Reaction #1334954

Reaction equation

ethyl acetate

5-amino-4-(3-{2-[(tert-butoxycarbonyl)amino]ethyl}ureido)-1-methylpyrazole

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

sodium iodide

→

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

Yield 5.2%

Solvents

water

N,N-dimethylformamide

N,N-dimethylformamide

Conditions

Workup

1. 1
   workup.STIRRINGThe whole mixture was stirred at 32° C. for 4 hours
2. 2
   OtherTo the resulting reaction mixture
3. 3
   OtherThe aqueous layer was separated
4. 4
   Washthe organic layer was washed with 10% aqueous sodium trifluoroacetate solution and brine
5. 5
   Dryingdried over anhydrous sodium sulfate
6. 6
   Filtrationfiltered
7. 7
   ConcentrationThe filtrate was concentrated to about 5 ml in vacuo
8. 8
   workup.ADDITIONThe concentrate was poured into diisopropyl ether (75 ml)
9. 9
   Filtrationthe resulting precipitate was collected by filtration
10. 10
    Otherdried in vacuo
11. 11
    workup.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. 12
    workup.STIRRINGThe resulting solution was stirred at room temperature for 4 hours
13. 13
    workup.ADDITIONpoured into diisopropyl ether (80 ml)
14. 14
    FiltrationThe resulting precipitate was collected by filtration
15. 15
    Otherdried in vacuo
16. 16
    Otherto give a crude product (380 mg), which
17. 17
    Otherwas purified by preparative high-performance liquid chromatography (HPLC)
18. 18
    workup.ADDITIONThe eluate containing a desired product
19. 19
    Concentrationwas concentrated to about 30 ml in vacuo
20. 20
    Otherchromatographed on Diaion®
21. 21
    Wash(Mitsubishi Chemical Corporation) eluting with 30% aqueous 2-propanol
22. 22
    ConcentrationThe eluate was concentrated to about 30 ml in vacuo

Procedure

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.

Source