Phosphorus oxychloride → Benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-allyloxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate

Participants

Reaction Conditions

Reaction Steps

Phosphorus oxychloride (7.0 ml) was added under ice-cooling to a solution of N,N-dimethylformamide (5.8 ml) in tetrahydrofuran (11 ml). The mixture was cooled until the precipitate appeared. Tetrahydrofuran (107 ml) was then added to this mixture, and the mixture was stirred for 20 minutes at 0° C. 2-(2-Formamidothiazol-4-yl)-2-allyloxyiminoacetic acid (syn isomer) (13.2 g) was added to the mixture. The resultant mixture was stirred at 0° C. to give an activated acid solution. On the other hand, to a suspension of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate monohydrochloride (20 g) in tetrahydrofuran (200 ml) was added bis(trimethylsilyl)urea (36.2 g) at ambient temperature. The mixture was stirred at 36°-38° C. for 40 minutes to give a clear solution. To this solution was added the activated acid solution obtained above at once at -20° C. The mixture was stirred at -20°~12° C. for 40 minutes. To this mixture was added a mixture of ethyl acetate (700 ml) and water. The separated organic layer was washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate and concentrated to give a solid. The solid was recrystallized from diisopropyl ether to give benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-allyloxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (25.5 g).

Provenance & Evidence