Ethyl Acetate → Ceftolozane

To a solution of benzhydryl 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-iodomethyl-3-cephem-4-carboxylate (810 mg) in N,N-dimethylformamide (2.4 ml) was added N-(trimethylsilyl)acetamide (656 mg), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added a solution of 4-(3-{2-[(tert-butoxycarbonyl)amino]ethyl}ureido)-1-methyl-5-triphenylmethylaminopyrazole (640 mg) in methylene chloride (10 ml). The whole mixture was stirred at room temperature for 26 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 (80 ml), and the resulting precipitate was collected by filtration and dried in vacuo. To a solution of the resulting solid in methylene chloride (2.38 ml) were added anisole (0.79 ml) and trifluoroacetic acid (1.58 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 (635 mg), which 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 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 (54 mg) as an amorphous solid.

1. stirringThe whole mixture was stirred at room temperature for 26 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 (80 ml)
9. filtrationthe resulting precipitate was collected by filtration
10. customdried in vacuo
11. additionTo a solution of the resulting solid in methylene chloride (2.38 ml) were added anisole (0.79 ml) and trifluoroacetic acid (1.58 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 (635 mg), which
17. customwas purified by preparative 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-19fd1c1a941744a8a72bb29af15cf709

Source dataset

uspto-grants-2006_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07129232B2