Morpholine → HCID 50906574, compound

HRID 1431320Notes

Reaction equation

HRID 1431320 reaction equation
Br[C:2]1[CH:3]=[C:4]([N:14]([CH3:34])[C:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=3[F:25])[N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:16]=2[CH3:33])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+].[NH:75]1[CH2:80][CH2:79][O:78][CH2:77][CH2:76]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]>[N:8]1([C:5]2[C:4]([N:14]([CH3:34])[C:15]3[C:24]4[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=4[F:25])[N:18]=[C:17]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[C:16]=3[CH3:33])=[CH:3][C:2]([N:75]3[CH2:80][CH2:79][O:78][CH2:77][CH2:76]3)=[CH:7][N:6]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1

Participants

8

Reactant 4

HCID 8083MorpholineHCID 23676156Sodium t-butoxideHCID 59631098HCID 59631098, compoundHCID 672859322-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl

Product 1

HCID 50906574HCID 50906574, compound

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A stirred mixture of N-(5-bromo-2-morpholinopyridin-3-yl)-5,7-difluoro-N,3-dimethyl-2-(pyridin-2-yl)quinolin-4-amine (12.0 mg, 0.023 mmol), tris(dibenzylideneacetone)dipalladium (0) (2.1 mg, 2.280 μmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl (2.2 mg, 4.56 μmol), and sodium tert-butoxide (15 mg, 0.153 mmol) in toluene (2 mL) was purged three times with argon and placed under vacuum three times. Before heating, morpholine (9.93 μL, 0.114 mmol) was added and the mixture was heated to 100° C. Stirring continued for 21 h. After which the reaction was cooled to rt, diluted with water and extracted with EtOAc (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was dissolved in MeOH and purified by HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution) to yield N-(2,5-di-4-morpholinyl-3-pyridinyl)-5,7-difluoro-N,3-dimethyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CD3OD) δ ppm 8.66 (1H, d, J=4.7 Hz), 8.01 (1H, m), 7.78 (1H, d, J=7.8 Hz), 7.61-7.67 (1H, m), 7.60 (1H, d, J=2.7 Hz), 7.51 (1H, m), 7.23 (1H, m), 7.10 (1H, br. s.), 3.82-3.92 (4H, m), 3.35-3.44 (4H, m), 3.31 (4H, m), 3.17-3.28 (4H, m), 2.46 (3H, br. s.), 1.94-2.04 (3H, s); Mass Spectrum (ESI) m/e=533.2 (M+1).

Workup

  1. customwas purged three times with argon
  2. temperatureBefore heating
  3. temperatureAfter which the reaction was cooled to rt
  4. extractionextracted with EtOAc (3×10 mL)
  5. dry with materialThe combined organic layers were dried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. dissolutionThe crude product was dissolved in MeOH
  9. custompurified by HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution)

Sources & evidence

ORD record
ord-2e039179f81547888888d1100ac5bc79
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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