2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → N-(2,5-di-4-morpholinylphenyl)-5-fluoro-3,8-dimethyl-2-(2-pyridinyl)-4-quinolinamine

HRID 1431323Notes

Reaction equation

HRID 1431323 reaction equation
C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.O1CCN(C2C(N)=CC(N3CCOCC3)=CN=2)CC1.[O:54]1[CH2:59][CH2:58][N:57]([C:60]2[CH:66]=[CH:65][C:64]([N:67]3[CH2:72][CH2:71][O:70][CH2:69][CH2:68]3)=[CH:63][C:61]=2[NH2:62])[CH2:56][CH2:55]1.Cl[C:74]1[C:83]2[C:78](=[C:79]([CH3:85])[CH:80]=[CH:81][C:82]=2[F:84])[N:77]=[C:76]([C:86]2[CH:91]=[CH:90][CH:89]=[CH:88][N:87]=2)[C:75]=1[CH3:92].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:57]1([C:60]2[CH:66]=[CH:65][C:64]([N:67]3[CH2:68][CH2:69][O:70][CH2:71][CH2:72]3)=[CH:63][C:61]=2[NH:62][C:74]2[C:83]3[C:78](=[C:79]([CH3:85])[CH:80]=[CH:81][C:82]=3[F:84])[N:77]=[C:76]([C:86]3[CH:91]=[CH:90][CH:89]=[CH:88][N:87]=3)[C:75]=2[CH3:92])[CH2:58][CH2:59][O:54][CH2:55][CH2:56]1

Participants

9

Reactant 5

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 288098152,5-DimorpholinobenzenamineHCID 596310462,5-Dimorpholinopyridin-3-amineHCID 596312654-Chloro-5-fluoro-3,8-dimethyl-2-(pyridin-2-yl)quinoline

Product 1

HCID 59631156N-(2,5-di-4-morpholinylphenyl)-5-fluoro-3,8-dimethyl-2-(2-pyridinyl)-4-quinolinamine

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
120 °C

Procedure

To a stirred solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (27.0 mg, 0.056 mmol), 2,5-dimorpholinopyridin-3-amine (37.0 mg, 0.140 mmol), 2,5-dimorpholinoaniline (55.0 mg, 0.21 mmol), 4-chloro-5-fluoro-3,8-dimethyl-2-(pyridin-2-yl)quinoline (100.0 mg, 0.35 mmol) and Pd2dba3 (13.0 mg, 0.014 mmol) in toluene (3.5 mL) was added sodium t-butoxide (84.0 mg, 0.87 mmol). The reaction mixture was heated to 120° C. and stirred for 45 min. The reaction was cooled to rt and diluted with water (25 mL). The mixture was extracted with EtOAc (3×10 mL) and DCM (1×10 mL). The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0 to 100% EtOAc in DCM) to give the desired products N-(2,5-di-4-morpholinylphenyl)-5-fluoro-3,8-dimethyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.69 (1H, br. m.), 8.22 (1H br m), 8.02-8.12 (1H, m), 7.89 (1H, br. m.), 7.40 (2H, m), 7.28 (1H, m), 6.98-7.15 (2H, m), 6.24 (1H, br. s.), 3.87-4.00 (4H, br m), 3.80 (4H, br m), 3.09 (8H, br. m.), 2.77 (3H, s), 2.32 (3H, s); Mass Spectrum (ESI) m/e=514.3 (M+1). Further elution gave N-(2,5-di-4-morpholinyl-3-pyridinyl)-5-fluoro-3,8-dimethyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.68 (1H, ddd, J=4.9, 1.8, 1.0 Hz), 8.08 (1H, d, J=7.8 Hz), 7.90 (1H, m), 7.82 (1H, br d), 7.60 (1H, d, J=2.5 Hz), 7.40-7.48 (1H, m), 7.37 (1H, m), 7.07 (1H, dd, J=13.6, 7.9 Hz), 6.47 (1H, br. s.), 3.88-4.00 (4H, m), 3.75-3.85 (4H, m), 3.23 (4H, br. s.), 3.03-3.13 (4H, m), 2.78 (3H, s), 2.31 (3H, s); Mass Spectrum (ESI) m/e=515.2 (M+1).

Workup

  1. temperatureThe reaction was cooled to rt
  2. extractionThe mixture was extracted with EtOAc (3×10 mL) and DCM (1×10 mL)
  3. dry with materialThe organic layers were dried over magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe crude product was purified by column chromatography on silica gel (0 to 100% EtOAc in DCM)

Sources & evidence

ORD record
ord-30a9aee1ee764b309bb2c15bffee59ec
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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