Method for purifying polymer impurities in lipoic acid

Abstract

The invention discloses a method for purifying polymer impurities in lipoic acid, and belongs to the technical field of medicine synthesis. For effectively controlling known impurities in lipoic acid and ensuring the quality of a lipoic acid product, the invention provides the method for purifying the polymer impurities in lipoic acid, wherein the method comprises the steps: dissolving a lipoic acid crude product with an acetone aqueous solution at the temperature of 20-40 DEG C, filtering, adding diluted hydrochloric acid into filtrate, and filtering to obtain a wet product; and dissolving the wet product with ethyl acetate at the temperature of 35-45 DEG C, separating water, adding saturated sodium chloride into an organic phase, separating liquid, adding cyclohexane into the organic phase, filtering with silica gel, adding cyclohexane into filtrate, cooling, crystallizing, filtering and drying to obtain a refined product. According to the method, various impurities in the crude product can be efficiently purified, the purity of the refined product reaches 99.9% or above, and the impurities A and B are far lower than the specified standard of the pharmacopeia, so that the impurities A and B meet the medication standard of the raw material medicine for the injection.

Description

Technical field [0001] The present invention belongs to the field of drug synthesis, and more particularly to the purification method of polymer impurities in sulfuric acid. Background technique [0002] In the prior art, there are many literatures in the synthesis method of thionic acid, mainly using chemical synthesis. It is different from the start of the raw material, which is generally divided into adipic acid (US2980716) and cyclohexanone method (US2993056). The technology is more mature and the industrialized process route is adipic acid method. The adipic acid method is a five-step reaction of adipic acid, single chloride, Fuke addition, reduction and other five-step reaction to obtain 6,8-dichloroalkate Ethyl ester, the reaction is as follows: [0003] [0004] The preparation process of producers of many sulfuric acids in China is a ring-reactive reaction with 6,8-dichloronate as a raw material, and hydrolyzed reaction is synthesized to thioculite acid, including the ...

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Problems solved by technology

[0016] The existing methods add activated carbon, diatomaceous earth and other adsorption and filter aids, or add silica gel to stir and absorb and then filter, but the above methods cannot effectively and completely remove the polymer impurity B

In addition, there is also a purification method using column chromatography, but column chromatography will use a large amount of solvent, and for the variety of lipoic acid, the chromatographic eluent will also lead to the production of polymer impurity B during high temperature concentration

Therefore, for lipoic acid, which has a low market price, column chromatography purification is not a purification method suitable for industrial mass production, because this method will greatly increase the cost of lipoic acid and cannot completely remove the polymer impurity B

[0017] CN102603709B, CN103058989B and CN101607955A also disclose a preparation and / or purification method of lipoic acid, but these documents do not mention the content of research and treatment for impurity B

This method has realized the control to the known impurity B in lipoic acid, but the amount of solvent used is relatively large, and the temperature during dissolving is the reflux temperature of solvent, and the excessive temperature is unfavorable for thermal filtration operation and avoids the generation of impurity B, and its The operation time is long and the purification yield is low, which is not conducive to industrial production

[0019] Lipoic acid injections are widely used clinically. If the impurity B in lipoic acid is not strictly controlled, the accumulation of impurities caused by long-term medication will cause harm to patients

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