Arylmethyl-, 3-Heteroarylmethyl-, and 3-Fluoromethyl-3-cephems

The Ciba-Geigy researchers, attempting cleavage of the 2-cephem benz-hydryl esters (213) with trifluoroacetic acid in the presence of anisole, found that, besides an ester cleavage, a mixture of para- and ortho-substituted anisyl derivatives (214 and 215) was obtained. Similarly, the use of other types of aromatic C-nucleophiles (i.e., phenol, thiophene) in the same type of reactions gave compounds of similar structure (216). 

TABLE XX Minimum Inhibitory Concentration Values of 3-Arylmethylcephalosporins  

aureus Penicillin-resistant 5. aureus E. coli K. pneumoniat 

Muller and others (1975) described the preparation of 3-fluoromethyl-3-cephem esters and their corresponding acids. The deacetyl-2-cephem benzhydryl ester (218) was treated with 2-chloro-l,l,2-trifluorotriethyl-amine, and after chromatography 3-fluoromethyl-2-cephem ester (219) was isolated in 36% yield as a crystalline substance. Oxidation of 219 with m-chloroperbenzoic acid yielded the sulfoxide (220) which was subsequently reduced to 3-fluoromethyl-3-cephem ester 221. Treatment of 221 with PCls-pyridine at -5 to - 10 C resulted in side-chain cleavage and isolation of the nucleus (221, R = H) in 74% yield. Reacylation of 221 with the mixed anhydride, made from (V-BOC-D-phenylglycine and isobutylchloroformate, provided 222 from which the crystalline acid (223) was prepared by treatment with trifluoroacetic acid in anisole. The acid displayed only low antibacterial activity in vitro and in vivo, because it is unstable in aqueous solution. 

This group was also able to prepare 3-difluoromethyl-3-cephem (225) by treatment of the aldehyde (224) with 7 equiv of piperidino sulfur trifluoride. The ester protective group in 225 was removed with trifluoroacetic acid, and subsequently the side-chain amide was cleaved with PCI5 in pyridine, giving the nucleus (227). Acylation of 227 afforded the 

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