Dimethylformamide → 5-bromo-1-methyl-3-(pyrimidin-4-ylamino)pyridin-2(1H)-one

HRID 592666Notes

Reaction equation

HRID 592666 reaction equation
Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.N[C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C[N:67](C=O)C>C(Cl)Cl.CO.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].O1CCOCC1>[Br:8][C:6]1[CH:7]=[C:2]([NH:67][C:14]2[CH:15]=[CH:16][N:17]=[CH:12][N:13]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1

Participants

10

Reactant 5

HCID 6228DimethylformamideHCID 79782-AminopyrimidineHCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 36143503,5-Dibromo-1-methylpyridin-2(1H)-one

Product 1

HCID 580440945-bromo-1-methyl-3-(pyrimidin-4-ylamino)pyridin-2(1H)-oneYield 58%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolventHCID 21226129Dichloromethane methanolSolvent

Conditions

Temperature
100 °C

Procedure

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 3,5-dibromo-1-methylpyridin-2(1H)-one (2.00 g, 21.0 mmol), 2-aminopyrimidine (5.61 g, 21.0 mmol), cesium carbonate (13.7 g, 42.1 mmol), DMF (5 mL) and 1,4-dioxane (70 mL). After bubbling nitrogen through the resulting suspension for 30 min, Xantphos (1.10 g, 1.89 mmol) and tris(dibenzylideneacetone)dipalladium(0) (963 mg, 1.05 mmol) were added. A reflux condenser was attached to the flask, and the reaction mixture was heated at 100° C. for 4 h. After this time, the mixture was cooled to room temperature and diluted with 90:10 methylene chloride/methanol (150 mL) and water (100 mL), and the layers were separated. The aqueous layer was extracted with 90:10 methylene chloride/methanol (50 mL), and the combined organic layers were washed with brine and dried over sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (silica, 90:10 methylene chloride/methanol) to afford 142a in 58% yield (3.42 g) as an amorphous light green solid: mp 217-219° C.; 1H NMR (500 MHz, CDCl3) δ 9.29 (s, 1H), 8.77 (s, 1H), 8.72 (d, J=2.5 Hz, 1H), 8.36 (d, J=6.0 Hz, 1H), 7.69 (d, J=2.5 Hz, 1H), 7.37 (dd, J=5.5, 1.0 Hz, 1H), 3.53 (s, 3H); LCMS (ESI+) m/z 281.0 (M+H).

Workup

  1. customA 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet
  2. customAfter bubbling nitrogen through the resulting suspension for 30 min
  3. customA reflux condenser was attached to the flask
  4. temperatureAfter this time, the mixture was cooled to room temperature
  5. customthe layers were separated
  6. extractionThe aqueous layer was extracted with 90:10 methylene chloride/methanol (50 mL)
  7. washthe combined organic layers were washed with brine
  8. dry with materialdried over sodium sulfate
  9. customThe drying agent was removed by filtration
  10. concentrationThe filtrate was concentrated under reduced pressure
  11. customthe resulting residue was purified by flash column chromatography (silica, 90:10 methylene chloride/methanol)

Sources & evidence

ORD record
ord-6392322d6c92401e81e1394f6f41a260
Source dataset
uspto-grants-2016_01
Patent number
US09238655B2

Reaction notes

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