Process Development for Synthesizing the Cephalosporin Antibiotic

Article Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Process Development for Synthesizing the Cephalosporin Antibiotic Cefotaxime in Batch and Flow Mode Matthias Pieper,† Mario Kumpert,‡ Burghard König,§,∥ Herbert Schleich,§ Thomas Bayer,*,‡ and Harald Gröger*,† †

Chair of Organic Chemistry I, Faculty of Chemistry, Bielefeld University, Universitätsstr. 25, 33615 Bielefeld, Germany Fachbereich Chemieingenieurwesen, Provadis School of International Management and Technology AG, Industriepark Höchst, Gebäude B 835, 65926 Frankfurt am Main, Germany § Anti-Infectives Business Unit, Sandoz GmbH, Biochemiestrasse10, 6250 Kundl, Austria 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.

‡

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.

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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)-(2aminothiazol-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 triphenylphosphine are used. Thus, the main objective of this work was to develop an environmentally friendly and economically attractive alternative 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

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 7aminocephalosporanic 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, cephalosporin 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 cephalosporins. 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-4yl)methoxyiminoacetic acid (Scheme 1). Ceftazidime and © XXXX American Chemical Society

Received: March 2, 2018

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DOI: 10.1021/acs.oprd.8b00064 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

Scheme 1. Representative Examples of Cephalosporin-Based Antibiotics

Scheme 2. Industrial Standard Process for the Production of Cefotaxime (1)

economical reagent, and the only byproduct of this reaction is nontoxic 4-toluenesulfonic acid.7 These advantages make 4 an attractive coupling reagent. In contrast to the use of 4, the use of methylene chloride as an unhealthy and environmentally problematic solvent and dimethylacetamide as a further hazardous solvent required evaluation of alternative solvents. Another important factor for an economical process is the reaction temperature. Typically such reactions are conducted at very low temperature because of, e.g., selectivity issues. At the same time, for technical processes cooling is a very expensive step in industrial productions of chemicals when temperatures of less than −20 °C have to be obtained. Typically, reaction temperatures below −20 °C represent a

significant cost factor, e.g., because of the use of liquid nitrogen as an expensive component for cooling. Another important criterion is related to the scale-up of processes running at such a low temperature: because of the unfavorable surface to volume ratio at a larger scale, rapid removal of the reaction heat while keeping the reaction temperature low represents a challenge. A solution for this problem could be the use of a continuous flow setup for this process, since flow systems often enable a very high surface to volume ratio, which leads to a high heat transfer capacity and other phenomena coming from microeffects that are discussed at a later stage of this article.8 However, for the transfer to a continuous flow setup, clear reaction solutions are advantageous since plugging or B



Article

Figure 1. Model reaction for amidation at the 7′-position of 7-aminocephalosporanic acid (2).

Table 1. Screening for Solvent 1e

a T = 0 °C for the first step. bT = −5 °C for the first step. c1.5-fold amount of solvent 1 for the solution of 4. dDouble amount of solvent 1 for the solution of 4. eColoring is based on the CHEM21 selection guide of classical and less classical solvents,9 which ranks solvents in terms of safety, health, and environmental criteria: green stands for recommended, yellow for problematic, red for hazardous, and white for no data.

sedimentation typically cause problems in continuously operating reactions. One of the main problems in the reaction transfer is the occurrence of particles during the formation of the mixed anhydride. Thus, in the next step different solvents were tested with respect to their conversion to cefotaxime and solubility properties of the mixed anhydride. As a first step, we focused on the identification of preferred reaction parameters. A very important factor for a successful reaction appears to be the dissolution of 7-ACA (2). 7-ACA is nearly insoluble in organic solvents, and only in combination with triethylamine solutions of 7-ACA can be obtained. As an alternative to methylene chloride, the more environmentally preferred solvents water and methanol in combination with triethylamine can be used to dissolve 7-ACA, thus representing

suitable alternatives for the use of methylene chloride as solvent 2 (Figure 1). However, because of the protic character of water and methanol, these solvents can react with the mixed anhydride 5. Thus, methylene chloride was chosen initially as solvent 2. The reaction temperature of the first reaction should be low enough to stabilize the mixed anhydride 5 formed from 4 and 3. For this step, the temperature is fixed at −11 °C since this temperature could be reached with a simple cooling mixture of ice and sodium chloride. As the reaction between 5 and 2 is highly exothermic, the temperature of the second step was selected to be below −30 °C in order to avoid an unfavored increase in the reaction temperature during the amide formation process. C



Article

Table 2. Screening for Solvent 2b

T = 0 °C for the second step. bColoring is based on the CHEM21 selection guide of classical and less classical solvents,9 which ranks solvents in terms of safety, health, and environmental criteria: green stands for recommended and red for hazardous.

a

Table 3. Screening of Alternative Bases

entry

base

reaction yield (%)

1 2 3 4 5 6

triethylamine 1,8-diazabicyclo[5.4.0]undec-7-ene 1,1,3,3-tetramethylguanidine diisopropylamine dicyclohexylamine pyridinea

100 29 38 24 87 22

a

Addition of triethylamine was required in this case in order to dissolve 7-ACA (2).

Screening for Solvent 1. Considering these above reaction conditions (−11 °C for step 1, −30 °C for step 2), different aprotic solvents were tested as an alternative for dimethylacetamide as solvent 1. The best results were achieved using polar aprotic solvents like propylene carbonate, εcaprolactone, N-methyl-2-pyrrolidone, N,N′-dimethylpropyleneurea, and tetramethylurea (Table 1). In contrast, low yields were found with more apolar solvents such as ketones, esters, and tetrahydrofurans. None of these solvents, however, turned out to be an alternative for dimethylacetamide as solvent 1, since only dimethylacetamide resulted in full conversion to cefotaxim (1). In all cases, the mixture containing the mixed anhydride in solvent 1 was a suspension with different amounts of solid. Although this heterogeneity of the reaction mixture is suitable for a batch process, it represents a limitation for extending the process toward a continuously running flow process as an attractive option for conducting this reaction. Screening for Solvent 2. The second step consisted of testing three different solvents that are known to dissolve 7ACA in combination with triethylamine for use as solvent 2 (Table 2). Since no alternative for dimethylacetamide was found as solvent 1 (as described above), it was fixed as solvent 1 for this study. For solvent 2, water and methanol were tested as alternatives to methylene chloride. It is noteworthy that the

use of methanol leads to a nearly full conversion to 1, which is comparable to the use of methylene chloride. The use of water also leads to a high conversion, but the formation of a suspension during the second reaction step makes this synthesis unattractive for use in a flow setup. Thus, methanol represents an interesting alternative to methylene chloride because the use of a chlorinated solvent can be avoided. Screening for Alternative Bases. In the next step, different alternatives for triethylamine were tested with respect to their conversion to 1 and solubility properties of the mixed anhydride. For this screening, the previously examined best reaction conditions utilizing dimethylacetamide as solvent 1 and methylene chloride as solvent 2 were applied together with different organic bases to test their influence on the solubility of 5 and conversion to 1. The results of this screening study are shown in Table 3. Besides a quantitative reaction yield when triethylamine was used, the best result was achieved when dicyclohexylamine was used as an alternative to triethylamine, with a product yield of 87%. All of the tested bases, however, led to lower conversion in comparison with triethylamine, and a higher solubility for the first reaction step was not observed. Thus, a change of triethylamine to one of the other tested bases would not lead to any advantages. D



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Development of a Flow Process in a Tube Reactor with a Diameter in the Millimeter Range. Today most of the common processes in the production of fine chemicals are handled discontinuously in batch mode. A large portion of these processes for the production of antibiotics were developed over 30 years ago and still persist nowadays. In terms of sustainability and new operating windows, continuous tube reactor technology, e.g., microreactors and flow reactors with diameters in the millimeter range, represent an attractive option for continuous production of cephalosporins. Currently there are already examples of continuous processes, e.g., in microstructured reactors, in the field of organic synthesis.10 A main structural difference between stirred vessels and continuous tube reactor devices is the surface to volume ratio, or specific surface area (av), which affects the heat exchange, as shown in Table 4.

that the diffusion effects in microreactors dominate: the radial diffusion compensates for the concentration differences along the tube.13 However, because of the presence of solid particles, a continuous tube reactor with a diameter in the millimeter range was used instead of a microreactor for our purpose. For the given reaction, a tube of fluorinated ethylene propylene (FEP) was used as “flow reactor”. The diameter had to be larger than that in common microreactors to prevent fouling and blocking problems because the mixed anhydride 5 is not completely soluble in dimethylacetamide. Furthermore, for the suspension a peristaltic pump was used. A negative impact of the pump pulsations on the mixing behavior was not observed. For this system, the heat transfer coefficient k is expected to fall between those of the plate heat exchanger and the stirred tank reactor in Table 4, even if the chosen reactor system has a higher specific surface area. Because FEP has a low thermal conductivity and the reaction was carried out at low velocities, the k value is expected to be lower than in a plate heat exchanger with diameter dH = 10 mm but still superior in comparison with a stirred tank reactor. The reaction system was built as shown in Figure 2. B100 and B200 contain the starting material mixtures. With respect to the stable hold time of the starting material mixtures in both of the feed tanks, the solution of 7-ACA was stored at 0 °C and is stable under these conditions. The suspension of the mixed anhydride is stable for at least 1 h. In this connection, 7-ACA was a clear solution when triethylamine was used. The mixed anhydride 5 formed from 3 and 4 leads to a suspension, which was stirred all the time to avoid sedimentation. The peristaltic pumps (P100 and P200) transport the raw material solutions to the Y-shaped polypropylene mixer (M100).14 The reactor (R100) consists of a 10 mL tube submerged in butyl glycol as a cooling material. The cooling bath was tempered with a cooling jacket through which the butyl glycol was permanently pumped. The reaction mixture is collected in B300. With an inner diameter of 4 mm, the reactor tube has a specific surface

Table 4. Heat Transfer Coefficient k and Specific Heat Transfer Surface Area av for Stirred Tank Reactors, Microstructured Reactors, and Plate Heat Exchangers11 parameter k (liquid/liquid) (W m−2 K−1) av (m2/m3)

microreactor (dH = 0.1 mm)a

plate heat exchanger (dH = 10 mm)a

stirred tank reactor

ca. 26000

ca. 2500

ca. 300

40000

400

ca. 40

a

dH is the diameter.

Microstructured reactors can be used in a laboratory environment to study kinetics in flow reactors. Because of the small channel diameter (

Process Development for Synthesizing the Cephalosporin Antibiotic

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