Coupling of ethyl glyoxylate derivative (I) with Boc-L-Alanine (II) by means of EDC and DMAP in DMF provides compound (III), whose ethyl ester is subjected to saponification by treatment with NaOH in EtOH to furnish carboxylic acid (IV). Condensation of (IV) with methoxyamine (NH2OMe) in THF/H2O yields methoxyimino acetic acid derivative (V), which is then coupled to pivaloyloxymethyl 7-amino-3-cephem-4-carboxylate (VI) in CH2Cl2 by means of phosphorus oxychloride (POCl3) in DMF/EtOAc and N-trimethylsilylacetamide to give compound (VII). Finally, the desired compound is obtained after treatment of (VII) with TFA and anisole in CH2Cl2 for Boc removal . Alternatively, methoxyimino acetic acid derivative (V) can be converted into intermediate (VII) by coupling with 7-amino-3-cephem-4-carboxylic acid (VIII) by means of POCl3 in DMF/EtOAc and N-trimethylsilylacetamide in CH2Cl2 to provide derivative (IX), followed by condensation with iodomethyl pivalate (X) by means of potassium acetate in DMF.
Coupling of pivaloyloxymethyl 7-amino-3-cephem-4-carboxylate (VI) and methoxyimino acetic acid derivative (XI) by means of POCl3 and pyridine in CH2Cl2 gives compound (XII) (alternatively (XII) can be obtained by condensation of ceftizoxime (CZX) (XIII) with iodomethyl pivalate (X) in N,N-dimethylacetamide (DMAc) in the presence of dicyclohexylamine). Coupling of (XII) with Boc-L-alanine (II) by means of EDC and DMAP in CH2Cl2 gives intermediate (VII), whose Boc protecting group is removed by treatment with either HCl/isopropanol in formic acid or TFA and anisole in CH2Cl2. Yet another strategy can be followed, involving the coupling of pivaloyloxymethyl 7-amino-3-cephem-4-carboxylate (VI) with derivative (XIV) by means of Et3N in N,N-dimethylacetamide.