Phosphorus oxychloride → Benzhydryl 7-[2-(2-formamido-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylate

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Reaction Steps

Vilsmeier reagent prepared from N,N-dimethylformamide (0.42 ml) and phosphorus oxychloride (0.527 ml) was suspended in dry tetrahydrofuran (30.5 ml). To a suspension was added 2-(2-formamido-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid (syn isomer, 2.8 g) under ice-cooling with stirring and then the solution was stirred at the same temperature for an hour to prepare the activated acid solution. To the solution of benzhydryl 7-amino-3-ethylthio-3-cephem-4-carboxylate hydrochloride (2.0 g) and monotrimethylsilylacetamide (5.7 g) in methylene chloride (40 ml) was added the activated acid solution obtained above all at once at -0° C. and the mixed solution was stirred at -20° to -10° C. for an hour. After water and ethyl acetate (150 ml) were added to the resultant solution, the mixture was adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give benzhydryl 7-[2-(2-formamido-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylate (syn isomer, 12.8 g), mp. 143° to 148° C.

Provenance & Evidence