Cephalosporin derived from

Capturing desired products from aqueous reaction mixtures (in a form useful for further synthesis steps) using monomeric agents is well known. We successfully applied such a technology to the extractive esterification of cephalosporin derivatives from a filtered cephalosporin fermentation broth65 and a solution of a 3-... 

Methylene Cephalosporins and 3-Heteroatom Cephalosporins. A number of clinically important cephalosporins have a hydrogen or a heteroatom at C-3 instead of a methyl or substituted methyl, requiring removal of the C-3 methyl from either of the commercially available starting materials. Removal is conveniently achieved via ozonolysis of an exocydic methylene group, and a number of routes have been developed to produce such 3-methylene cephalosporins from both penicillins and cephalosporins derived from cephalosporin C. Industrially, the most viable routes to 3-methylenecephams are via penicillins, and thus the penicillins serve as the precursors for the C-3 heteroatom cephalosporins (87). This chemistry has been reviewed rather extensively, along with the... 

Penicillin and Cephalosporin Derivatives from Reactions of Heterocycles with Ketenes... 

In the case of thienamycin (Fig. lb) the absolute stereochemistry at C-5 was unambiguously deterrnined from the ene-lactam (16). The resultant (R)-aspartic acid (17) demonstrated that the absolute stereochemistry at C-5 of thienamycin is (R), corresponding to that found in the C-5 position of both penicillins and cephalosporins. Confirmation of the stereochemical assignments in both thienamycin (2) and the olivanic acid MM 13902 (3, n = 0) has been confirmed by x-ray crystallography (19,21,22). The stmctural determination of the nonsulfated derivatives from S. olivaceus (23), PS-5 (5) (5), the carpetimycins (6), and the asparenomycins (7) followed a similar pattern. 

In these papers, the carboxylic acid to be protected was a stable, unsubstituted compound. Harsh conditions were acceptable for both formation and cleavage of the amide. Typically, a simple secondary amide is very difficult to cleave. As the pKa of the conjugate acid of an amide decreases, the rate of hydrolysis of amides derived from these amines increases. The dimethylamide of a cephalosporin was prepared as follows using 2,2 -dipyridyl disulfide. ... 

Ceftiofur (57) differs from the preceding cephalosporin derivatives in that it ha.s a thioester moiety at C-3. This can be introduced by displacement of the C-3 acetyl group of 7-aminocepha-losporanic acid (40) with hydrogen sulfide and esterification with 2-furylcarboxylic acid to give synthon 5reacted with trimethylsilylated oximinoether derivative 55 (itself obtained from the corresponding acid by reaction with dicyclohexylcarbodiimide and 1-hydroxy-benzotriazole) to produce, after deprotecting, ceftiofur (57) [18]. 

The (5-lactam antibiotics are now so extensively described that we cannot attempt to summarize the literature. Since our emphasis is on sulfur, we note that the sulfur atoms of the thiazolidine or dihydrothiazine rings derive from a common tripeptide, 8-(L-a-aminoadipyl)-L-cysteinyl-D-valine 1, ACV or Arnstein tripeptide . ACV is converted to a (5-lactam structure, isopenicillin N 2 and thereafter, the two pathways diverge, i.e. to benzylpenicillin 3 or to cephalosporin C 4 (Scheme 1). There have been extensive studies of the genes and enzymes involved in (5-lactam biosynthesis.18,19... 

Scheme 6.92 Generation of the cephalosporin-derived cyclic allene 450 from the cephalosporin / -S-oxide triflate 449 and trapping of450 by (Z)-/J-deuterostyrene, furan, 2-acetylfuran, furan-3-carboxylic acid dimethylamide, N-tert-butoxycarbonylpyrrole, pyrrole and N-methylpyrrole.

Scheme 6.93 Generation ofthe cephalosporin-derived cyclic allene 458 from the cephalosporin a-S-oxide triflate 457 and trapping of 458 by furan.

Intermediates such as 224 resulting from the nudeophilic addition of C,H-acidic compounds to allenyl ketones such as 222 do not only yield simple addition products such as 225 by proton transfer (Scheme 7.34) [259]. If the C,H-acidic compound contains at least one carbonyl group, a ring dosure is also possible to give pyran derivatives such as 226. The reaction of a similar allenyl ketone with dimethyl mal-onate, methyl acetoacetate or methyl cyanoacetate leads to a-pyrones by an analogous route however, the yields are low (20-32%) [260], The formation of oxaphos-pholenes 229 from ketones 227 and trivalent phosphorus compounds 228 can similarly be explained by nucleophilic attack at the central carbon atom of the allene followed by a second attack of the oxygen atom of the ketone at the phosphorus atom [261, 262], Treatment of the allenic ester 230 with copper(I) chloride and tributyltin hydride in N-methylpyrrolidone (NMP) affords the cephalosporin derivative 232 [263], The authors postulated a Michael addition of copper(I) hydride to the electron-... 

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]. 

Cephalosporins such as cefixime (5.40) and cefotaxime (5.41) undergo epimerization at C(7) under alkaline conditions without preliminary /3-lactam ring opening. The epimerization is believed to begin with the removal of the acidic H-atom at C(7). The acidity of this proton derives from the resonance effect of the neighboring carbonyl group (Fig. 5.13) enhanced by the presence of electron-withdrawing substituents at C(3 ) [113][114],... 

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. 

The penicillins, cephalosporins, carbapenems, and monobactams all work in basically the same way. However, they have different therapeutic uses which derive from several factors which organisms are susceptible to which agent, which may be taken orally and which mnst be injected, which do and do not penetrate into the central nervons system, and so forth. The target of these antibiotics is the bacterial cell wall. 

Cefditoren pivoxil (12 Spectracef TAP Pharmaceuticals, 2001) is an oral prodrug of cefditoren (13), a derivative of cephalosporin isolated from Cephalosporium species. The prodrug is readily hydrolyzed by intestinal esterases to the microbiologically active cephalosporin cefditoren (13)... 

The quinolone antibiotics feature as the one main gronp of antibacterial agents that is totally synthetic, and not derived from or based upon natural products, as are penicillins, cephalosporins, macrolides, tetracyclines, and aminoglycosides. The first of these compounds to be employed clinically was nalidixic acid more recent drugs in current use include ciprofloxacin, norfloxacin, and ofloxacin... 

In the cases of a series of allyl chlorides derived from the antibiotic cephalosporin, reduction leads to a delocalised carbanion, which is protonated on die ester... 

Cephalosporins display an antibiotic mechanism of action identical to that of the penicillins. Cephalosporin C (Figure 1.14) is the prototypic natural cephalosporin and is produced by the fungus Cephalosporium acremonium. Most other members of this family are semi-synthetic derivatives of cephalosporin C. Chemical modification normally targets side-chains at position 3 (the acetoxymethyl group) or 7 (derived from D-a-aminoadipic acid). 

COPD exacerbations. Therefore, in exacerbation treatment with antibiotics is justified when the patient has at least two of three features of increased dyspnea, increased sputum volume, and sputum pu-rulence. Antibiotic choice will depend on local experience derived from local bacteriological sensitivity data. Older, less costly compounds such as tetracycline, doxycycline, amoxicillin, erythromycin, cefaclor etc. are often as effective as newer, more expensive ones. If resistant organisms are suspected or when the severity of the patients clinical condition puts them at high-risk of treatment failure, a second or third generation cephalosporin, fluoroquinolone, newer macrolide or broad-spectrum penicillin may be preferred. In cases of recurrent infection prolonged courses of antibiotics continuous or intermittent, may be useful. 

The cephalosporins are semisynthetic antibiotics derived from products of various microorganisms, including Cephalosporium and Streptomyces. All cephalosporins... 

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. 

Imines derived from cephalosporin esters 4 can be alkylated in a similar manner4 (see Table 3). 

The cephalosporins are semisynthetic -lactams derived from cephalosporin C, a natural antibiotic. Their active basic nucleus consists of a six-membered dihydrothiazine ring fused to a -lactam ring (Fig. 3.3.2). Cephalosporins have some desirable quality characteristics that are generally deficient in penicillins. The popularity and usefulness of cephalosporins results from their resistance to many... 

---