反应详情

温度

-15 °C

A solution of acryloyl chloride (26 mg, 0.29 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-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 132, 120 mg, 0.26 mmol) in THF (3 mL), which was cooled in an ice/methanol bath to approx −15° C. The mixture was stirred for 1 h, gradually warming to 0° C. The mixture was then diluted with CH2Cl2 (50 mL) and washed with sat. NaHCO3 (50 mL). The resulting aqueous wash solution was further extracted with CH2Cl2 (2×25 mL) and the combined organic solutions were then dried (MgSO4) and concentrated in vacuo onto silica. Part-purification was achieved by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 and impure product containing fractions were combined and concentrated in vacuo. Purification by FCC, eluting with 0-2% 7N methanolic ammonia in CH2Cl2 and then eluting with 0-3% CH3OH in CH2Cl2 gave the title compound (19 mg, 14%) as a cream foam; 1H NMR (CDCl3): 1.82-1.97 (4H, m), 2.00-2.06 (2H, m), 2.13-2.24 (1H, s), 2.25-2.39 (1H, m), 2.29 (3H, s), 2.67-2.98 (4H, m), 3.17-3.26 (3H, m), 3.66 (1H, br s), 3.86 (3H, s), 4.18 (2H, t), 5.64-5.71 (1H, m), 6.30-6.47 (2H, m), 6.78 (1H, s), 6.81 (1H, d), 7.44 (1H, s), 8.06 (1H, s), 8.34 (1H, d), 9.24 (1H, s), 9.40 (1H, s); m/z: ES+ MH+ 515.15.

1. temperaturegradually warming to 0° C
2. washwashed with sat. NaHCO3 (50 mL)
3. extractionThe resulting aqueous wash solution was further extracted with CH2Cl2 (2×25 mL)
4. dry with materialthe combined organic solutions were then dried (MgSO4)
5. concentrationconcentrated in vacuo onto silica
6. customPart-purification
7. washeluting with 0-5% 7N methanolic ammonia in CH2Cl2 and impure product
8. additioncontaining fractions
9. concentrationconcentrated in vacuo
10. customPurification by FCC
11. washeluting with 0-2% 7N methanolic ammonia in CH2Cl2
12. washeluting with 0-3% CH3OH in CH2Cl2