2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → HCID 59631092, compound

HRID 1431742Notes

Reaction equation

HRID 1431742 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:66]=[CH:65][N:64]=[C:63]([N:67]3[CH2:71][CH2:70][CH2:69][CH2:68]3)[CH:62]=2)[C:50]=1[CH3:72].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]>[F:59][C:57]1[CH:56]=[C:55]([F:60])[CH:54]=[C:53]2[C:58]=1[C:49]([NH:47][C:43]1[CH:44]=[N:45][CH:46]=[C:41]([N:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)[CH:42]=1)=[C:50]([CH3:72])[C:51]([C:61]1[CH:66]=[CH:65][N:64]=[C:63]([N:67]3[CH2:68][CH2:69][CH2:70][CH2:71]3)[CH:62]=1)=[N:52]2

Participants

7

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 583477375-Morpholinopyridin-3-amineHCID 59631468HCID 59631468, compound

Product 1

HCID 59631092HCID 59631092, 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 (0.021 g, 0.044 mmol), 5-morpholinopyridin-3-amine (0.060 g, 0.33 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(2-(pyrrolidin-1-yl)pyridin-4-yl)quinoline (0.10 g, 0.28 mmol) and Pd2dba3 (0.010 g, 0.011 mmol) and sodium tert-butoxide (0.067 g, 0.70 mmol) in toluene (2.8 mL) at 100° C. for 5 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/methanol/ammonium hydroxide (90/9/1)). The desired 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 pure product 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(2-(pyrrolidin-1-yl)pyridin-4-yl)quinolin-4-amine. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.44 (1H, s), 8.43 (1H, d, J=2.0 Hz), 7.86 (1H, dd, J=8.8, 2.4 Hz), 7.79 (1H, d, J=2.4 Hz), 7.56-7.60 (2H, m), 7.34-7.39 (1H, m), 6.57 (1H, d, J=8.6 Hz), 6.54 (1H, t, J=2.3 Hz), 3.68-3.75 (4H, m), 3.47 (4H, t, J=6.5 Hz), 3.06-3.11 (4H, m), 2.19 (3H, s), 1.95-2.01 (4H, m). Mass Spectrum (ESI) m/e=503.1 (M+1).

Workup

  1. customwas prepared
  2. customThe crude product was purified by column chromatography on silica gel (0 to 100% DCM/methanol/ammonium hydroxide (90/9/1))
  3. customThe desired product was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution)
  4. additionThe desired fractions were concd then diluted with EtOAc
  5. washAfter washing twice with satd aqueous sodium bicarbonate solution
  6. customthe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-0b4e467dafb54651a52dfa608da49d5a
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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