反应详情

To a stirred mixture of 7-amino-3-acetoxymethylceph-3-em-4-carboxylic acid (5.44 g.) and acetonitrile (25 ml.) under argon at ambient temperature (22°-24°) was added N-trimethylsilyl-1-trimethylsilyloxyvinylamine (4.93 ml.) over 2 minutes and the mixture stirred at ambient temperatures for 2.5 hours to give a clear orange solution. To this solution, cooled in ice, was added 1-(2,2-diethoxyethyl)-3-trimethylsilylcarbodiimide (4.6 g.) over 2 minutes, followed by conc. sulphuric acid (1.06 ml.) over 13 minutes, the temperature of the reaction mixture being maintained below 7°. The solution temperature was maintained at 0° for 30 minutes, then more 1-(2,2-diethoxyethyl)-3-trimethylsilylcarbodiimide (0.46 g.) and more conc. sulphuric acid (95 1.) were added, the temperature of the reaction mixture being maintained below 3°. After another 30 minutes at 0° further additions of the same amount of these reagents were made. The golden yellow solution was maintained at 0° for 1 hour and then (for convenience) stored at -20° under argon for 2 days. To this solution of trimethylsilyl 3-acetoxymethyl-7-[2-(2,2-diethoxyethyl)-3-trimethylsilyl]guanidinoceph-3-em-4-carboxylate stirred in an ice bath was added boron trifluoride acetic acid complex (40% w/w; 7.3 ml.) over 6 minutes, the temperature of the reaction mixture being maintained below 5°. The temperature of the solution was maintained at 0°-1° for 7.5 hours and then (for convenience) stored at -20° under argon for 18 hours. The solution was diluted with ice-cold water (100 ml.), the temperature of the mixture being maintained below 5° and then extracted with cold dichloromethane (60 ml.; 2×40 ml.). The aqueous layer was diluted with more ice-cold water (100 ml.) and the pH adjusted to 4 with 9N aqueous sodium hydroxide solution (10 ml.). The solution was applied to a column of Diaion HP-20 resin (160 ml. bed volume) made up in deionised water. The resin was washed with water (160 ml.) and then the product was eluted with acetonitrile/water 20:80 v/v. The fraction (ca. 110 ml.) rich in product was allowed to stand for 1 hour at room temperature whereupon the product cyrstallised out as finse colourless needles. The mixture was stored at 0° for 2 days and the solid was filtered off, washed with cold acetonitrile (2×5 ml.) and dried in vacuo to give 3-acetoxymethyl-7-(imidazol-2-yl)aminoceph-3-em-4-carboxylic acid (3.94 g.) having the following analysis: strength (HPLC comparison with an authentic sample of known strength) 88.5%, water content 9.7%.

1. customto give a clear orange solution
2. temperatureTo this solution, cooled in ice
3. temperaturethe temperature of the reaction mixture being maintained below 7°
4. temperatureThe solution temperature was maintained at 0° for 30 minutes
5. temperaturethe temperature of the reaction mixture being maintained below 3°
6. waitAfter another 30 minutes at 0° further additions of the same amount of these reagents were made
7. temperatureThe golden yellow solution was maintained at 0° for 1 hour
8. wait(for convenience) stored at -20° under argon for 2 days
9. additionwas added boron trifluoride acetic acid complex (40% w/w; 7.3 ml.) over 6 minutes
10. temperaturethe temperature of the reaction mixture being maintained below 5°
11. temperatureThe temperature of the solution was maintained at 0°-1° for 7.5 hours
12. wait(for convenience) stored at -20° under argon for 18 hours
13. temperaturethe temperature of the mixture being maintained below 5°
14. extractionextracted with cold dichloromethane (60 ml.; 2×40 ml.)
15. additionThe aqueous layer was diluted with more ice-cold water (100 ml.)
16. washThe resin was washed with water (160 ml.)
17. washthe product was eluted with acetonitrile/water 20:80 v/v
18. waitto stand for 1 hour at room temperature whereupon the product
19. waitThe mixture was stored at 0° for 2 days
20. filtrationthe solid was filtered off
21. washwashed with cold acetonitrile (2×5 ml.)
22. customdried in vacuo