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Preparation method of high purity fenofibric acid

A fenofibric acid, high-purity technology, applied in the field of preparation of high-purity fenofibric acid, can solve the problems of unpredictable trace impurities in the product, low purity of fenofibric acid, and increased burden on patients, etc., to achieve convenient medicinal use Effects of review, drug cost reduction, and simple preparation process

Active Publication Date: 2013-10-23
SHANDONG DANHONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

All of the above methods can synthesize fenofibric acid and have good yields, but the above methods have the disadvantage that the purity of fenofibric acid obtained is not high, and the purity is about 90-95%.
[0005] As a drug, the low purity greatly restricts its practical application, and there are many existing methods for purifying compounds, and the purification methods combined by these methods are countless, but the unavoidable trace impurities in the products obtained by different purification methods are not. Unpredictable
As the public and drug supervision departments pay more and more attention to the safety of drugs, if the trace impurities are different from those in the products of the original drug factory, the safety impact of these impurities needs to be explained, and expensive safety tests and clinical trials are often required to be repeated , but cannot directly learn from the relevant data of the original research pharmaceutical factory, which increases the cost of medicines and increases the burden on patients

Method used

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  • Preparation method of high purity fenofibric acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1 Synthesis of fenofibric acid (tetrabutylammonium bromide catalyzed condensation reaction to synthesize fenofibric acid)

[0045] Weigh 1.00kg of 4-chloro-4'-hydroxybenzophenone, add it to a 20L dry reaction kettle, then add 8.6L of acetone, stir and dissolve, then add 1kg of sodium hydroxide and 138g of tetrabutylammonium bromide . Heat to reflux state, stir for 1 hour, add dropwise 3L of acetone solution of chloroform with a concentration of 1.55kg / 3.0L during stirring, and react at 60°C for 6 hours after the dropwise addition is completed.

Embodiment 2

[0046] The crude purification of embodiment 2 fenofibric acid

[0047]After the reaction in Example 1 was completed, the solvent was concentrated at 40°C until there was no distillate, and then 13L of purified water was added dropwise at room temperature (25°C, the same below). Then add 3.2L of methyl tert-butyl ether to the aqueous solution (water phase), stir for 30 minutes, let stand to separate layers, and keep the water phase. The aqueous phase was continuously extracted with methyl tert-butyl ether as above, and extracted three times in total. Then, add 220g activated carbon (can be purchased from Shanghai Activated Carbon Factory Co., Ltd., specification: Type 767 Needle Class I) to the obtained water phase for decolorization for 0.5 hours, filter the filter bottle, and adjust the pH of the filtrate to 6mol / L hydrochloric acid. 1.5 (room temperature), a large amount of solid precipitated. Filter, wash the filter cake with purified water until the pH of the washed wate...

Embodiment 3

[0048] The refining of embodiment 3 fenofibric acid crude product

[0049] Add 1.3kg of the crude product of fenofibric acid obtained in Example 2 into a 20L three-necked flask, add 13L of toluene, start stirring and heating, and keep warm for 30 minutes when the temperature is raised to 110°C. Then turn off the stirring and filter while it is hot. The filtrate is transferred to a 20L reactor to cool down naturally. During this period, crystals are precipitated. When it is lowered to room temperature, it is placed in a refrigerator at 10°C for 12 hours, then suction filtered, and the filter cake is washed twice with toluene. (Use 500ml of toluene each time), drain.

[0050] Collect the filter cake, dry it (about 1250g) and put it into a 20L three-necked bottle, then add 9.2L of pure water, adjust the pH to 9.5 with sodium hydroxide, and add 6mol / L hydrochloric acid dropwise after the fenofibric acid is completely dissolved When the pH reached 1.5, a white solid was precipitat...

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Abstract

The invention provides a preparation method of high purity fenofibric acid. The preparation method successively comprises the following steps: reacting to produce fenofibric acid; crudely purifying of the fenofibric acid to obtain a fenofibric acid crude product; and refining the fenofibric acid to obtain the high purity fenofibric acid. The high purity fenofibric acid prepared by the preparation method has a purity of more than 99.5%, and is safe and reliable.

Description

technical field [0001] The invention belongs to the field of medicine preparation, in particular, the invention relates to a preparation method of high-purity fenofibric acid. Background technique [0002] Fenofibrate is one of the most commonly used lipid-lowering drugs in clinical practice, and it was approved for marketing by the US FDA in 2008. Compared with fenofibrate, fenofibric acid is an active substance metabolized in the body, which has extremely high solubility in the small intestine area, thus increasing the bioavailability of fenofibric acid, and the bioavailability is not affected by food influences. At the same time, since fenofibric acid is the actual active ingredient, the specification of fenofibric acid is much smaller than that of fenofibrate for the same therapeutic effect, and the side effects are correspondingly reduced. [0003] Therefore, there are many reports on the direct application of fenofibric acid to blood lipid-lowering drugs at present, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C59/90C07C51/367C07C51/093C07C51/42A61K31/192A61P3/06
Inventor 张登科李旭
Owner SHANDONG DANHONG PHARMA
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