Sodium Iodide → Ceftolozane

To a solution of benzhydryl 7β-[(Z)-2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (500 mg) in N,N-dimethylformamide (1.0 ml) was added sodium iodide (100 mg), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added a solution of 5-amino-4-(3-{2-[(tert-butoxycarbonyl)amino]ethyl}ureido)-1-methylpyrazole (216 mg) in N,N-dimethylformamide (1.0 ml). The whole mixture was stirred at 32° C. for 4 hours. To the resulting reaction mixture were added ethyl acetate (50 ml) and water (50 ml). The aqueous layer was separated, and the organic layer was washed with 10% aqueous sodium trifluoroacetate solution and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to about 5 ml in vacuo. The concentrate was poured into diisopropyl ether (75 ml), and the resulting precipitate was collected by filtration and dried in vacuo. To a solution of the resulting solid in methylene chloride (1.8 ml) were added anisole (0.6 ml) and trifluoroacetic acid (1.2 ml). The resulting solution was stirred at room temperature for 4 hours and poured into diisopropyl ether (80 ml). The resulting precipitate was collected by filtration and dried in vacuo to give a crude product (380 mg), which was purified by preparative high-performance liquid chromatography (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 with concentrated hydrochloric acid and chromatographed on Diaion® HP-20 (Mitsubishi Chemical Corporation) eluting with 30% aqueous 2-propanol. The eluate was concentrated to about 30 ml in vacuo and lyophilized to give 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-{3-amino-4-[3-(2-aminoethyl)ureido]-2-methyl-1-pyrazolio}methyl-3-cephem-4-carboxylate (21 mg) as an amorphous solid.

1. stirringThe whole mixture was stirred at 32° C. for 4 hours
2. customTo the resulting reaction mixture
3. customThe aqueous layer was separated
4. washthe organic layer was washed with 10% aqueous sodium trifluoroacetate solution and brine
5. dry with materialdried over anhydrous sodium sulfate
6. filtrationfiltered
7. concentrationThe filtrate was concentrated to about 5 ml in vacuo
8. additionThe concentrate was poured into diisopropyl ether (75 ml)
9. filtrationthe resulting precipitate was collected by filtration
10. customdried in vacuo
11. additionTo a solution of the resulting solid in methylene chloride (1.8 ml) were added anisole (0.6 ml) and trifluoroacetic acid (1.2 ml)
12. stirringThe resulting solution was stirred at room temperature for 4 hours
13. additionpoured into diisopropyl ether (80 ml)
14. filtrationThe resulting precipitate was collected by filtration
15. customdried in vacuo
16. customto give a crude product (380 mg), which
17. customwas purified by preparative high-performance liquid chromatography (HPLC)
18. additionThe eluate containing a desired product
19. concentrationwas concentrated to about 30 ml in vacuo
20. customchromatographed on Diaion®
21. wash(Mitsubishi Chemical Corporation) eluting with 30% aqueous 2-propanol
22. concentrationThe eluate was concentrated to about 30 ml in vacuo

ORD record

ord-7a45198b58bf4a5bad2d69551b33248a

Source dataset

uspto-grants-2006_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07129232B2