30 min, (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methanaminium methanesulfonate (0.84 g, 2.27 mmol) was added in one portion followed by additional DIEA (1.1 ml, 6.14 mmol). The resulting suspension was stirred for 1.5 h and allowed to warm to room temperature. After 1.5 h, the reaction was quenched by the addition of 1 N HCl (20 ml) and the precipitated solid was filtered, washed with water and air-dried. The crude product was purified further by reslurrying with acetonitrile (10 mL) followed by precipitation from DMF (5 mL) water. The product was isolated by filtration, washed with Et2O and dried in vacuo to give 1-(3-chloro-4-(trifluoromethyl)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea as an off-white solid (420 mg, 40%). HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 45/55, CH3CN/0.1% H3PO4, 4.76 min (98.7%); mp: 274-276° C.; 1H NMR (DMSO-d6) δ 1.90-2.16 (m, 1H), 2.26-2.45 (m, 1H), 2.59 (d, J=19.6 Hz, 1H), 2.82-3.00 (m, 1H), 4.25-4.52 (m, 4H), 5.11 (dd, J=5.0, 13.3 Hz, 1H), 7.05 (t, J=5.9 Hz, 1H), 7.39-7.49 (m, 2H), 7.53 (s, 1H), 7.69 (dd, J=4.2, 8.2 Hz, 2H), 7.91 (s, 1H), 9.32 (s, 1H), 10.98 (s, 1H); 13C NMR (DMSO-d6) δ 22.50, 31.20, 42.83, 47.12, 51.58, 115.58, 118.19, 118.60, 118.98, 121.44, 121.94, 122.96, 125.05, 126.93, 128.31, 128.38, 130.38, 131.14, 142.41, 144.32, 145.28, 154.66, 167.92, 171.00, 172.85. LCMS: MH=495; Anal Calcd for C22H18ClF3N4O4+0.28H2O: C, 52.86%; H, 3.74%; N, 11.21%; Cl, 7.09%; F; 11.40%. Found: C, 52.60%; H, 3.41% ; N, 11.01%; Cl, 7.23%; F, 11.63%.
