头孢克肟及其关键中间体7-AVCA的合成工艺改进

Improvement on the synthesis of cefi xime and 7-AVCA

目的研究头孢克肟及其关键中间体7-AVCA的合成工艺,以酶解法替代传统化学裂解法。方法经工艺考察及改进,最终确定以GCLE为起始原料,经关键中间体7-AVCA制备头孢克肟适合于生产的工艺。结果所制得的头孢克肟质量好,总收率为64%。其中采用的酶解法工艺不仅解决了环保治理的瓶颈问题,同时改进工艺获得的中间体7-AVCA的质量明显优于其他方法,优质的7-AVCA从源头上起到提高下游原料药头孢克肟产品的含量及稳定性,降低杂质的作用。头孢克肟的结构经1H-NMR、IR和UV分析确证,色谱纯度经HPLC检测大于99%。结论本文工艺与文献相比,操作简化,收率提高,产品质量优异,节能环保,适合于产业化。

Objective Synthetic process of cefixime and its key intermediate 7-Amino-3- ethenyl-8-oxo-5-thia- 1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid （7-AVCA） was introduced. Enzymatic Hydrolysis was a substitute for Chemical Cleavage of Mismatch. Methods With studying and improving, the synthetic route was finalized as follows： Taking 4-methoxybenzyl-3-（chloromethyl）-8-oxo-7-（2-phenylacetamido）-5-thia- 1-azabicyclo[4,2,0] oct- 2-ene-2-carboxylate （GCLE） as the starting material, the key intermediate 7-AVCA was synthesized by the step of enzyme hydrolysis. Results The target compound was obtained with total yield of 64%. Environmental problems was solved by the improved process and the high-quanlity 7-AVCA was of advantage to get the better cefixime with increasing contents, improving stability and low impurity level. The structure of cefixime was confirmed by 1H-NMR, IR and UV, and the HPLC purity was above 99%. Conclusion With the above process, Cefixime was synthesized with a simpler procedure and a higher yield comparing with the report in the literatures. The process of enzyme hydrolysis contributing to energy conservation and environment protection was suitable for the industrialization.