反应详情

To a solution of 3,3-difluoro-4-(4-methoxyphenyl)piperidine trifluoroacetate (67 mg, 0.2 mmol) in DMF (0.8 mL) was added 3-bromo-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one (from Example 49, step C, 96 mg, 0.35 mmol) and DIPEA (0.1 mL, 0.6 mmol). The mixture was stirred at rt for 18 h, then raised to 80° C. for 2 h. The mixture was cooled, the solvent was removed under vacuum and the residue was purified via silica gel chromatography, eluting with a gradient from 0 to 100% ethyl acetate in hexanes to yield 62 mg of 3-(3,3-difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one (along with 20 mg of the sideproduct, 1-(3-fluoro-4-methylphenyl)-3-hydroxypyrrolidin-2-one). LCMS (method U) RT 3.755 min, m/z 419.3 (M+H+); 1H NMR (500 MHz, chloroform-d) δ 7.51 (d, J=11.9, 2H), m 7.26-7.26 (3H), m 7.20 (1H), 6.90 (d, J=8.7) 3.82 (s, 3H), 3.65-3.78 (m, 3H), 3.2-3.45 (m, 3H), 2.87-3.00 (m, 1H), 2.72-2.85 (m, 0.4H), 2.65 (t, 0.5H), 2.37-2.48 (m, 1H), 2.27 (s, 3H), 2.1-2.25 (m, 2H), 1.87-1.95 (m, 1H). Chiral HPLC (method A-2) revealed that the chirality present in the starting material for step A had been lost.

1. temperatureraised to 80° C. for 2 h
2. temperatureThe mixture was cooled
3. customthe solvent was removed under vacuum
4. customthe residue was purified via silica gel chromatography
5. washeluting with a gradient from 0 to 100% ethyl acetate in hexanes