Penicillin acylase-catalyzed synthesis of N-bromoacetyl-7-aminocephalosporanic acid, the key intermediate for the production of cefathiamidine

Bioresour Bioprocess. 2016;3(1):49. doi: 10.1186/s40643-016-0127-3. Epub 2016 Nov 19.

Abstract

Background: Enzymatic approaches have become promising alternatives to chemical methods for the production of semi-synthetic β-lactam antibiotics. In this work, enzymatic synthesis of N-bromoacetyl-7-aminocephalosporanic acid (N-bromoacetyl-7-ACA), the key intermediate for the production of cefathiamidine, was reported for the first time.

Results: Of the immobilized penicillin acylases (PAs) tested, PGA-750 was the best biocatalyst. Optimization of the biocatalytic process was conducted. The optimal acyl donor, molar ratio of acyl donor to 7-ACA, pH, temperature, 7-ACA concentration, and enzyme dosage were methyl bromoacetate, 3, 7.5, 20 °C, 50 mmol/L and 4 U/mL, respectively. Under the optimal conditions, enzymatic N-acylation of 7-ACA with methyl bromoacetate afforded the desired product with the yield of 85% in 2 h, where the synthesis/hydrolysis (S/H) ratio was approximately 1.5. The immobilized enzyme PGA-750 exhibited good operational stability, and the relative yields of approximately 90% and 63% were achieved, respectively, when it was reused in 7th and 11th batch.

Conclusions: An enzymatic approach to N-bromoacetyl-7-ACA, the key intermediate for the industrial production of cefathiamidine, has been developed successfully in a fully aqueous medium. The present work may open up a novel opportunity for the production of cefathiamidine through a simple and green process.Graphical abstractEnzymatic synthesis of N-bromoacetyl-7-ACA, the key intermediate for the production of cefathiamidine, was reported for the first time.

Keywords: 7-Aminocephalosporanic acid; Cephalosporins; Enzyme catalysis; Penicillin acylase; Semi-synthetic antibiotics.