Cesium carbonate → (R)-tert-Butyl 4-(6-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-3-yl)-3-methylpiperazine-1-carboxylate

HRID 1026420Notes

Reaction equation

HRID 1026420 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+].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>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>[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 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 36143503,5-Dibromo-1-methylpyridin-2(1H)-oneHCID 86683717(R)-tert-Butyl 4-(6-Aminopyridin-3-yl)-3-methylpiperazine-1-carboxylate

Product 1

HCID 86683718(R)-tert-Butyl 4-(6-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-3-yl)-3-methylpiperazine-1-carboxylateYield 67.6%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

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), 109b (1.0 g, 3.4 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (2.7 g, 10.2 mmol), and cesium carbonate (2.2 g, 6.8 mmol). After bubbling nitrogen through the resulting mixture for 30 minutes, XantPhos (198 mg, 0.34 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (313 mg, 0.34 mmol) were added, and the reaction mixture was heated at 100° C. for 5 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous layer was separated and extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with brine (50 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 30:1 DCM/MeOH to afford 109c as a yellow solid (1.1 g, 63%). MS: [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. temperatureAfter this time the reaction was cooled to room temperature
  5. filtrationfiltered
  6. customThe filtrate was partitioned between ethyl acetate (100 mL) and water (100 mL)
  7. customThe aqueous layer was separated
  8. extractionextracted with ethyl acetate (100 mL×3)
  9. washThe combined organic layer was washed with brine (50 mL)
  10. dry with materialdried over sodium sulfate
  11. customThe drying agent was removed by filtration
  12. concentrationthe filtrate was concentrated under reduced pressure
  13. customThe residue was purified on flash column
  14. washeluting with 30:1 DCM/MeOH

Sources & evidence

ORD record
ord-8637383a43a1497493ba559a7a5b500c
Source dataset
uspto-grants-2014_05
Patent number
US08729072B2

Reaction notes

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