Morpholine → N-(2-(2,2-dimethyl-4-morpholinyl)-5-(4-morpholinyl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine

HRID 1431347Notes

Reaction equation

HRID 1431347 reaction equation
Br[C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[CH:24][C:25]=3[F:27])[N:20]=[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:18]=2[CH3:35])[C:5]([N:8]2[CH2:13][CH2:12][O:11][C:10]([CH3:15])([CH3:14])[CH2:9]2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+].[NH:76]1[CH2:81][CH2:80][O:79][CH2:78][CH2:77]1>C1(C)C=CC=CC=1.O.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]>[CH3:14][C:10]1([CH3:15])[O:11][CH2:12][CH2:13][N:8]([C:5]2[C:4]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([F:28])=[CH:24][C:25]=4[F:27])[N:20]=[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:18]=3[CH3:35])=[CH:3][C:2]([N:76]3[CH2:81][CH2:80][O:79][CH2:78][CH2:77]3)=[CH:7][N:6]=2)[CH2:9]1

Participants

8

Reactant 4

HCID 8083MorpholineHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 59631452N-(5-bromo-2-(2,2-dimethylmorpholino)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine

Product 1

HCID 50906788N-(2-(2,2-dimethyl-4-morpholinyl)-5-(4-morpholinyl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A stirred mixture of N-(5-bromo-2-(2,2-dimethylmorpholino)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (0.061 g, 0.11 mmol), 2-dicyclohexylphosphino-2′,4′,6′,-tri-i-propyl-1,1′-biphenyl (0.011 g, 0.023 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.011 g, 0.012 mmol), and sodium tert-butoxide (0.034 g, 0.35 mmol) in dry toluene (1.0 mL) was purged three times with argon and placed under vacuum three times. Before heating, morpholine (0.05 mL, 0.57 mmol) was added via syringe, then the mixture was heated to 100° C. After 21 h, the reaction was cooled to rt, then diluted with water and extracted three times with EtOAc. The organic extractions were combined and washed twice with brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. After dissolving in MeOH then syringe filtration, the mixture was purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were concentrated then diluted with EtOAc. After washing twice with satd aq. sodium carbonate solution and once with brine, the solvent was removed under reduced pressure to yield N-(2-(2,2-dimethyl-4-morpholinyl)-5-(4-morpholinyl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, MeOH) δ ppm 8.71 (1H, d, J=5.1 Hz), 8.06 (1H, td, J=7.7, 1.8 Hz), 7.84 (1H, d, J=7.8 Hz), 7.64 (3H, m), 7.29 (1H, ddd, J=13.7, 9.0, 2.3 Hz), 6.53 (1H, d, J=2.7 Hz), 4.03 (7H, m), 3.16 (7H, m), 2.10 (3H, s), 1.41 (6H, m). Mass Spectrum ESI (pos.) m/e: 547.3 (M+H)+.

Workup

  1. customwas purged three times with argon
  2. temperatureBefore heating
  3. temperaturethe reaction was cooled to rt
  4. extractionextracted three times with EtOAc
  5. extractionThe organic extractions
  6. washwashed twice with brine
  7. dry with materialAfter drying over anhydrous sodium sulfate and filtration
  8. customthe organic solvent was removed under reduced pressure
  9. dissolutionAfter dissolving in MeOH
  10. filtrationsyringe filtration
  11. customthe mixture was purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution)
  12. concentrationThe desired fractions were concentrated
  13. additionthen diluted with EtOAc
  14. washAfter washing twice with satd aq. sodium carbonate solution and once with brine
  15. customthe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-0b547029d0df47efa29a4e4eb033ceb2
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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