Phosphorus oxychloride → 7beta-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(cyclopropyloxyimino)acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate

Phosphorous oxychloride (0.31 ml) was added to a mixture of N,N-dimethylformamide (0.25 ml) and ethyl acetate (1 ml) under ice-cooling. The mixture was stirred at the same temperature for 10 minutes to give a suspension. To the suspension was added 2-cyclopropyloxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (1.18 g) and tetrahydrofuran (15 ml) and the mixture was stirred under ice-cooling for 30 minutes to give an activated acid solution. On the other hand, to a suspension of 1- [(7β-amino-4-carboxy-3-cephem-3-yl)methyl]pyridinium chloride hydrochloride (1.3 g) in tetrahydrofuran (20 ml) was added N-trimethylsilyl-acetamide (8.5 g). The suspension was stirred at ambient temperature for an hour to give a clear solution. To the solution was added the activated acid solution prepared above at -30° C. and the mixture was stirred at -20° C. to -5° C. for 30 minutes and under ice-cooling for an hour. The mixture was poured into ethyl acetate (300 ml) to give precipitates. The precipitates were collected. To the precipitates was added a mixture of anisole (14 ml) and trifluoroacetic acid (4.3 ml) under ice-cooling. The mixture was stirred for 1.5 hours at ambient temperature. The mixture was concentrated in vacuo and poured into ice-water (50 ml). The mixture was adjusted to pH 5 with saturated aqueous solution of sodium bicarbonate. The aqueous solution was washed with ethyl acetate and subjected to column chromatography on a non-ionic adsorption resin "Diaion HP-20" (30 ml). After the column was washed with water, the elution was carried out with 2% isopropyl alcohol. The fractions containing the object compound were collected, combined, evaporated to remove isopropyl alcohol in vacuo, and finally lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol- 3-yl)-2-(cyclopropyloxyimino)acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer)(260 mg).

1. temperaturecooling
2. customto give a suspension
3. stirringthe mixture was stirred under ice-
4. temperaturecooling for 30 minutes
5. customto give an activated acid solution
6. stirringThe suspension was stirred at ambient temperature for an hour
7. customto give a clear solution
8. additionTo the solution was added the activated acid solution
9. customprepared above at -30° C.
10. stirringthe mixture was stirred at -20° C. to -5° C. for 30 minutes and under ice-
11. temperaturecooling for an hour
12. customto give
13. customprecipitates
14. customThe precipitates were collected
15. additionTo the precipitates was added
16. additiona mixture of anisole (14 ml) and trifluoroacetic acid (4.3 ml) under ice-
17. temperaturecooling
18. stirringThe mixture was stirred for 1.5 hours at ambient temperature
19. concentrationThe mixture was concentrated in vacuo
20. additionpoured into ice-water (50 ml)
21. washThe aqueous solution was washed with ethyl acetate
22. washAfter the column was washed with water
23. washthe elution
24. additionThe fractions containing the object compound
25. customwere collected
26. customevaporated
27. customto remove isopropyl alcohol in vacuo

ORD record

ord-bffc7c7680814fefab825819f09163f9

Source dataset

uspto-grants-1989_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US04861769