Phosphorus oxychloride → Benzhydryl 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylate-1-oxide

HRID 434869Notes

Reaction equation

HRID 434869 reaction equation
[NH2:1][CH:2]1[C:37](=[O:38])[N:4]2[C:5]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[C:6]([CH2:10][O:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])[CH2:7][S:8](=[O:9])[C@H:3]12.C[Si](CC(N)=O)(C)C.[CH3:47][O:48][N:49]=[C:50]([C:54]1[N:58]=[C:57]([NH2:59])[S:56][N:55]=1)[C:51](O)=[O:52].P(Cl)(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.CN(C)C=O>[CH3:47][O:48][N:49]=[C:50]([C:54]1[N:58]=[C:57]([NH2:59])[S:56][N:55]=1)[C:51]([NH:1][CH:2]1[C:37](=[O:38])[N:4]2[C:5]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])=[C:6]([CH2:10][O:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])[CH2:7][S:8](=[O:9])[C@H:3]12)=[O:52]

Participants

9

Reactant 5

HCID 24813Phosphorus oxychlorideHCID 357676Acetamide, 2-(trimethylsilyl)-HCID 516892Sodium BicarbonateHCID 533952072-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetic acidHCID 70526114Benzhydryl 7-amino-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylate-1-oxide

Product 1

HCID 131712704Benzhydryl 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylate-1-oxideYield 72.8%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent3×

Procedure

A mixture of benzhydryl 7-amino-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylate-1-oxide (1.33 g) and trimethylsilylacetamide (0.65 g) in dry methylene chloride (40 ml) was stirred for 2.5 hours at room temperature and then cooled to -20° C. (A solution). On the other hand, to a mixture of 2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (0.50 g) in dry methylene chloride (12.5 ml) was added phosphorus oxychloride (1.6 ml) under ice-water cooling followed by stirring for 2 hours at room temperature. To the mixture was added a solution of N,N-dimethylformamide (0.99 ml) in dry methylene chloride (2 ml) followed by stirring for 50 minutes under ice-water cooling. Thus obtained solution was added to the A solution obtained above, followed by stirring for an hour at -30° to -20° C. The reaction mixture was poured into a mixture of a saturated aqueous solution of sodium bicarbonate (35 ml) and water (35 ml). The methylene chloride layer was separated therefrom and the remaining aqueous layer was further extracted with methylene chloride (50 ml×2). The methylene chloride layer and the extract were combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated charcoal and evaporated under reduced pressure. The residue was washed with diethyl ether and dried to give benzhydryl 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylate-1-oxide (syn isomer) (1.3 g).

Workup

  1. temperaturecooled to -20° C. (A solution)
  2. stirringby stirring for 2 hours at room temperature
  3. stirringby stirring for 50 minutes under ice-water cooling
  4. additionThus obtained solution was added to the A solution
  5. customobtained above,
  6. stirringby stirring for an hour at -30° to -20° C
  7. customThe methylene chloride layer was separated
  8. extractionthe remaining aqueous layer was further extracted with methylene chloride (50 ml×2)
  9. washwashed with a saturated aqueous solution of sodium chloride
  10. dry with materialdried over magnesium sulfate
  11. additiontreated with activated charcoal
  12. customevaporated under reduced pressure
  13. washThe residue was washed with diethyl ether
  14. customdried

Sources & evidence

ORD record
ord-a4cf797d7cf7494ca75269c59e6ff1e1
Source dataset
uspto-grants-1983_08
Patent number
US04399278

Reaction notes

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