阿维巴坦合成工艺改进

Improved synthesis of avibactam

目的改进阿维巴坦的合成方法。方法以(S)-1-(苄氧羰基)-5-氧代吡咯烷-2-羧酸为起始原料,经亲电加成、亲核取代、环化、还原、脱Cbz、酰化保护、亲核取代、脱保护、分子内脲化、水解、氨解、脱苄基、磺酸酯化、成盐、离子交换共13步反应得到阿维巴坦的钠盐,并优化各步反应条件。结果与结论优化后的工艺路线具有收率高、步骤少、操作简便、适合大量制备等优点,13步反应总收率为30.6%[以(S)-1-(苯甲氧基羰基)-5-酮基吡咯啶-2-羧酸计]终产品HPLC纯度99.5%。

To improve the synthetic process of avibactam,a β-lactamase inhibitor,was prepared from（S）-1-（benzyloxycarbonyl）-5-oxopyrrolidine-2-carboxylic acid through thirteen steps,including the electrophilic addition,nucleophilic substitution,cyclization,reduction,de-Cbz,acylation protection,nucleophilic substitution,deprotection,intramolecular urea formation hydrolysis,ammonolysis,debenzylation,sulfonate,salt formation and ion exchange.The target compound was synthesized with the overall yield of 30.6%[calculated from（S）-1-（benzyloxycarbonyl）-5-oxopyrrolidine-2-carboxylic acid].The improved process with high yield and less steps is easy to operate and suitable for large scale preparation.