A series of 7B-[2-(5-aminooxadiazol-3-yl)-2-Z-methoximinoacetamido]-3-cephem-4-carboxylic acids (7a-g) were synthesized and evaluated microbiologically. Although somewhat less active than cefotaxime 7a~g showed good antimicrobial activity against a wide variety of Gram-positive and Gram-negative bacteria. The ~-lactamase stability of 7a and 7f was also discussed.Reports concerning the microbiological evaluation of novel aminoheterocyclic methoxime cephalosporin derivatives1) have prompted us to describe the synthesis and in vitro biological evaluation of a similar series of aminooxadiazole methoxime cephalosporins (1). The requisite aminooxadiazole methoximinoacetic acid (6) was prepared from the appropriately substituted amide oxime 3 as outlined in Scheme 1. Ethyl 2-methoximinocyanoacetate (2a) was reacted with hydroxylamine to produce 3a as a single isomer of unknown geometry. Very subtle changes in the procedure and/or the purity of the starting nitrile greatly affected the yield of 3a presumably in part due to the formation of the corresponding hydroxamic acid. Attempts to circumvent the poor yields of 3a by first converting 2a to imidate ester 2b seemed plausible; however reactions of 2a with either anhydrous HC1 -EtOH5) or NaOCH3 -EtOH3) failed to produce 2b.Acylation of 3a with trichloroacetyl chloride and subsequent ring closure yielded 5-trichloro-[1,2,4]oxadiazole 4 as a mixture of isomers. Reaction of 3a with p-toluenesulfonyl chloride (p-TsCl) -2,6-lutidine yielded 3b. Reaction of 3b in the manner described above (trichloroacetyl chloride) also yielded 4 as well as TsCI suggesting conversion back to 3a prior to reaction with trichloroacetyl chloride. An ether solution of 4 was added dropwise to liquid ammonia at -33°C and the resulting mixture was stirred overnight allowing the ammonia to evaporate. The residue was triturated with Et20 and filtered, leaving a substantial amount of insoluble material which was shown by NMR to be the E-amino carboxamide 5b. The filtrate was concentrated and recrystallized from EtOH to yield the Z-amino ester 5a. This material was shown by NMR and TLC to be a single isomer, which when
