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

HRID 1431522Notes

Reaction equation

HRID 1431522 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]=[CH:69][C:70]([N:73]([CH3:75])[CH3:74])=[N:71][CH:72]=2)[C:56]=1[CH3:76].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]>[CH3:75][N:73]([CH3:74])[C:70]1[N:71]=[CH:72][C:67]([C:57]2[C:56]([CH3:76])=[C:55]([NH:47][C:46]3[C:41]([N:38]4[CH2:39][CH2:40][O:35][CH2:36][CH2:37]4)=[N:42][CH:43]=[C:44]([N:48]4[CH2:49][CH2:50][O:51][CH2:52][CH2:53]4)[CH:45]=3)[C:64]3[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=3[F:65])[N:58]=2)=[CH:68][CH:69]=1

Participants

7

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 596310435-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-N,N-dimethylpyridin-2-amineHCID 596310462,5-Dimorpholinopyridin-3-amine

Product 1

HCID 675078742-(6-(dimethylamino)pyridin-3-yl)-N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methylquinolin-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), 2,5-dimorpholinopyridin-3-amine (0.095 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), 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)-N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methylquinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (1H, dd, J=2.4, 0.6 Hz), 7.85 (1H, dd, J=8.9, 2.4 Hz), 7.74 (1H, d, J=5.9 Hz), 7.57-7.63 (1H, m), 7.55 (1H, d, J=2.7 Hz), 7.34-7.45 (1H, m), 6.78 (1H, d, J=8.4 Hz), 6.40 (1H, d, J=2.5 Hz), 3.61-3.80 (8H, m), 3.16 (2H, br. s.), 3.11 (6H, s), 2.95-3.02 (4H, m), 2.13 (3H, s). Mass Spectrum (ESI) m/e=562.3 (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-99cadb3953b8496da2edf1e76b37c68c
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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