反应详情

温度

60 °C

A mixture of 3-bromo-1-(4-methylbenzyl)pyrrolidin-2-one (Intermediate 2, 450 mg, 1.68 mmol), (±)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (313 mg, 1.5 mmol) and triethylamine (23 mL, 16.8 mmol) was stirred at 60° C. for 1 h, followed by heating at 85° C. for 1 h, 120° C. for 1 h and at 140° C. for 1 h. The mixture was cooled and then quenched with 40 mL of water and extracted with 3×50 mL of chloroform. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified via silica gel chromatography (24 g column, gradient of 0-80% ethyl acetate/petroleum ether) to yield 375 mg of (±)-rel-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one as a mixture of four diastereomers. LCMS (method F) RT 1.84 min (74% AP), m/z 395.2 (M+H+); 1H NMR (300 MHz, DMSO-d6) δ ppm 7.31-7.41 (m, 8H) 6.86 (d, J=9.07 Hz, 2H) 4.66 (s, 1H) 3.73 (s, 3H) 3.49 (s, 2H) 2.59 (d, J=10.58 Hz, 2H) 2.32-2.47 (m, 3H) 1.89 (td, J=12.65, 4.53 Hz, 2H) 1.56 (d, J=11.71 Hz, 2H).

1. temperatureby heating at 85° C. for 1 h, 120° C. for 1 h and at 140° C. for 1 h
2. temperatureThe mixture was cooled
3. customquenched with 40 mL of water
4. extractionextracted with 3×50 mL of chloroform
5. dry with materialThe combined organic layers were dried over Na2SO4
6. filtrationfiltered
7. concentrationconcentrated under vacuum
8. customThe residue was purified via silica gel chromatography (24 g column, gradient of 0-80% ethyl acetate/petroleum ether)