The methylation of ethyl 3-oxo-2-hydroxyiminobutyrate (I) with dimethyl sulfate and Na2CO3 in methanol gives ethyl 3-oxo-2-methoxyiminobutyrate (II), which is brominated with Br2 in CHCl3 to afford ethyl 4-bromo-3-oxo-2-methoxyiminobutyrate (III). The cyclization of (III) with thiourea (A) in refluxing ethanol affords ethyl 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate (IV), which is acylated with chloroacetyl chloride in dimethylacetamide to yield ethyl 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetate (V). The hydrolysis of (V) with KOH in ethanol-water gives the corresponding free acid (VI), which is treated with PCl5 in methylene chloride to obtain the acyl chloride (VII). The condensation of tert-butyl 7-aminocephalosporanate (VIII) with (VII) by means of pyridine in methylene chloride gives tert-butyl 7-[alpha-methoxyimino-(2-chloroacetamidothiazol-4-yl)acetamido]cephalosporanate (IX), which is desacylated with thiourea and triethylbenzylammonium bromide in THF-ethanol yielding tert-butyl 7-[alpha-methoxyimino-alpha-(2-aminothiazol-4-yl)acetamido]cephalosporanate (X), which is hydrolyzed with trifluoroacetic acid to afford the free cephalosporanic acid (Xl). Finally, this compound is condensed with 1-methyl-5-mercaptotetrazol (XII) by means of NaHCO3 and triethylbenzylammoniurn bromide in water.
The condensation of (VII) or the free acid (VI) by means of pyridine or isobutyl chloroformate, respectively, with 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (XIII) gives 7-[alpha-(2-chloroacetylamidothiazol-4-yl)-alpha-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (XIV), which is finally desacylated with thiourea (A) and benzyltriethylammonium bromide as before.