Method for refining fenbufen

Abstract

The invention discloses a method for refining fenbufen, which comprises the following steps of: (1) adding acetone, purified water and an adsorbent into a fenbufen crude product according to a certain proportion, heating to 50-60 DEG C, and keeping the temperature and stirring for 0.5 hour; (2) filtering while the solution is hot, keeping the temperature of the filtrate at 50-60 DEG C, stirring for 15 minutes, and then cooling to 20-25 DEG C; and (3) preserving heat at 20-25 DEG C, crystallizing for 1 hour, filtering, and drying to obtain the refined fenbufen product. Compared with the prior art, the method has the advantages that the variety and the dosage of the used organic solvent can be reduced, and the generation and the production cost of waste liquid are reduced; the content of related substances and chlorides in the product is obviously reduced, and the quality of the product meets the standards of Chinese Pharmacopoeia 2025 edition; the process is simple and convenient, the operation conditions are safe and mild, the method is suitable for industrial production, the refining yield can reach 95% or above, and the purity can reach 99.9% or above.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and relates to a method for refining fenbufen. Background Art

[0002] The pharmaceutical name of fenbufen is biphenylbutyric acid, and its chemical name is 3-(4-biphenylcarbonyl)propionic acid. It is a long-acting non-steroidal anti-inflammatory drug, mainly used for the treatment of rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and gout, and can also be used for toothache, postoperative pain, and traumatic pain. This drug was developed by the Leberle Laboratory of American Cyanamid Company, and the preparation method of fenbufen was disclosed in the US Patent US3966960 in 1976. It has the advantages of significant curative effect, long-lasting action, simple synthesis process, low price, and relatively mild toxic and side effects. After entering the human body, fenbufen is metabolized into diphenylacetic acid to take effect. Its anti-inflammatory and analgesic effect is 5-10 times stronger than that of aspirin and equal to that of phenylbutazone; but it is weaker than indomethacin. Its antipyretic effect is equal to that of aspirin and phenylbutazone. Clinical trials have shown that the incidence of side effects of fenbufen on the gastrointestinal tract and central nervous system is lower than that of aspirin and other non-steroidal anti-inflammatory drugs.

[0003] There are not many reports on the refining method of fenbufen at present. The refining methods of fenbufen crude products include ethanol recrystallization method and sodium carbonate-sulfuric acid method.

US Patent US3966960

Li Chunqiu et al. Synthesis of non-steroidal anti-inflammatory drug biphenylbutyric acid [J]. Pharmaceutical Industry, 1981, 9: 14

Han Changri. Improvement of the synthesis method of fenbufen in Chinese Patent CN90109612.1

[0004] During the experiment according to the above preparation method, the filter cakes obtained in some batches were sticky, and the products obtained after drying were khaki, while the Chinese Pharmacopoeia requires fenbufen to be a white or almost white crystalline powder. The reason is that some khaki polymers are formed during the chemical synthesis of fenbufen, and these polymers are difficult to effectively remove through the refining processes of the sodium carbonate-sulfuric acid method and ethanol recrystallization method. These polymers make the product turn khaki. The existing refining methods of fenbufen cannot effectively reduce these polymers and impurities. Therefore, it is of great significance to develop a refining method for fenbufen to reduce the impurity content, improve the product color, and enhance the product quality. Summary of the Invention

[0005] The object of the present invention is to provide a refining method for fenbufen in view of the defects of the existing technology. Compared with the existing technology, this method can effectively reduce the polymers and impurities in the crude product, improve the product color, and meet the standards of the 2025 edition of the Chinese Pharmacopoeia; it has the advantages of simple method, high yield, mild conditions, low cost, little environmental pollution, and being suitable for industrial production.

[0006] To achieve the above object, the present invention provides the following technical solutions:

[0007] A method for refining fenbufen, comprising the following steps:

[0008] (1) Add acetone, purified water, and activated carbon to the crude fenbufen, heat to 50 - 60 °C, and keep stirring for 0.5 hour.

[0009] (2) Filter while it is hot, keep the filtrate at 50 - 60 °C and stir for 30 minutes. Then cool down to 20 - 25 °C.

[0010] (3) Crystallize at 20 - 25 °C for 1 hour, filter, and dry to obtain the refined fenbufen.

[0011] In a method for refining fenbufen, in step (1), the weight ratio of acetone to the crude fenbufen is 5:1 - 8:1.

[0012] In a method for refining fenbufen, in step (1), the weight ratio of purified water to the crude fenbufen is 1:1 - 8:1.

[0013] In a method for refining fenbufen, in step (1), the adsorbent is activated carbon with a weight ratio of 0.05:1 to fenbufen.

[0014] Preparation method of ibufenac crude product: Add dichloromethane, anhydrous aluminum trichloride, and succinic anhydride into a reaction flask, start stirring and cool the system to -5 to 5 °C. After cooling, add biphenyl, continue stirring for 1 hour, pour the reactants into a mixture of concentrated hydrochloric acid and ice, distill off dichloromethane, perform hot filtration, recrystallize the obtained solid with alkaline water and water respectively, and then adjust the acidity to obtain ibufenac crude product.

[0015] The focus of the present invention lies in the purification method of ibufenac, and the obtained ibufenac has low impurity content and good stability, which mainly depends on the use of solvents in the purification process. Acetone and purified water are selected as the recrystallization solvents through screening in the present invention. The screening process is as follows:

[0016] After the ibufenac crude product is treated with the following different solvents respectively, the impurity content in each sample is shown in Table 1. The analysis of impurities in ibufenac is carried out according to the related substance analysis method in the Chinese Pharmacopoeia 2025 edition.

[0017] Table 1 Impurity content in each sample after the ibufenac crude product is treated with different solvents

[0018]

[0019] Note: Although the experimental data of related substances for the solvent dichloromethane:acetone (1:5) in the above table are relatively excellent, the yield is about 20% lower than that of the present invention.

[0020] Table 2 Analyze the product obtained in the present invention, and the analysis data table of its properties, related substances and melting point

[0021]

[0022] The present invention has the following advantages compared with the prior art:

[0023] 1) The two-step purification process of the sodium carbonate-sulfuric acid method and ethanol recrystallization method is eliminated. The new purification method has a simple process, mild reaction conditions, easy process control, is suitable for industrial production, and the yield can reach more than 95%;

[0024] 2) It can effectively remove the polymers formed during the chemical synthesis of the ibufenac crude product, solve the problems of difficult product filtration and the product being yellowish-brown after drying;

[0025] 3) It can effectively reduce the impurities of ibufenac to meet the standards of the Chinese Pharmacopoeia 2025 edition. Description of the Drawings

[0026] Figure 1 Liquid chromatogram of ibufenac prepared in Example 1

[0027] Figure 2 Liquid chromatogram of ibufenac prepared in Example 2

[0028] Figure 3 Liquid chromatogram of fenbufen prepared in Example 3

[0029] Figure 4 Liquid chromatogram of fenbufen prepared in Example 4

[0030] Figure 5 Liquid chromatogram of fenbufen prepared in Example 5 (the present invention) Detailed implementation manners

[0031] The present invention will be further described below in conjunction with examples, so that those skilled in the art can better understand the present invention. The examples are only explanatory and in no way limit the scope of the present invention.

[0032] Example 1:

[0033] Add 46.3 kg of methanol to 5.85 kg of crude fenbufen, add 0.3 kg of activated carbon with stirring, heat the system to reflux, and keep stirring for 0.5 hour after all the solids in the system are completely dissolved. Filter while it is hot, and cool the filtrate to 20 - 25 °C. Keep stirring at 20 - 25 °C for 1 hour for crystallization, filter, and dry to obtain 4.5 kg of refined fenbufen, with a yield of 76.9%.

[0034] Example 2:

[0035] Add 47.4 kg of absolute ethanol to 6.0 kg of crude fenbufen, add 0.3 kg of activated carbon with stirring, heat the system to reflux, and keep stirring for 0.5 hour after all the solids in the system are completely dissolved. Filter while it is hot, and cool the filtrate to 20 - 25 °C. Keep stirring at 20 - 25 °C for 1 hour for crystallization, filter, and dry to obtain 4.36 kg of refined fenbufen, with a yield of 72.7%.

[0036] Example 3:

[0037] Add 39.7 kg of isopropanol to 5.05 kg of crude fenbufen, add 0.25 kg of activated carbon with stirring, heat the system to reflux, and keep stirring for 0.5 hour after all the solids in the system are completely dissolved. Filter while it is hot, and cool the filtrate to 20 - 25 °C. Keep stirring at 20 - 25 °C for 1 hour for crystallization, filter, and dry to obtain 3.37 kg of refined fenbufen, with a yield of 66.7%.

[0038] Example 4:

[0039] Add 39.7 kg of acetone and 13.3 kg of methylene chloride to 5.02 kg of crude fenbufen. While stirring, add 0.25 kg of activated carbon. Heat the system to reflux. After all the solids in the system are completely dissolved, keep stirring for 0.5 hour while maintaining the temperature. Filter while it is hot. Cool the filtrate to 20 - 25 °C. Keep stirring and crystallize for 1 hour at 20 - 25 °C. Filter and dry to obtain 4.39 kg of refined fenbufen with a yield of 87.5%.

[0040] Example 5:

[0041] Add 23.5 kg of crude fenbufen to 184 kg of acetone. While stirring, add 235 kg of purified water and 1.18 kg of activated carbon. Heat to 50 - 60 °C and keep stirring for 0.5 hour. Filter while it is hot. Keep stirring the filtrate at 50 - 60 °C for 15 minutes. Cool the filtrate to 20 - 25 °C. Crystallize at 20 - 25 °C for 1 hour, then filter and dry to obtain 22.7 kg of refined fenbufen with a yield of 96.6%.

[0042] Table 3: Comparative analysis data of the properties, related substances, yield, etc. of fenbufen prepared in Examples 1 - 5

[0043]

[0044] Note: There has always been an unknown impurity in this product, namely the "routine impurity" in the table. The retention time varies slightly with different methods and chromatographic columns. The "other maximum impurity" is the largest impurity after removing this "routine impurity".

[0045] The above detection results show that for the fenbufen prepared in each example, its impurity limit, properties and melting point all meet the requirements of the Chinese Pharmacopoeia, indicating that the new refining process of the present invention can effectively decolorize and control impurities, and obtain refined fenbufen with stable process.

Claims

1. A method for refining fenbufen, characterized in that: The steps include: (1) adding acetone, purified water and adsorbent to the crude fenbufen, heating to 50-60° C., and stirring for 0.5 hour; (2) Filter while hot, keep the filtrate at 50-60°C and stir for 30 minutes, then cool it down to 20-25°C; (3) keeping the temperature at 20-25° C. for crystallization for 1 hour, filtering, and drying to obtain a refined fenbufen product; The invention is characterized in that: in step (1), the adsorbent is activated carbon with a weight ratio of 0.05:1 to fenbufen.

2. A method for refining fenbufen as claimed in claim 1, characterized in that: In step (1), the weight ratio of acetone to the crude fenbufen product is 5:1 to 8:

1.

3. A method for refining fenbufen as claimed in claim 1, characterized in that: In step (1), the weight ratio of the purified water to the crude fenbufen product is 1:1 to 8:1.

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