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Preparation method of sulbactam

A technology of palladium-carbon catalyst and reaction liquid, which is applied in the synthesis of sulbactam and the field of pharmaceutical organic chemical synthesis, can solve the problems of complicated process, low product yield, and increased process complexity, and achieve simple reaction process and product purity High, good effect of product turbidity

Inactive Publication Date: 2006-06-14
GUANGZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the existing third step reaction in the three-step reaction process of preparing sulbactam with 6-APA as the main raw material——in the synthetic technology method of preparing sulbactam through reduction debromination of dibromopenicillane sulfonic acid, there are as follows Insufficient: 1. The prior art mainly adopts zinc powder or magnesium powder as reducing agent to carry out reductive debromination. In the production process, zinc powder or magnesium powder is required to have higher purity, and at the same time, it is still necessary to acidify the surface of zinc powder or magnesium powder. Washing and purifying to ensure the quality of the product, the existing technology increases the complexity of the process, the reaction process has poor stability, and the product yield is low
2. Another fatal shortcoming of sulbactam prepared by reductive debromination using zinc powder or magnesium powder as a reducing agent in the prior art is that the product inevitably contains a trace amount of zinc or magnesium. When the product is tested for turbidity , it is difficult to meet the requirements of the 2000 Pharmacopoeia of the People's Republic of China
The shortcoming of this method is that the activity of the hydrogenation catalyst Raye Ni is low, and the reaction can be carried out smoothly only when the reaction pressure is as high as 7MPa.
High requirements on equipment, complex process, large investment, virtually increased production costs

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] 220mL of ethyl acetate L solution containing 29.5% dibromopenicillane sulfonic acid was added into a 500mL magnetically stirred autoclave, and 2g of a palladium-carbon catalyst with a metal palladium loading of 5% was added, the autoclave was sealed, and nitrogen gas was introduced into the autoclave again. Empty, repeat the replacement twice, then feed hydrogen and vent twice, finally feed hydrogen to a pressure of 0.2MPa, stir the reaction rapidly at 40°C, observe the pressure change in the autoclave, and continuously replenish hydrogen to keep the pressure constant. When the pressure in the kettle remains constant, continue to stir and react for 2 hours, empty the hydrogen in the kettle, take out the reaction solution, filter and recover the catalyst, and distill the ethyl acetate under reduced pressure in a constant temperature water bath at 35°C and a pressure of 0.007Mpa while the reaction solution is stirring. After ester crystallization, add 150mL of water, conti...

Embodiment 2

[0017] With 250mL of ethyl acetate solution containing 26.7% dibromopenicillane sulfonic acid, add 13g of palladium-carbon catalyst with metal palladium load of 5%, seal the autoclave, feed nitrogen and then vent, repeat replacement 4 times, and then pass Add hydrogen and vent 3 times, and finally introduce hydrogen to 0.4MPa pressure, react at 30°C, continue to stir and react for 1h when the pressure in the kettle remains unchanged, take out the reaction solution, recover the catalyst, and reduce the pressure of the reaction solution at 35°C to 0.005Mpa Ethyl acetate was evaporated to crystallization, cooled to 0°C and crystallized and filtered to obtain 42.23g of crude sulbactam product, the one-way yield of the product was 88.7%, and the filtrate was 128mL, extracted with 50mL×2 ethyl acetate, and combined with the next batch of reaction solution .

[0018] Add 42.23 g of the above-mentioned white solid sulbactam crude product into 600 mL of distilled water, heat up to 35°C...

Embodiment 3

[0020] With 220mL of ethyl acetate solution containing 25% dibromopenicillane sulfonic acid, add 2g of palladium-carbon catalyst with a metal palladium load of 5%, seal the autoclave, feed nitrogen and then vent, repeat replacement twice, and then Inject hydrogen and vent 3 times, finally introduce hydrogen to 0.4MPa pressure, react at 35°C, continue to stir and react for 1h when the pressure in the kettle remains constant, take out the reaction liquid, recover the catalyst, and reduce the pressure of the reaction liquid at 35°C to 0.008Mpa Evaporate ethyl acetate until crystallization, cool to 8°C and crystallize and filter to obtain 33.76g of crude sulbactam product, the one-way yield of the product is 86.1%, and the filtrate is 112mL, extracted with 50mL×2 ethyl acetate, and combined with the next batch of reaction solution .

[0021] Add 33.76g of the above-mentioned white solid sulbactam crude product into 350mL of distilled water, heat up to 40°C to dissolve completely, ...

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PUM

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Abstract

The present invention relates to a preparation method of sulbactam. Said method includes the following steps: using palladium-carbon as catalyst, using hydrogen gas as reducing agent, making dibromopenicillanic sulfone acid undergo the process of debromination and reduction at 0.2-0.6MPa, then making the reaction product undergo the processes of adsorption treatment by means of active carbon and purification so as to obtain the invented sulbactam whose yield is above 90%.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a synthesis method of medical organic chemistry, in particular to a synthesis method of sulbactam. Background technique [0002] Sulbactam has a strong and irreversible inhibitory effect on β-lactamase, and can be used in combination with a variety of β-lactam antibiotics to produce an obvious synergistic effect at a lower concentration. Using 6-APA as raw material, in the presence of hydrobromic acid, bromine is used as brominating agent to carry out double bromination reaction, then oxidized by potassium permanganate, and then debrominated with zinc powder or magnesium powder as reducing agent. The β-lactamase inhibitor - sulbactam was prepared through three-step reaction. In the existing third step reaction in the three-step reaction process of preparing sulbactam with 6-APA as the main raw material——in the synthetic technology method of preparing sulbactam through reduction ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D499/04C07D499/86
Inventor 王正平刘莹
Owner GUANGZHOU UNIVERSITY
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