2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → N-(2,5-di(4-morpholinyl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(1-methyl-1H-indol-5-yl)-4-quinolinamine

HRID 1431412Notes

Reaction equation

HRID 1431412 reaction equation
C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:68]=[C:69]3[C:73](=[CH:74][CH:75]=2)[N:72]([CH3:76])[CH:71]=[CH:70]3)[C:56]=1[CH3:77].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:38]1([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:68]=[C:69]5[C:73](=[CH:74][CH:75]=4)[N:72]([CH3:76])[CH:71]=[CH:70]5)[C:56]=3[CH3:77])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:39][CH2:40][O:35][CH2:36][CH2:37]1

Participants

8

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 596310462,5-Dimorpholinopyridin-3-amineHCID 596312144-chloro-5,7-difluoro-3-methyl-2-(1-methyl-1H-indol-5-yl)quinoline

Product 1

HCID 59631299N-(2,5-di(4-morpholinyl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(1-methyl-1H-indol-5-yl)-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 (0.022 g, 0.047 mmol), 2,5-dimorpholinopyridin-3-amine (0.093 g, 0.350 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(1-methyl-1H-indol-5-yl)quinoline (0.1 g, 0.292 mmol) and Pd2dba3 (10.7 mg, 0.012 mmol) in toluene (2.92 mL) was added sodium t-butoxide (0.070 g, 0.73 mmol). The reaction mixture was heated to 120° C. and stirring continued for 2 h. The reaction was cooled to rt and diluted with water (15 mL). The mixture was extracted with EtOAc (2×15 mL) and DCM (1×15 mL). The organic layers were combined and washed with brine (1×20 mL) and dried over magnesium sulfate. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-di(4-morpholinyl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(1-methyl-1H-indol-5-yl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 7.87 (1H, s), 7.66 (3H, m), 7.46 (2H, s), 7.15 (1H, d, J=3.1 Hz), 6.94-7.04 (1H, m), 6.57 (1H, d, J=2.9 Hz), 6.43 (1H, br. s.), 3.89-3.96 (4H, m), 3.88 (3H, s), 3.83-3.87 (4H, m), 3.30 (4H, br s), 3.03-3.14 (4H, m), 2.20 (3H, s). Mass Spectrum (ESI) m/e=571.3 (M+1).

Workup

  1. temperatureThe reaction was cooled to rt
  2. extractionThe mixture was extracted with EtOAc (2×15 mL) and DCM (1×15 mL)
  3. washwashed with brine (1×20 mL)
  4. dry with materialdried over magnesium sulfate
  5. customThe crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc)

Sources & evidence

ORD record
ord-d24638aa644943d0a0d1ae1fb0f36e55
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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