反应详情

A solution of (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) in dichloromethane (30 mL) was purged with nitrogen for 3 min. And then Hoveyda-Grubbs Catalyst 2nd Generation (73.1 mg, 0.116 mmol) was added. The resulting green solution was heated to reflux for 5 hours. The reaction was quenched with 2-mercaptonicotinic acid (30.1 mg, 0.194 mmol) and washed with saturated Na2CO3, and brine. Dried over MgSO4, filtered, and concentrated in vacuo. The brown residue was purified by BIOTAGE® column, eluted with gradient 5%˜50% ethyl acetate-hexane to afford the desired product (2R,6S,13aS,14aR,16aS,Z)-ethyl 2-(biphenyl-4-yl)-6-(tert-butoxycarbonylamino)-2-(butylthio)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (59 mg, 0.074 mmol, 76% yield) as an off-white solid. 1H NMR (500 MHz, MeOD) δ ppm 0.83 (t, 3 H) 1.14-1.37 (m, 8 H) 1.38-1.54(m, 17 H) 1.52-1.68 (m, 4 H) 1.79-1.95 (m, 1 H) 1.97-2.10 (m, 1 H) 2.25-2.37 (m, 2 H) 2.37-2.49 (m, 2 H) 2.53 (dd, J=12.51, 10.07 Hz, 1 H) 2.88 (dd, J=12.51, 7.02 Hz, 1 H) 3.97-4.08 (m, 2 H) 4.07-4.22 (m, 3 H) 4.50 (dd, J=10.22, 2.90 Hz, 1 H) 5.17 (d, J=10.68 Hz, 1 H) 5.34 (t, J=9.77 Hz, 1 H) 5.56-5.68 (m, 1 H) 7.30-7.41 (m, 1 H) 7.41-7.50 (m, 2 H) 7.60 (d, J=8.24 Hz, 4 H) 7.77 (d, J=8.24 Hz, 2 H). LC-MS (retention time: 3.55 min, method C), MS m/z 718 (M+H).

1. temperatureThe resulting green solution was heated
2. temperatureto reflux for 5 hours
3. washwashed with saturated Na2CO3, and brine
4. dry with materialDried over MgSO4
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. customThe brown residue was purified by BIOTAGE® column
8. washeluted with gradient 5%˜50% ethyl acetate-hexane