公斤级阿维巴坦钠的合成工艺

Synthesis of avibactam sodium in kilogram scale

摘要:

摘要：用药物合成设计手段对阿维巴坦钠的合成工艺进行改进并实现公斤级规模放大。以廉价易得的L-焦谷氨酸为原料，经酯化、叔丁氧羰基保护、硫叶立德开环、苄氧胺盐酸盐缩合、脱叔丁氧羰基、合成哌啶环、构建5位手性碳、异构体拆分得到高纯度草酸盐。草酸盐经氨解、分子内脲化、脱苄基、磺酸酯化、成季铵盐和钠离子交换反应得到阿维巴坦钠。本工艺反应条件温和，后处理操作简便，工艺更绿色。实现阿维巴坦钠公斤级制备工艺，总收率19.7%，HPLC纯度99.8%。

Abstract:

Abstract: We here reported a process for synthesis of avibactam sodium in kilogram scale by drug design. High purity oxalate was synthesized from L-pyroglutamic acid by esterification, tert-butoxycarbonyl protection, sulfur ylide ring opening, condensation of benzyloxyamine hydrochloride, de-tert-butoxycarbonyl, synthesis of piperidine ring, construction of the chiral carbon in position 5, isomer resolution. Oxalate gets avibactam sodium through ammonolysis, intramolecular urealization, debenzylation, sulfonic acid esterification, quaternary ammonium salt and sodium ion exchange reaction. The process not only involves mild reaction conditions, easy work-up methods, but also has a greener process. The total yield of avibactam sodium in kilogram scale was 19.7％, and HPLC purity 99.8％.