Cesium carbonate → tert-Butyl 2-(4-(6-Bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)phenyl)-4-methyl-3-oxopiperazine-1-carboxylate

HRID 1772080Notes

Reaction equation

HRID 1772080 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13](=[O:14])[N:12]([CH3:15])[CH2:11][CH2:10][N:9]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:4][CH:3]=1.Br[C:24]1[C:25](=[O:32])[N:26]([CH3:31])[CH:27]=[C:28]([Br:30])[N:29]=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:30][C:28]1[N:29]=[C:24]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[C:13](=[O:14])[N:12]([CH3:15])[CH2:11][CH2:10][N:9]3[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:4][CH:3]=2)[C:25](=[O:32])[N:26]([CH3:31])[CH:27]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 130629693,5-Dibromo-1-methyl-1H-pyrazin-2-oneHCID 66634693Tert-butyl 2-(4-aminophenyl)-4-methyl-3-oxopiperazine-1-carboxylate

Product 1

HCID 86699861tert-Butyl 2-(4-(6-Bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)phenyl)-4-methyl-3-oxopiperazine-1-carboxylateYield 60%

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, nitrogen inlet and reflux condenser was charged with tert-butyl 2-(4-aminophenyl)-4-methyl-3-oxopiperazine-1-carboxylate 102j (880 mg, 2.88 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (770 mg, 2.88 mmol), cesium carbonate (2.06 g, 6.34 mmol) and 1,4-dioxane (20 mL). After bubbling nitrogen through the resulting solution for 30 minutes, Xantphos (166 mg, 0.288 mmol) and tris(dibenzylidene acetone)dipalladium(0) (47 mg, 0.144 mmol) were added and the reaction mixture was heated at reflux for 18 h. After this time the reaction was cooled to room temperature, partitioned between ethyl acetate (50 mL) and water (50 mL), and filtered, and the filter cake was washed with ethyl acetate (2×25 mL). The organic layer was separated, washed with brine (50 mL) and dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography to afford 102k (850 mg, 60%) as an orange foam: 1H NMR (300 MHz, CDCl3) δ 7.28 (s, 1H), 7.16 (d, 2H, J=8.4 Hz), 6.65 (d, 2H, J=8.4 Hz), 5.65 (s, 1H), 4.02 (m, 1H), 3.51 (m, 1H), 3.30 (m, 3H), 3.05 (s, 3H), 1.47 (s, 9H), MS (ESI+) m/z 492.1 (M+H).

Workup

  1. customA 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet
  2. temperaturereflux condenser
  3. customAfter bubbling nitrogen through the resulting solution for 30 minutes
  4. temperaturethe reaction mixture was heated
  5. temperatureat reflux for 18 h
  6. custompartitioned between ethyl acetate (50 mL) and water (50 mL)
  7. filtrationfiltered
  8. washthe filter cake was washed with ethyl acetate (2×25 mL)
  9. customThe organic layer was separated
  10. washwashed with brine (50 mL)
  11. dry with materialdried over magnesium sulfate
  12. customThe drying agent was removed by filtration
  13. concentrationthe filtrate concentrated under reduced pressure
  14. customThe residue was purified by column chromatography

Sources & evidence

ORD record
ord-78890f672d5f41a08e3d9ffa12df9b61
Source dataset
uspto-grants-2016_02
Patent number
US09249123B2

Reaction notes

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