2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → HCID 59631567, compound

HRID 1431722Notes

Reaction equation

HRID 1431722 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]=[N:69][C:70]([N:73]3[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]3)=[CH:71][CH:72]=2)[C:56]=1[CH3:79].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:68]=[N:69][C:70]([N:73]5[CH2:74][CH2:75][NH:76][CH2:77][CH2:78]5)=[CH:71][CH:72]=4)[C:56]=3[CH3:79])=[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 59631316HCID 59631316, compound

Product 1

HCID 59631567HCID 59631567, compound

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

The Buchwald coupled product was prepared according to Procedure S using of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.020 g, 0.043 mmol), 2,5-dimorpholinopyridin-3-amine (0.085 g, 0.32 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(6-(piperazin-1-yl)pyridin-3-yl)quinoline (0.1 g, 0.27 mmol), Pd2dba3 (0.009 g, 0.011 mmol) and sodium tert-butoxide (0.064 g, 0.67 mmol) in toluene (3.3 mL) at 100° C. for 2.1 h. The crude product was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were concd then diluted with EtOAc. After washing twice with satd aqueous sodium bicarbonate solution, the solvent was removed under reduced pressure to yield desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(6-(piperazin-1-yl)pyridin-3-yl)quinolin-4-amine. 1H NMR (500 MHz, CD2Cl2) δ ppm 8.50 (1H, d, J=2.2 Hz), 7.89 (1H, dd, J=8.6, 2.4 Hz), 7.63 (1H, d, J=10.0 Hz), 7.61 (1H, d, J=2.7 Hz), 7.51-7.56 (1H, m), 6.99 (1H, ddd, J=13.3, 8.7, 2.4 Hz), 6.81 (1H, d, J=8.8 Hz), 6.34 (1H, d, J=2.4 Hz), 3.85 (4H, m), 3.78-3.83 (4H, m), 3.73-3.78 (4H, m), 3.12-3.21 (4H, m), 2.97-3.05 (4H, m), 2.22 (3H, s). Mass Spectrum (ESI) m/e=603.2 (M+1).

Workup

  1. customwas prepared
  2. customThe crude product was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution)
  3. additionThe desired fractions were concd then diluted with EtOAc
  4. washAfter washing twice with satd aqueous sodium bicarbonate solution
  5. customthe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-7c7117f803774d4b83a511f50fe6cfd8
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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