Process Development for Synthesizing the Cephalosporin Antibiotic Cefotaxime in Batch and Flow Mode,Organic Process Research & Development

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Process Development for Synthesizing the Cephalosporin Antibiotic Cefotaxime in Batch and Flow Mode
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2018-07-23 00:00:00 , DOI: 10.1021/acs.oprd.8b00064
Matthias Pieper ₁ , Mario Kumpert ₂ , Burghard König ₃ , Herbert Schleich ₃ , Thomas Bayer ₂ , Harald Gröger ₁

Affiliation

The pharmaceutically active substance cefotaxime, a commercial cephalosporin-type antibiotic, is accessible in an amide-bond-forming reaction from 7-aminocephalosporanic acid as the amine donor and nonactivated (Z)-(2-aminothiazol-4-yl)-methoxyiminoacetic acid as the acid component with 4-toluenesulfonyl chloride as a coupling reagent, leading to only toluenesulfonic acid as an easy-to-separate byproduct. In this work, optimization of a batch process for this reaction is described as well as the extension toward a continuous process in a tube reactor with a diameter in the millimeter range. An opportunity to avoid the utilization of a chlorinated solvent system has been identified, thus contributing to the development of an ecologically friendly process. It was further shown that a higher reaction temperature of up to −10 °C is possible for the reaction when the process is conducted in a continuously operating fashion, which is an advantage from the perspective of energy demand. Thus, compared with the batch process, the continuous process turned out to be superior with respect to energy consumption and in terms of safety issues because of better heat dissipation for exothermic reactions. It also provides an opportunity to work in different process operating windows. A higher space-time yield represents a further advantage of the continuous process.

中文翻译：

分批和流动模式合成头孢菌素抗生素头孢噻肟的工艺开发

头孢噻肟类药物活性物质是一种商用头孢菌素型抗生素，可通过酰胺键形成反应从7-氨基头孢烷酸作为胺供体获得且未活化（Z）-（2-氨基噻唑-4-基）-甲氧基亚氨基乙酸作为酸成分，以4-甲苯磺酰氯为偶联剂，仅产生甲苯磺酸作为易分离的副产物。在这项工作中，描述了该反应的间歇过程的优化以及在直径为毫米范围的管式反应器中向连续过程的扩展。已经确定了避免使用氯化溶剂系统的机会，从而为发展生态友好的工艺做出了贡献。进一步表明，当该方法以连续操作方式进行时，该反应可能具有高达-10℃的较高反应温度，这从能量需求的角度来看是有利的。因此，与批处理相比，事实证明，由于放热反应的散热效果更好，因此连续过程在能耗和安全性方面均具有优势。它还提供了在不同的过程操作窗口中工作的机会。较高的时空产率代表了连续过程的另一个优点。

更新日期：2018-07-23

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