Sulfur- and 3-Nitrogen-Substituted Cephems

The discovery that cefaclor and CGP 9000 are potent and orally active antimicrobial agents gave a strong impetus to continue chemical modifications at the C-3 position. 

A similar displacement of a more reactive mesylate substrate (176, X = CH3) was also carried out with heterocyclic thiol (5-mercapto-l-methyltetrazol) by following the same sequence of reactions. After removal of the ester and amino protecting groups, 1-methyltetrazolyl thioether was isolated in crystalline form. 

Conversion of the 3-thiomethyl ether (180) to the sulfone (181) was accomplished by oxidation with 2 equiv of m-chloroperbenzoic acid. Reduction of the sulfoxide group in 181 with phosphorous trichloride in DMF gave the methylsulfonyl derivative (182). Removal of the protective groups by a known procedure yielded the acid (183) which was devoid of biological activity. 

Antibacterial in vitro and in vivo tests show that among the thioethers prepared the 3-thiomethyl-3-cephem has inhibitory activity comparable to that of the corresponding oxygen analog (Table XVI). The 3-thiomethyl compound has a half-life, as determined in phosphate buffer at pH 7.4 and 37°C, of 2.5 hr (Scartazzini, 1977). 

The finding that the 3-amino-3-cephem (185) is readily available on treatment of the enol ester (184) with ammonium chloride and pyridine in ethanol induced Scartazzini and co-workers (1975) to utilize this in- 

---