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

Participants

Reaction Conditions

Reaction Steps

A mixture of 2-(6-methoxypyridin-3-yl)-5-morpholinoaniline (60.7 mg, 0.21 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (50.9 mg, 0.17 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl, (X-Phos) (13.9 mg, 0.029 mmol), tris(dibenzylideneacetone)dipalladium (0) (6.5 mg, 7.10 μmol), and sodium tert-butoxide (43.3 mg, 0.45 mmol) in dry toluene (1.5 mL) was degassed by nitrogen. The resulting reaction was heated to 100° C. and monitored with TLC and LC-MS. After 21 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (10-30% EtOAc in hexanes) to afford an impure orange residue. The light orange film was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a light yellow solid as 5,7-difluoro-N-(2-(6-methoxypyridin-3-yl)-5-morpholinophenyl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.68 (1H, ddd, J=4.8, 1.7, 1.0 Hz), 8.13 (1H, m), 7.99 (1H, td, J=7.7, 1.7 Hz), 7.78 (1H, dt, J=7.8, 1.0 Hz), 7.69 (2H, m), 7.55 (2H, m), 7.43 (1H, m), 7.06 (1H, d, J=8.4 Hz), 6.69 (1H, dd, J=8.4, 0.6 Hz), 6.66 (1H, m), 6.26 (1H, d, J=2.3 Hz), 3.80 (3H, s), 3.72 (4H, m), 3.05 (4H, m), 2.09 (3H, s). Mass Spectrum (pos.) m/e: 540.3 (M+1).

Provenance & Evidence