반응 #56565

반응 방정식

2-methyl-7-amino-3-cephem-4-carboxylic acid

trimethylsilylacetamide

2-methoxyimino-2-(2-trifluoroacetylaminothiazol-4-yl)acetic acid

phosphorus oxychloride

2-methoxyimino-2-(2-trifluoroacetylimino-2,3-dihyrothiazol-4-yl)acetic acid

→

2-methyl-7-[2-methoxyimino-2-(2-trifluoroacetylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid

용매

ethyl acetate

ethyl acetate

water

dimethylformamide

반응 조건

후처리

1. 1
   온도ice-cooling
2. 2
   workup.STIRRINGthe mixture was stirred for 30 minutes at 40° C.
3. 3
   온도under cooling at 3° to 5° C.
4. 4
   workup.STIRRINGthe mixture was stirred for 40 minutes at the same temperature
5. 5
   workup.ADDITIONThus obtained solution was added to a solution, which
6. 6
   기타was prepared
7. 7
   workup.STIRRINGby stirring
8. 8
   온도under cooling at -25° to -20° C.
9. 9
   workup.STIRRINGwith stirring
10. 10
    workup.ADDITIONwas added
11. 11
    온도under ice-cooling
12. 12
    workup.STIRRINGthe mixture was stirred for about 5 minutes at the same temperature
13. 13
    기타The ethyl acetate layer was separated from the reaction mixture
14. 14
    추출the remaining aqueous layer was extracted with ethyl acetate (20 ml.×2)
15. 15
    세척washed with water
16. 16
    workup.ADDITIONwater (50 ml.) was added
17. 17
    온도cooling
18. 18
    workup.STIRRINGstirring
19. 19
    기타the aqueous layer was separated
20. 20
    세척After washing the aqueous layer with ethyl acetate, ethyl acetate (70 ml.)
21. 21
    workup.ADDITIONwas added
22. 22
    온도cooling
23. 23
    workup.STIRRINGstirring
24. 24
    기타The ethyl acetate layer was separated from the mixture
25. 25
    추출the remaining aqueous layer was extracted with ethyl acetate (30 ml.)
26. 26
    세척washed with an aqueous solution of sodium chloride
27. 27
    기타dried
28. 28
    농축concentrated till the total volume
29. 29
    workup.ADDITIONTo the residue was added diethyl ether (20 ml.)
30. 30
    workup.STIRRINGthe mixture was stirred for about 1 hour
31. 31
    여과The precipitates were collected by filtration
32. 32
    세척washed with diethyl ether
33. 33
    기타dried

실험 절차

To dimethylformamide (0.54 g.) was added dropwise phosphorus oxychloride (1.13 g.) under stirring and ice-cooling, and the mixture was stirred for 30 minutes at 40° C., and then dried ethyl acetate (13 ml.) was added thereto. To the mixture was gradually added 2-methoxyimino-2-(2-trifluoroacetylaminothiazol-4-yl)acetic acid (syn isomer), which can be represented as 2-methoxyimino-2-(2-trifluoroacetylimino-2,3-dihyrothiazol-4-yl)acetic acid (syn isomer), (2.0 g.) under cooling at 3° to 5° C., and the mixture was stirred for 40 minutes at the same temperature. Thus obtained solution was added to a solution, which was prepared by stirring a mixture of 2-methyl-7-amino-3-cephem-4-carboxylic acid (1.44 g.) and trimethylsilylacetamide (9.78 g.) in dried ethyl acetate (30 ml.) for 5 to 10 minutes at 35° to 40° C., under cooling at -25° to -20° C. with stirring. The mixture was stirred for 1 hour at the same temperature, and cold water was added thereto under ice-cooling, and then the mixture was stirred for about 5 minutes at the same temperature. The ethyl acetate layer was separated from the reaction mixture, and the remaining aqueous layer was extracted with ethyl acetate (20 ml.×2). The ethyl acetate layers were combined together, washed with water and then water (50 ml.) was added thereto. The mixture was adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate, under ice-cooling and stirring, and the aqueous layer was separated therefrom. After washing the aqueous layer with ethyl acetate, ethyl acetate (70 ml.) was added thereto. The mixture was adjusted to pH 2.5 with 10% hydrochloric acid under ice-cooling and stirring. The ethyl acetate layer was separated from the mixture, and the remaining aqueous layer was extracted with ethyl acetate (30 ml.). The ethyl acetate layers were combined together, washed with an aqueous solution of sodium chloride, dried and then concentrated till the total volume became about 10 ml. To the residue was added diethyl ether (20 ml.) and the mixture was stirred for about 1 hour. The precipitates were collected by filtration, washed with diethyl ether and then dried to give 2-methyl-7-[2-methoxyimino-2-(2-trifluoroacetylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-methoxyimino-2-(2-trifluoroacetylimino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (2.2 g.), mp. 197° to 198° C. (dec.). The remaining filtrate was concentrated, and the residue was washed with diethyl ether and then dried to give the same object compound (0.3 g.).

출처