Phosphorus oxychloride → 7-[2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid

HRID 1074764Notes

Reaction equation

HRID 1074764 reaction equation
[NH2:1][CH:2]1[C:12](=[O:13])[N:4]2[C:5]([C:9]([OH:11])=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12.C(=O)(O)[O-].[Na+].P(Cl)(Cl)(Cl)=O.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=[N:34][O:35][CH3:36])[C:31](O)=[O:32])[N:29]=1.C[Si](CC(N)=O)(C)C>O.CC(C)=O.C(OCC)(=O)C.CN(C)C=O>[NH2:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=[N:34][O:35][CH3:36])[C:31]([NH:1][CH:2]2[C:12](=[O:13])[N:4]3[C:5]([C:9]([OH:11])=[O:10])=[CH:6][CH2:7][S:8][C@H:3]23)=[O:32])[N:29]=1

Participants

10

Reactant 5

HCID 24813Phosphorus oxychloride2×HCID 1252162-(2-Aminothiazole-4-yl)-2-methoxyiminoacetic acidHCID 357676Acetamide, 2-(trimethylsilyl)-HCID 516892Sodium BicarbonateHCID 12941984(6R)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid2×

Product 1

HCID 1317124447-[2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acidYield 61.4%

Reagents, catalysts & solvents 4

HCID 180AcetoneSolventHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent3×

Procedure

7-Amino-3-cephem-4-carboxylic acid (1.7 g.) and sodium bicarbonate (2.84 g.) were dissolved in a mixture of water (35 ml.) and acetone (35 ml.). On the other hand, phosphorus oxychloride (1.95 ml.) was added dropwise to a suspension of 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic acid (syn-isomer: 3.42 g.) in dry ethyl acetate (34 ml.) over 10 minutes at 0° to 6° C., and the mixture was stirred at the same temperature for 30 minutes. To the solution was added dropwise a solution of trimethylsilylacetamide (2.39 g.) in ethyl acetate (5 ml.) at 0° to 6° C. over 20 minutes, and the mixture was stirred for 20 minutes. After phosphorus oxychloride (1.95 ml.) was added dropwise to the mixture at the above temperature over 10 minutes, the mixture obtained thus was stirred for 30 minutes. And further, dimethylformamide (1.29 ml.) was added dropwise to the mixture over 10 minutes at the same temperature and stirred for one hour to give a clear solution. The solution was added dropwise to the solution of 7-amino-3-cephem-4-carboxylic acid at -5° to 5° C., over 30 minutes, at pH 6.5 to 7.5, and the reaction mixtures was stirred for one hour at the same temperature. Ethyl acetate (200 ml.) was added to the resultant solution, and the aqueous layer was separated, washed with methylene chloride, bubbled with nitrogen gas and adjusted to pH 4 with acetic acid. The solution was subjected to column chromatography on macroporous, non-ionic adsorption resin "Diaion HP-20" (Trade mark: manufactured by Mitsubishi Chemical Industries Ltd.) and eluted with 20% aqueous solution of isopropyl alcohol. The eluate was concentrated under reduced pressure and lyophilized to give 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer: 2.0 g.). The product was identified with the authentic sample by IR and NMR spectrum.

Workup

  1. stirringthe mixture was stirred for 20 minutes
  2. customthe mixture obtained thus
  3. stirringwas stirred for 30 minutes
  4. stirringstirred for one hour
  5. customto give a clear solution
  6. customthe reaction mixtures
  7. stirringwas stirred for one hour at the same temperature
  8. customthe aqueous layer was separated
  9. washwashed with methylene chloride
  10. custombubbled with nitrogen gas
  11. washeluted with 20% aqueous solution of isopropyl alcohol
  12. concentrationThe eluate was concentrated under reduced pressure

Sources & evidence

ORD record
ord-304f863e9233460f8520b823d53cce13
Source dataset
uspto-grants-1983_07
Patent number
US04393059

Reaction notes

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