Cesium carbonate → HCID 57449784, compound

HRID 1431710Notes

Reaction equation

HRID 1431710 reaction equation
[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[N:11][CH:12]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:32])=[CH:28][C:29]=2[F:31])[N:24]=[C:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:22]=1[CH3:39]>CN(C=O)C.O>[F:31][C:29]1[CH:28]=[C:27]([F:32])[CH:26]=[C:25]2[C:30]=1[C:21]([O:13][C:9]1[CH:8]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:12]=[N:11][CH:10]=1)=[C:22]([CH3:39])[C:23]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)=[N:24]2

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 57421817HCID 57421817, compoundHCID 596310254-Chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline

Product 1

HCID 57449784HCID 57449784, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
23 °C

Procedure

To a vial containing 5-morpholinopyridin-3-ol (67.3 mg, 0.37 mmol) in DMF (3 mL) was added cesium carbonate (0.26 g, 0.8 mmol) in portions. The mixture was stirred at 23° C. for 15 minutes, then 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (90.7 mg, 0.31 mmol) was added in portions. Upon complete addition, the mixture was warmed to 100° C. After 18 h, the reaction mixture was diluted with water then subsequently extracted five times with EtOAc. The organic extractions were then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-45% of a premixed solution of 89:9:1 DCM:methanol:ammonium hydroxide in DCM) to afford light yellow film that 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 aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a light yellow solid as 4-(5-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yloxy)pyridin-3-yl)morpholine. 1H NMR (500 MHz, CDCl3) δ ppm 8.74 (1H, d, J=4.6 Hz), 8.12 (1H, d, J=2.4 Hz), 7.98 (2H, m), 7.68 (1H, dd, J=9.4, 1.3 Hz), 7.59 (1H, d, J=2.2 Hz), 7.43 (1H, sxt, J=4.4 Hz), 7.02 (1H, ddd, J=11.4, 8.9, 2.4 Hz), 6.87 (1H, s), 3.93 (4H, m), 3.29 (4H, m), 2.41 (3H, s). Mass Spectrum (pos.) m/e: 435.1 (M+H)+.

Workup

  1. additionUpon complete addition
  2. temperaturethe mixture was warmed to 100° C
  3. waitAfter 18 h
  4. extractionthen subsequently extracted five times with EtOAc
  5. extractionThe organic extractions
  6. washwere then washed one time with brine
  7. dry with materialdried over anhydrous magnesium sulfate
  8. filtrationAfter filtration and concentration
  9. customthe residue was purified on silica gel (0-45% of a premixed solution of 89:9:1 DCM:methanol:ammonium hydroxide in DCM)
  10. customto afford light yellow film that
  11. customwas further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution.) The desired fractions
  12. additionwere concd then diluted with EtOAc
  13. washAfter washing twice with satd aq. sodium bicarbonate solution and once with brine
  14. customthe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-3e5b552e1ccb4bf4a8eb07a833ca3ec8
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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