Process Development for Synthesizing the Cephalosporin Antibiotic Cefotaxime in Batch and Flow Mode Matthias Pieper, † Mario Kumpert, ‡ Burghard Kö nig, §,∥ Herbert Schleich, § Thomas Bayer,* ,‡ and Harald Grö ger* ,† † Chair of Organic Chemistry I, Faculty of Chemistry, Bielefeld University, Universitä tsstr. 25, 33615 Bielefeld, Germany ‡ Fachbereich Chemieingenieurwesen, Provadis School of International Management and Technology AG, Industriepark Hö chst, Gebä ude B 835, 65926 Frankfurt am Main, Germany § Anti-Infectives Business Unit, Sandoz GmbH, Biochemiestrasse10, 6250 Kundl, Austria 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-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. T he discovery and development of antibiotics and their therapeutic use against many different bacterial illnesses are among the most important achievements of humankind. In 2013 the development of antibiotics was mentioned as one of “Nine Ways That Changed the World”, 1 which underlines the high importance of antibiotics for therapeutic use. Among various types of antibiotics, β-lactam antibiotics are the largest class in terms of production volume. The group of β-lactam antibiotics can be divided into two main groups: penicillins and cephalosporins. 2 In most cases the antibacterial active substances are semisynthetic compounds that are synthesized from 6-aminopenicillanic acid (as a penicillin derivative) or 7- aminocephalosporanic acid (7-ACA) (as a cephalosporin C derivative). 2 For the production of 7-ACA, which is the backbone of almost all cephalosporin-based antibiotics, a modern and green process by means of biocatalysis has been developed. 3 The starting material of this process, cephalospo- rin C, is available by a fermentation process. The cleavage of the side chain is carried out by means of an enzymatic process, providing elegant access to 7-ACA. This environmentally friendly method replaced a chemical process that led to a large amount of waste. 3 However, the antibacterial activities of cephalosporin C and 7-ACA are very low. Thus, derivatization at the 3′- and 7′-position is needed in order to obtain the desired potent (semisynthetic) pharmaceutically active cepha- losporins. In a comparison of the chemical structures of different commercialized cephalosporin-based antibiotics like cefepime, cefotaxime, ceftriaxone, and cefpodoxime, it is noteworthy that in all of these cases the amino group at the 7′-position of 7-ACA is amidated with (Z)-(2-aminothiazol-4- yl)methoxyiminoacetic acid (Scheme 1). Ceftazidime and cefixime, two other cephalosporins, use similar side chains at the 7′-position with different oximes. Starting from 7-ACA, the easiest accessible β-lactam antibiotic product is cefotaxime (1) because no derivatization at the 3′-position is required. Today the most common method for the synthesis of 1 is still based on the use of S-(benzo[d]thiazol-2-yl)-(Z)-(2- aminothiazol-4-yl)methoxyiminothioacetate as an activated acid for amidation at the 7′-position. 4 However, this process and the synthesis of the activated intermediate, which are illustrated in Scheme 2, lead to a large amount of waste (as illustrated by the red-colored reagents and component fragments that are required but do not occur in the later product molecule 1). 5 For example, for the formation of the activated acid intermediate, as required reagents the dimer 2,2′-dithiobis(benzothiazole) and reagents like triphenylphos- phine are used. Thus, the main objective of this work was to develop an environmentally friendly and economically attractive alter- native route toward the production of 1, which we chose as a model product for the aforementioned cephalosporin-type antibiotics. In particular, we were interested in making use of flow-reactor technologies to overcome existing limitations. As substrate components, we used the readily available 7-ACA (2) and nonactivated ( Z )-(2-aminothiazol-4-yl)- methoxyiminoacetic acid (3). It is known from literature that 7-ACA or derivatives at the 3′-position undergo a reaction with the side chain precursor 3 with 4-toluenesulfonyl chloride (4) as a coupling reagent. 6 Compound 4 is a readily available and Received: March 2, 2018 Article pubs.acs.org/OPRD Cite This: Org. Process Res. Dev. XXXX, XXX, XXX-XXX © XXXX American Chemical Society A DOI: 10.1021/acs.oprd.8b00064 Org. Process Res. Dev. XXXX, XXX, XXX−XXX Downloaded via UNIV OF SOUTH DAKOTA on July 23, 2018 at 13:15:29 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.