Preparation of Penicillin N and Isopenicillin N

Penicillin N and isopenicillin N (D- and L-4-carboxy-4-amino-n-butyl-penicillin) were synthetized from 6-aminopenicillanic acid (6-APA) by two different methods.In the first synthesis the mixed anhydrides of the two enantiomers of the 1-benzylester of 2-carbobenzyloxyaminoadipic acid were prepared and by condensation with 6-APA, the L- and D-isomers of 4-benzyloxycarbonyl-4-carbobenzyloxy-amino-n-butylpenicillin were obtained. By hydrogenation of these two epimers in the presence of Pd/C, isopenicillin N and penicillin N were obtained. This hydrogenolysis was incomplete, but by chromatography on a column of Sephadex G10, it was possible to purify these penicillins and to remove 4-carboxy-4-carbobenzyl-oxyamino-n-butylpenicillin.In the second synthesis, the 1-benzylesters of L- and D-2-azidoadipic acid were transformed into the acid chloride, and by reaction with 6-APA, the two epimers of 4-benzyloxycarbonyl-4-azido-n-butylpenicillin were prepared. By hydrogenation of these compounds in the presence of Pd/C, isopenicillin N and penicillin N were obtained. Both penicillins were also purified by chromatography on Sephadex G10.