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

Abstract

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-4yl)-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.

General Synthesis of Industrial Cephalosporin‐Based Antibiotics Through Amidation with Tosyl Chloride as a Coupling Reagent

“…In the subsequent step, this mixed anhydride is added to a solution of 7‐ACA ( 2 ) in methanol (or alternatively dichloromethane according to an earlier method) to form cefotaxime ( 3a ; Scheme ). We could further demonstrate that this process exemplified for cetoxamine ( 3a ) works efficiently in a batch as well as flow fashion …”

“…Representative examples of the cephalosporin antibiotics of the third generation, which are also graphically shown in Scheme , are the commercial antibiotic drugs cefotaxime ( 3a ), cefepime ( 3b ), cefpodoxime ( 3c ), cefpodoxime proxetil ( 3d ), and ceftriaxone ( 3e ). Related products with a different substitution pattern at the oxime group in the acyl moiety are cefixime ( 3f ) and ceftazidime ( 3g ) …”

“…Very recently, based on a literature methodology we reported an alternative method for such an amidation exemplified for the amidation of 7‐ACA ( 2 ) with ( Z )‐(2‐amino‐thiazol‐4‐yl)methoxy‐iminoacetic acid ( 4 ) under formation of the antibiotic drug cefotaxime ( 3a ) . This amidation is based on the utilization of 4‐toluenesulfonyl chloride (Tos‐Cl) as a readily available and economically attractive coupling reagent in combination with methanol as one of the solvent components.…”

“…This amidation is based on the utilization of 4‐toluenesulfonyl chloride (Tos‐Cl) as a readily available and economically attractive coupling reagent in combination with methanol as one of the solvent components. Besides being a readily available economical reagent produced by sulfonation of toluene with chlorosulfonic acid, a further advantage of Tos‐Cl is that in the desired amidation process 4‐toluenesulfonyl acid as a compound with a relatively low hazard potential is formed as a by‐product . This leads to a favorable process considering atom economics.…”

Synthesis of the Antibiotic Precursor Thiazolyl‐7‐Aminocephalosporanic Acid in a Microstructured Flow System

“…Using a one‐step enzymatic process (Scheme ), 7‐ACA ( 2 ) is generated by a direct hydrolytic cleavage of the acyclic amide bond . 7‐ACA ( 2 ) can be modified at the 3′‐ and 7′‐position via chemical organic synthesis, today in batch mode in stirred‐tank reactors .…”