Reaction Steps
A mixture of 3-bromo-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one (from Example 50, step B) (0.145 g, 0.51 mmol), 4-(3,3-difluoropiperidin-4-yl)phenol (0.06 g, 0.28 mmol, E-2a from Example 56 step B) and 0.2 mL of triethylamine (1.4 mmol) was heated at 120° C. for 1 h. The cooled reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water and brine, and then it was dried over Na2SO4, filtered, and concentrated to afford 3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one as a pair of diastereomers. These diastereomers were separated via preparative HPLC (method B) to yield 3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one homochiral Examples 56 P-1 (10.7 mg) and P-2 (5.5 mg). The relative and absolute configurations of Examples 56 P-1 and P-2 were not determined and are arbitrarily named P-1 and P-2 based on the order of elution during the HPLC purification. Data for P-1: pale yellow solid; LCMS (method O) RT 1.21 min (95.8% AP) m/z 419.0 (M+H+); 1H NMR (400 MHz, methanol-d4) δ ppm 1.55 (m, 3H) 1.78-1.90 (m, 1H), 1.90-2.01 (M, 1H), 2.1-2.2 (m, 1H), 2.21-2.35 (m, 1H), 2.49 (m, 1H), 2.80-2.99 (m, 1H), 3.01-3.10 (m, 4H), 3.33-3.38 (m, 3H), 3.63 (t, 1H), 5.40 (m, 1H), 6.75 (m, 2H), 7.09-7.15 (m, 4H), 7.38-7.41 (m, 2H); 19F NMR δ ppm-76.948, -102.623, -103.262, -115.103, -115.743, -117.043. Data for P-2: solid; LCMS (methods N, O) 99% AP; 1H NMR (400 MHz, methanol-d4) δ ppm 1.59 (d, J=7.03 Hz, 3H) 1.79-1.90 (m, 1H) 2.01-2.23 (m, 3H) 2.62-2.72 (m, 1H) 2.86-3.19 (m, 5H) 3.40-3.74 (m, 2H) 4.36-4.56 (m, 1H) 5.28-5.48 (m, 1H) 6.76 (d, J=9.04 Hz, 2H) 7.08-7.19 (m, 4H) 7.30-7.42 (m, 2H); 19F NMR δ ppm-76.938, -102.480, -012.630, -103.120, -103.146, -103.269, -114.559, -115.124, -115.199, -115.763, -116.990, -117.049.
