Reaction #436718

Reaction equation

5-amino-4-formamidomethyl-1-(2-triphenylmethyloxyethyl)pyrazole

trimethylsilyl iodide

diisopropylethylamine

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-formamidomethyl-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate

Yield 6.5%

Solvents

dichloromethane

N,N-dimethylformamide

water

ethyl acetate

Conditions

Workup

1. 1
   Temperaturecooling
2. 2
   Temperaturecooling for 2 hours
3. 3
   workup.ADDITIONTo the reaction mixture was added
4. 4
   workup.STIRRINGhad been stirred under ice-
5. 5
   Temperaturecooling for 0.5 hour
6. 6
   workup.STIRRINGThe reaction mixture was stirred at room temperature for 22 hours
7. 7
   OtherThe organic layer was separated
8. 8
   Dryingdried over magnesium sulfate
9. 9
   FiltrationThe magnesium sulfate was filtered off
10. 10
    Concentrationthe filtrate was concentrated to about 20 ml in vacuo
11. 11
    workup.ADDITIONThe concentrate was poured into diisopropyl ether (150 ml)
12. 12
    Filtrationthe resulting precipitate was collected by filtration
13. 13
    Otherdried in vacuo
14. 14
    workup.ADDITIONTo a solution of the resulting solid in methylene chloride (9 ml) were added anisole (3 ml) and trifluoroacetic acid (6 ml)
15. 15
    workup.STIRRINGThe resulting solution was stirred at room temperature for 3 hours
16. 16
    workup.ADDITIONpoured into diisopropyl ether (300 ml)
17. 17
    FiltrationThe resulting precipitate was collected by filtration
18. 18
    Otherdried in vacuo
19. 19
    workup.DISSOLUTIONThe obtained powder was dissolved in a phosphate buffer (pH 7)
20. 20
    workup.ADDITIONThe solution containing the objective compound
21. 21
    Otherwas purified by preparative HPLC utilizing ODS column
22. 22
    workup.ADDITIONThe eluate containing a desired product
23. 23
    Concentrationwas concentrated in vacuo
24. 24
    Otherchromatographed on Diaion®
25. 25
    Wash(Mitsubishi Chemical Corporation) eluting with 20% aqueous 2-propanol
26. 26
    OtherThe eluate was evaporated in vacuo

Procedure

To a solution of 5-amino-4-formamidomethyl-1-(2-triphenylmethyloxyethyl)pyrazole (2.06 g) in dichloromethane (10 ml) were added trimethylsilyl iodide (1.38 ml) and diisopropylethylamine (1.68 ml) under ice-cooling, and the mixture was stirred under ice-cooling for 2 hours. To the reaction mixture was added a mixture 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 (2 g) and sodium iodide (364 mg) in N,N-dimethylformamide (4 ml) which had been stirred under ice-cooling for 0.5 hour. The reaction mixture was stirred at room temperature for 22 hours and added to a mixture of ethyl acetate and water. The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated to about 20 ml in vacuo. The concentrate was poured into diisopropyl ether (150 ml), and the resulting precipitate was collected by filtration and dried in vacuo. To a solution of the resulting solid in methylene chloride (9 ml) were added anisole (3 ml) and trifluoroacetic acid (6 ml). The resulting solution was stirred at room temperature for 3 hours and poured into diisopropyl ether (300 ml). The resulting precipitate was collected by filtration and dried in vacuo. The obtained powder was dissolved in a phosphate buffer (pH 7), and the solution was adjusted to about pH 6 with saturated aqueous sodium hydrogencarbonate solution. The solution containing the objective compound was purified by preparative HPLC utilizing ODS column. The eluate containing a desired product was concentrated in vacuo. The concentrate was adjusted to about pH 2 with concentrated hydrochloric acid and chromatographed on Diaion® HP-20 (Mitsubishi Chemical Corporation) eluting with 20% aqueous 2-propanol. The eluate was evaporated 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-formamidomethyl-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (103 mg) as an amorphous solid.

Source