反应详情

To a suspension of Vilsmeier reagent prepared from N,N-dimethylformamide (0.158 ml) and phosphoryl chloride (0.187 ml) in tetrahydrofuran (1 ml) was added a solution of 4-chloro-2-difluoromethoxyimino-3-oxobutyric acid (0.4 g) in tetrahydrofuran (4 ml) under ice-cooling with stirring. After stirred at the same temperature for 30 minutes, this activated acid solution was added to a solution of bis(trifluoroacetic acid) salt of 7β-amino-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (0.80 g) and N-(trimethylsilyl)acetamide (2.9 g) in tetrahydrofuran (20 ml) under ice-cooling. The mixture was stirred at the same temperature for 1.5 hours. To the resultant mixture was added a solution of thiourea (230 mg) in N,N-dimethylacetamide (2.3 ml) at ambient temperature. After stirred at 30°-35° C. for 4 hours, the resultant solution was poured into a mixture of n-hexane (30 ml) and diisopropyl ether (50 ml). The precipitated mass was triturated in ethyl acetate and dried under reduced pressure. The dried glassy mass was dissolved in water (20 ml) and the aqueous solution was washed with ethyl acetate twice, adjusted to pH 2.0 with 5% aqueous sodium bicarbonate solution, and subjected to column chromatography on macroporous nonionic adsorption resin "Diaion HP-20". The column was washed with water and the object compound was eluted with 30% aqueous methanol. The fraction containing the object compound was concentrated under reduced pressure and the residue was lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-(difluoromethoxyimino)acetamido]-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer) (0.25 g).

1. temperaturecooling
2. stirringAfter stirred at the same temperature for 30 minutes
3. temperaturecooling
4. stirringThe mixture was stirred at the same temperature for 1.5 hours
5. stirringAfter stirred at 30°-35° C. for 4 hours
6. customThe precipitated mass was triturated in ethyl acetate
7. customdried under reduced pressure
8. dissolutionThe dried glassy mass was dissolved in water (20 ml)
9. washthe aqueous solution was washed with ethyl acetate twice
10. washThe column was washed with water
11. washthe object compound was eluted with 30% aqueous methanol
12. additionThe fraction containing the object compound
13. concentrationwas concentrated under reduced pressure