2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → N-(3-chloro-5-morpholinophenyl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine

Temperature

120 °C

To a stirred solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.026 g, 0.055 mmol), 3-chloro-5-morpholinoaniline (0.088 g, 0.41 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.1 g, 0.34 mmol) and Pd2dba3 (0.013 g, 0.014 mmol) in toluene (3.40 mL) was added sodium t-butoxide (0.083 g, 0.860 mmol). The reaction mixture was heated to 120° C. and stirred for 45 min. The reaction was then cooled to rt and diluted with water (25 mL). The mixture was extracted with EtOAc (2×10 mL) and DCM (1×10 mL). The organic layers were combined and washed with brine (1×20 mL) and dried over magnesium sulfate. The crude product was purified by column chromatography on basic alumina (0 to 50% EtOAc in hexane) to give the desired product N-(3-chloro-5-(4-morpholinyl)phenyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.72 (1H, ddd, J=4.9, 1.8, 1.0 Hz), 7.85-7.92 (1H, dt, J=7.9, 1.8 Hz), 7.79-7.85 (1H, d, J=7.9 Hz), 7.67 (1H, br. s), 7.38 (1H, ddd, J=7.5, 4.8, 1.2 Hz), 7.02 (2H, ddd, J=13.7, 8.6, 2.5 Hz), 6.49-6.54 (1H, m), 6.36 (1H, m), 6.27 (1H, m), 3.79-3.90 (4H, m), 3.09-3.23 (4H, m), 2.17 (3H, s). Mass Spectrum (ESI) m/e=467.2 (M+1).

1. temperatureThe reaction was then cooled to rt
2. extractionThe mixture was extracted with EtOAc (2×10 mL) and DCM (1×10 mL)
3. washwashed with brine (1×20 mL)
4. dry with materialdried over magnesium sulfate
5. customThe crude product was purified by column chromatography on basic alumina (0 to 50% EtOAc in hexane)

ORD record

ord-588048e48c2c43288629d3097c979033

Source dataset

uspto-grants-2015_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08940724B2