반응 #56566

반응 방정식

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

trimethylsilylacetamide

2-methoxyimino-2-(2-formylimino-2,3-dihydrothiazol-4-yl)acetic acid

sodium bicarbonate

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

phosphorus oxychloride

→

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

용매

ethyl acetate

ethyl acetate

water

dimethylformamide

반응 조건

후처리

1. 1
   온도under cooling to 5° to 10° C.
2. 2
   workup.STIRRINGthe mixture was stirred for 30 minutes at 40° C.
3. 3
   workup.ADDITIONwas added
4. 4
   workup.STIRRINGthe mixture was stirred for 40 minutes at 3° to 5° C
5. 5
   workup.ADDITIONThus obtained solution was added to a solution, which
6. 6
   기타was prepared
7. 7
   workup.STIRRINGby stirring
8. 8
   workup.STIRRINGwith vigorous stirring
9. 9
   온도under cooling to -25° C
10. 10
    workup.STIRRINGThe mixture was stirred for 1 hour at -20° to -15° C. and for 30 minutes at -10° to -5° C
11. 11
    workup.STIRRINGthe mixture was further stirred for 20 minutes at the same temperature
12. 12
    workup.DISSOLUTIONto dissolve the precipitates
13. 13
    기타the aqueous layer was separated
14. 14
    workup.ADDITIONTo the aqueous layer was added ethyl acetate
15. 15
    기타the ethyl acetate layer was separated
16. 16
    추출The remaining aqueous layer was further extracted with ethyl acetate
17. 17
    세척washed with a saturated aqueous sodium chloride solution
18. 18
    건조dried over magnesium sulfate
19. 19
    workup.ADDITIONtreated with an activated charcoal
20. 20
    농축concentrated
21. 21
    여과collected by filtration
22. 22
    기타dried

실험 절차

To dimethylformamide (6.42 g.) was added dropwise phosphorus oxychloride (12.5 g.) over 20 minutes with stirring under cooling to 5° to 10° C., and the mixture was stirred for 30 minutes at 40° C., and then ethyl acetate (200 ml.) was added thereto with vigorous stirring. After the mixture was cooled to 3° C., 2-methoxyimino-2-(2-formylaminothiazol-4-yl)acetic acid (syn isomer), which can be represented as 2-methoxyimino-2-(2-formylimino-2,3-dihydrothiazol-4-yl)acetic acid (syn isomer), (18.34 g.) was added thereto, and then the mixture was stirred for 40 minutes at 3° to 5° C. 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 (17.1 g.) and trimethylsilylacetamide (84 g.) in ethyl acetate (300 ml.) for 1 hour at room temperature, with vigorous stirring under cooling to -25° C. The mixture was stirred for 1 hour at -20° to -15° C. and for 30 minutes at -10° to -5° C. To the mixture was added water (200 ml.) at room temperature, and the mixture was further stirred for 20 minutes at the same temperature. After a saturated aqueous sodium bicarbonate solution was added to the mixture in order to dissolve the precipitates, the aqueous layer was separated. To the aqueous layer was added ethyl acetate, and the mixture was adjusted to pH 2 with 2 N hydrochloric acid, and then the ethyl acetate layer was separated. The remaining aqueous layer was further extracted with ethyl acetate. The ethyl acetate layers were combined together, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, treated with an activated charcoal and then concentrated. Thus obtained crystalline residue was pulverized in diethyl ether, collected by filtration and then dried to give white crystals of 2-methyl-7-[2-methoxyimino-2-(2-formylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-methoxyimino-2-(2-formylimino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (32.2 g.). This compound was recrystallized from methanol to give white crystals of the pure object compound, mp 174° to 204° C. (dec.).

출처