N-methyl-2-pyrrolidone → 3-(5,7-Difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-morpholinobenzonitrile

Participants

Reaction Conditions

Reaction Steps

To a stirred solution of N-(3-chloro-5-morpholinophenyl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (0.059 g, 0.13 mmol) in 1-methylpyrrolidin-2-one (1.26 mL, 0.13 mmol) was added palladium bis(trifluoroacetate) (0.013 g, 0.038 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-triisopropyl-biphenyl (0.036 g, 0.076 mmol) followed by tri-n-butyltin cyanide (0.040 g, 0.13 mmol). The reaction was heated to 160° C. for 36 h. A further 0.3 eq of palladium bis(trifluoroacetate) and 0.6 eq of 2-(dicyclohexylphosphino)-2′,4′,6′,-triisopropyl-biphenyl were added. Heating continued at 160° C. for a further 3 h. After which, the reaction was cooled to 23° C. The crude product was filtered through a plug of alumina eluting with EtOAc. The organics were washed with water, dried over MgSO4 and filtered and evaporated in vacuo. The crude product was purified by column chromatography on alumina (0 to 50% EtOAc/hexane)) to give the desired product 3-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-morpholinobenzonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (1H, ddd, J=4.9, 1.8, 1.0 Hz), 8.62 (1H, s), 8.02 (1H, td, J=7.6, 1.8 Hz), 7.91 (1H, dt, J=7.8, 1.1 Hz), 7.65-7.70 (1H, m), 7.45-7.54 (2H, m), 6.81 (1H, dd, J=2.1, 1.3 Hz), 6.56 (1H, t, J=2.1 Hz), 6.34 (1H, d, J=1.2 Hz), 3.69 (4H, m), 3.09 (4H, m), 2.19 (3H, s). Mass Spectrum (ESI) m/e=458.2 (M+1).

Provenance & Evidence