Avibactam intermediate compound disulfonic acid gemini quaternary ammonium salt and preparation method thereof

The technology of a gemini quaternary ammonium salt and disulfonic acid is applied in the preparation of amino compounds, the preparation of organic compounds, chemical instruments and methods, etc., and can solve the problems of unfavorable industrial scale-up production, complicated operation, difficult to remove solvents, etc. The effect of industrial scale-up production, simple process operation and high product purity

Active Publication Date: 2020-10-02
山东大医精诚药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But quaternary ammonium salts such as tetrabutyl ammonium acetate and sulfonic acid binding effect are poor, feed equivalent is higher, raw material price is more expensive, and the purity of this sulfonic acid quaternary ammonium salt intermediate is not high, and this not only increases production cost, and is harmful to Subsequent product quality has a certain impact
At the same time, this route uses high-boiling n-butyl acetate washing reaction system and toxic crystallization solvent 4-methyl-2-pentanone, which is not easy to remove residual solvent, and the operation is cumbersome, which affects the product quality of subsequent avibactam sodium
Therefore, this route is not conducive to industrial scale-up production

Method used

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  • Avibactam intermediate compound disulfonic acid gemini quaternary ammonium salt and preparation method thereof
  • Avibactam intermediate compound disulfonic acid gemini quaternary ammonium salt and preparation method thereof
  • Avibactam intermediate compound disulfonic acid gemini quaternary ammonium salt and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] (2S,5R)-6-(Benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (2.00g, 1.00eq), 10% palladium carbon (0.05g,), sulfur trioxide trimethylamine complex (1.13g, 1.12eq), triethylamine (0.20ml, 0.2eq), isopropanol (8ml) and water (8ml) were sequentially added to 50ml In the reaction flask, hydrogen gas was introduced under the condition of stirring until the reaction was complete. Remove palladium carbon by suction filtration and wash the filter cake with water, wash the filtrate once with ethyl acetate (12ml), then add N 1 ,N 1 ,N 1 ,N 4 ,N 4 ,N 4 - Hexabutyl-1,4-butanediammonium bromide (2.60g, 0.61eq), kept at 40°C for reaction. Extract with dichloromethane (12ml×2), combine the organic phases and rotary evaporate, then add a mixed solvent of ethanol and ethyl acetate to crystallize, filter, wash and dry to obtain the avibactam intermediate disulfonic acid gemini quaternary ammonium compound 1 (2.42g, yield 70%), HPLC relative purity 99.6%.

[0027] The ...

Embodiment 2

[0029] (2S,5R)-6-(Benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (2.00g, 1.00eq), 10% palladium carbon (0.05g,), sulfur trioxide trimethylamine complex (1.13g, 1.12eq), triethylamine (0.20ml, 0.2eq), isopropanol (8ml) and water (8ml) were sequentially added to 50ml In the reaction flask, hydrogen gas was introduced under the condition of stirring until the reaction was complete. Remove palladium carbon by suction filtration and wash the filter cake with water, wash the filtrate once with ethyl acetate (12ml), then add 72% N 1 ,N 1 ,N 1 ,N 4 ,N 4 ,N 4 - Hexabutyl-1,4-butanediammonium bromide (1.87g, 0.44eq), kept at 40°C for reaction. Extract with dichloromethane (10ml), then add 28% N 1 ,N 1 ,N 1 ,N 4 ,N 4 ,N 4- Hexabutyl-1,4-butanediammonium bromide (0.73g, 0.17eq), keep the reaction at 40°C, extract with dichloromethane (10ml), combine the dichloromethane phases and rotary evaporate, add ethyl acetate The ester solvent was crystallized, filtered an...

Embodiment 3

[0032] (2S,5R)-6-(Benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (2.00g, 1.00eq), 10% palladium carbon (0.05g,), sulfur trioxide trimethylamine complex (1.13g, 1.12eq), triethylamine (0.20ml, 0.2eq), isopropanol (8ml) and water (8ml) were sequentially added to 50ml In the reaction flask, hydrogen gas was introduced under the condition of stirring until the reaction was complete. Remove palladium carbon by suction filtration and wash the filter cake with water, wash the filtrate once with ethyl acetate (12ml), then add 72% N 1 ,N 1 ,N 1 ,N 4 ,N 4 ,N 4 - Hexabutyl-1,4-butanediammonium bromide (1.87g, 0.44eq), kept at 40°C for reaction. Extract with dichloromethane (10ml), add water (4ml) and isopropanol (4ml) to the aqueous phase, add 28% N 1 ,N 1 ,N 1 ,N 4 ,N 4 ,N 4 - Hexabutyl-1,4-butanediammonium bromide (0.73g, 0.17eq), keep the reaction at 40°C, extract with dichloromethane (10ml), combine the dichloromethane phases and rotary evaporate, add ethyl ...

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Abstract

The invention discloses an avibactam intermediate compound, disulfonic acid gemini quaternary ammonium salt, and a preparation method thereof, and relates to medical compounds and organic chemical synthesis, and the preparation method of the avibactam intermediate compound disulfonic acid gemini quaternary ammonium salt comprises the following steps: (1) carrying out hydrogenolysis sulfonation reaction on (2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-formamide; (2) after the reaction in the previous step is completed, performing suction filtration, washing filtrate once, and adding gemini quaternary ammonium salt for reaction; and (3) after the reaction in the previous step is completed, carrying out extraction, rotary evaporation and crystallization. Compared with the prior art,the method has the advantages that the operation is simple, the raw materials are easy to obtain, the cost is lower, the dosage of the gemini quaternary ammonium salt is lower, the purity of the obtained disulfonic acid gemini quaternary ammonium salt is higher, and the HPLC relative purity of avibactam sodium generated by sodium salt exchange of the disulfonic acid gemini quaternary ammonium salt is greater than 99.5%, so that the process is suitable for large-scale production.

Description

technical field [0001] The invention relates to the field of pharmaceutical compounds and organic chemical synthesis, in particular to an avibactam intermediate compound and a preparation method thereof. Background technique [0002] Avibactam sodium, chemical name: [(1R,2S,5R)-2-(aminocarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]sulfuric acid - Sodium salt, belonging to diazabicyclooctone compound, it is a new type of β-lactamase inhibitor, which can effectively inhibit class A, class C and part of class D β-lactamase. In 2015, the compound preparation of avibactam and ceftazidime was approved by the US FDA for the treatment of severe infections caused by drug-resistant bacteria, and its effect is significantly higher than that of clavulanic acid, sulbactam and tazobactam that have been marketed . Therefore, avibactam has broad application prospects, but the difficulty of avibactam synthesis hinders its industrial production and wider application. [0003] At present,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/08C07C211/63C07C209/00
CPCC07D471/08C07C211/63
Inventor 乔红炜王帅陈照行张睿魏宏成
Owner 山东大医精诚药业有限公司
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