Diethyl (ethoxymethylene)malonate → Ethyl 8-hydroxy-2-methyl-1-oxo-3,4-dihydropyrrolo[1,2-a]pyrazine-7-carboxylate

HRID 494090Notes

Reaction equation

HRID 494090 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][C:3]1=[O:8].C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>C1(C)C=CC=CC=1>[OH:11][C:12]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:8])[C:4]=12

Participants

6

Reactant 4

HCID 6871Diethyl (ethoxymethylene)malonateHCID 8028TetrahydrofuranHCID 2733832Lithium HexamethyldisilazideHCID 43990421-Methylpiperazin-2-one

Product 1

HCID 59750503Ethyl 8-hydroxy-2-methyl-1-oxo-3,4-dihydropyrrolo[1,2-a]pyrazine-7-carboxylate

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 1-methylpiperazin-2-one (183 g, 1.6 mol) and diethyl ethoxymethylenemalonate (346 g, 1.6 mol) in toluene (12 L) was heated at 100° C. overnight. The resultant mixture was concentrated under vacuum. The residue was dissolved in anhydrous THF (8 L), brought to reflux under an atmosphere of nitrogen, and treated with a solution of lithium bis(trimethylsilyl)amide in THF (1 M, 1.05 eq). The reaction mixture was allowed to cool to room temperature and concentrated under vacuum. The residue was partitioned between methylene chloride and dilute aqueous HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with ethyl acetate, cooled to −20° C., and the solid precipitated was filtered to provide the title compound.

Workup

  1. concentrationThe resultant mixture was concentrated under vacuum
  2. dissolutionThe residue was dissolved in anhydrous THF (8 L)
  3. temperatureto reflux under an atmosphere of nitrogen
  4. temperatureto cool to room temperature
  5. concentrationconcentrated under vacuum
  6. customThe residue was partitioned between methylene chloride and dilute aqueous HCl
  7. extractionThe organic extract
  8. washwas washed with brine
  9. dry with materialdried over anhydrous magnesium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated under vacuum
  12. customThe residue was triturated with ethyl acetate
  13. temperaturecooled to −20° C.
  14. customthe solid precipitated
  15. filtrationwas filtered

Sources & evidence

ORD record
ord-1570a28d4e8d4c51806bbcdb25585ad5
Source dataset
uspto-grants-2009_05
Patent number
US07538112B2

Reaction notes

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