Sulfuric Acid → (S)-ethyl 6-(2-ethoxy-2-oxoacetyl)-2-ethyl-8-methoxy-4-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate

HRID 1019827Notes

Reaction equation

HRID 1019827 reaction equation
Br[C:2]1[N:6]2[C@@H:7]([CH3:14])[CH2:8][N:9]([CH2:12][CH3:13])[C:10](=[O:11])[C:5]2=[C:4]([O:15][CH3:16])[C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].C([Li])CCC.[C:27](OCC)(=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29].OS(O)(=O)=O>C1COCC1>[CH2:31]([O:30][C:28](=[O:29])[C:27]([C:2]1[N:6]2[C@@H:7]([CH3:14])[CH2:8][N:9]([CH2:12][CH3:13])[C:10](=[O:11])[C:5]2=[C:4]([O:15][CH3:16])[C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:33])[CH3:32]

Participants

6

Reactant 4

HCID 1118Sulfuric AcidHCID 7268Diethyl OxalateHCID 86624798(S)-Ethyl 6-bromo-2-ethyl-8-methoxy-4-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylateHCID 178418339Butyllithium

Product 1

HCID 68230591(S)-ethyl 6-(2-ethoxy-2-oxoacetyl)-2-ethyl-8-methoxy-4-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylateYield 67%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
20 °C

Procedure

(S)-Ethyl 6-bromo-2-ethyl-8-methoxy-4-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (0.70 mol) was dissolved in THF (4500 ml) at 20° C. Molecular sieves (4 Å; 250 g) were added. The mixture was stirred for 30 min at 20° C., and was then cooled to −78° C. A solution of n-Butyllithium (2.5 M; 0.77 mol) was added dropwise below −65° C. The mixture was stirred for 1 h at −78° C. Diethyl oxalate (1.6 mol) in THF (600 ml) was added dropwise below −65° C. and then it was stirred for 3 h. The mixture was poured into a solution of aqueous H2SO4 (4200 ml, 2 M) and THF (3500 ml). The organic layer was separated and the aqueous layer was re-extracted with ethyl acetate (3×2000 ml). The combined organic layers were collected and evaporated. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 100:0 to 1:1). The pure fractions were collected and the organic solvent was evaporated. Yield: 170 g (67% yield).

Workup

  1. additionMolecular sieves (4 Å; 250 g) were added
  2. temperaturewas then cooled to −78° C
  3. stirringThe mixture was stirred for 1 h at −78° C
  4. stirringit was stirred for 3 h
  5. customThe organic layer was separated
  6. extractionthe aqueous layer was re-extracted with ethyl acetate (3×2000 ml)
  7. customThe combined organic layers were collected
  8. customevaporated
  9. customThe residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 100:0 to 1:1)
  10. customThe pure fractions were collected
  11. customthe organic solvent was evaporated

Sources & evidence

ORD record
ord-780802e5d44f4654b3d56db53b69a961
Source dataset
uspto-grants-2014_05
Patent number
US08716293B2

Reaction notes

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