Acryloyl chloride → N-(5-{[5-Cyano-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-4-methoxy-2-{4-methylpiperazin-1-yl}phenyl)prop-2-enamide

Participants

Reaction Steps

A solution of acryloyl chloride (39 mg, 0.43 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred solution of 2-{[5-amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4-(1-methylindol-3-yl)pyrimidine-5-carbonitrile (Intermediate 90, 200 mg, 0.43 mmol) and DIPEA (0.081 mL, 0.47 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/water bath. The mixture was stirred for 1.5 h and then diluted with CH2Cl2 (25 mL). This mixture was then washed with sat. NaHCO3 (50 mL). The aqueous washes were further extracted with CH2Cl2 (2×25 mL). The combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 5% 7N methanolic ammonia in CH2Cl2 gave the title compound together with some residual starting material. Further purification by FCC, eluting with 0-5% CH3OH in CH2Cl2 gave a residue after concentration of the appropriate fractions in vacuo. This residue was dissolved in a small amount of CH2Cl2 and trituration with diethyl ether gave a solid that was collected by filtration and dried in vacuo to give the title compound (106 mg, 48%) as a cream solid; 1H NMR: 2.27 (3H, s), 2.57 (4H, br s), 2.92 (4H, br s), 3.74 (3H, s), 3.91 (3H, s), 5.70 (1H, d), 6.17 (1H, d), 6.63 (1H, dd), 6.90 (1H, s), 7.01 (1H, br s), 7.25 (1H, s), 7.52 (1H, d), 7.88 (1H, br s), 8.02 (1H, s), 8.48 (1H, s), 8.67 (1H, s), 9.03 (1H, s), 9.40 (1H, s); m/z: ES+ MH+ 523.27.

Provenance & Evidence