反应详情

温度

-15 °C

A solution of acryloyl chloride (13 mg, 0.14 mmol) in THF (1 mL) was added dropwise to a stirred solution of 4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-6-methoxy-N-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 160, 100 mg, 0.13 mmol) in THF (3 mL), which was cooled in an ice/CH3OH bath to approximately −15° C. The mixture was stirred for 1 h and allowed to warm to −0° C. The mixture was then diluted with CH2Cl2 (50 mL) and the resulting solution was washed with sat. NaHCO3 (50 mL). The aqueous solution was further extracted with CH2Cl2 (2×25 mL) and the combined organic solutions were dried (MgSO4) and concentrated in vacuo onto silica. Patrial purification by FCC, eluting with 0-3.5% 7N methanolic ammonia in CH2Cl2 provided some of the title compound. Further purification by FCC, eluting with 0-1.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (33 mg, 49%) as a yellow solid; 1H NMR: 1.77 (1H, s), 1.94-2.15 (1H, m), 2.10 (3H, s), 2.29 (1H, d), 2.39-2.48 (1H, m), 2.87 (1H, s), 3.11-3.20 (1H, m), 3.33-3.42 (2H, m), 3.81 (3H, s), 4.26-4.34 (1H, m), 5.68 (1H, dd), 6.18 (1H, dd), 6.53 (1H, dd), 6.67 (1H, s), 7.04 (1H, td), 7.21 (1H, d), 7.36-7.43 (1H, m), 8.03 (1H, s), 8.08 (1H, s), 8.30 (1H, d), 8.42 (1H, d), 8.73-8.79 (2H, m), 9.41 (1H, s); m/z: ES+ MH+ 511.16.

1. temperatureto warm to −0° C
2. washthe resulting solution was washed with sat. NaHCO3 (50 mL)
3. extractionThe aqueous solution was further extracted with CH2Cl2 (2×25 mL)
4. dry with materialthe combined organic solutions were dried (MgSO4)
5. concentrationconcentrated in vacuo onto silica
6. customPatrial purification by FCC
7. washeluting with 0-3.5% 7N methanolic ammonia in CH2Cl2