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Paper | Special issue | Vol 37, No. 1, 1994, pp.477-486
Published online, 1st January, 1970
DOI: 10.3987/COM-93-S37
Isomerism of Cephalosporin Esters; Theoretical and Practical Aspects

Emil Pop,* Marcus E. Brewster, Antonie Dinculescu, Ming-Ju Huang, and Nicholas Bodor

*Pharmos Corporation, 2 Innovation Drive, Alachua, FL 32615, U.S.A.

Abstract

Attempts to prepare 1,4-dihydropyridine targetor based chemical delivery systems (CDS) for 7-(thiophene-2-acetamido) cephalosporanic acid (cephalotin) (1) are reported. Reaction of 1 with hydroxyethylnicotinamide resulted in a mixture of δ2 and δ3 isomers of the 3-pyridinylcarbonylamino esters of 1; after chromatographic separation the δ3 isomer was N-methylated and the resulting quaternary pyridinium salt was reduced with sodium dithionite to give the CDS. Attempts to attach the dihydropyridine moiety to 1 as an acyloxyalkyl ester failed. Relative stabilities of the δ3 and δ2 isomers of cephalotin acid and methyl ester, as reflected by theoretically (AM1 and PM3) calculated heats of formation (δHf) indicated that kinetic and mechanistic, rather than thermodynamic factors are responsible for the isomerization of the esters.