The reaction of 7-beta-(D-5-phthalimido-5-carboxylvaleramido)-3-hydroxy-methyl-3-cephem-4-carboxylic acid (I) with diketene in CH2Cl2 gives the 3-(3-oxobutyryloxy)methyl derivative (II), which is treated with triethylamine-N,N-dimethylaniline, dimethyldichlososilane and PCl5 to obtain 7-beta-amino-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid (III).The acylation of (III) with 4-chloro-3-oxobutyryl chloride (A) and triethylamine in CH2Cl2 affords the amide (IV), which is condensed with thiourea (B) by means of NaHCO3 in acetone yielding the thiazole derivative (V). Finally, this compound is condensed with 5-mercapto-1-[2-(N,N-dimethylamino)ethyl-1H-tetrazole (VI) by means of NaHCO3 in hot water.
The condensation of 7-acetoacetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid (VII) with the mercaptane (VI) by means of NaHCO3 in hot water gives 7-beta-amino-3-[1-[2-(N,N-dimethylamino)ethyl]-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (VIII), which is then condensed with 2-aminothiazol-4-ylacetic acid (IX) by means of N-hydroxysuccinimide and dicyclohexylcarbodiimide in THF. The free amino group of (VIII) is acylated with Cl2 and diketene giving the 4-chloro-3-oxobutyramido derivative (X), which is finally cyclized with thiourea (B) by means of NaHCO3 in acetone.