Reaction #546820

Reaction equation

tert-butyl (4S)-4-{[2-(tert-butoxycarbonylamino)acetyl]amino}-5-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-5-oxopentylcarbamate

potassium iodide

4-methoxybenzyl 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylate

N-(trimethylsilyl)acetamide

→

7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[3-amino-4-({(2S)-5-amino-2-[(aminoacetyl)amino]pentanoyl}amino)-2-methyl-1-pyrazolio]methyl-3-cephem-4-carboxylate

Yield 4.2%

Solvents

ethyl acetate

N,N-dimethylformamide

Conditions

Workup

1. 1
   workup.STIRRINGthe mixture was stirred at room temperature for 30 minutes
2. 2
   workup.STIRRINGthe whole mixture was stirred at 40° C. for 4 hours
3. 3
   Washthe mixture was washed successively with brine (50 ml), 10% aqueous sodium trifluoroacetate solution (50 ml) and brine (50 ml)
4. 4
   Dryingdried over anhydrous magnesium sulfate
5. 5
   Filtrationfiltered
6. 6
   ConcentrationThe filtrate was concentrated to about 5 ml in vacuo
7. 7
   workup.ADDITIONThe concentrate was poured into diisopropyl ether (120 ml)
8. 8
   Filtrationthe resulting precipitate was collected by filtration
9. 9
   Otherdried in vacuo
10. 10
    workup.ADDITIONTo a solution of the solid in methylene chloride (4.5 ml) were added anisole (1.5 ml) and trifluoroacetic acid (3.0 ml)
11. 11
    workup.STIRRINGThe resulting solution was stirred at room temperature for 16 hours
12. 12
    workup.ADDITIONpoured into diisopropyl ether (120 ml)
13. 13
    FiltrationThe resulting precipitate was collected by filtration
14. 14
    Otherdried in vacuo
15. 15
    Otherto give a crude product (1.42 g), which
16. 16
    Otherwas purified by preparative HPLC
17. 17
    workup.ADDITIONThe eluate containing a desired product
18. 18
    Concentrationwas concentrated to about 20 ml in vacuo
19. 19
    OtherThe concentrate was further purified by preparative HPLC
20. 20
    Washeluting with 8% acetonitrile/water
21. 21
    ConcentrationThe eluate was concentrated to about 10 ml in vacuo

Procedure

To a solution of 4-methoxybenzyl 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (1.0 g) in N,N-dimethylformamide (3 ml) was added N-(trimethylsilyl)acetamide (965 mg) and the mixture was stirred at room temperature for 30 minutes. To the solution was added potassium iodide (341 mg) and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added tert-butyl (4S)-4-{[2-(tert-butoxycarbonylamino)acetyl]amino}-5-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-5-oxopentylcarbamate (1.27 g), and the whole mixture was stirred at 40° C. for 4 hours. To the reaction mixture was added ethyl acetate (100 ml) and the mixture was washed successively with brine (50 ml), 10% aqueous sodium trifluoroacetate solution (50 ml) and brine (50 ml), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to about 5 ml in vacuo. The concentrate was poured into diisopropyl ether (120 ml) and the resulting precipitate was collected by filtration and dried in vacuo. To a solution of the solid in methylene chloride (4.5 ml) were added anisole (1.5 ml) and trifluoroacetic acid (3.0 ml). The resulting solution was stirred at room temperature for 16 hours and poured into diisopropyl ether (120 ml). The resulting precipitate was collected by filtration and dried in vacuo to give a crude product (1.42 g), which was purified by preparative HPLC utilizing ODS column. The eluate containing a desired product was concentrated to about 20 ml in vacuo. The concentrate was further purified by preparative HPLC utilizing ODS column eluting with 8% acetonitrile/water. The eluate was concentrated to about 10 ml in vacuo. The resulting solution was lyophilized to give 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[3-amino-4-({(2S)-5-amino-2-[(aminoacetyl)amino]pentanoyl}amino)-2-methyl-1-pyrazolio]methyl-3-cephem-4-carboxylate (46.3 mg) as an amorphous solid.

Source