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Preparation and use of silybum marianum di-partial succinate and salt thereof

A technology of dimetasuccinate and silibinin, which is applied in pharmaceutical formulations, medical preparations containing active ingredients, and the digestive system, and can solve complex extraction and washing operations, side reactions, and influence on product purity and quality, etc. question

Active Publication Date: 2008-11-12
SHANDONG INST OF PHARMA IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The synthesis of silibinin dimetasuccinate introduced in foreign literature mainly involves the reaction of silibinin in pyridine solution and succinic anhydride under heating conditions. Since silibinin is unstable to heat and alkali, It is easy to produce a series of side reactions, which affects the purity and quality of the product, and the extraction and washing operations with acidic ethyl acetate are complicated. Therefore, it is an inevitable choice to improve its synthesis process. We combined a large number of experiments and finally explored In addition to the production process suitable for industrial production

Method used

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  • Preparation and use of silybum marianum di-partial succinate and salt thereof
  • Preparation and use of silybum marianum di-partial succinate and salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0010] Add 48.2 grams (0.1 moles) of silibinin, 30.3 grams (0.3 moles) of triethylamine, and 40 grams (0.4 moles) of succinic anhydride to a garden flask with a drying system containing 500 milliliters of dichloromethane , stirring at room temperature, G254 thin layer detection tracking (developing agent is chloroform: methanol: ethyl acetate: water = 15:6:15:1, the reaction is completed in about 2 hours, the organic layer is washed with 10% hydrochloric acid, and then washed with water, The organic layer was dried over anhydrous sodium sulfate, and was concentrated to obtain 61.4 grams of white solid (yield was 90%).60 grams of silybin succinate methyl ester of gained were dissolved in 100 milliliters of methanol, at room temperature and hydrogen Sodium oxide solution was reacted to obtain 60 grams of alcohol-insoluble sodium salt with a yield of 94%.

Embodiment 2

[0012] Add 48.2 grams (0.1 moles) of silibinin, 30.3 grams (0.3 moles) of triethylamine, and 40 grams (0.4 moles) of succinic anhydride to a round-bottomed flask with a drying system filled with chloroform, and stir at room temperature For about 2.5 hours, wash the organic layer with 10% hydrochloric acid, wash with water, dry the organic layer with anhydrous sodium sulfate, and concentrate to obtain 60.5 grams of white solid (yield 88.6%)

Embodiment 3

[0014] 48.2 grams (0.1 moles) of silibinin, 30.3 grams (0.3 moles) of triethylamine, and 40 grams (0.4 moles) of succinic anhydride were added to a garden flask with a drying system filled with ethyl acetate, at room temperature Stir for about 4 hours, wash the organic layer with 10% hydrochloric acid, wash with water, dry the organic layer with anhydrous sodium sulfate, and concentrate to obtain 58.3 g of white solid (yield: 85.4%).

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Abstract

The invention discloses a novel preparation method and a use of silybin diethylene glycol succinate and salts thereof. The preparation method can be realized through the following technique that: silybin reacts with butanedioic anhydride in an appropriate organic solvent to synthesize silybin succinic acid monomethyl ester, and then the silybin succinic acid monomethyl ester reacts with sodium hydroxide in a specific medium to generate florfenicol succinic acid ester sodium salt. The preparation method mainly overcomes the disadvantages that the prior synthetic method is unstable to heat and alkali, easy to produce a series of side reactions to affect the purity and quality of products, fussy and complex to operate. The novel method is simple, stable, high in yield and suitable for industrial mass production. Meanwhile, the novel method increases the solubility of the silybin and improves the problem of low bioavailability, thereby developing the effect of protecting liver and providing theoretical basis for clinical use.

Description

Technical field: [0001] The invention relates to medicines for treating liver diseases, in particular silybin dimesuccinate and its salts, which are easily soluble in water and meet the requirements of medicine. Background technique [0002] Silymarin has a strong hepatoprotective effect and is clinically used in the treatment of acute and chronic hepatitis, cirrhosis and liver injury caused by metabolic toxicity. Silymarin has been sold in foreign countries, and there are several domestic manufacturers. In foreign countries, Madaus AG of Germany imported it to China in 1999. The trade name is Ligalon, which is used for acute and chronic hepatitis, early liver cirrhosis, fatty liver and Toxic liver damage, such as liver damage caused by drinking a lot of alcohol or taking certain specific drugs, can also take this product to protect the liver. Steatosis, inhibition of alanine aminotransferase elevation. In various models of toxic liver damage, silymarin neutralized the tox...

Claims

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Application Information

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IPC IPC(8): C07D407/04A61K31/357A61P1/16
Inventor 刘宪华宋海波张岱州任业明王功霞
Owner SHANDONG INST OF PHARMA IND
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