反应详情

温度

2 °C

To a stirred solution of N′-[4-(1H-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (Intermediate 66, 96 mg, 0.22 mmol) in CH2Cl2 (15 mL) at 2° C. was added DIPEA (0.039 mL, 0.22 mmol) and acryloyl chloride (0.018 mL, 0.22 mmol). The resulting solution was stirred at 2° C. for 0.25 h, then allowed to warm to r.t. and stirred for a further 3.5 h. The mixture was then diluted with CH3OH (10 mL), loaded directly onto silica. Purification by FCC, eluting with 0-10% CH3OH in CH2Cl2 (containing 1% concentrated ammonia (aq) gave the an off-white solid which appeared to contain DIPEA.HCl according to MNR analysis. The solid was then dissolved in a 1:1 mixture of CH2Cl2/2-methyltetrahydrofuran (30 mL) and the resulting solution was washed with NaOH solution (2M, 2×30 mL), water (2×30 mL) and then sat. brine (30 mL). The organic solution was dried (MgSO4) and concentrated in vacuo to give the title compound (2 mg, 2%) as a white solid after trituration with diethyl ether. The liquors from the trituration were concentrated in vacuo to give a second sample of the title compound (10 mg, 9%) as a white solid; 1H NMR: 2.27 (3H, s), 2.55 (4H, s), 2.82-2.95 (4H, m), 3.84 (3H, d), 5.73 (1H, d), 6.24 (1H, dd), 6.62 (1H, dd), 6.89 (1H, s), 7.07-7.21 (2H, m), 7.25 (1H, d), 7.46 (1H, d), 7.89 (1H, s), 8.29 (1H, d), 8.32 (1H, d), 8.42 (1H, s), 8.69 (1H, s), 9.01 (1H, s); m/z: ES+ MH+ 484.62.

1. temperatureto warm to r.t.
2. stirringstirred for a further 3.5 h
3. customPurification by FCC
4. washeluting with 0-10% CH3OH in CH2Cl2 (
5. additioncontaining 1% concentrated ammonia (aq)
6. customgave the an off-white solid which
7. washthe resulting solution was washed with NaOH solution (2M, 2×30 mL), water (2×30 mL)
8. dry with materialThe organic solution was dried (MgSO4)
9. concentrationconcentrated in vacuo