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A kind of refining preparation process of high-purity avibactam

A preparation process, high-purity technology, applied in the direction of organic chemistry, etc., can solve the problems of inconspicuous effect, unsatisfactory API impurity residue, etc., and achieve the effect of reducing the content

Active Publication Date: 2020-06-23
GUANGXI ENANTIOTECH PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The impurity removal method reported in the literature includes recrystallization of ethyl acetate, absolute ethanol, and acetone to remove impurities. By repeating the above purification process, it is found that the residual amount of intermediate a reaches 0.9%. Even after multiple purifications, the effect is still not obvious and cannot be satisfied. API impurity residue less than 0.1%

Method used

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  • A kind of refining preparation process of high-purity avibactam
  • A kind of refining preparation process of high-purity avibactam
  • A kind of refining preparation process of high-purity avibactam

Examples

Experimental program
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Effect test

Embodiment 1

[0027] (1) Synthesis of Avibactam Crude Product

[0028] Add 120 g of raw material intermediate a, 82.7 g of sodium isooctanoate, and 540 ml of absolute ethanol into a three-neck flask, react at 30°C for 10 h, and obtain 62 g of crude avibactam by suction filtration, with a purity (HPLC) of 96.3%;

[0029] (2) Crude refined

[0030] Add the crude product (50g) into 1L of 2-butanone, heat to 50-60°C to dissolve the solid, cool to 0-10°C to crystallize for 1 hour, filter with suction, and dry under reduced pressure at 50°C to obtain 43g of the refined product of white crystals. The yield is 86%, the purity (HPLC) is 99.8%, and the maximum is 0.05%.

Embodiment 2

[0032] Add the crude product (30 g) prepared in Example 1 into 1 L of 2-butanone, heat to 50-60°C to dissolve the solid, cool to 0-10°C to crystallize for 1 hour, filter with suction, and dry under reduced pressure at 50°C to obtain white The crystallized refined product is 25g, the yield is 83%, the purity (HPLC) is 99.7%, and the maximum purity is 0.04%.

Embodiment 3

[0034] Add the crude product (30 g) prepared in Example 1 into 1 L of acetone, heat to 50°C to dissolve the solid, cool to 0-10°C to crystallize for 1 hour, filter with suction, and dry under reduced pressure at 50°C to obtain 23 g of the refined product of white crystals , 76% yield, 99.8% purity (HPLC), maximum 0.05% impurity.

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Abstract

The invention discloses a refining preparation technology of high-purity avibactam. The refining preparation technology comprises the following steps: (1), adding an intermediate alpha and sodium isooctanoate into a solvent A, reacting for 10-15 hours, and treating to obtain crude avibactam; (2), adding the crude avibactam into a solvent B, heating for dissolving, and refining a mixture to obtainpurified avibactam, wherein the solvent B is at least one of anhydrous ethanol, acetone and 2-butanone. By the refining preparation technology, the 2-butanone is used as a purifying solvent for impurity removal, a relatively good technical effect is achieved, the contents of main impurity raw materials such as the intermediate alpha as well as technological impurities in the crude avibactam can besignificantly reduced, and HPLC detection shows that the purity of the avibactam reaches 99.7% or above and the impurity limits are lower than 0.1%.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry and relates to a process for refining and preparing high-purity avibactam. Background technique [0002] Avibactam (Avibactam, NXL-104) belongs to the diazabicyclooctone compound and is currently the most promising new type of β-lactamase inhibitor. Compared with the three marketed β-lactamase inhibitors, it has a long-acting and reversible covalent binding to the enzyme, and does not induce β-lactamase production. [0003] β-lactamase serine nucleophilic attack on the avibactam amide bond, open the ring to form a covalent conjugate, and obtain the enzyme-inhibitor complex, which is in the form of enzyme inhibition, and does not undergo hydrolysis, and then forms a lactam ring through cyclization Get Avibactam again. The rate of ring opening caused by nucleophilic attack is much higher than that of ring closure, so that β-lactamase is basically in an inhibited state. During this proce...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/08
CPCC07D471/08
Inventor 李彦雄徐亮毛波
Owner GUANGXI ENANTIOTECH PHARM CO LTD
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