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Synthetic method of furbenicillin acid

A technology of furbenicillin acid and a synthetic method, which is applied in the field of synthesis of semi-synthetic antibiotics, can solve problems such as environmental pollution, complicated processes, large toxic and side effects, and achieves shortening of technological operation procedures, superior quality and cost, and improved product quality. Effect

Active Publication Date: 2010-08-18
朗致集团江西医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] 1. The solvent phase used in the condensation process step is a mixed system of water and organic solvent. Because the acid anhydride avoids water, part of the acid anhydride is hydrolyzed and destroyed, resulting in poor quality of the finished product furbenicillin sodium salt, and the content is only about 65% (high-efficiency liquid phase chromatography), with large toxic and side effects;
[0007] 2. This process can not directly obtain the furbenicillin acid solid. After the product is condensed, it is directly freeze-dried after several extractions of alkalization, acidification, and alkalization. The process is cumbersome and the yield is low, only about 70%, and the cost is high ;
[0008] 3. The highly toxic solvent toluene used in the preparation process is likely to cause environmental pollution

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Add 210kg of dichloroethane and 16.5kg of 6-APA into a dry reaction tank, add 27kg of triethylamine and stir to dissolve, dissolve in about 1.5 hours, cool down to 0°C, and press into a high-level tank for later use.

[0031] In another dry reaction tank, add 320kg dichloroethane and 21kg sodium α-furylureidophenylacetate, add 0.09kg N-methylmorpholine and 7.3kg ethyl chloroformate sequentially at room temperature, and react for 1.5h under stirring , lower the temperature to -10°C, add dropwise to the 6-APA amine salt solution in the high-level tank, after the drop, keep the temperature at -5~0°C for 1 hour.

[0032] The reaction liquid was warmed up to room temperature, alkalized with 5% aqueous sodium hydroxide solution until the pH of the solution was 5.5-6.7, and left to stand to separate the phases of the solution and recover the organic phase. Add 120L ethyl acetate to the water phase, add 9% dilute hydrochloric acid dropwise, acidify to pH=2-3, let stand to separ...

Embodiment 2

[0034] Add 180kg of chloroform and 16kg of 6-APA into a dry reaction tank, add 27kg of diisopropylamine and stir to dissolve, dissolve in about 1.5 hours, cool down to 0°C, and press into a high-level tank for later use.

[0035] In another dry reaction tank, add 370kg of chloroform and 21kg of sodium α-furyl ureidophenylacetate, add 0.11kg of N-ethylmorpholine and 7.5kg of ethyl chloroformate sequentially at room temperature, and react for 1.5h under stirring. Cool down to -10°C, add dropwise to the 6-APA amine salt solution in the high-level tank, and keep it at -5~0°C for 1 hour after dropping.

[0036] The reaction solution was warmed up to room temperature, basified with 8% sodium carbonate aqueous solution until the pH of the solution was 5.5-6.7, and allowed to stand still to separate the phases of the solution and recover the organic phase. Add 120L of ethyl acetate to the water phase, add dropwise 6% phosphoric acid to acidify to pH=2-3, let stand to separate the laye...

Embodiment 3

[0038] Add 200kg of trichloroethane and 16kg of 6-APA into a dry reaction tank, add 20kg of diethylamine and stir to dissolve, dissolve in about 1.5 hours, cool down to 0°C, and press into a high-level tank for later use.

[0039] In another dry reaction tank, add 310kg trichloroethane and 21kg sodium α-furylureidophenylacetate, add 0.18kg N-ethylmorpholine and 7.8kg ethyl chloroformate sequentially at room temperature, and react for 1.5h under stirring , lower the temperature to -10°C, add dropwise to the 6-APA amine salt solution in the high-level tank, after the drop, keep the temperature at -5~0°C for 1 hour.

[0040]The reaction solution was warmed up to room temperature, basified with 10% aqueous sodium bicarbonate solution until the pH of the solution was 5.5-6.7, and allowed to stand still to separate the phases of the solution and recover the organic phase. Add 180L of chloroform to the water phase, add 3% sulfuric acid dropwise to acidify to pH=2-3, let stand to sepa...

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Abstract

The invention relates to a method for synthesizing furbenicillin acid, which comprises the following steps: adding 6-APA into halogenated alkane, and dissolving the 6-APA by an alkalizer to obtain a solution a; dissolving alpha-furanuride sodium phenylacetate in the halogenated alkane, and esterifying the solution to obtain an estolide solution b of alpha-furanuride phenyl acetic acid; and after the solution a and the solution b are subjected to a condensation reaction at a temperature of between 20 DEG C below zero and zero DEC, adjusting pH to be between 5.5 and 6.7 to make the solution split phase, reclaiming an organic phase, adding an extracting agent into a water phase, acidifying and layering the solution, and dripping the extracting agent into the organic phase to separate out furbenicillin acid crystal. The method for synthesizing the furbenicillin acid fully adopts water avoidance reaction, the yield of products reaches more than 78 percent, the purity is improved to more than 90 percent, the content of the total impurities is reduced to below 10 percent, and the method has the advantages of simple production process and stable quality.

Description

technical field [0001] The invention relates to a synthetic method of semi-synthetic antibiotics, in particular to a synthetic method of furbenicillin sodium intermediate furbenicillin acid. Background technique [0002] Furbenicillin (alias furobenzylpenicillin, furbenzylpenicillin, furbucillin) is an α-urea derivative of aminopenicillin, a semi-synthetic broad-spectrum antibiotic, and has a strong effect on Pseudomonas aeruginosa, and its antibacterial test in vitro It is about 16 times stronger than carbenicillin, similar to piperacillin, and other antibacterial effects are similar to ampicillin. Clinically, it is mainly used for various infections caused by sensitive bacteria such as Pseudomonas aeruginosa, Escherichia coli and Proteus, such as respiratory tract infection, hepatobiliary system infection, urinary tract infection and sepsis. [0003] Fubenicillin was first developed by Bristol & Mayer Company of the United States. It was first developed and listed in my ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D499/60
Inventor 刘秀兰陆晨阳李忠华李祖文郭锦玉周改平任青花张毅
Owner 朗致集团江西医药有限公司
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