Orally active pivaloyloxymethyl 3-(isoxazolidin-5-yl)cephalosporins.

Manyof potent cephalosporins with aminothiazolyl-oxyimino groups in the C-7 side chain generally show the poor absorption by oral administration. To increase the intestinal absorption, esterifications of the carboxylic acid in cephem have been achieved. The esters of prodrugs are mostly diacylacetals of formaldehyde or acetaldehyde.1} These esters are rapidly hydrolyzed by esterase to give the active parent antibiotic after absorption from the intestinal tract. In the preceding paper, we have described the syntheses and antibacterial activities of new 3(isoxazolidin-5-yl)cephalosporins having aminothiazolyl-oxyimino side chains.2) Most of the compounds were converted to prodrug-esters, which were evaluated the absorption by oral administration. This report describes the syntheses and biological activities of pivaloyloxymethyl 7-[(Z)-2-(2aminothiazol-4-yl)-2-(methoxyimino)acetamido] -3[(£)and (i?)-2-methylisoxazolidin-5-yl]-3-cephem4-carboxylates (6 and 7). The reaction of pivaloyloxymethyl 7-phenylacetamido-3-vinyl-3-cephem-4-carboxylate (1) with Nmethylnitrone, generated from 38%formalin and iV-methylhydroxylamine hydrochloride in the presence of sodium acetate in situ, at 90°C gave two diastereomeric 3-(2-methylisoxazolidin-5-yl)-3cephems (2 and 3) in 78% yield (Fig. 1). These isomers were isolated on silica gel chromatography. 3'-(5')-Isomer 2 was treated with phosphorous pentachloride, pyridine and methanol to give 7-amino derivative 4. The amino group of 4 was acylated with (Z)-2-(methoxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid by A^TV'-dicyclohexylcarbodiimide (DCC) and JV-hydroxybenzotriazole (HOBT) method to give 5 in good yield. The