反应详情

To dimethylformamide (1.1 g.) was dropwise added phophorus oxychloride (1.5 g.) under stirring and ice-cooling, and the mixture was stirred for 30 minutes at 40° C. To the mixture was added ethyl acetate (10 ml.), and the mixture was cooled to -20° to -10° C. with stirring. To the mixture was added a solution of 2-hydroxy-2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetic acid, which can be represented as 2-hydroxy-2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetic acid, (1.1 g.) in ethyl acetate (15 ml.) below -20° C. under stirring, and then the mixture was stirred for 30 minutes at the same temperature. Thus obtained mixture was added all at once to the cooled solution prepared in the similar manner as in Example 1 from 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-amino-3-cephem-4-carboxylic acid (1.9 g.), bis(trimethylsilyl)acetamide (6 ml.) and ethyl acetate (20 ml.). The mixture was stirred for 30 minutes at -40° C. and further for 1.5 hours at -20° to -10° C. After the reaction, the reaction mixture was poured into 5% sodium bicarbonate aqueous solution, and the aqueous layer was separated. The remaining ethyl acetate layer was further extracted with 5% sodium bicarbonate aqueous solution. Thus obtained aqueous layer and the solution were combined together and washed with diethyl ether. To the aqueous layer was added ethyl acetate, and the mixture was adjusted to pH 1 to 2 with 10% hydrochloric acid and then the ethyl acetate layer was separated. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride and then dried over magnesium sulfate. After distillation of the solvent, the residue was pulverized in diethyl ether and then collected by filtration to give pale brown powder of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-formyloxy-2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-formyloxy-2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (0.86 g.).

1. temperatureice-cooling
2. stirringthe mixture was stirred for 30 minutes at 40° C
3. temperaturethe mixture was cooled to -20° to -10° C.
4. stirringwith stirring
5. stirringunder stirring
6. stirringthe mixture was stirred for 30 minutes at the same temperature
7. additionThus obtained mixture was added all at once to the cooled solution
8. stirringThe mixture was stirred for 30 minutes at -40° C. and further for 1.5 hours at -20° to -10° C
9. customAfter the reaction
10. customthe aqueous layer was separated
11. extractionThe remaining ethyl acetate layer was further extracted with 5% sodium bicarbonate aqueous solution
12. washwashed with diethyl ether
13. additionTo the aqueous layer was added ethyl acetate
14. customthe ethyl acetate layer was separated
15. washThe ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride
16. dry with materialdried over magnesium sulfate
17. distillationAfter distillation of the solvent
18. filtrationcollected by filtration