反应详情

To a solution of 4-methoxybenzyl 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (681 mg) in N-methylmorpholine (2 ml) was added 1,3-bis(trimethylsilyl)urea (1.02 g) and the mixture was stirred at room temperature for 30 minutes. To the solution was added potassium iodide (183 mg) and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added di-tert-butyl {(Z)-[((1S)-1-{[(tert-butoxycarbonyl)amino]methyl}-2-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-2-oxoethyl)amino]methylylidene}biscarbamate (939 mg) and the whole mixture was stirred at 35° C. overnight. To the resulting reaction mixture was added ethyl acetate (1.7 L) and the mixture was washed successively with water, 10% aqueous sodium thiosulfate solution, 10% aqueous sodium trifluoroacetate solution and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated to about 1 L in vacuo. The concentrate was poured into diisopropyl ether and the resulting precipitate was collected by filtration and dried in vacuo. To a solution of the solid in methylene chloride (3.6 ml) were added anisole (1.2 ml) and trifluoroacetic acid (3.6 ml). The resulting solution was stirred at room temperature for 4 hours and poured into diisopropyl ether. The resulting precipitate was collected by filtration and dried in vacuo to give a crude product. The crude product was purified by preparative HPLC utilizing ODS column. The eluate containing a desired product was concentrated to about 30 ml in vacuo. The concentrate was adjusted to about pH 3 by addition of concentrated hydrochloric acid and chromatographed on Diaion (registered trademark) HP-20 eluting with 30% aqueous 2-propanol. The eluate was concentrated to about 30 ml in vacuo and 1 equivalent of 0.1M aqueous sulfuric acid solution was added. The mixture was lyophilized to give 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(3-amino-4-{[(2S)-3-amino-2-(guanidino)propanoyl]amino}-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylic acid hydrogensulfate (115 mg) as an amorphous solid.

1. stirringthe mixture was stirred at room temperature for 30 minutes
2. stirringthe whole mixture was stirred at 35° C. overnight
3. customTo the resulting reaction mixture
4. washthe mixture was washed successively with water, 10% aqueous sodium thiosulfate solution, 10% aqueous sodium trifluoroacetate solution and brine
5. dry with materialdried over magnesium sulfate
6. filtrationfiltered
7. concentrationThe filtrate was concentrated to about 1 L in vacuo
8. additionThe concentrate was poured into diisopropyl ether
9. filtrationthe resulting precipitate was collected by filtration
10. customdried in vacuo
11. additionTo a solution of the solid in methylene chloride (3.6 ml) were added anisole (1.2 ml) and trifluoroacetic acid (3.6 ml)
12. stirringThe resulting solution was stirred at room temperature for 4 hours
13. additionpoured into diisopropyl ether
14. filtrationThe resulting precipitate was collected by filtration
15. customdried in vacuo
16. customto give a crude product
17. customThe crude product was purified by preparative HPLC
18. additionThe eluate containing a desired product
19. concentrationwas concentrated to about 30 ml in vacuo
20. additionThe concentrate was adjusted to about pH 3 by addition of concentrated hydrochloric acid
21. customchromatographed on Diaion (registered trademark)
22. washeluting with 30% aqueous 2-propanol
23. additionwas added