The iodination of trichloroaniline (VIII) via diazotization produced iodide (IX). Subsequent Heck reaction of iodide (IX) with tert-butyl acrylate (X) furnished tert-butyl trichlorocinnamate (XI), which was condensed with the sodium salt of methyl mercaptoacetate (XII), yielding thioether (XIII). After acid cleavage of the tert-butyl ester of (XIII), the resulting carboxylic acid (XIV) was coupled with glycine tert-butyl ester via activation as the corresponding N-hydroxysuccinimidyl ester. Then, saponification of the methyl ester group of (XV) afforded the intermediate acid (XVI).
Acylation of the cephem nucleus (XX) with the intermediate acid (XVI) via activation with either DCC or the Vilsmeier reagent provided amide (XXI). The ester groups of (XXI) were then cleaved with trifluoroacetic acid to give acid (XXII). Finally, condensation of (XXII) with pyridine thione (VII) furnished the title compound.
N-(3-Aminopropyl)morpholine (I) was protected as the N-Boc derivative (II) and then quaternized with iodomethane to produce the ammonium salt (III). Subsequent acid deprotection of (III) gave amine (IV). Treatment of 2,6-dimethyl-4-pyrone (V) with Lawesson抯 reagent in toluene yielded the thiono derivative (VI), which was coupled with amine (IV) to afford the pyridine thione (VII).
An improved procedure for the synthesis of intermediate (XVI) was further developed. Heck coupling of iodide (IX) with acrylic acid formed cinnamic acid (XVIII). This was converted to the corresponding acid chloride upon treatment with Vilsmeier reagent, and subsequent coupling with glycine tert-butyl ester gave amide (XIX). Selective chlorine displacement in (XIX) by means of the lithium salt of methyl mercaptoacetate, followed by in situ hydrolysis with LiOH, afforded acid (XVI).