Phosphate → 7-Methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carbaldehyde

HRID 1158868Notes

Reaction equation

HRID 1158868 reaction equation
[N+](C1C=CC(COC(C2N3[C@H](SC=2)C(C(OC(=O)C)[C:21]2[N:22]=[C:23]4[CH2:28][N:27]([CH3:29])[C:26](=[O:30])[CH2:25][N:24]4[CH:31]=2)(Br)C3=O)=O)=CC=1)([O-])=O.P([O-])([O-])([O-])=O.[C:44](OCC)(=[O:46])C>C1COCC1.C(#N)C.[Zn]>[CH3:29][N:27]1[C:26](=[O:30])[CH2:25][N:24]2[C:31]([CH:44]=[O:46])=[CH:21][N:22]=[C:23]2[CH2:28]1

Participants

7

Reactant 3

HCID 1061PhosphateHCID 8857Ethyl AcetateHCID 68688112(5R,6RS)-6-[Acetoxy-(7-methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester

Product 1

HCID 219414297-Methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carbaldehyde

Reagents, catalysts & solvents 3

HCID 23994ZincCatalystHCID 6342AcetonitrileSolventHCID 8028TetrahydrofuranSolvent

Procedure

(5R,6RS)-6-[Acetoxy-(7-methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (481 mg) was dissolved in THF (6.7 mL) and acetonitrile (3.1 mL). Freshly activated Zn dust (1.92 g) and 0.5 M phosphate buffer (pH 6.5, 9.9 mL) were added to the mixture. The reaction vessel was covered with foil to exclude light. The reaction mixture was vigorously stirred for 2 h at room temperature. The reaction solution was mixed with ethyl acetate and filtered through a pad of Celite. The pad was washed with water and the aqueous layer was separated. The aqueous layer was cooled to 3° C. and 1 M NaOH was added to adjust pH to 8.0. The mixture was concentrated under high vacuum at 35° C. and lyophilized. The residue was separated by the preparative HPLC (Inertsil ODS-2, GL Science Inc., 10×250 mm, 0.05 mol/L phosphate buffer (pH 7.1): CH3CN=93:7, 4.0 mL/min.). The separated fractions of (5R),(6Z)-6-(7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt and (5R),(6E)-6-(7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt were cooled to 3° C. and 1 M NaOH was added to adjust pH to 8.0 respectively. Each solution was concentrated under high vacuum at 35° C. Each concentrate was applied to Diaion HP-21 (60 mL, Mitsubishi Kasei Co. Ltd.) resin column chromatography. After adsorbing, the column was eluted with water and then with 5% acetonitrile-water. The combined fractions were concentrated under high vacuum at 35° C. and lyophilized to give the title compound (5R),(6Z)-6-(7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt as a yellow amorphous solid (125 mg, 44.4%, Mp 115-117° C. (dec)) and compound (5R),(6E)-6-(7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt as yellow amorphous solid (19 mg, 6.7%) respectively.

Workup

  1. filtrationfiltered through a pad of Celite
  2. washThe pad was washed with water
  3. customthe aqueous layer was separated
  4. temperatureThe aqueous layer was cooled to 3° C.
  5. addition1 M NaOH was added
  6. concentrationThe mixture was concentrated under high vacuum at 35° C.
  7. customThe residue was separated by the preparative HPLC (Inertsil ODS-2, GL Science Inc., 10×250 mm, 0.05 mol/L phosphate buffer (pH 7.1): CH3CN=93:7, 4.0 mL/min.)
  8. temperatureThe separated fractions of (5R),(6Z)-6-(7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt and (5R),(6E)-6-(7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt were cooled to 3° C.
  9. addition1 M NaOH was added
  10. concentrationEach solution was concentrated under high vacuum at 35° C
  11. washthe column was eluted with water
  12. concentrationThe combined fractions were concentrated under high vacuum at 35° C.

Sources & evidence

ORD record
ord-aadc6e9120dc47538f317483db9879aa
Source dataset
uspto-grants-2010_10
Patent number
US07812014B2

Reaction notes

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