The condensation of 2-(methoxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (I) with 7-aminocephalosporanic acid (II) by means of dicyclohexylcarbodiimide in CH2Cl2 gives 7-[2-(methoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]cephalosporanic acid (III), which is deprotected by means of formic acid in water yielding 7-[2-(methoxyimino)-2-(2-aminothiazol-4-yl)acetamido]cephalosporanic acid (IV). Finally, this compound is condensed with 5-(carboxymethyl)-2-mercapto-4-methyl-1,3-thiazole (V) by means of NaHCO3 or NaOH in hot water.
Using a different protection strategy, aminoacid (IV) was protected as the N-phenylacetyl derivative (VII) by treatment with acid chloride (VI). Subsequent DCC-mediated coupling with the cephem derivative (III) furnished (VIII). The N-phenylacetyl group was then selectively removed by enzymatic hydrolysis with penicillin G amidase.
In a further procedure, 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetic acid (IV) was activated as the mixed anhydride (V) by treatment with tosyl chloride and triethylamine. After protection of the cephem thioether (III) by silylation with either chlorotrimethylsilane or with bis(trimethylsilyl)acetamide, coupling with the mixed anhydride (V) gave rise to the title compound.
Displacement of the acetate group of 7-aminocephalosporanic acid (I) with the mercapto thiazole (II) yielded thioether (III). This was then acylated with 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetic acid (IV) in the presence of DCC and HOBt to furnish the corresponding amide.