2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 2-(6-(dimethylamino)pyridin-3-yl)-5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine

HRID 1431531Notes

Reaction equation

HRID 1431531 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[CH:42]=[C:43]([NH2:47])[CH:44]=[N:45][CH:46]=2)[CH2:37][CH2:36]1.Cl[C:49]1[C:58]2[C:53](=[CH:54][C:55]([F:60])=[CH:56][C:57]=2[F:59])[N:52]=[C:51]([C:61]2[CH:62]=[CH:63][C:64]([N:67]([CH3:69])[CH3:68])=[N:65][CH:66]=2)[C:50]=1[CH3:70].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:69][N:67]([CH3:68])[C:64]1[N:65]=[CH:66][C:61]([C:51]2[C:50]([CH3:70])=[C:49]([NH:47][C:43]3[CH:44]=[N:45][CH:46]=[C:41]([N:38]4[CH2:39][CH2:40][O:35][CH2:36][CH2:37]4)[CH:42]=3)[C:58]3[C:53](=[CH:54][C:55]([F:60])=[CH:56][C:57]=3[F:59])[N:52]=2)=[CH:62][CH:63]=1

Participants

7

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 583477375-Morpholinopyridin-3-amineHCID 596310435-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-N,N-dimethylpyridin-2-amine

Product 1

HCID 596313262-(6-(dimethylamino)pyridin-3-yl)-5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.023 g, 0.048 mmol), 5-morpholinopyridin-3-amine (0.064 g, 0.36 mmol), 5-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-N,N-dimethylpyridin-2-amine (0.1 g, 0.30 mmol) and Pd2dba3 (0.011 g, 0.012 mmol) and sodium tert-butoxide (0.072 g, 0.75 mmol) in toluene (3.0 mL) at 100° C. for 2 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 2-(6-(dimethylamino)pyridin-3-yl)-5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (2H, m), 7.87 (1H, dd, J=8.8, 2.5 Hz), 7.79 (1H, d, J=2.3 Hz), 7.56-7.59 (2H, m), 7.36 (1H, ddd, J=12.6, 9.5, 2.5 Hz), 6.76 (1H, d, J=8.8 Hz), 6.55 (1H, t, J=2.2 Hz), 3.70 (4H, m), 3.11-3.06 (10H, m), 2.19 (3H, s). Mass Spectrum (ESI) m/e=477.2 (M+1).

Workup

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

Sources & evidence

ORD record
ord-d7ee9d85ac9442c38542330838f0257e
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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