Process Development for Synthesizing the Cephalosporin Antibiotic Cefotaxime in Batch and Flow Mode

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.