Cesium carbonate → 2-[2-(4-Fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(2-fluoropyridin-4-yl)-3H-pyrimidin-4-one

HRID 2278546Notes

Reaction equation

HRID 2278546 reaction equation
Cl[C:2]1[N:7]=[C:6]([CH2:8][C:9]([N:11]2[C:19]3[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[NH:5][C:4](=[O:21])[CH:3]=1.[F:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[CH2:13][CH2:12][N:11]2[C:9](=[O:10])[CH2:8][C:6]1[NH:5][C:4](=[O:21])[CH:3]=[C:2]([C:27]2[CH:26]=[CH:25][N:24]=[C:23]([F:22])[CH:28]=2)[N:7]=1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 120601642-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineHCID 1363786742-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-chloro-3H-pyrimidin-4-one

Product 1

HCID 1360984932-[2-(4-Fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(2-fluoropyridin-4-yl)-3H-pyrimidin-4-one

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

130 mg of 6-chloro-2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-3H-pyrimidin-4-one, 3 ml of 1,4-dioxane, 104 mg of 2-fluoropyridine-4-boronic acid pinacol ester, 50 mg of tetrakis(triphenylphosphine)palladium(0), and 0.58 ml of an aqueous 1.5 M cesium carbonate solution are successively placed in a three-necked round-bottomed flask under argon and with stirring. The mixture is heated at a temperature of 100° C. for 20 hours, and then filtered while hot. After cooling to ambient temperature, the filtrate is concentrated to dryness under reduced pressure. The residue is taken up in a mixture of 20 ml of dichloromethane and 30 ml of water. After settling out, the organic phase is separated and the aqueous phase is extracted with dichloromethane. The aqueous phase is concentrated to dryness under reduced pressure. The residue is taken up in a mixture of 30 ml of ethyl acetate and a few drops of ethanol, and then washed with 5 ml of water. After settling out, the organic phase is separated and the aqueous phase is extracted with 2×20 ml of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is taken up in 1 ml of dioxane and the mixture is refluxed, and then filtered through sintered glass. After drying of the isolated solid, 44 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(2-fluoropyridin-4-yl)-3H-pyrimidin-4-one are obtained in the form of a beige solid, the characteristics of which are the following:

Workup

  1. filtrationfiltered while hot
  2. temperatureAfter cooling to ambient temperature
  3. concentrationthe filtrate is concentrated to dryness under reduced pressure
  4. additionThe residue is taken up in a mixture of 20 ml of dichloromethane and 30 ml of water
  5. customthe organic phase is separated
  6. extractionthe aqueous phase is extracted with dichloromethane
  7. concentrationThe aqueous phase is concentrated to dryness under reduced pressure
  8. additionThe residue is taken up in a mixture of 30 ml of ethyl acetate and a few drops of ethanol
  9. washwashed with 5 ml of water
  10. customthe organic phase is separated
  11. extractionthe aqueous phase is extracted with 2×20 ml of ethyl acetate
  12. dry with materialdried over magnesium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated to dryness under reduced pressure
  15. temperaturethe mixture is refluxed
  16. filtrationfiltered through sintered glass
  17. dry with materialAfter drying of the isolated solid, 44 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(2-fluoropyridin-4-yl)-3H-pyrimidin-4-one
  18. customare obtained in the form of a beige solid

Sources & evidence

ORD record
ord-8c0a1a1c654f4764b3c25abb3929d3ec
Source dataset
uspto-grants-2015_09
Patent number
US09133168B2

Reaction notes

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