反应详情

To an iced slurry of (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylnon-8-enoyl)-4-(butylthio)pyrrolidine-2-carboxylic acid (126 mg, 0.198 mmol), (1R,2S)-ethyl 1-amino-2-vinylcyclopropanecarboxylate (36.8 mg, 0.237 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium phosphate (HATU, 113 mg, 0.297 mmol) in dichloromethane (4 mL) was added N,N-diisopropylethylamine (0. 104 mL, 0.594 mmol). The formed light brown solution was stirred at room temperature overnight. Diluted with ethyl acetate, washed it with 5% citric acid, 0.1 M NaOH, and brine, dried over MgSO4, filtered, and concentrated. The resulting brown residue was purified by BIOTAGE® column, eluted with gradient 5˜45% ethyl acetate-hexane to afford the desired product (1R,2S)-ethyl 1-((2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylnon-8-enoyl)-4-(butylthio)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate (75 mg, 0.097 mmol, 49.0% yield) as a white film. 1H NMR (500 MHz, MeOD) δ ppm 0.75-0.90 (m, 3 H) 1.24-1.54 (m, 24 H) 1.61 (tt, J=9.00, 4.27 Hz, 1 H) 1.65-1.77 (m, 2 H) 1.86 (d, J=7.32 Hz, 1 H) 1.94-2.11 (m, 2 H) 2.19-2.41 (m, 3 H) 2.41-2.51 (m, 1 H) 2.77 (dd, J=13.12, 7.02 Hz, 1 H) 3.03 (dd, J=12.51, 7.63 Hz, 1 H) 3.94-4.04 (m, 1 H) 4.09-4.24 (m, 3 H) 4.35 (t, J=7.48 Hz, 1 H) 5.07-5.18 (m, 1 H) 5.24-5.36 (m, 1 H) 5.70-5.86 (m, 2 H) 7.30-7.41 (m, 1 H) 7.46 (t, J=7.63 Hz, 2 H) 7.58-7.75 (m, 6 H). LC-MS (retention time: 3.72 min, method C), MS m/z 774 (M-C2 H4).

1. washwashed it with 5% citric acid, 0.1 M NaOH, and brine
2. dry with materialdried over MgSO4
3. filtrationfiltered
4. concentrationconcentrated
5. customThe resulting brown residue was purified by BIOTAGE® column
6. washeluted with gradient 5˜45% ethyl acetate-hexane