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Preparation method of flurbiprofen axetil

A technology of flurbiprofen axetil and fluoroaniline, which is applied in the field of preparation of flurbiprofen axetil, can solve the problems of low heat transfer efficiency, impossibility, purification, etc., and achieve high reaction selectivity, easy-to-obtain raw material sources, and excellent reaction conditions mild effect

Active Publication Date: 2014-09-10
哈药集团股份有限公司 +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In terms of purification, since flurbiprofen axetil is a liquid, it cannot be purified by recrystallization
The current purification method is mainly through silica gel column chromatography. In addition, there are also reports in the literature that the method of vacuum distillation is used, but in actual operation, the temperature of vacuum distillation is too high, the heat transfer efficiency is low, and the sample is exposed to high temperature for a long time. Decomposition of biprofen axetil
Although silica gel column chromatography is a good purification method, it is not suitable for large-scale production, because its strong adsorption force will lead to product loss and reduce yield, and the amount of solvent and silica gel required is large, which greatly increases the cost of the product

Method used

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  • Preparation method of flurbiprofen axetil
  • Preparation method of flurbiprofen axetil
  • Preparation method of flurbiprofen axetil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1 Preparation of compound 4-bromo-2-fluoroaniline

[0043] Dissolve 111.12g (1.0mol) of o-fluoroaniline in 50ml of N,N-dimethylformamide, and lower the reaction temperature to -30°C while stirring. Dissolve 14.30g (0.5mol) DBDMH in 75ml N,N-dimethylformamide, and slowly add it dropwise to the o-fluoroaniline solution, and control the temperature between -25°C and -20°C during the dropwise addition. After the dropwise addition was completed, the reaction was continued for 30 min. Then pour the reaction solution into 500ml of extraction solution (ethyl acetate:n-hexane=1:5), stir and add 300ml of 5% sodium hydroxide aqueous solution, extract and separate layers. The aqueous layer was extracted once more with the extraction solution. The organic layers were combined, washed three times with 100 ml of water, and once with 100 ml of saturated brine. Dry over anhydrous sodium sulfate and concentrate in vacuo to obtain 182 g of the product with a yield of 95.8%.

Embodiment 2

[0044] Example 2 Preparation of 4-bromo-2-fluorobiphenyl

[0045] Add 110.4g (1.6mol) of sodium nitrite into a mixed solution of 250ml of water and 2400ml of benzene, heat to 65°C~70°C, and stir vigorously. Dissolve 152.0g (0.8mol) of compound 3 and 96.1g (1.6mol) of glacial acetic acid in 800ml of benzene, and slowly drop the above mixed solution into the reaction solution, control the speed of dropping, and put the whole dropwise The time is controlled at about 5 hours. After the dropwise addition was completed, the heating reaction was continued for 3 h, and the reaction was stopped. The reaction solution was extracted after cooling down to room temperature, and the organic phase was washed three times with 900 ml of sodium sulfate solution and once with 600 ml of saturated brine. After vacuum concentration, the crude product was dissolved in 800ml 85% sulfuric acid solution, extracted 3 times with 2000ml n-hexane, then the organic phase was washed 5 times with 2000ml 5% ...

Embodiment 3

[0046] Example 3 Preparation of 4-bromo-2-fluorobiphenyl

[0047] Add 110.4g (1.6mol) of sodium nitrite into a mixed solution of 250ml of water and 2400ml of benzene, heat to 65°C~70°C, and stir vigorously. Dissolve 152.0g (0.8mol) of compound 3 and 261.4g (1.6mol) of trichloroacetic acid in 800ml of benzene, and slowly drop the above mixed solution into the reaction solution, control the speed of dropping, and drop the entire The time is controlled at about 5 hours. After the dropwise addition was completed, the heating reaction was continued for 3 h, and the reaction was stopped. The reaction solution was extracted after cooling down to room temperature, and the organic phase was washed three times with 900 ml of sodium sulfate solution and once with 600 ml of saturated brine. After vacuum concentration, the crude product was dissolved in 800ml 85% sulfuric acid solution, extracted 3 times with 2000ml n-hexane, then the organic phase was washed 5 times with 2000ml 5% aqueo...

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Abstract

The invention relates to a preparation method of flurbiprofen axetil. The method comprises the following steps of: preparing 4-bromine-2-fluoroanili from fluoroaniline under the action of 1,3- dibromo-5,5-dimethyl hydantoin; condensing 4-bromine-2-fluoroanili with benzene under the action of a catalyst and sodium nitrite to synthesize 4-bromine-2-fluorobiphenyl; carrying out grignard reaction and acidity reaction on the 4-bromine-2-fluorobiphenyl and 2-bromine sodium propionate under the action of a catalyst to generate 2-(2- fluorine-4-biphenylyl) propionic acid; condensing the 2-(2- fluorine-4-biphenylyl) propionic acid with 1-chloroacetic ethyl acetate to generate a target compound flurbiprofen axetil; and carrying out molecular distillation on the flurbiprofen axetil crude product to obtain a flurbiprofen axetil final product.

Description

technical field [0001] The invention relates to a preparation method of flurbiprofen axetil, belonging to the technical field of medicine. Background technique [0002] Flurbiprofen axetil chemical name: (±) 2-(2-fluoro-4-biphenyl)propionate-1-acetoxyethyl ester [0003] The structural formula is: [0004] [0005] Molecular formula: C 19 h 19 FO 4 [0006] Molecular weight: 330.36 [0007] Flurbiprofen axetil is a new type of non-steroidal anti-inflammatory analgesic drug, which is the prodrug of flurbiprofen and the first non-steroidal targeted analgesic drug approved by SFDA. Flurbiprofen axetil has a certain lipophilicity, and its targeting effect and fat-soluble characteristics make it easy to cross cells. After entering the human body, it can target and gather at surgical incisions and inflammation sites, and is rapidly hydrolyzed under the action of carboxylesterase to generate fluorine. Biprofen reduces prostaglandin synthesis by inhibiting cyclooxygenase (...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C69/65C07C67/11
Inventor 袁淑杰王丽娜齐岩葛存慧李郑武王孝文李金花席珊珊高晶宋紫玉
Owner 哈药集团股份有限公司
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