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

Participants

Reaction Steps

A solution of acryloyl chloride (53.4 mg, 0.59 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred mixture of 4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 103, 270 mg, 0.59 mmol) and DIPEA (0.112 mL, 0.65 mmol) in CH2Cl2 (10 mL), which was cooled in an ice/water bath. The mixture was stirred for 1.5 h and was then diluted with CH2Cl2 (25 mL) and washed with sat. NaHCO3 (50 mL). The aqueous washes were extracted with CH2Cl2 (2×25 mL). The combined organic solutions were then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 provided the title compound mixed together with diacylated material. This material was dissolved in CH2Cl2 and triturated with diethyl ether. The resulting precipitate was collected by filtration, washed with diethyl ether (10 mL) and air dried to give impure product (120 mg) as a yellow solid. This solid was purified by crystallisation from CH3CN to give the title compound (47 mg, 0.092 mmol, 16%) as a yellow solid. All the residues were combined, concentrated in vacuo and crystallised from CH3CN to give a second crop of the title compound (26 mg, 0.051 mmol, 9%) as a yellow solid. Total yield of title compound=73 mg, 24%; 1H NMR: (CDCl3) 1.87-1.99 (1H, m), 2.11-2.24 (1H, m), 2.30 (6H, s), 2.83-2.95 (1H, m), 3-3.19 (4H, m), 3.88 (3H, s), 3.99 (3H, s), 5.75 (1H, dd), 6.34 (1H, dd), 6.44 (1H, dd), 6.79 (1H, s), 7.20 (1H, d), 7.23-7.32 (2H, m) partially obscured by CDCl3 peak, 7.37-7.42 (1H, m), 7.67 (1H, s), 8.08 (1H, d), 8.38 (1H, d), 8.46 (1H, s), 9.00 (1H, s), 9.71 (1H, s); m/z: ES+ MH+ 512.26.

Provenance & Evidence