Reaction Steps
To a mixture of 3-bromo-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one (0.134 g, 0.47 mmol, from Example 50, step B) and 4-(3,3-difluoropiperidin-4-yl)phenol (0.05 g, 0.23 mmol, E-1a from Example 56, step D) was added triethylamine (0.16 mL, 1.2 mmol) and the resulting mixture was heated at 120° C. for 1 h. After cooling, the reaction was partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed with water and brine, then dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified via preparative HPLC (method B) to yield the homochiral Examples 56 P-3 and P-4 3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one diastereomers. The relative and absolute configurations of Examples 56 P-3 and P-4 were not determined and are arbitrarily named P-3 and P-4 based on the order of elution during the HPLC purification. Data for P-3: 11.5 mg pale yellow solid, LCMS (method O) RT 1.23 min (99.8% AP), m/z 419.0 (M+H+); 1H NMR (400 MHz, methanol-d4) δ ppm 1.55 (d, J=7.2, 3H), 1.83 (m, 1H), 1.91-1.99 (m, 1H), 2.10-2.30 (m, 2H), 2.57-2.64 (q, 1H), 2.82-3.95 (m, 3H), 3.07-3.20, (m, 1H), 3.33-3.42 (m, 2H), 3.67 (t, J=9, 1H), 5.40 (d, J=7.2, 1H), 6.75 (m, 2H), 7.09-7.15 (m, 4H), 7.37-7.41 (m, 2H); 19F NMR δ ppm-102.515, -103.158, -114.576, -115.216, -117.070. Data for P-4: 13.7 mg pale yellow solid; LCMS (method O) RT 1.215 min (100% AP), m/z 419.0 (M+H+); 1H NMR (400 MHz, methanol-d4) δ ppm 1.59 (d, J=6.4, 3H), 1.80-1.90 (m, 1H), 2.01-2.29 (m, 3H), 2.53 (t, 1H), 2.81-2.97 (m, 3H), 3.01-3.25 (m, 3H), 3.34-3.43 (m, 1H), 3.64 (t, J=8.8, 1H), 5.42 (d, J=7.2, 1H), 6.74-6.77 (m, 2H), 7.09-7.16 (m, 4H), 7.35-7.38 (m, 2H); 19F NMR δ ppm-102.632, -103.271, -115.162, -115.801, -116.989.
