反应详情

温度

0 °C

Acryloyl chloride (0.100 mL, 1M in THF, 0.1 mmol) was added dropwise to a fine slurry of 2-{[5-amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4-(1H-indol-3-yl)pyrimidine-5-carbonitrile (Intermediate 99, 47 mg, 0.10 mmol) and DIPEA (0.027 mL, 0.16 mmol) in THF (2 mL) at −10° C. over a period of 2 minutes under N2. The mixture was then stirred at 0° C. for 10 minutes then allowed to warm to r.t. over 20 minutes. The mixture was then cooled again to −10° C. and further acryloyl chloride (0.06 mL, 1M in THF, 0.06 mmol) was added dropwise. The mixture was stirred at 0° C. for a further 10 minutes, then allowed to warm to r.t. over 20 minutes. The mixture was then concentrated in vacuo and the resulting reside was dissolved in CH2Cl2 (2 mL). This solution was washed with sat. NaHCO3 (1 mL), dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1.5-7% 7N methanolic ammonia in CH2Cl2 gave a residue that was washed with CH3OH (0.1 mL) and dried in air to give the title compound (11 mg, 20%) as a cream crystalline solid; 1H NMR: 2.28 (3H, s), 2.54-2.65 (4H, m), 2.93 (4H, s), 3.75 (3H, s), 5.71 (1H, d), 6.18 (1H, d), 6.64 (1H, dd), 6.91 (2H, m), 7.18 (1H, s), 7.47 (1H, d), 8.02 (1H, s), 8.52 (1H, s), 8.67 (1H, s), 9.04 (1H, s), 9.40 (1H, s), 11.99 (1H, s); m/z: ES+ MH+ 509.

1. temperatureto warm to r.t. over 20 minutes
2. temperatureThe mixture was then cooled again to −10° C.
3. stirringThe mixture was stirred at 0° C. for a further 10 minutes
4. temperatureto warm to r.t. over 20 minutes
5. concentrationThe mixture was then concentrated in vacuo
6. dissolutionthe resulting reside was dissolved in CH2Cl2 (2 mL)
7. washThis solution was washed with sat. NaHCO3 (1 mL)
8. dry with materialdried (MgSO4)
9. concentrationconcentrated in vacuo
10. customPurification by FCC
11. washeluting with 1.5-7% 7N methanolic ammonia in CH2Cl2
12. customgave a residue that
13. washwas washed with CH3OH (0.1 mL)
14. customdried in air