Cephalosporin nucleus

Chemical Modification. The chemistry and synthetic strategies used in the commercial synthesis of cephalosporins have been reviewed (87) and can be broadly divided into ( /) Selection of starting material penicillin precursors must be rearranged to the cephalosporin nucleus (2) cleavage of the acyl side chain of the precursor (2) synthesis of the C-7 and C-3 side-chain precursors (4) acylation of the C-7 amino function to introduce the desked acylamino side chain (5) kitroduction of the C-3 substituent and 6) protection and/or activation of functional groups that may be requked. 

In the synthesis of ceftazidime (40) (Fig. 8), the protected, preassembled arninothiazole side chain [68672-66-2] (60) is coupled to a protected 7-ACA first and the C-3 displacement step carried out last. By way of contrast, in the synthesis of ceftriaxone (39) (Fig. 9), the preformed C-3 substituent is introduced onto the cephalosporin nucleus in the first step and then the acyl-amino side chain is introduced. This last step is noteworthy for two reasons in that it demonstrates the use of an activated thio ester in the coupling step and that no protecting group chemistry is requited (192,193). 

There has also been extensive activity towards the replacement of the entire chemical route to 7-ADCA (Scheme 1.14) with a biocatalytic one. This is somewhat more complex than the above example, as the penicillin fermentation product requires ring expansion as well as side-chain hydrolysis in order to arrive at the desired nucleus. The penicillin nucleus can be converted to the cephalosporin nucleus using expandase enzymes, a process that occurs naturally during the biosynthesis of cephalosporin C by Acremonium chryso-genum and cephamycin C by Streptomyces clavuligems from isopenicUhn N (6-APA containing a 6-L-a-aminoadipoyl side chain). ... 

The cephalosporin nucleus is synthesized with a beta-lactam ring attached to a six-membered dihydrothiazine ring. Unlike the penicillin nucleus, the cephalosporin nucleus is much more resistant to beta-lactamase. Moreover, it has large areas for possible modifications. Modifications Rj in the acyl side chain alter the antibacterial activity, while modifications of R2 are associated with changes in the pharmacokinetics and metabolic parameters of the drug. 

Lactam antibiotics are natural or semisynthetic compounds whose basic nuclear structure consists of a -lactam ring coupled to a thiazolidine (five-membered) or a dihydrothiazine (six-membered) ring to form the penicillin or cephalosporin nucleus, respectively. To those nuclei, various side chains that determine most of the properties of the different -lactams are attached. All members of this group of antibiotics are readily attacked at the -lactam nitrogen by nucleophilic reagents such as hydroxyl ions, alcohols, and primary amines, as well as by secondary amines. They are also susceptible to electrophilic attack at both the... 

A consequence of the development of the large number of cephalosporins is that the molecular structures have become more and more complex. Alterations in the cephalosporin molecule have resulted in differences between cephalosporins in spectrum of activity, protein binding, peak serum level, serum half-life, route of excretion, cerebrospinal fluid levels and toxicity. Cephalosporins are semi-synthetic antibiotics derived from 7-aminocephalosporanic acid, which is also called the cephalosporin nucleus. The cephem ring ( nucleus") is composed of a (3-lactam ring fused with a dihydrothiazine ring (Figure 1). 

The cephalosporin nucleus was reported to be labile to ultraviolet light (260 nm). The decomposition of an aqueous solution of cephalosporin C, measured by loss of biological activity, was 90 within half an hour. 

This situation changed when an efficient chemical method was developed at Eli Lilly in Indianapolis, which would remove the side-chain of cephalosporin C to produce a bare cephalosporin nucleus, the so-called 7-aminocephalosporanic acid, from which a whole range of semi-synthetic cephalosporins could be produced. Of these, cephaloridine and cephalothin were the most widely used. Of even greater significance was the invention of some very clever chemistry, also by the Lilly group, which involved the conversion of the penicillin nucleus into the cephalosporin nucleus in a short sequence of chemical transformations (Fig. 2.2). This meant that the very cheap penicillin G could be converted into what became the best-selling cephalopsorin cephalexin (Keflex). This had excellent oral bioavailability, was very stable to metabolism, and resisted the actions of penicillinases. The other semi-synthetic cephalosporin that came to be widely used was cefaclor... 

Figure 12.2-8. Production of 7-ADCA has undergone remarkable changes. In the early days (left-hand side), chemical ring expansion of penicillin C resulted in the formation of the cephalosporin nucleus. The phenylacetyl moiety was then removed chemically. Later on, this last step was replaced by a biocatalytic step using penicillin amidase (middle). On the right hand side, a completely new route is presented. Dicarboxyl-7-ADCA is obtained directly by fermentation. A dicarboxyl amidase is used to remove the dicarboxyl group.

The development of commercial process technology for the penicillin nucleus (6-APA) and the cephalosporin nucleus (7-ACA) opened the way for chemical... 

In the crucial final step in the Cefalexin synthesis, the cephalosporin nucleus 7-ADCA is coupled with phenylglycine amide or ester. This is one of the first industrial examples of a synthesis reaction performed by enzymes. Until then, enzymes were mainly employed for hydrolysis the deacylation of penicillin G to give 6-APA (not shown), that of cephalosporin G to give 7-ADCA (Fig. 16) as well as the kinetic resolution of the DL-phenylglycine derivatives (Fig. 16) are examples. Also, similar processes were developed for other semi-synthetic antibiotics derived from phenylglycine and 4-hydroxyphenyl-glycine (Fig. 17). 

With some cephalosporin-allergic patients, in addition to recognition of the R1 structure, the R2 side chain and/or the whole cephalosporin molecule are recognized by sernm IgE antibodies. This was demonstrated by employing drug-solid phases prepared by linking HSA to the carboxyl group at position 4 on the cephalosporin nucleus. 

Chemical modification of the cephalosporin nucleus has taken two major approaches acylation of the 7-amino position and variation of the 3 -substituent. It has been known for many years that it is possible to effect a displacement of the acetoxyl group by nitrogen and sulfur nucleophiles (Bradshaw et al., 1968 Perlman, 1977), and some of the resultant products have been found to be highly active, broad-spectrum antibiotics of clinical importance. 

The significant observation that the introduction of a 7a-methoxy substituent into the cephalosporin nucleus confers -lactamase stability upon... 

We were unable to find the cephalosporin nucleus, 7-ACA, in fermentations of C. acremonium, but an attempt to obtain it by controlled acid hydrolysis of cephalosporin C was suggested by the relative acid stability of the 3-lactam ring of the latter. Experiments with Bronwen Loder (1959) showed that small amounts of 7-ACA could in fact be prepared in this way and that 7-ACA could be acylated to yield cephalosporins with higher activity than cephalosporin C. Whereas some of the procedures we had used in the isolation of penicillin N proved helpful in the isolation of 6-APA, the procedure introduced by the Beecham group for the phenylacetylation of 6-APA on paper facilitated our own work on 7-ACA. 

In addition to these deacylation or transacylation methods, much effort has been directed towards the introduction of a 7a-methoxy substituent into the cephalosporin nucleus. Such methods have also usually been applicable to penicillins. One of the first methods developed made use of the diazo intermediate (211) derived from 7-aminocephalosporanic acid (183). Treatment with bromo-azide yielded a mixture of isomers (212), which with silver tetrafluoroborate and methanol formed (213). Reduction and acylation readily followed. The stereoselective addition of methoxide to... 

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