Cephalosporin 7-substituted

The next advance came when it was discovered that cephalosporins substituted at the 7-position were active. 

For a viable commercial process, the selection of materials and the choice of synthetic route is governed primarily by cost, not by overall yield. The selection of starting material is dictated usually by the desked C-3 substituent. For cephalosporins containing 3-acetoxymethyl or 3-(substituted)methyl such as 3-thiomethyl and 3-aminomethyl derived moieties, the most dkect synthetic route is from cephalosporin C, whereas pencillin V or G is the preferred starting material for the synthesis of the C-3 methyl cephalosporins. The three chemical transformations (2), (5), and 6) can potentially be carried out in a variety of ways, the precise sequence being determined by a balance of competing factors such as cost and optimization of yield (87). 

Because the integrity of the dihydrothiazine ring and its C-4 carboxyl substituent is crucial to useful antimicrobial activity, reactions involving this part of the cephalosporin molecule are usually undesirable. The possibilities for sulfur oxidation or alkylation, substitution at C-2 which is adjacent to both sulfur and a double bond, double bond isomerization and addition reactions, and the influence of a free carboxylic acid must all be considered in designing reactions to selectively modify other cephalosporin functionalities. 

A number of di- and trisubstituted hydrazides of penicillin and cephalosporin derivatives were prepared to study the effect of A-substitution on ease of oxidative cleavage. ... 

Benzenesulfenamide and a number of substituted benzenesulfenamides (compounds B, C, and D) have been prepared to protect the 7-amino group in cephalosporins. They are cleaved by sodium iodide (CH3OH, CH2CI2, AcOH, 0°, 20 min, 53% yield from sulfenamide B)."... 

There are very few totally synthetic antibiotics presently on the market. One of these is the 1-oxacephem, moxalactam (96). One may speculate that the enhanced potency of moxa-1actam stems in part from the substitution of the smaller oxygen atom for the sulfur normally present in the six-membered ring of cephalosporins thereby enhancing the reactivity of the adjoining four-membered ring. It is also partly a measure of the present stage of development of chemical synthesis and of the relative economics of production of 7-aminocephalosporanic acid that such an involved synthesis apparently is economically competitive. 

The method developed for the assembly of 2-166 has a broad scope. Scheme 2.39 shows a variety of differently C-3-substituted cephalosporins obtained from allene 2-164 in yields ranging from 68% to 95%. 

Some empirical observations are significant in this respect. For example, the demand for brand products is fairly sensitive to the price of generics, and even in some cases to the price of brand name therapeutic substitutes. In an estimate of the parameters of the demand function of brand products and generics in the cephalosporin submarket in the USA, a high price elasticity was observed between brand products and generics, and also in some cases, although to a lesser extent, between therapeutic substitutes.4... 

In contrast, with penicillins, cephalosporins, and monobactams where the substituents are cis to each other across the C3 - C4 bond, clockwise rotation can occur without conflict with protein side chains, and will leave the path open for the water molecule to attack and hydrolyze the ester group in B (Scheme 10). Thus, czs-substituted monobactam, as well as penicillins and cephalosporins are rapidly hydrolyzed by class C enzymes (Scheme 10). If this rotation could be prevented by a suitable structural modification, the access of the water molecule to the ester bond will be blocked, which would result in increased stability of the acyl-enzyme complex. 

Scheme 6.91 Nucleophilic substitutions at the cephalosporin triflate 416 and mesylate 443, believed to proceed via the cyclic allenes 417 and 444, respectively.

Some cephalosporins can be both substrates and inhibitors of /3-lactamases. The acyl-enzyme intermediate can undergo either rapid deacylation (Fig. 5.4, Pathway a) or elimination of the leaving group at the 3 -position to yield a second acyl-enzyme derivative (Fig. 5.4, Pathway b), which hydrolyzes very slowly [35][53], Thus, cephalosporins inactivate /3-lactamases by a mechanism similar to that described above for class-II inhibitors. It has been hypothesized that differences in the rate of deacylation of the acyl-enzyme intermediates derive from their different abilities to form H-bonds. A H-bond to NH in Fig. 5.4, Pathway a, may be necessary to assure a catalytically essential conformation of the enzyme, whereas the presence of a H-bond acceptor in Fig. 5.4, Pathway b, may drive the enzyme to an unproductive conformation. The ratio between hydrolysis and elimination, and, consequently, the relative importance of substrate and inhibitor behaviors of cephalosporins, is determined by the nature of the leaving group at C(3 ). An appropriate substitution at C(3 ) of cephalosporins may, therefore, increase the /3-lactamase inhibitory properties and yield potentially better antibiotics [53]. 

The /3-lactam structure can also react with active-serine hydrolases other than PBPs and /3-lactamases. It has been shown that appropriately substituted cephalosporins (e.g., 5.18) are potent mechanism-based inactivators of human leukocyte elastase (HLE, EC 3.4.21.37), a serine endopeptidase involved in the pathogenesis of pulmonary emphysema and other connective tissue diseases [57-60]. Subsequent work has demonstrated that substituted /3-lactams such as 5.19 or 5.20 are more stable HLE inhibitors and have improved potencies [61-63]. 

Now we turn to a discussion of the influence of a-substitution at C(6) or C(7) on the chemical reactivity of the lactam ring (Table 5.4,B). This substitution has been introduced mainly to improve lactamase stability (see Sect. 5.2.2.2). The insertion of an additional a-substituent at C(6) or C(7) of penicillins or cephalosporins, respectively, has a relatively small effect on the rate of base hydrolysis [82] [83], 6a-Methoxypenicillin is hydrolyzed at a rate that is approximately half that observed for the unsubstituted parent penicillin. This decrease is due mainly to unfavorable steric interaction between the... 

Penicillins C(6a)-substitution Cephalosporins C(7a))-substitution Inductive and steric effects Steric effect of R = MeO => approx, twofold decrease Steric effect of R = Me => ca. 10-fold decrease Decreased [73][82][83]... 

Fig. 5.8. An a-amino group in the acylamido side chain off)-lactams increases the rate of degradation in alkaline media by favoring an intramolecular nucleophilic reaction yielding piper-azine-2,5-dione products (e.g., 5.31 and 5.33). a) a-(2-Amino-2-phenylacetyl)cephalosporins b) arylglycine-substituted monobactams c) 6a-epiampicitlin (5.32). 

Stannyl cuprates couple with vinyl halides or triflates [16c-d, 85], and a vinyl stannane produced this way has been used in the synthesis of 7-[( )-alkylidene]-cephalosporins [117]. Vinyl substitution reactions starting from dihydrofurans are... 

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