3) The reaction of the 7-aminocephem derivative (VI) with ethyl acetoacetate (IX) at room temperature gives the 3-aminocrotonate derivative (X), which is esterified with dioxolone (II) as before yielding the ester derivative (XI). The acidic (HCl) hydrolysis of (XI) in methanol-dichloromethane affords the 7-aminocephem derivative (XII) , which is finally condensed with 2-O-(tert-butoxycarbonyl-L-alanyl)mandelic acid (VII) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane to yield the protected product (V), already obtained.
1) The esterification of 7-[(R)-mandelamido]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (KY-087; I) with 4-bromomethyl-5-methyl-1,3-dioxol-2-one (II) by means of potassium acetate in DMF gives the corresponding ester (KY-106; III), which is condensed with tert-butoxycarbonyl-L-alanine (IV) by means of dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridine (DMP) in dichloromethane affording the protected final product (V). Finally, this compound is deprotected with HCl in methanol-acetone.
2) The reaction of 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (VI) with 2-O-(tert-butoxycarbonyl-L-alanyl)mandelic acid (VII) by means of triethylamine in THF gives the corresponding amide (VIII), which is then esterified with dioxolone (II) as before to afford the protected product (V), already obtained.