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

Temperature

100 °C

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)+.

1. customwas purged three times with argon
2. temperaturethe mixture was cooled to rt
3. customas is without purification
4. customwas purged three times with argon
5. temperaturethe mixture was heated to 100° C
6. waitAfter 19 h
7. temperaturethe reaction was cooled to rt
8. additionthen treated with 1M NaOH solution
9. extractionAfter extracting twice with DCM:MeOH (95:5)
10. dry with materialdried over anhydrous magnesium sulfate
11. filtrationAfter filtration and concentration the residue
12. customwas purified on silica gel (0-65% of 89:9:1 DCM:MeOH:ammonium hydroxide solution in DCM)
13. customto afford a light orange film that
14. customwas further purified with HPLC 10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution
15. concentrationThe desired fractions (Prep. HPLC Retention time was −10.5 min) were concentrated
16. additionthen diluted with EtOAc
17. washAfter washing twice with satd aq. sodium bicarbonate solution and once with brine
18. customthe solvent was removed under reduced pressure

ORD record

ord-1fb0adc9a760462e903e1c171f48b162

Source dataset

uspto-grants-2015_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08940724B2