2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 8-chloro-3-methyl-2-(4-methylpyridin-2-yl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine

HRID 1431538Notes

Reaction equation

HRID 1431538 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](=[C:54]([Cl:59])[CH:55]=[CH:56][CH:57]=2)[N:52]=[C:51]([C:60]2[CH:65]=[C:64]([CH3:66])[CH:63]=[CH:62][N:61]=2)[C:50]=1[CH3:67].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]>[Cl:59][C:54]1[CH:55]=[CH:56][CH:57]=[C:58]2[C:53]=1[N:52]=[C:51]([C:60]1[CH:65]=[C:64]([CH3:66])[CH:63]=[CH:62][N:61]=1)[C:50]([CH3:67])=[C:49]2[NH:47][C:43]1[CH:44]=[N:45][CH:46]=[C:41]([N:38]2[CH2:39][CH2:40][O:35][CH2:36][CH2:37]2)[CH:42]=1

Participants

7

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 583477375-Morpholinopyridin-3-amineHCID 596311454,8-Dichloro-3-methyl-2-(4-methylpyridin-2-yl)quinoline

Product 1

HCID 596311068-chloro-3-methyl-2-(4-methylpyridin-2-yl)-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 (0.021 g, 0.044 mmol), 5-morpholinopyridin-3-amine (0.060 g, 0.33 mmol), 4,8-dichloro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (0.084 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 1.6 h. The crude product was purified by column chromatography on alumina (0 to 50% EtOAc in hexanes). 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 cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution, the solvent was removed under reduced pressure to yield pure product 8-chloro-3-methyl-2-(4-methylpyridin-2-yl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (1H, s), 8.57 (1H, d, J=4.9 Hz), 8.02 (1H, dd, J=8.6, 1.2 Hz), 7.92 (1H, dd, J=7.5, 1.1 Hz), 7.82 (1H, d, J=2.5 Hz), 7.77 (1H, s), 7.53-7.57 (1H, m), 7.52 (1H, m), 7.34-7.36 (1H, m), 6.57 (1H, t, J=2.3 Hz), 3.68-3.72 (4H, m), 3.05-3.09 (4H, m), 2.47 (3H, s), 2.22 (3H, s). Mass Spectrum (ESI) m/e=446.1 (M+1).

Workup

  1. customwas prepared
  2. customat 100° C.
  3. customfor 1.6 h
  4. customThe crude product was purified by column chromatography on alumina (0 to 50% EtOAc in hexanes)
  5. customThe desired product was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution.) The desired fractions
  6. additionwere cond then diluted with EtOAc
  7. washAfter washing twice with satd aq. sodium bicarbonate solution
  8. customthe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-4115d9ab2f3c4eca9fa3e7b4fde41b14
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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