反应详情

Chlorosulphonyl isocyanate (226 ml) was added to a solution of triethylamine (10 ml) in methyl acetate (3.8 l). The resulting clear solution was cooled to -15° and a suspension of (6R,7R)-3-hydroxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid (763 g) in methyl acetate (2.3 l), pre-cooled to -15°, was added over 10 minutes. The residual solid was rinsed in with methyl acetate (700 ml). The mixture was stirred at -5° for 30 minutes, a clear solution being obtained after 10 minutes. Water (1.2 l) at 18° was added rapidly to the reaction mixture, the temperature rising quickly to 10° and then slowly to 17°. The mixture was stirred for 60 minutes at 15° to give a thick, white suspension. Methyl acetate (3.6 l) was added followed by a steady addition of a solution of sodium hydroxide (288 g) in water (5.2 l). This gave a clear two-phase mixture at 26° with a pH of 2.35. The layers were separated and the upper, organic layer was washed with a solution of sodium chloride (600 g) in water (2 l). The two aqueous layers were washed sequentially with methyl acetate (2 l). The organic layers were bulked, stirred with Norit SX Plus charcoal (76 g) for 30 minutes and filtered through a bed of Hyflo Supercel, the bed being washed with methyl acetate (1.5 l). The filtrate and wash were combined and stirred at 20° whilst a solution of sodium 2-ethylhexanoate (338 g) in a mixture of methyl acetate (2 l) and water (40 ml) was added over 20 minutes to give a white suspension with a pH of 5.5. The suspension was stirred for 10 minutes and filtered, and the cake was washed with methyl acetate (5×1 l), sucked dry, and dried at 30° in vacuo for 24 hours to give cefuroxime sodium (851.9 g); [α]D20 +60°, (c0.5; 0.1M pH 4.5 buffer); λmax (H2O) 273 nm (E1 cm1 % 387); impurities by HPLC 2.0%.

1. temperatureThe resulting clear solution was cooled to -15°
2. temperaturepre-cooled to -15°
3. additionwas added over 10 minutes
4. washThe residual solid was rinsed in with methyl acetate (700 ml)
5. customa clear solution being obtained after 10 minutes
6. customrising quickly to 10°
7. customslowly to 17°
8. stirringThe mixture was stirred for 60 minutes at 15°
9. customto give a thick, white suspension
10. customThis gave a clear two-phase mixture at 26° with a pH of 2.35
11. customThe layers were separated
12. washthe upper, organic layer was washed with a solution of sodium chloride (600 g) in water (2 l)
13. washThe two aqueous layers were washed sequentially with methyl acetate (2 l)
14. stirringstirred with Norit SX Plus charcoal (76 g) for 30 minutes
15. filtrationfiltered through a bed of Hyflo Supercel
16. washthe bed being washed with methyl acetate (1.5 l)
17. washThe filtrate and wash
18. stirringstirred at 20° whilst a solution of sodium 2-ethylhexanoate (338 g) in a mixture of methyl acetate (2 l) and water (40 ml)
19. additionwas added over 20 minutes
20. customto give a white suspension with a pH of 5.5
21. stirringThe suspension was stirred for 10 minutes
22. filtrationfiltered
23. washthe cake was washed with methyl acetate (5×1 l)
24. customsucked dry
25. customdried at 30° in vacuo for 24 hours