Cesium carbonate → 1-(2-(7-methoxyquinolin-4-yloxy)ethyl)-5-phenylpyrimidin-2(1H)-one

HRID 1878770Notes

Reaction equation

HRID 1878770 reaction equation
[OH:1][CH2:2][CH2:3][N:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[N:6][C:5]1=[O:16].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:29][O:28][C:24]1[CH:23]=[C:22]2[C:27]([C:18]([O:1][CH2:2][CH2:3][N:4]3[CH:9]=[C:8]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:7]=[N:6][C:5]3=[O:16])=[CH:19][CH:20]=[N:21]2)=[CH:26][CH:25]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 2734941(1,1'-Binaphthalen)-2-yldi-tert-butylphosphineHCID 106078294-Chloro-7-methoxyquinolineHCID 598429971-(2-hydroxyethyl)-5-phenylpyrimidin-2(1H)-one

Product 1

HCID 598430371-(2-(7-methoxyquinolin-4-yloxy)ethyl)-5-phenylpyrimidin-2(1H)-oneYield 31%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

To a 10 mL round bottomed flask was added 1-(2-hydroxyethyl)-5-phenylpyrimidin-2(1H)-one (0.043 g, 0.20 mmol), 4-chloro-7-methoxyquinoline (0.042 g, 0.22 mmol), toluene (2.0 mL) and cesium carbonate (0.071 g, 0.22 mmol). The reaction was carefully evacuated and then backfilled with N2. This was repeated twice. Then racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (0.020 g, 0.050 mmol) and palladium(II) acetate (0.0089 g, 0.040 mmol) were added. The reaction was again carefully evacuated and then backfilled with N2. This was repeated twice. The mixture was then heated at 80° C. for 3 h. After cooling to room temperature, the mixture was poured into aq. NaHCO3 (50 mL) and extracted with EtOAc (100 mL). This produced a bad emulsion so the mixture was filtered through Celite. The Celite plug was eluted with 10% MeOH/CH2Cl2 and the aqueous phase was extracted with 25% iPrOH/CHCl3. The EtOAc extract, MeOH/CH2Cl2 eluent and the iPrOH/CHCl3 extracts were combined, dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (0 to 1% MeOH (2M in NH3)/CH2Cl2 afforded 1-(2-(7-methoxyquinolin-4-yloxy)ethyl)-5-phenylpyrimidin-2(1H)-one (0.023 g, 31% yield) as an off-white solid. MS (ESI, pos. ion.) m/z: 374 (MH+). Calc'd exact mass for C22H19N3O3: 373. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.87 (s, 3 H), 4.50 (t, J=4.8 Hz, 2 H), 4.59 (t, J=4.9 Hz, 2 H), 6.93 (d, J=5.3 Hz, 1 H), 7.02 (dd, J=9.2, 2.5 Hz, 1 H), 7.29 (d, J=2.5 Hz, 1 H), 7.37 (t, J=7.3 Hz, 1 H), 7.47 (t, J=7.6 Hz, 2 H), 7.60 (d, J=7.4 Hz, 2 H), 8.00 (d, J=9.2 Hz, 1 H), 8.63 (d, J=5.1 Hz, 1 H), 8.81 (d, J=3.5 Hz, 1 H), 8.97 (d, J=3.5 Hz, 1 H).

Workup

  1. customThe reaction was carefully evacuated
  2. customThe reaction was again carefully evacuated
  3. temperatureAfter cooling to room temperature
  4. additionthe mixture was poured into aq. NaHCO3 (50 mL)
  5. extractionextracted with EtOAc (100 mL)
  6. customThis produced a bad emulsion so the mixture
  7. filtrationwas filtered through Celite
  8. washThe Celite plug was eluted with 10% MeOH/CH2Cl2
  9. extractionthe aqueous phase was extracted with 25% iPrOH/CHCl3
  10. extractionThe EtOAc extract
  11. dry with materialdried (Na2SO4)
  12. concentrationconcentrated onto silica
  13. customPurification by silica gel chromatography (0 to 1% MeOH (2M in NH3)/CH2Cl2

Sources & evidence

ORD record
ord-55233ff54f6240ba80aaf76e50ccccec
Source dataset
uspto-grants-2012_11
Patent number
US08314087B2

Reaction notes

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