反应详情

温度

-40 °C

To dimethylformamide (2.24 g.) was dropwise added phosphorus oxychloride (2.36 g.) over 10 minutes under stirring and ice-cooling, and the mixture was stirred for 30 minutes at 40° C. To the mixture was added ethyl acetate (40 ml.), and the mixture was cooled at -20° to -15° C. with stirring. To the mixture was added 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylic acid, which can be represented as 2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylic acid, (4.0 g.) and the mixture was stirred for 30 minutes at the same temperature. Thus obtained mixture was added to the solution, which was prepared by stirring the mixture of bis(trimethylsilyl)acetamido (15 ml.) and 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-amino-3-cephem-4-carboxylic acid (6.35 g.) in ethyl acetate (50 ml.) at room temperature for 10 minutes, by adding dimethylformamide (6 ml.) thereto and then cooling to -40° C. The solution was stirred for 30 minutes at -40° C. and for 30 minutes at -20° C., and then the reaction mixture was poured into 5% sodium bicarbonate aqueous solution. The aqueous layer was separated from the mixture, washed with ethyl acetate, and the precipitates were filterred. The precipitates were washed with a mixture of acetone and water, and the washings were extracted with ethyl acetate, and then the extract was washed with sodium chloride aqueous solution and water in turn. On the other hand, to the aqueous filtrate was added ethyl acetate, and the mixture was adjusted to pH 1 to 2. The ethyl acetate layer was separated from the mixture and combined with the above obtained ethyl acetate extract together. The combined ethyl acetate layer was washed with water, dried over magnesium sulfate and then treated with activated charcoal. After distillation of the solvent from the ethyl acetate layer, the remaining residue was pulverized in diethyl ether, collected by filtration and then dried to give yellowish brown powder of 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid which can be represented as 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, (3.2 g.).

1. customover 10 minutes
2. temperatureice-cooling
3. stirringthe mixture was stirred for 30 minutes at 40° C
4. temperaturethe mixture was cooled at -20° to -15° C.
5. stirringwith stirring
6. stirringthe mixture was stirred for 30 minutes at the same temperature
7. additionThus obtained mixture was added to the solution, which
8. customwas prepared
9. stirringby stirring
10. stirringThe solution was stirred for 30 minutes at -40° C. and for 30 minutes at -20° C.
11. customThe aqueous layer was separated from the mixture
12. washwashed with ethyl acetate
13. washThe precipitates were washed with a mixture of acetone and water
14. extractionthe washings were extracted with ethyl acetate
15. washthe extract was washed with sodium chloride aqueous solution and water in turn
16. additionOn the other hand, to the aqueous filtrate was added ethyl acetate
17. customThe ethyl acetate layer was separated from the mixture
18. customabove obtained ethyl acetate
19. extractionextract together
20. washThe combined ethyl acetate layer was washed with water
21. dry with materialdried over magnesium sulfate
22. additiontreated with activated charcoal
23. distillationAfter distillation of the solvent from the ethyl acetate layer
24. filtrationcollected by filtration
25. customdried