Sodium Carbonate → 4-Amino-6-(5-((5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)amino)-6-(4-morpholinyl)-3-pyridinyl)-5-pyrimidinecarbonitrile

Participants

Reaction Conditions

Reaction Steps

A stirred mixture of N-(5-bromo-2-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (0.23 g, 0.45 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride DCM complex (0.037 g, 0.046 mmol), bis(pinacolato)diboron (0.23 g, 0.91 mmol), and potassium acetate (0.14 g, 1.4 mmol) in dry DMF (5.0 mL) was purged three times with argon and placed under vacuum three times, then the mixture was heated to 100° C. After 2.5 h, the mixture was cooled to rt and used as is without purification. Mass Spectrum (ESI) m/e=478.1 (M+1). A stirred mixture of 4-amino-6-chloropyrimidine-5-carbonitrile (0.047 g, 0.30 mmol), mostly 5-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-6-morpholinopyridin-3-ylboronic acid (0.22 g, 0.45 mmol), tetrakis(triphenylphosphine)palladium (0.035 g, 0.030 mmol), and 2.0M sodium carbonate (0.60 mL, 1.200 mmol) in DMF (5.00 mL) was purged three times with argon and placed under vacuum three times, then the mixture was heated to 100° C. After 19 h, the reaction was cooled to rt then treated with 1M NaOH solution. After extracting twice with DCM:MeOH (95:5), the organics were combined and dried over anhydrous magnesium sulfate. After filtration and concentration the residue was purified on silica gel (0-65% of 89:9:1 DCM:MeOH:ammonium hydroxide solution in DCM) to afford a light orange film that was further purified with HPLC 10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution. The desired fractions (Prep. HPLC Retention time was −10.5 min) were concentrated 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 4-amino-6-(5-((5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)amino)-6-(4-morpholinyl)-3-pyridinyl)-5-pyrimidinecarbonitrile. 1H NMR (400 MHz, CDCl3) δ ppm 8.80 (1H, m), 8.66 (1H, d, J=2.3 Hz), 8.62 (1H, s), 7.94 (2H, m), 7.68 (1H, d, J=8.6 Hz), 7.40 (1H, ddd, J=6.9, 4.8, 2.0 Hz), 7.29 (1H, d, J=2.0 Hz), 7.22 (1H, d, J=11.0 Hz), 7.03 (1H, ddd, J=13.4, 8.5, 2.7 Hz), 5.68 (2H, s), 3.95 (4H, br. s.), 3.62 (4H, m), 2.30 (3H, s). Mass Spectrum ESI (pos.) m/e: 552.1 (M+H)+.

Provenance & Evidence