Refining method of avibactam sodium intermediate

Abstract

The invention discloses a refining method of an avibactam sodium intermediate 1. The method comprises the step of refining a crude product of the avibactam sodium intermediate 1 in a good solvent dichloromethane and poor solvent methyl tert-butyl ether system to obtain the high-purity avibactam sodium intermediate 1. According to the refining method provided by the invention, the content of an isomer impurity A and a ring-opening impurity B can be effectively reduced, the purity is improved, the total purity of the refined avibactam sodium intermediate 1 is greater than 99.9%, the isomer impurity A and the ring-opening impurity B are both less than 0.05%, the other single impurities are all less than 0.10%, the reagents are conventional and easy to obtain, the operation is simple and safe and the method is very suitable for industrial amplification under conventional production conditions.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, in particular to avibactam sodium intermediate 1(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane -The refining method of 2-carboxamide, especially a method for reducing the content of isomer impurity A and / or ring-opening impurity B in avibactam sodium intermediate 1. Background technique [0002] Avibactam sodium (Avibactam) is a novel non-β-lactam structure β-lactamase inhibitor developed by Novexel. Avibactam sodium belongs to diazabicyclooctone compound, which itself does not have obvious antibacterial activity, but acts by inhibiting β-lactamase. Avibactam sodium can inhibit type A (including ESBL and KPC), part of type C and part of type D β-lactamases. Therefore, when used in combination with penicillium, cephalosporin and carbapenem antibiotics, it has broad-spectrum antibacterial activity, especially against Escherichia coli and Klebsiella pneumoniae containing ...

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Problems solved by technology

[0007] Both routes involve the key avibactam sodium intermediate 1(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carba In the preparation of amides, since the subsequent conversion of the ester functional group of the starting material involves alkaline conditions, there is isomerization, and the main isomer impurity A will be produced during the preparation of intermediate 1, which is similar in structure and property to intermediate 1. Purification is difficult, and impurities are easily transferred to the raw material drug in the follow-up, which affects the safety of medication

In addition, because the bridged ring structure is unstable under acid and alkali conditions, it will also produce polar ring-opening impurities.

At present, the purification of intermediate 1 is rarely reported in the open literature. The purification method disclosed in the patent CN 103649051A needs to be purified with unconventional solvent chlorobutane, and the removal of impurities similar in structure to avibactam sodium intermediate 1 is limited. High purity cannot be guaranteed

[0008] In order to ensure the safety of follow-up preparations and clinical medication, it is necessary to strictly control the single impurity in avibactam sodium intermediate 1, so as to avoid the residue of impurities or transfer to the raw material drug, preferably all controlled below 0.10%, while the existing conventional Purification process is not possible

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