Reaction Steps
Mix ethanol (120 mL), glacial acetic acid (15 mL), water (3.0 mL, 164.7 mmol), trifluoroacetic acid (6.2 mL, 82.4 mmol), (±)-5-(3-trifluoromethoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-3-(4-trifluoromethyl-phenylamino)-1,5-dihydro-pyrrol-2-one (30.0 g, 54.9 mmol), and 2,5-dimethoxy-tetrahydrofuran (10.7 mL, 82.4 mmol). Warm the solution to 50° C. and stir the reaction mixture for 15-18 hours. Discontinue heating the solution, add water (35 mL), and cool the reaction mixture to −19° C. Filter the slurry and wash the solid with a 1:4 mixture of water-methanol (20 mL). Transfer the filtrate to a separatory funnel and wash with 6% brine (280 mL), add 6% brine (100 mL), methanol (40 mL), diethyl ether (100 mL), and saturated sodium bicarbonate solution (43 mL) to the organic phase. Separate the layers, add methanol (60 mL) to the organic phase, and concentrate the solution to approximately 1 volume containing (±)-5-(3-trifluoromethoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidine-2,3-dione. Add methanol (60 mL) and (R)-4-chloro-alpha-methylbenzylamine (7.8 mL, 55.0 mmol) and stir at room temperature for 24 hours. Monitor the reaction by HPLC for completion (Method B), then cool the solution to −7° C. and continue stirring at this temperature for 72 hours. Add a pre-mixed solution of potassium hydroxide (0.69 g, 10.5 mmol) in methanol (11 mL) to the reaction mixture, warm the solution to 10° C., and stir for an additional 4 hours. Cool the solution to −7° C., filter the slurry, and rinse the resultant product with methanol (5 mL×3). Dry the solid under vacuum to obtain (R)-1-(4-trifluoromethyl-phenyl)-3-[1(R)-(4-chloro-phenyl)-ethylamino]-5-(3-trifluoromethoxy-phenyl)-1,5-dihydro-pyrrol-2-one (12.3 g, 47.7%) as a white solid: HPLC (Method B) retention time: 4.3 minutes. MS (m/z): 539.0 (M−1). 1H NMR (500 MHz, DMSO-d6) δ 7.76 (d, 2H, J=8.5 Hz), 7.62 (d, 2H, J=9.0 Hz), 7.38-7.36 (m, 2H), 7.30-7.27 (m, 3H), 7.10 (dd, 1H, J=8.5, 1.0 Hz), 7.05 (d, 1H, J=7.5 Hz), 6.95 (s, 1H), 6.06 (d, 1H, J=8.0 Hz), 5.96 (d, 1H, J=3.0 Hz), 5.22 (d, 1H, J=3.0 Hz), 4.35-4.32 (m, 1H), 1.43 (d, 3H, J=6.5 Hz).
