反应详情

The Buchwald coupled products were prepared according to Procedure H using a solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.021 g, 0.044 mmol), 5-(3-methylmorpholino)-2-morpholinopyridin-3-amine (0.092 g, 0.33 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-3-yl)quinoline (0.08 g, 0.28 mmol), Pd2dba3 (0.010 g, 0.011 mmol) and sodium tert-butoxide (0.066 g, 0.69 mmol) in toluene (2.8 mL) at 100° C. for 27 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/MeOH/ammonium hydroxide (90/9/1)) to give the desired product 5,7-difluoro-3-methyl-N-(5-(3-methylmorpholino)-2-morpholinopyridin-3-yl)-2-(pyridin-3-yl)quinolin-4-amine. The mixture of enantiomers was separated on chiral IC (3×8×15 cm) using 30% isopropanol (0.1% DEA)/CO2, at a flow rate of 100 bar 70 mL/min, (230 nM, injection vol.: 1.5 mL, 4 mg/mL) to give both enantiomers with an ee of 99%; The initial peak (R)-5,7-difluoro-3-methyl-N-(5-(3-methylmorpholino)-2-morpholinopyridin-3-yl)-2-(pyridin-3-yl)quinolin-4-amine or (S)-5,7-difluoro-3-methyl-N-(5-(3-methylmorpholino)-2-morpholinopyridin-3-yl)-2-(pyridin-3-yl)-quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.89 (1H, m), 8.01 (1H, td, J=7.8, 1.8 Hz), 7.90 (1H, m), 7.77 (1H, br. s), 7.66 (1H, m), 7.53-7.46 (3H, m), 6.33 (1H, m), 3.82-3.47 (10H, m), 3.02-2.88 (5H, m), 2.12 (3H, s), 0.92 (3H, br. s.). Mass Spectrum (ESI) m/e=533.2 (M+1). Further elution gave (S)-5,7-difluoro-3-methyl-N-(5-(3-methylmorpholino)-2-morpholinopyridin-3-yl)-2-(pyridin-3-yl)quinolin-4-amine or (R)-5,7-difluoro-3-methyl-N-(5-(3-methylmorpholino)-2-morpholinopyridin-3-yl)-2-(pyridin-3-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.89 (1H, m), 8.01 (1H, td, J=7.8, 1.8 Hz), 7.90 (1H, m), 7.77 (1H, br. s), 7.66 (1H, m), 7.53-7.46 (3H, m), 6.33 (1H, m), 3.82-3.47 (10H, m), 3.02-2.88 (5H, m), 2.12 (3H, s), 0.92 (3H, br. s.). Mass Spectrum (ESI) m/e=533.2 (M+1). These compounds were arbitrarily assigned as R and S.

1. customwere prepared
2. customat 100° C.
3. customfor 27 h
4. customThe crude product was purified by column chromatography on silica gel (0 to 100% DCM/MeOH/ammonium hydroxide (90/9/1))