Potassium Iodide → (6R,7R)-3-[[5-amino-4-(azetidin-3-ylcarbamoylamino)-1-methylpyrazol-2-ium-2-yl]methyl]-7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-carboxypropan-2-yloxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

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 (1.48 g) in N,N-dimethylformamide (3.0 ml) was added N-(trimethylsilyl)acetamide (1.42 g), and the mixture was stirred at room temperature for 30 minutes. To the solution was added potassium-iodide (504 mg) and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added a solution of tert-butyl 3-[({[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)amino]-1-azetidinecarboxylate (1.20 g) in N,N-dimethylformamide (2.2 ml), and the whole mixture was stirred at 50° C. for 16 hours. To the resulting reaction mixture was added ethyl acetate (200 ml), and the solution was washed successively with water (50 ml), 10% aqueous sodium trifluoroacetate solution (50 ml×2) and brine (50 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to about 10 ml in vacuo. The concentrate was poured into diisopropyl ether (160 ml), and the resulting precipitate was collected by filtration and dried in vacuo. To a solution of the solid in methylene chloride (8.64 ml) were added anisole (2.88 ml) and trifluoroacetic acid (8.64 ml). The resulting solution was stirred at room temperature for 3 hours and poured into diisopropyl ether (160 ml). The resulting precipitate was collected by filtration and dried in vacuo to give a crude product (2.22 g), which was purified by preparative HPLC utilizing ODS column eluting with a mixture of acetonitrile and phosphate buffer (pH 5.5). The eluate containing a desired product was concentrated to about 20 ml in vacuo. The concentrate was desalted by preparative HPLC utilizing ODS column, and the fraction eluted with 8% aqueous acetonitrile was concentrated to about 10 ml in vacuo and lyophilized to give 3-[(3-amino-4-{[(3-azetidinylamino)carbonyl]amino}-2-methyl-1-pyrazolio)methyl]-7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-cephem-4-carboxylate (220 mg) as an amorphous solid.

1. stirringthe mixture was stirred at room temperature for 30 minutes
2. stirringthe whole mixture was stirred at 50° C. for 16 hours
3. customTo the resulting reaction mixture
4. washthe solution was washed successively with water (50 ml), 10% aqueous sodium trifluoroacetate solution (50 ml×2) and brine (50 ml)
5. dry with materialdried over anhydrous sodium sulfate
6. filtrationfiltered
7. concentrationThe filtrate was concentrated to about 10 ml in vacuo
8. additionThe concentrate was poured into diisopropyl ether (160 ml)
9. filtrationthe resulting precipitate was collected by filtration
10. customdried in vacuo
11. additionTo a solution of the solid in methylene chloride (8.64 ml) were added anisole (2.88 ml) and trifluoroacetic acid (8.64 ml)
12. stirringThe resulting solution was stirred at room temperature for 3 hours
13. additionpoured into diisopropyl ether (160 ml)
14. filtrationThe resulting precipitate was collected by filtration
15. customdried in vacuo
16. customto give a crude product (2.22 g), which
17. customwas purified by preparative HPLC
18. washeluting with a mixture of acetonitrile and phosphate buffer (pH 5.5)
19. additionThe eluate containing a desired product
20. concentrationwas concentrated to about 20 ml in vacuo
21. washthe fraction eluted with 8% aqueous acetonitrile
22. concentrationwas concentrated to about 10 ml in vacuo

ORD record

ord-2f4a86f3d7ce4f2f905feea3ef261f0d

Source dataset

uspto-grants-2006_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07129232B2