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

HRID 519292Notes

Reaction equation

HRID 519292 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])[C@H:10]([CH3:21])[CH2:9]2)=[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>[Br:29][C:27]1[CH:28]=[C:23]([NH:1][C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:10]([CH3:21])[CH2:9]3)=[CH:4][CH:3]=2)[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=1

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 49840989(R)-tert-Butyl 4-(6-aminopyridin-3-yl)-2-methylpiperazine-1-carboxylate

Product 1

HCID 86683712(R)-tert-Butyl 4-(6-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino) pyridine-3-yl)-2-methylpiperazine-1-carboxylateYield 48.3%

Reagents, catalysts & solvents 2

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

Procedure

A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (15 mL), 108b (800 mg, 2.7 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (720 mg, 2.7 mmol), and cesium carbonate (1.76 g, 5.4 mmol). After bubbling nitrogen through the suspension for 3 minutes, Xantphos (78 mg, 0.14 mmol) and tris(dibenzylideneacetone)dipalladium(0) (128 mg, 0.14 mmol) were added. The system was subject to three cycles of vacuum/argon flash and heated at reflux for 3 h. It was then cooled to room temperature and filtered. The filtrate was partitioned between ethyl acetate (30 mL) and water (30 mL). The aqueous layer was separated and extracted with ethyl acetate (50 mL×2). The combined organic layer was washed with brine (50 mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on flash column chromatography eluting with 10:1 dichloromethane/methanol to afford 108c as a yellow solid (624 mg, 47%). LCMS: [M+H]+ 480

Workup

  1. customA 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser
  2. customAfter bubbling nitrogen through the suspension for 3 minutes
  3. temperatureheated
  4. temperatureat reflux for 3 h
  5. filtrationfiltered
  6. customThe filtrate was partitioned between ethyl acetate (30 mL) and water (30 mL)
  7. customThe aqueous layer was separated
  8. extractionextracted with ethyl acetate (50 mL×2)
  9. washThe combined organic layer was washed with brine (50 mL)
  10. dry with materialdried over anhydrous 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 chromatography
  14. washeluting with 10:1 dichloromethane/methanol

Sources & evidence

ORD record
ord-a6306891705e4bec943b6c15b3ba490e
Source dataset
uspto-grants-2015_08
Patent number
US09115152B2

Reaction notes

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