Alternative Synthesis of Cefamandole with Biocatalytic Acylation Catalyzed by Immobilized Cephalosporin-Acid Synthetase

Abstract

Abstract The processes of the biocatalytic acylation of 1-methyl-5-mercapto-1,2,3,4-tetrazolil-7-amino-cephalosporanic acid (7-TMCA) and 7-aminocephalosporanic acid (7-ACA) by methyl ester of mandelic acid (MEMA) were optimized with an immobilized cephalosporin-acid synthetase as the biocatalyst. Under optimized conditions in water-organic medium containing 43% (vol/vol) of ethylene glycol at 30°С with a spontaneous pH gradient in the range of 8.0–6.0, the following yields of biocatalytic transformations were reached: (80.8 ± 1.9)% for 7‑TMCA acylation (at a concentration of 100–120 mМ) resulted in cefamandole (CFM) production, and (88.6 ± 2.0)% for 7-ACA acylation of (at concentration of 140–170 mМ) resulted in a semiproduct of CFM (S-p CFM) formation. In the second process, the concentration of the target β-lactam product in the final reaction mixture is one and a half times higher than that with the first one. In light of the undoubted environmental benefits of the chemical transformation of S-p CFM to CFM over the process of the chemical production of 7-TMCA from 7-ACA, we conclude that the second pathway of combined chemical and biocatalytic CFM synthesis is preferable.