Preparation method of avibactam intermediate compound

A technology for intermediates and compounds, applied in the field of avibactam intermediate compounds and preparation, can solve the problems of expensive raw materials, cumbersome post-processing, impact on product quality and the like, and achieves simple process operation, high product purity, and easy raw materials. the effect

Inactive Publication Date: 2020-05-08
BEIJING YAOCHENG HUIREN TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the purity of the quaternary ammonium salt intermediate is not high, which has a certain impact on the quality of subsequent products
The raw materials of this route are more expensive, the stability of some intermediates is not good, and the aftertreatment is cumbersome. At the same time, this route uses n-butyl acetate with a high boiling point for washing and 4-methyl-2-pentanone with toxicity. Remove, affecting the quality of subsequent products
Therefore, this route is not conducive to industrial scale-up production

Method used

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  • Preparation method of avibactam intermediate compound
  • Preparation method of avibactam intermediate compound
  • Preparation method of avibactam intermediate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] (2S,5R)-6-(Benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (5g, 18.2mmol), palladium Carbon (125mg, 10% palladium), sulfur trioxide trimethylamine complex (2.78g, 1.12eq), triethylamine (0.5ml, 0.2eq), isopropanol (25ml) and water (25ml) were sequentially added to 100ml for reaction In the bottle, hydrogen gas was introduced under the condition of stirring, and the reaction was completed at room temperature. Remove palladium carbon by suction filtration and wash the filter cake with water, wash the filtrate once with 25ml ethyl acetate (25ml), then add 1,1-dipentylcyclohexamethylene ammonium bromide (7g, 1.2eq), keep at 40 Under the condition of ℃, react for 2h. Extract with dichloromethane (25ml×2), combine the organic phases and rotary evaporate, then add ethanol and ethyl acetate (3:1) solvent to crystallize at 5°C, filter, wash and dry to obtain 5.8g of avibactam intermediate compound (the step yield was 63%).

[0026] Take by weighing 5g of sulfonic...

Embodiment 2

[0028] (2S,5R)-6-(Benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (5g,), palladium on carbon ( 125mg, 10% palladium), sulfur trioxide trimethylamine complex (2.78g, 1.12eq), triethylamine (0.5ml, 0.2eq), isopropanol (25ml) and water (25ml) were sequentially added to a 100ml reaction flask , Introduce hydrogen gas under stirring conditions, and react until complete at 30°C. Remove palladium carbon by suction filtration and wash the filter cake with water, wash the filtrate once with 25ml ethyl acetate, then add 80% 1,1-dipentylcyclohexamethylene ammonium bromide (5.6g), keep the reaction at 40°C 2h. Extract with dichloromethane (25ml×2), then add the remaining 20% ​​of 1,1-dipentylcyclohexamethylene ammonium bromide (1.4g) and react at 40°C for 2h, use di Chloromethane extraction (25ml×2), combined organic phase and rotary evaporation, added ethanol and ethyl acetate solvent to crystallize at 5°C, filtered, washed and dried to obtain 5.56g avibactam intermediate ...

Embodiment 3

[0030] (2S,5R)-6-(Benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (5g,), palladium on carbon ( 125mg, 10% palladium), sulfur trioxide trimethylamine complex (2.78g, 1.12eq), triethylamine (0.5ml, 0.2eq), isopropanol (25ml) and water (25ml) were sequentially added to a 100ml reaction flask , Introduce hydrogen gas under stirring conditions, and react until complete at 30°C. Remove the palladium carbon by suction filtration and wash the filter cake with water, wash the filtrate once with 25ml ethyl acetate, then add 1,1-dibutylcyclohexamethylene ammonium bromide (8.7g, 1.5eq), keep the reaction at 40°C for 2h . Extract with dichloromethane (25ml * 2), combine the organic phase rotary evaporation, add ethanol and ethyl acetate solvent and crystallize under the condition of 5 ℃, then filter, wash and dry to obtain 5.67g avibactam intermediate compound (yield 62%).

[0031] Weigh 5 g of quaternary ammonium salt and dissolve it in ethanol (25 ml), add dropwise the et...

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Abstract

The invention relates to medical compounds and organic chemical synthesis, in particular to an avibactam intermediate compound and a preparation method thereof. The preparation method of the avibactamintermediate compound comprises the following steps: (1) carrying out a hydrogenation sulfonation reaction on (2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-formamide; (2) after the reactionin the previous step is completed, carrying out washing once, and adding quaternary ammonium bromide for a reaction; and (3) after the reaction is finished, performing extracting, and then carrying out rotary evaporation and crystallizing. Compared with the prior art, the method of the invention has the advantages that operation is simple, raw materials are easy to obtain, cost is low, the purityof an obtained sulfonic acid quaternary ammonium salt is high, and the purity of avibactam sodium generated by sodium salt exchange of the sulfonic acid quaternary ammonium salt is 99.5T, so the method 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. 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. It belongs to the diazabicyclooctone compound and has two chiral centers. It is very different from the classic β-lactamase inhibitors. The structure of avibactam sodium has the characteristics of reversible recovery and long-term inhibitory effect Enzyme action, is a non-β-lactam inhibitor. The solid ratio compound preparation of avibactam sodium and ceftazidime was approved by the US FDA in 2015 for the treatment of complicated abdominal infection and complicated urinary tract infection in adults. [0003] At present, the main preparation method for avibactam sodium is the synthetic route disclosed in the patent CN103649...

Claims

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Application Information

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IPC IPC(8): C07D471/08C07D295/037
CPCC07D471/08C07D295/037
Inventor 乔红炜陈照行魏宏成
Owner BEIJING YAOCHENG HUIREN TECH CO LTD
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