反应详情

To a solution of benzhydryl 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (5.82 g) in N,N-dimethylformamide (12 ml) was added sodium iodide (1.44 g). After stirring at room temperature for 1 hour, 4-(tert-butoxycarbonylaminomethyl)-5-(tritylamino)-1-[2-(trityloxy)ethyl]-1H-pyrazole (14.8 g) was added to the mixture. The stirring was continued at 35° C. for 24 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and added to diisopropyl ether (500 ml) dropwise. The resulting precipitate was collected by filtration. The filter cake was washed with diisopropyl ether and dried over phosphorous pentoxide in vacuo. The solid (15.6 g) was dissolved in dichloromethane (47 ml), and to the solution were added anisole (16 ml) and trifluoroacetic acid (32 ml) successively. After stirring at room temperature for 3 hours, the reaction mixture was poured into diisopropyl ether (500 ml). The precipitate was collected by filtration, washed with diisopropyl ether and dried over phosphorous pentoxide in vacuo. The crude product was dissolved in a phosphate buffer (pH 7.0) and purified by preparative HPLC (eluent: pH 7.0 phosphate buffer and acetonitrile). The eluate was subjected to column chromatography on Diaion® HP-20 (Mitsubishi Chemical Corporation) and freeze-dried to give 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[3-amino-4-aminomethyl-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (940 mg).

1. waitThe stirring was continued at 35° C. for 24 hours
2. extractionextracted with ethyl acetate
3. washThe organic layer was washed with brine
4. dry with materialdried over magnesium sulfate
5. filtrationfiltered
6. customevaporated in vacuo
7. dissolutionThe residue was dissolved in ethyl acetate (50 ml)
8. additionadded to diisopropyl ether (500 ml) dropwise
9. filtrationThe resulting precipitate was collected by filtration
10. washThe filter cake was washed with diisopropyl ether
11. dry with materialdried over phosphorous pentoxide in vacuo
12. dissolutionThe solid (15.6 g) was dissolved in dichloromethane (47 ml)
13. additionto the solution were added anisole (16 ml) and trifluoroacetic acid (32 ml) successively
14. stirringAfter stirring at room temperature for 3 hours
15. additionthe reaction mixture was poured into diisopropyl ether (500 ml)
16. filtrationThe precipitate was collected by filtration
17. washwashed with diisopropyl ether
18. dry with materialdried over phosphorous pentoxide in vacuo
19. dissolutionThe crude product was dissolved in a phosphate buffer (pH 7.0)
20. custompurified by preparative HPLC (eluent: pH 7.0 phosphate buffer and acetonitrile)
21. custom(Mitsubishi Chemical Corporation) and freeze-dried