反应详情

温度

60 °C

To a solution of 4-((3R,4R)-3-fluoropiperidin-4-yl)phenol trifluoroacetate, from step B (120 mg, 0.39 mmol) in DMF (2.0 mL) was added K2CO3 (134 mg, 0.97 mmol) and racemic 3-bromo-1-(3-fluoro-4-methyl-phenyl)pyrrolidin-2-one (106 mg, 0.39 mmol, from step C). The mixture was heated to 60° C. and stirred for 30 min. It was then allowed to cool to rt and stirred overnight, followed by the addition of 50 mL of EtOAc, which induced precipitation of a solid. The solid was removed by filtration and discarded, and the filtrate was concentrated in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 0-100% ethyl acetate/hexanes to give 110 mg of (R and S) 3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one) as a mixture of two diastereomers. A portion (35 mg) of the diastereomer mixture was separated (chiral HPLC method H) into homochiral example 49 P-1 (14 mg) and P-2 (14 mg). Data for P-1 (S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)-pyrrolidin-2-one: Chiral HPLC (method H-2) RT 6.97 min, 98% AP; 1H NMR (500 MHz, methanol-d4) δ 7.60-7.52 (m, 1H), 7.32-7.22 (m, 2H), 7.12 (d, J=8.5 Hz, 2H), 6.76 (d, J=8.5 Hz, 2H), 4.72-4.65 (m, 1H), 4.63-4.55 (m, 1H), 3.84 (d, J=9.2 Hz, 4H), 3.51-3.44 (m, 1H), 2.87-2.80 (m, 1H), 2.76-2.68 (m, 1H), 2.64-2.54 (m, 1H), 2.53-2.46 (m, 1H), 2.37-2.30 (m, 1H), 2.26 (d, J=1.4 Hz, 3H), 2.24-2.18 (m, 1H), 1.84 (br s, 3H). Data for P-2 (R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)-pyrrolidin-2-one: Chiral HPLC (method H-2) RT 8.84 min, 99.3% AP; 1H NMR (500 MHz, methanol-d4) δ 7.56 (dd, J=12.0, 1.9 Hz, 1H), 7.32-7.23 (m, 2H), 7.12 (d, J=8.4 Hz, 2H), 6.80-6.73 (m, 2H), 4.70-4.63 (m, 1H), 4.60-4.54 (m, 1H), 3.88-3.77 (m, 5H), 3.23-3.17 (m, 2H), 3.07 (d, J=10.7 Hz, 2H), 2.75-2.68 (m, 2H), 2.64-2.48 (m, 4H), 2.33 (dd, J=6.6, 2.4 Hz, 2H), 2.26 (d, J=1.5 Hz, 5H), 2.21 (dd, J=12.7, 9.6 Hz, 2H), 1.90-1.83 (m, 4H).

1. temperatureto cool to rt
2. stirringstirred overnight
3. customprecipitation of a solid
4. customThe solid was removed by filtration
5. concentrationthe filtrate was concentrated in vacuo
6. customThe residue was purified via silica gel chromatography
7. washeluting with a gradient of 0-100% ethyl acetate/hexanes