反应详情

n-BuLi (2.8 M solution in hexanes, 183 μL, 0.513 mmol) was added to a cooled (−50° C.) solution of 3,5-bis-trifluoromethylaniline (84.5 μL, 0.545 mmol) in THF (3 mL). The resulting dark brown colored solution was slowly warmed to room temperature and stirred for an hour. A solution of 3-benzyloxymethyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step a, 100 mg, 0.27 mmol) in THF (2 mL) was added and the solution was stirred for 2 h at 70° C. The reaction mixture was then cooled to room temperature, AcOH (100 μL) was added and the solution was purified by automated flash chromatography (SiO2, 10→50% EtOAc/hexanes) followed by preparative HPLC (15→85% gradient of MeCN—H2O with 0.1% TFA). The pure fractions were lyophilized to afford 3-benzyloxymethyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid (3,5-bis-trifluoromethylphenyl)-amide (15 mg, 10% yield). LC-MS: Rt (retention time): 3.38 min, MS: (ES) m/z 565.2 (M+H+). 1H NMR (400 MHz, DMSO-d6) δ 10.2 (s, 1H), 8.28 (s, 2H), 7.8 (s, 1H), 7.2-7.28 (m, 5H), 7.05-7.15 (m, 3H), 4.5-4.58 (m, 2H), 4.03 (d, 1H, J=8 Hz), 3.86-3.92 (m, 2H), 3.6 (d, 1H, J=8 Hz), 3.08 (d, 1H, J=16 Hz), 2.64 (d, 1H, J=16 Hz), 2.05 (s, 3H), 2.06 (s, 3H).

1. additionwas added
2. stirringthe solution was stirred for 2 h at 70° C
3. temperatureThe reaction mixture was then cooled to room temperature
4. customthe solution was purified by automated flash chromatography (SiO2, 10→50% EtOAc/hexanes)