2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(1-methyl-1H-indol-4-yl)quinolin-4-amine

HRID 1431479Notes

Reaction equation

HRID 1431479 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:75]=[CH:74][CH:73]=[C:72]3[C:68]=2[CH:69]=[CH:70][N:71]3[CH3:76])[C:56]=1[CH3:77].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]>[O:35]1[CH2:40][CH2:39][N:38]([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:75]=[CH:74][CH:73]=[C:72]5[C:68]=4[CH:69]=[CH:70][N:71]5[CH3:76])[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)[CH2:37][CH2:36]1

Participants

7

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 596310462,5-Dimorpholinopyridin-3-amineHCID 596314804-chloro-5,7-difluoro-3-methyl-2-(1-methyl-1H-indol-4-yl)quinoline

Product 1

HCID 59631115N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(1-methyl-1H-indol-4-yl)quinolin-4-amine

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

The Buchwald prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.020 g, 0.042 mmol), 2,5-dimorpholinopyridin-3-amine (0.083 g, 0.32 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(1-methyl-1H-indol-4-yl)quinoline (0.090 g, 0.26 mmol), Pd2dba3 (9.62 mg, 10.50 mmol) and sodium tert-butoxide (0.068 g, 0.71 mmol) in toluene (2.6 mL) at 120° C. for 3.5 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(1-methyl-1H-indol-4-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 7.79 (3H, d, J=11.5 Hz), 7.65 (1H, m), 7.63 (1H, d, J=2.7 Hz), 7.45 (1H, d, J=8.2 Hz), 7.38 (1H, app t, J=8.2 Hz), 7.22 (1H, d, J=0.6 Hz), 7.09 (1H, d, J=3.1 Hz), 7.02 (3H, ddd, J=13.5, 8.6, 2.5 Hz), 6.41 (1H, d, J=2.3 Hz), 6.25 (1H, d, J=3.1 Hz), 3.93 (4H, br. s), 3.87 (3H, s), 3.84 (4H, m), 3.25 (4H, br. s), −3.07 (4H, br. s.), 2.03 (3H, s). Mass Spectrum (ESI) m/e=571.3 (M+1).

Workup

  1. customThe Buchwald prepared
  2. customat 120° C.
  3. customfor 3.5 h
  4. customThe crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc)

Sources & evidence

ORD record
ord-02a6c2f5a1e84951aceb1fb94aa30b11
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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