Reaction #436724

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-tert-butoxycarbonylaminomethyl-1-ethyl-5-tritylaminopyrazole

→

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

Yield 21.1%

Solvents

N,N-dimethylformamide

water

Conditions

Workup

1. 1
   OtherThe organic layer was separated
2. 2
   Washwashed with brine (15 ml)
3. 3
   Dryingdried over anhydrous magnesium sulfate
4. 4
   FiltrationThe magnesium sulfate was filtered off
5. 5
   Otherthe filtrate was evaporated to about 5 ml under reduced pressure
6. 6
   workup.ADDITIONThe concentrate was poured into diisopropyl ether (150 ml)
7. 7
   Filtrationthe resulting precipitate was collected by filtration
8. 8
   Otherdried in vacuo
9. 9
   workup.ADDITIONTo a solution of the resulting solid in methylene chloride (4.5 ml) were added anisole (1.5 ml) and trifluoroacetic acid (3 ml)
10. 10
    workup.STIRRINGThe resulting solution was stirred at room temperature for 3 hours
11. 11
    workup.ADDITIONpoured into diisopropyl ether
12. 12
    FiltrationThe resulting precipitate was collected by filtration
13. 13
    Otherdried in vacuo
14. 14
    workup.DISSOLUTIONThe obtained powder was dissolved in a phosphate buffer (pH 7)
15. 15
    workup.ADDITIONThe solution containing the objective compound
16. 16
    Otherwas purified by preparative HPLC utilizing ODS column
17. 17
    workup.ADDITIONThe eluate containing a desired product
18. 18
    Concentrationwas concentrated in vacuo
19. 19
    Otherchromatographed on Diaion®
20. 20
    Wash(Mitsubishi Chemical Corporation) eluting with 20% aqueous 2-propanol
21. 21
    OtherThe eluate was evaporated in vacuo

Procedure

To a suspension of 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 (1 g) and sodium iodide (199 mg) in N,N-dimethylformamide (3 ml) was added 4-tert-butoxycarbonylaminomethyl-1-ethyl-5-tritylaminopyrazole (1.17 g), and the mixture was stirred at room temperature for 47 hours. The reaction mixture was added to a mixture of ethyl acetate (30 ml) and water (20 ml). The organic layer was separated, washed with brine (15 ml), and dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated to about 5 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 (4.5 ml) were added anisole (1.5 ml) and trifluoroacetic acid (3 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-aminomethyl-2-ethyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (155 mg) as an amorphous solid.

Source