Cesium carbonate → (S)-3-[[5-(4-Boc-2-methyl-1-piperazinyl)-2-pyridyl]amino]-5-bromo-1-methylpyridin-2(1H)-one

HRID 1185037Notes

Reaction equation

HRID 1185037 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]2[CH3:21])=[CH:4][CH:3]=1.Br[C:23]1[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=[C:27]([Br:29])[CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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].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.O1CCOCC1>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[N:7][C:2]([NH:1][C:23]3[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=[C:27]([Br:29])[CH:28]=3)=[CH:3][CH:4]=2)[C@@H:9]([CH3:21])[CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 36143503,5-Dibromo-1-methylpyridin-2(1H)-oneHCID 86683730(3S)-tert-Butyl 4-(6-Aminopyridin-3-yl)-3-methylpiperazine-1-carboxylate

Product 1

HCID 86683729(S)-3-[[5-(4-Boc-2-methyl-1-piperazinyl)-2-pyridyl]amino]-5-bromo-1-methylpyridin-2(1H)-oneYield 83%

Reagents, catalysts & solvents 3

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Procedure

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (50 mL), 105b (4.0 g, 13.7 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (5.5 g, 20.8 mmol), and cesium carbonate (11 g, 35 mmol). After bubbling nitrogen through the resulting mixture for 30 minutes, XantPhos (272 mg, 0.47 mmol) and tris(dibenzylideneacetone)dipalladium(0) (430 mg, 0.47 mmol) were added, and the reaction mixture was heated at reflux for 3 h. After this time the reaction was cooled to room temperature, partitioned between ethyl acetate (300 mL) and water (300 mL), and filtered. The aqueous layer was separated and extracted with ethyl acetate (150 mL×2). The organic layers were combined, washed with brine (150 mL), and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on flash column eluting with 50:1 CH2Cl2/methanol to afford 105c as a yellow solid (5.4 g, 83%). LCMS: [M+H]+ 478

Workup

  1. customA 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer
  2. temperaturereflux condenser
  3. customAfter bubbling nitrogen through the resulting mixture for 30 minutes
  4. temperaturethe reaction mixture was heated
  5. temperatureat reflux for 3 h
  6. custompartitioned between ethyl acetate (300 mL) and water (300 mL)
  7. filtrationfiltered
  8. customThe aqueous layer was separated
  9. extractionextracted with ethyl acetate (150 mL×2)
  10. washwashed with brine (150 mL)
  11. dry with materialdried over sodium sulfate
  12. customThe drying agent was removed by filtration
  13. concentrationthe filtrate was concentrated under reduced pressure
  14. customThe residue was purified on flash column
  15. washeluting with 50:1 CH2Cl2/methanol

Sources & evidence

ORD record
ord-5276cafd05534b93960d86d540520ff4
Source dataset
uspto-grants-2014_03
Patent number
US08669251B2

Reaction notes

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