Reaction #436736

Reaction equation

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

ethyl acetate

4-(3-tert-butoxycarbonylaminopropyl)-1-(2-triphenylmethyloxyethyl)-5-tert-butoxycarbonylaminopyrazole

→

7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[3-amino-4-(3-aminopropyl)-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate

Yield 7.7%

Solvents

N,N-dimethylformamide

water

Conditions

Workup

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

Procedure

To a suspension of a mixture 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 (1 g) and sodium iodide (182 mg) in N,N-dimethylformamide (2 ml) was added 4-(3-tert-butoxycarbonylaminopropyl)-1-(2-triphenylmethyloxyethyl)-5-tert-butoxycarbonylaminopyrazole (1.52 g), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was 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 evaporated to about 20 ml under reduced pressure. 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 (3 ml) were added anisole (1 ml) and trifluoroacetic acid (2 ml). The resulting solution was stirred at room temperature for 3 hours and poured into diisopropyl ether. The resulting precipitate was collected by filtration and dried in vacuo. The obtained powder was dissolved in a phosphate buffer (pH 7) and 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-(3-aminopropyl)-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (61 mg) as an amorphous solid.

Source