Separation of avibactam by gemini quaternary ammonium salt: Extraction, precipitation, and application in large-scale production

Abstract

β-lactamase inhibitors have important clinical significance to restore the antibacterial effect of antibiotics. Non-β-lactam β-lactamase inhibitor represented by avibactam contained a sulfonic acid group, which posed a considerable challenge to separation and purification. To separate avibactam, eight gemini quaternary ammonium salts were developed for extraction, and the extraction conditions were investigated and optimized. Notably, some gemini quaternary ammonium salts can directly precipitate avibactam in aqueous solution with the excellent yield and purity. The probable mechanism of precipitation was studied by critical micelle concentration, transmission electron microscopy, and nuclear magnetic resonance assays. The precipitation process of gemini quaternary ammonium salt N,N,N,N′,N′,N′-hexabutylbutanediammonium dibromide was successfully applied in separation and purification of a 2 kg avibactam production, showing unique efficient and green advantages. Our research offered an effective and scale-up approach to separation and purification of β-lactamase inhibitor containing sulfonic acid group.