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Sulbactam preparation method

A technology of potassium permanganate and sulfuric acid, applied in the field of sulbactam preparation, can solve the problems of poor storage stability, unstable content, yellowing and the like, and achieve the effects of reducing by-products, improving yield and good product stability

Inactive Publication Date: 2011-02-09
JIANGSU HUAXU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Both use strong alkali and strong reducing agent. The color of the product is unstable, and it will turn yellow after a few days, which will affect downstream products. The color is unqualified, the content is unstable, and the storage stability is poor, which will directly cause the product to not be sold normally.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0010] In a 2000ML four-neck flask, add 600ML dichloromethane and 180ML 2.5N sulfuric acid, stir and cool to below 0°C, add 28ML bromine and 25g sodium nitrite, add 40g 6-APA in portions at 0±0.2°C, and control the temperature Below 5°C, stir the reaction for 1 hour, then lower the temperature to below 0°C, add dropwise 20% sodium bisulfite aqueous solution below 0°C until the color of bromine fades, let stand to separate the phases, and extract the water phase with 100ML dichloromethane for 3 times , combined the organic phases, and washed twice with 100ML saturated aqueous sodium chloride solution to obtain 6,6-dibromopenicillanic acid;

[0011] Transfer the upper 6,6-dibromopenicillanic acid phase into a 2000ML beaker. Add 250ML distilled water and stir, cool to below 5°C, add 4NNaHCO dropwise 3 The aqueous solution was left to separate to pH=7, the organic phase was extracted 3 times with 80ML deionized water, the aqueous phase was combined, and the aqueous phase was trans...

Embodiment 2

[0014] In a 2000L reaction kettle, add 600L dichloromethane and 180L 2.5N sulfuric acid, stir and cool to below 0°C, add 28L bromine and 25Kg sodium nitrite, add 40Kg 6-APA in portions at 0±0.2°C, and control the temperature to low Stir the reaction at 5°C for 1 hour, then lower the temperature to below 0°C, add dropwise 20% aqueous sodium bisulfite solution below 0°C until the color of bromine fades, let stand to separate the phases, and extract the aqueous phase with 100L dichloromethane three times, The organic phases were combined and washed twice with 100L saturated aqueous sodium chloride solution to obtain 6,6-dibromopenicillanic acid;

[0015] Transfer the 6,6-dibromopenicillanic acid phase obtained above into a 2000L reaction kettle. Add 250L tap water and stir, cool to below 5°C, add 4NNaHCO dropwise 3 The aqueous solution was left to separate to pH=7, the organic phase was extracted 3 times with 80L deionized water, the water phase was combined, and the water phase ...

Embodiment 3

[0018] In a 1000ML four-neck flask, add 300ML dichloromethane and 90ML 2.5N hydrobromic acid, stir and cool to below 0°C, add 14ML bromine and 12.5g sodium nitrite, at 0±0.2°C, add 20g 6-APA in portions , control the temperature below 5°C, stir the reaction for 1h, then lower the temperature to below 0°C, add dropwise 20% aqueous sodium bisulfite solution below 0°C until the color of bromine fades, let stand to separate phases, and use 50ML dichloromethane for the water phase Extracted 3 times, combined the organic phases, washed 2 times with 50ML saturated aqueous sodium chloride solution to obtain 6,6-dibromopenicillanic acid;

[0019] Transfer the upper 6,6-dibromopenicillanic acid phase into a 1000ML beaker. Add 125ML distilled water and stir, cool to below 5°C, add 4NNaHCO dropwise 3 The aqueous solution was left to separate to pH=7, the organic phase was extracted 3 times with 40ML deionized water, the aqueous phase was combined, and the aqueous phase was transferred to ...

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PUM

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Abstract

The invention discloses a sulbactam preparation method. In the method, 6-amino penicillanic acid (6-APA) serving as a raw material undergoes a dibromination reaction with bromine serving as a bromating agent in the presence of sulfuric acid or hydrobromic acid; the product of the dibromination reaction is oxidized by potassium permanganate; the product of the oxidization is subjected to debromination by using zinc powder or magnesium powder as a reducing agent; and thus, the sulbactam is prepared. In a manganese dioxide removing process in an oxidization phase, 50-percent sulfuric acid and 20 to 28-percent hydrogen peroxide are added alternately; in a pH value adjusting process in a reduction phase, the pH value is adjusted by adding sodium bicarbonate; and in a layer-based extraction process in the reduction phase, an organic layer is washed by 4 to 10 percent solution of potassium permanganate first till red color is stable and then washed by saturated aqueous solution of sodium chloride. Thus, byproducts are reduced, the yield of main products is increased, the product is very stable and avoids turning yellow, and a good basis is provided by down-stream products.

Description

technical field [0001] The invention relates to a pharmaceutical organic chemical synthesis method, in particular to a preparation method of sulbactam. Background technique [0002] Using 6-APA as raw material, in the presence of sulfuric acid or hydrobromic acid, bromine is used as brominating agent to carry out double bromination reaction, then oxidized by potassium permanganate, and then deoxidized by using zinc powder or magnesium powder as reducing agent. Bromine, β-lactamase inhibitor - sulbactam is obtained through three steps of bromination, oxidation and reduction. Existing in the second step in the three-step reaction process of preparing sulbactam with 6-APA as raw material, in the process of removing manganese dioxide in the oxidation process with potassium permanganate as oxidant, is to use alternately input Sulfuric acid and sodium bisulfite are used to realize; in the reduction stage to adjust the pH value operation, the pH value is adjusted by throwing stron...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D499/04C07D499/86
Inventor 卢标周灏
Owner JIANGSU HUAXU PHARMA
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