反应详情

To an iced slurry of (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(butylthio)pyrrolidine-2-carboxylic acid (60 mg, 0.105 mmol), (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide, p-toluenesulfonate salt, H2O (53.1 mg, 0.127 mmol), and HATU (60.1 mg, 0.158 mmol) in DCM (2 mL) was added N,N-diisopropylethylamine (0.055 mL, 0.316 mmol). The formed colorless slurry was stirred at room temperature for 5 h (it became light yellow solution). Diluted with DCM, quenched with 5% citric acid. The separated organic layer was washed with sat. sodium citrate and brine, dried over MgSO4, filtered, evaporated in vacuo. The residue was purified by BIOTAGE® column, eluted with gradient 5%-40% acetone-hexane to yield the desired product tert-butyl (S)-1-((2S,4R)-4-(biphenyl-4-yl)-4-(butylthio)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (69 mg, 0.082 mmol, 78% yield) as a white solid. 1H NMR (500 MHz, MeOD) ppm 0.83 (t, J=7.32 Hz, 3H), 1.03-1.12 (m, 10H), 1.19-1.36 (m, 4H), 1.35-1.49 (m, 4H), 1.48 (s, 9H), 1.88 (s, J=7.93, 5.49 Hz, 3H), 2.14-2.24 (m, 1H), 2.23-2.30 (m, 1H), 2.35 (t, J=11.60 Hz, 1H), 2.39-2.53 (m, 1H), 2.76-2.87 (m, 1H), 2.89-3.00 (m, 1H), 3.93 (dd, J=10.68, 641 Hz, 1H), 3.99 (d, J=10.99 Hz, 1H), 4.51 (d, J=10.07 Hz, 1H), 5.06 (d, J=10.99 Hz, 1H), 5.10-5.19 (m, 1H), 5.29 (d, J=17.09 Hz, 1H), 5.69-5.83 (m, 1H), 7.37 (t, J=7.32 Hz, 1H), 7.46 (t, J=7.78 Hz, 2H), 7.55-7.63 (m, 4H) 7.64-7.77 (m, 2H). LC-MS (retention time: 3.48 min, method B), MS m/z 781 (M+H).

1. customquenched with 5% citric acid
2. washThe separated organic layer was washed with sat. sodium citrate and brine
3. dry with materialdried over MgSO4
4. filtrationfiltered
5. customevaporated in vacuo
6. customThe residue was purified by BIOTAGE® column
7. washeluted with gradient 5%-40% acetone-hexane