Cephalosporin 7-thiomethyl

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). 

Cefmenoxime hydrochloride is a third generation cephalosporin antibiotic. Structurally, it possesses the (l-methyl-lH-tetrazoi-5-yl)thiomethyl moiety in the 3-position like several other compounds containing this structural element (moxalactam, cefoperazone, cefamandol), bleeding linked to vitamin K interaction has been reported. Cefmenoxime has activity similar to cefotaxime, ceftizoxime and moxalactam against E. coli, C. diversus, Klebsiella, P. Mirabilis, Salmonella, Shigella, Neiseria spp., S. pyogenes, S. Pneumoniae, and H. influenzae. It is relatively ineffective against Pseudomonas and Bacteroides. 

The addition of a methyl, methoxy or thiomethyl group at the 6-a-position of penicillin results in a reduction in antibacterial activity (Ho et al., 1973). In contrast, the addition of a 7-a-methoxy group to a cephalosporin results in compounds that are better transpeptidase enzyme inhibitors although they do not necessarily show better antibacterial properties (Indelicato and Wilham, 1974). 

Modification at C-2 of the cephalosporin skeleton has attracted limited interest, since those transformations which have been reported have not led to products with significantly improved antibiotic properties. Low-temperature methyl-thiolation of cephem sulphoxide (58) via its C-2 anion afforded thiomethyl derivative (59). The reaction proceeded stereospecifically from the least hindered side to give the a-isomer exclusively. When the reaction was carried out at a somewhat higher temperature (- 23 °C), the bis(methylthio)-compound... 

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