Phosphorus oxychloride → 7beta-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(cyclopropyloxyimino)acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate

Participants

Reaction Steps

Phosphorous oxychloride (0.31 ml) was added to a mixture of N,N-dimethylformamide (0.25 ml) and ethyl acetate (1 ml) under ice-cooling. The mixture was stirred at the same temperature for 10 minutes to give a suspension. To the suspension was added 2-cyclopropyloxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (1.18 g) and tetrahydrofuran (15 ml) and the mixture was stirred under ice-cooling for 30 minutes to give an activated acid solution. On the other hand, to a suspension of 1- [(7β-amino-4-carboxy-3-cephem-3-yl)methyl]pyridinium chloride hydrochloride (1.3 g) in tetrahydrofuran (20 ml) was added N-trimethylsilyl-acetamide (8.5 g). The suspension was stirred at ambient temperature for an hour to give a clear solution. To the solution was added the activated acid solution prepared above at -30° C. and the mixture was stirred at -20° C. to -5° C. for 30 minutes and under ice-cooling for an hour. The mixture was poured into ethyl acetate (300 ml) to give precipitates. The precipitates were collected. To the precipitates was added a mixture of anisole (14 ml) and trifluoroacetic acid (4.3 ml) under ice-cooling. The mixture was stirred for 1.5 hours at ambient temperature. The mixture was concentrated in vacuo and poured into ice-water (50 ml). The mixture was adjusted to pH 5 with saturated aqueous solution of sodium bicarbonate. The aqueous solution was washed with ethyl acetate and subjected to column chromatography on a non-ionic adsorption resin "Diaion HP-20" (30 ml). After the column was washed with water, the elution was carried out with 2% isopropyl alcohol. The fractions containing the object compound were collected, combined, evaporated to remove isopropyl alcohol in vacuo, and finally lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol- 3-yl)-2-(cyclopropyloxyimino)acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer)(260 mg).

Provenance & Evidence