From Penicillins

From Penicillins (Type C). The important problem of the relationship between penicillin, cephalosporin, and isothiazole derivatives has recently interested several research groups. This topic is also considered in Chapter 16. The anion of azetidinesulphenic acid (20) undergoes spontaneous fragmentation and re-cyclization, giving the isothiazolone derivative (21) in high yield. Direct treatment of penicillin sulphoxides with bases has previously given isothiazoles similarly, and further examples continue to be reported. The 4-mercapto- 

The base-catalysed epimerization of penicillins and their sulphoxides has been described recently. Epimerization of penicillin sulphoxides (23) in the presence of l,5-diazabicyclo[4,3,0]non-5-ene ( DBN ) is attended by the production of the isothiazolone (24), presupposing the occurrence of j3-elimination. The possible 

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L. G. Kadsen, Use of Semaglase in 6APA Production from Penicillin k/ pubhcation B 528, Novo Nordisk, Bagsvaerd, Denmark, 1990. 

A very efficient one-pot procedure for the production of 3-hydroxy-3-cephems (45) has been developed which gives the desired product in almost 80% overall yield from (43a) which is readily available from penicillin. TTie sequence of reactions is (1) mesylation to give (43b), (2) formation of enamine (43c), (3) bromination to afford (44) and (4) hydroly-sis/cyclization with hydrochloric acid in methanol to afford (45) which, in some cases, crystallizes directly from the reaction mixture (B-82MI51000). 

A 30 ml sample of broth from penicillin fermentation is filtered in the laboratory on a 3 cm2 filter at a pressure drop of 5 psi. The filtration time is 4.5 minutes. Previous studies have shown that the filter cake of Penicillium chrysogenum is significantly compressible with S = 0.5. If 500 litres of fermentation broth from a pilot plant have to be filtered in 1 hour, what size of filter is required for a pressure drop of 10 psi and 5 psi Neglect the resistance of the filter medium. 

The clavams differ from penicillins (based on the penam structure) in two respects, namely the replacement of S in the penicillin thiazolidine ring (Fig. 5.1) with oxygen in the clavam oxazolidine ring (Fig. 5.5 A) and the absence of the side-chain at position... 

APA from penicillin G, 7-ACA from cephalosporin C, 7-ADCA from desaacetoxy cephalosporin G Biotransformation in steroids, e.g. cortexolone to hydrocortisone and prednisolone Food additives Lactic Acid (now a bulk chemical for making polylactate). Citric acid, L-Glutamate, L-Lysine, etc. Vitamines C, B2, B12 Acarbose (antidiabetic drug)... 

Rasor and Tischer (1998) have brought out the advantages of enzyme immobilization. Examples of penicillin-G to 6-APA, hydrolysis of cephalospwrin C into 7-ACA, hydrolysis of isosorbide diacetate and hydrolysis of 5-(4-hydroxy phenyl) hydantom are cited. De Vroom (1998) has reported covalent attachment of penicillin acylase (EC 3.51.11) from E.Coli in a gelatine-based carrier to give a water insoluble catalyst assemblase which can be recycled many times, and is suitable for the production of semi-synthetic antibiotics in an aqueous environment. The enzyme can be applied both in a hydrolytic fashion and a synthetic fashion. 6-APA was produced from penicillin-G similarly, 7-ADCA was produced from desa acetoxycephalosporin G, a ring expansion product of penicillin G. 

Later in his career, Nagata s group made notable and useful synthetic contributions to the beta lactam field. This included developing an economically feasible synthetic method for the industrial manufacture of 1-oxacephems from penicillin G. These efforts led to the worldwide introduction in the 1980s of several clinically prominent and effective beta lactam antibiotics of the 1-oxacephem class including moxalactam. 

Semi-synthetic penicillins are accessed from 6-aminopenicillanic acid, (6-APA), derived from fermented penicillin G. Starting materials for semi-synthetic cephalosporins are either 7-aminodesacetoxycephalosporanic acid (7-ADCA), which is also derived from penicillin G or 7-aminocephalosporanic acid (7-ACA), derived from fermented cephalosporin C (Scheme 1.10). These three key building blocks are produced in thousands of tonnes annually worldwide. The relatively labile nature of these molecules has encouraged the development of mild biocatalytic methods for selective hydrolysis and attachment of side chains. 

Li D, Yang M, Hu J et al (2009) Antibiotic-resistance profile in environmental bacteria isolated from penicillin production waste water treatment plant and the receiving river. Environ Microbiol 11 (6) 1506-1517... 

Recovery of valuable products from penicillin, riboflavin, streptomycin, and vitamin B12 fermentation has been recommended as a viable waste control strategy when incorporated into animal feeds or supplements. Penicillin wastes, when recovered for animal feed, are reported to contain valuable growth factors, mycelium, and likewise evaporated spray-dried soluble matter [31,32,34]. 

There is an additional protection against residues, because antibiotics in meat tend to be destroyed by cooking.. For example, Broquist and Kohler found that chicken breast muscle containing 12 parts per million of chlortetracycline had 0.14 parts per million after roasting at 230 C for 15 minutes and no detectable amounts after half an hour. The original level of 12 ppm was about 60 times as high as would be produced by 400 ppm in the animal feed, without a withdrawal period W. The UK Swann Committee reported that the only possible effect of residues on consumers arose from penicillin in milk from cows treated for udder infections in which the withdrawal time for the antibiotic had not been observed. Cases of skin rashes were reported from the consumption of such milk by sensitive patients. The Committee commented that "there are no known instances in which harmful effects in human beings have resulted from antibiotic residues in food other than milk" ( ) ... 

The widespread occurrence of penicillin sensitivity, and the survival of penicillin residues in meat following cooking, led Katz to point out that "since up to 10% of the population is potentially sensitive to penicillin and its breakdown products, the risk is too great to be ignored," and to warn against injections unless these are carefully controlled. The use of withdrawal procedures should protect consumers against possible sensitivity reactions from penicillin residues. 

Hameed TK, Robinson JL. Review of the use of cephalosporins in children with anaphylactic reactions from penicillins. Can J Infect Dis 2002 13(4) 253-8. 

Penicillin amidase is used industrially to produce 6-aminopenicillanic acid (6-APA) from penicillin G or V (see section 4.5). Acid is produced during the process and this will inactivate the enzyme. One way of overcoming this problem is by using a fixed bed reactor with immobilized enzyme. The substrate is pumped very rapidly... 

Early examples of successful, highly diastereoselective alkylations of bicyclic /1-lactams include reactions of the enolates from penicillin and cephalosporin derivatives (e.g., 1 and 4). These enolates have also been used in aldol-type additions, acylations and in the preparation of hetero-substituted penicillins and cephalosporins1. 

It is derived from penicillin nucleus 6-aminopenicillanic acid. It has broad spectrum of activity against both gram positive and negative organisms. It is more potent than carbenicillin against Pseudomonas. 

Dawson and I (Biochim. Biophys. Acta 59, 103, 1961) studied the interaction of two phospholipases with their common substrate, lecithin, and concluded that the enzyme must extend an active site ( masculine enzyme) into the planar lecithin monolayer or bilayer, respectively, in order to reach the ester bond. The phospholipase A2 from penicillin notaton required a net negative charge at the substrate surface, the a toxin from Cl. welchii, a positive one, to facilitate penetration. 

Epidemiological studies carried out on humans are very useful because a hazard can be directly characterized without need for extrapolation. Unfortunately, the statistical power of this methodological tool is too weak to identify with the required accuracy the adverse effects of lower quantities of residues unlikely to produce acute toxic effects. The evidence of allergic effects in humans from penicillin residues is a fortunate exception. More frequently, useful information can be obtained for drugs also used in human medicine. 

Lamberet, G. and Menassa, A. 1983. Purification and properties of an acid lipase from Penicillin roqueforti J. Dairy Res. 50, 459-468. 

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