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

HRID 2278545Notes

Reaction equation

HRID 2278545 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.[CH3:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][N:24]=1.O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.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>[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]([CH3:22])[CH:28]=2)[N:7]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 312751,4-DioxaneHCID 164142742-Methylpyridine-4-boronic acid pinacol esterHCID 1363786742-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-chloro-3H-pyrimidin-4-one

Product 1

HCID 1360984922-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(2-methylpyridin-4-yl)-3H-pyrimidin-4-oneYield 32.4%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

120 mg of 6-chloro-2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-3H-pyrimidin-4-one, 96 mg of 2-methylpyridine-4-boronic acid pinacol ester, 45 mg of tetrakis(triphenylphosphine)palladium(0), 2.5 ml of 1,4-dioxane and 0.52 ml of an aqueous 1.5 M cesium carbonate solution are successively placed in a 5 ml microwave tube. The resulting suspension is stirred under microwave irradiation at a temperature of 100° C. for 2×1 hour. After cooling to ambient temperature, the reaction mixture is diluted with 6 ml of ethyl acetate and then filtered through Clarcel®. The solid is washed with 3 ml of ethyl acetate, and then the filtrate is treated with 12 ml of water and stirred at ambient temperature for 1.5 hours. After settling out, the organic phase is separated and the aqueous phase is extracted with 3×10 ml of ethyl acetate. The organic extracts are combined, washed with 10 ml of saturated brine, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 25 g cartridge of 15-40 μm silica, by making a solid deposit and eluting with a 95/5 v/v dichloromethane/methanol mixture at a flow rate of 25 ml/min. The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is taken up twice in diethyl ether, triturated, and then concentrated to dryness under reduced pressure. 46 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(2-methylpyridin-4-yl)-3H-pyrimidin-4-one are thus obtained in the form of a white crystalline powder, the characteristics of which are the following:

Workup

  1. temperatureAfter cooling to ambient temperature
  2. filtrationfiltered through Clarcel®
  3. washThe solid is washed with 3 ml of ethyl acetate
  4. additionthe filtrate is treated with 12 ml of water
  5. stirringstirred at ambient temperature for 1.5 hours
  6. customthe organic phase is separated
  7. extractionthe aqueous phase is extracted with 3×10 ml of ethyl acetate
  8. washwashed with 10 ml of saturated brine
  9. dry with materialdried over magnesium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated to dryness under reduced pressure
  12. customThe residue is purified by chromatography on a 25 g cartridge of 15-40 μm silica
  13. washeluting with a 95/5 v/v dichloromethane/methanol mixture at a flow rate of 25 ml/min
  14. additionThe fractions containing the desired product
  15. concentrationconcentrated to dryness under reduced pressure
  16. customtriturated
  17. concentrationconcentrated to dryness under reduced pressure

Sources & evidence

ORD record
ord-10c8b1e7a2544d7fbf2c6e764a56f723
Source dataset
uspto-grants-2015_09
Patent number
US09133168B2

Reaction notes

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