Beta-lactams processes

As already noted, beta-lactam antibiotics interfere with biosynthesis of the primary component of cell membranes—pepfidoglycan. Because of the fact that this process does not take place in human and other mammalian cells, beta-lactam antibiotics are relatively non-toxic to humans. 

Thus, beta-lactam antibiotics can inihibit the process of synthesis of bacterial cell membranes in different ways, thus causing them to die quickly. 

Some types of microorganisms, in particular Chromobacterium violaceum, which in the process of performing vital functions can synthesize specific beta-lactam antibiotics that have a monocyclic structure are called monobactams. Nocardicins, in particular nocardicin A, are examples of such monobactams. 

Beta-lactam antibiotics are generally costly and marketed at a price of around 100 to 165/kg. Thus, even 1 % increase in yield via improvement in separation efficiency would offer substantial cost benefit in -lactam production. For a typical production plant of capacity 5 x 10 kg/annum, a gross annual benefit of 50,000-250,000 can be expected 192]. The capital investment in LM process, a typical process, the flow design of which is shown in Fig. 7, is also likely to be low... 

Non-ribosomally processed peptides represent a large class of natural products of microbial origin. Pharmaceutically important examples are antibiotics of the beta-lactam type (e. g., cephalosporin C) and glycopeptides of the vancomycin class as well as the immunosuppressant cyclic undecapeptide cyclosporine (Fig. 3.4). 

Ruthenium is certainly the most versatile catalyst in oxygen transfer processes. The recently reported [19] highly selective oxidations of beta-lactams shown in Fig. 7 illustrate what is possible with these reagents. 

The permeation of most drugs through cellular membranes is by the process of passive diffusion, a nonsaturable process that follows first-order kinetics. Concentration gradient and lipid solubility of the drug are important determinants of the rate of diffusion. Only a few drug molecules are substrates for active transport processes (eg, tubular secretion of beta-lactam antibiotics) these are saturable at high concentrations. Only very small ions (eg, Li+) or drugs (eg, ethanol) may penetrate biomembranes via aqueous pores. 

Scheme 19.17 Nucleophilic opening of penicillin s beta-lactam. This process occurs under basic conditions and is driven by the energetics associated with relieving the considerable bond-angle strain present in the 4-membered-ring. Two pathways are shown (i) The top results in acylation of a biological surface that has a good nucleophile such as the terminal amino-group on a lysine amino acid residue and, (ii) The lower represents a ready hydrolytic ring-opening by a water molecule to produce an inactive degradation product called penicilloic acid.

Scheme 19.20 Intramolecular opening of penicillin s beta-lactam. This process occurs under acidic conditions and is driven by the energetics associated with relieving the considerable bond-angle strain present in the 4-membered beta-lactam ring.

Bruggink A, Roos E C, de Vroom E (1998). Penicillin acylase in the industrial production of beta-lactam antibiotics. Org. Process Res. Dev. 2 128-133. 

This is an excellent way of synthesizing the beta-lactam structure, and it has been the subject of several reviews (e.g.. Ref. 18). This is one of the reactions first reported by Staudinger, which is shown in Scheme 5.40. Many variants of this process have since been discovered. 

Another application of the Hantzsch process is found in the synthesis of a monobactam antibiotic, Tigemonam. The monobactams are follow-ups to the penicilMns, both families being unique as derivatives of azetidinones (beta-lactams). Tigemonam also possesses a thiazole ling, which component is synthesized as in Scheme 9.20 from thiourea (shown in the -SH tautomeric form) and the chloroketone 9.26. 

Although thiazole derivatives are important as pharmaceuticals and are found also in natural products, the fully reduced form has its own importance, and as noted in Chapter 3 it is incorporated in the famous antibiotic penicillin (9.32). Penicillin was first produced by large-scale fermentation procedures, but it can also be made synthetically. The first process was that of J. Sheehan (see Chapter 3, section 3.2.5). A major hurdle to be overcome was the construction of the beta-lactam moiety fused to the thiazolidine ring. The Sheehan synthesis of ben-zylpenicillin is shown in Scheme 9.23, but many other derivatives can be made by modifications of the procedure. The first step involves the... 

The penicillins and cephalosporins, collectively known as beta-lactam antibiotics, are among the most widely used and valuable antibiotics currently available. Ben-zylpenicilhn (penicillin G) and phenoxymethylpenicillin (penicillin V) are derived from Penicillium molds by fermentation, while half-synthetic penicillins are derived by chemical modification of the penicillin nucleus, 6-aminopenicillanic acid (6-APA), itself obtained either by splitting the side chain from benzylpenicillin through an enzymatic process or via a chemical deacylation reaction. 

The oxidation of the sugar-containing carboxylic acid 52, in the presence of acetate, leads to the unsymmetrical bis-acetal 53 [30]. In a similar manner, 0,N-acetals can be efficiently constructed from alpha-amino-acids [24]. This process has been employed as a key step in the synthesis of some beta-lactam antibiotics [31]. The oxidative decarboxylation of alpha-alkoxy acids 58 in methanol provides a simple and efficient route to the formation of MOM ethers and obviates the use of the highly toxic MOMCl [32]. Furthermore, Mark6 et al. demonstrated that Hofer-Moest reaction of dialkoxy carboxylic acids 60 offers an easy and general route to variously functionalized orthoesters [33]. These are usually difficult to prepare by alternative methodologies and some of them can only be assembled using this electrochemical process. 

Tramper, J., H. H. Beeftink, A. E. M. Janssen, L. P. Ooijkaas, J. L. van Roon, M. Strubel, and C. G. P. H. Schroen. 2001. Biocatalytic Production of Semi-Synthetic Cephalosporins Process Technology and Integration. In Synthesis of Beta-Lactam Antibiotics Chemistry, Biocatalysis and Process Integration, edited by A. Bruggink, 206-249. Springer-Verlag. 

Cheung, L. L. W., Yudin, A. K. (2010). Synthesis of highly substituted cyclobutane fused-iing systems from N-vinyl beta-lactams through a one-pot domino process. Chemistry - A European Journal, 16, 4100-4109. 

Boesten WHJ, Moody HM (1995) Process for the enzymatic preparation of a beta-lactam derivative. Patent WO 9503420... 

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