Methyl iodide → Ethyl 8-(benzyloxy)-2-methyl-1-oxo-6-propionyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate

HRID 494113Notes

Reaction equation

HRID 494113 reaction equation
[C:1]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]2=[C:6]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:3])[CH3:2].[CH3:28][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>CN(C=O)C.CC(OC)(C)C>[CH2:16]([O:15][C:6]1[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:4]([C:1](=[O:3])[CH2:2][CH3:28])[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]=12)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1

Participants

6

Reactant 3

HCID 6328Methyl iodideHCID 2733832Lithium HexamethyldisilazideHCID 68866335Ethyl 6-acetyl-8-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate

Product 1

HCID 68865236Ethyl 8-(benzyloxy)-2-methyl-1-oxo-6-propionyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 15413tert-Butyl methyl etherSolvent

Conditions

Temperature
-78 °C

Procedure

To a cold (−78° C.) solution of ethyl 6-acetyl-8-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (0.60 g, 1.62 mmol; Example 7, step 7) in anhydrous DMF (17 mL), a solution of lithium bis(trimethylsilyl)amide (1.94 mL, 1.94 mmol) in MTBE was added. The mixture was stirred at −78° C. for 15 minutes, treated with iodomethane (0.12 mL, 1.94 mmol), allowed to slowly warm up to room temperature, and stirred at the temperature overnight. The product mixture was concentrated under vacuum. The residue was partitioned between chloroform and dilute hydrochloric acid. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to preparation HPLC on C-18 stationary phase eluting with a gradient of methanol in water in the presence of ammonium acetate (1 g/L). Collection and concentration of appropriate fractions provided the title compound. The corresponding bis-methylated ketone was also isolated and was used for the preparation of Examples 60 & 61.

Workup

  1. temperatureto slowly warm up to room temperature
  2. stirringstirred at the temperature overnight
  3. concentrationThe product mixture was concentrated under vacuum
  4. customThe residue was partitioned between chloroform and dilute hydrochloric acid
  5. extractionThe organic extract
  6. washwas washed with brine
  7. dry with materialdried over anhydrous magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under vacuum
  10. customThe residue was subjected to preparation HPLC on C-18 stationary phase
  11. washeluting with a gradient of methanol in water in the presence of ammonium acetate (1 g/L)
  12. customCollection and concentration of appropriate fractions

Sources & evidence

ORD record
ord-d88115db248446278eb0b66357f2f58b
Source dataset
uspto-grants-2009_05
Patent number
US07538112B2

Reaction notes

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