Trifluoroacetic acid → 5,6-difluoro-N-(4-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine

Participants

Reaction Conditions

Reaction Steps

A resealable pressure bottle, under nitrogen, was charged with 5,6-difluoro-N-(4-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine (0.13 g, 0.26 mmol), 4-(4-methylpiperazin-1-yl)benzenamine (0.25 g, 1.31 mmol), TFA (0.12 ml, 1.58 mmol), and 2-propanol (10.00 ml, 0.03 M). The reaction vessel was sealed and the mixture stirred at 90° C. for 4 days. The reaction mixture was cooled to RT and concentrated to brown residue. The residue was purified by Biotage silica gel chromatography (2%-8% MeOH/Dichloromethane) followed by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA). The product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with ethyl acetate. The organic portion was dried with Na2SO4, filtered, and concentrated to afford 5,6-difluoro-N-(4-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine as a yellow solid. MS m/z=606.1 [M+H]+. Calc'd for C33H29F2N9O: 605.64.

Provenance & Evidence