CN101302212B - Preparation and use of silybum marianum di-partial succinate and salt thereof - Google Patents
Preparation and use of silybum marianum di-partial succinate and salt thereof Download PDFInfo
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- CN101302212B CN101302212B CN2008101380407A CN200810138040A CN101302212B CN 101302212 B CN101302212 B CN 101302212B CN 2008101380407 A CN2008101380407 A CN 2008101380407A CN 200810138040 A CN200810138040 A CN 200810138040A CN 101302212 B CN101302212 B CN 101302212B
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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:
The present invention relates to can be used for treating the medicine of hepatopathy, concrete is silybin bis-bias succinate and its esters, and this salt is soluble in water, is fit to medicinal requirement.
Background technology
Silymarin has stronger hepatoprotective effect, is used for the treatment of acute chronic hepatitis, liver cirrhosis and metabolism toxic liver injury clinically.The existing abroad commodity selling of silymarin; the man manufacturer of domestic existing number; external existing German Madaus AG 1999 in oneself in the people is to Chinese import; commodity are called Legalon; be used for acute, chronic hepatitis, first cirrhosis, fatty liver and toxic liver injury; as heavy drinking or take of the damage of certain specific medicament to liver; the clothes this product of can holding concurrently protection liver; its pharmacological action has confirmed to stablize the metabolism of liver plasma membrane and cell, can resist hepatic necrosis, alleviates steatosis, suppress Glutamate pyruvate transaminase rises.In various toxicity hepatic injury models, the poisoning that silymarin can neutralize and be caused by toxin, à-amanitin (toxicant of finding in the Amanita phalloides fungi), tetracol phenixin, GalN, thioacetamide.
Because silymarin solubleness in water is very little, bioavailability is lower, increase its solubleness in water so usually it is made various derivatives, abroad has it is made phosphoric acid ester and succinate, to improve its bioavailability, strengthened the effect of its liver protecting.
Foreign literature introduction synthetic mainly be the method for silybin bis-bias succinate be silibinin in pyridine solution and Succinic anhydried under the condition of heating, react, because silibinin is to heat and alkali instability, be easy to generate a series of side reaction, the purity and the quality of product have been influenced, and with acid ethyl acetate extraction, washing operation complexity, therefore, its synthesis technique is improved, selection is inevitable, we grope except being fit to the production technique of suitability for industrialized production finally in conjunction with a large amount of experiments.
Summary of the invention
GB2167414 has listed the synthetic method of silybin bis-bias succinate and its esters, we found through experiments its complicated operation, the purity of products obtained therefrom can only reach about 93%, can't adapt to industrial requirement, we are by a large amount of experimental datas, finally get through operational path, and successfully prepared water miscible salt.
Technological line and embodiment technological line are as follows:
Silibinin is reacted the synthetic silibinin monomethyl succinate that obtains with Succinic anhydried in appropriate organic solvent, reaction generates florfenicol sodium succinate salt with sodium hydroxide in specific medium then, the synthetic sample is through instrument detecting such as infrared, ultraviolet, nuclear-magnetism, mass spectrums, and the collection of illustrative plates of gained conforms to structure.
Embodiment
Embodiment one:
With silibinin 48.2 grams (0.1 mole), triethylamine 30.3 grams (0.3 mole), Succinic anhydried 40 grams (0.4 mole), join in the field flask that has dehumidification system that fills 500 milliliters of methylene dichloride, stirring at room, the G254 thin layer detects tracking, and (developping agent is a chloroform: methyl alcohol: ethyl acetate: water=15: 6: 15: 1, reaction in about 2 hours finishes, salt acid elution organic layer with 10%, wash with water again, the organic layer anhydrous sodium sulfate drying obtains white solid 61.4 grams (yield is 90%) through concentrating.Silibinin Succinic Acid methyl esters 60 grams of gained are dissolved in 100 ml methanol, at room temperature react with sodium hydroxide solution, obtain being insoluble to sodium salt 60 grams of alcohol, yield is 94%.
Embodiment two:
With silibinin 48.2 grams (0.1 mole), triethylamine 30.3 grams (0.3 mole), Succinic anhydried 40 grams (0.4 mole), join at the bottom of the garden that has dehumidification system that fills chloroform in the flask, about 2.5 hours of stirring at room, salt acid elution organic layer with 10%, washing with water, the organic layer anhydrous sodium sulfate drying obtains white solid 60.5 grams (yield 88.6%) through concentrating.
Embodiment three:
With silibinin 48.2 grams (0.1 mole), triethylamine 30.3 grams (0.3 mole), Succinic anhydried 40 grams (0.4 mole), join in the field flask that has dehumidification system that fills ethyl acetate, about 4 hours of stirring at room is with 10% salt acid elution organic layer, washing with water, the organic layer anhydrous sodium sulfate drying obtains white solid 58.3 grams (yield is 85.4%) through concentrating.
Embodiment four:
With silibinin 48.2 grams (0.1 mole), triethylamine 30.3 grams (0.3 mole), Succinic anhydried 40 grams (0.4 mole), join in the field flask that has dehumidification system that fills tetrahydrofuran (THF), about 5 hours of stirring at room is with 10% salt acid elution organic layer, washing with water, the organic layer anhydrous sodium sulfate drying obtains white solid 59.2 grams (yield is 86.7%) through concentrating.
Embodiment five:
With silibinin 48.2 grams (0.1 mole), triethylamine 30.3 grams (0.3 mole), Succinic anhydried 40 grams (0.4 mole), join in the field flask that has dehumidification system that fills dioxane, about 3 hours of stirring at room is with 10% salt acid elution organic layer, washing with water, the organic layer anhydrous sodium sulfate drying obtains white solid 61.5 grams (yield 90.1%) through concentrating.
Embodiment six:
To be dissolved in 100 ml distilled waters by silibinin sodium succinate 50 gram of embodiment 1 method gained, sterile filtration, aseptic subpackaged, make injection liquid, be injected in three dogs, thereby the dosage of about 6.7 milligrams/kilogram weight is provided.Collect blood plasma product behind the drug administration, and measure the concentration of silibinin, the concentration of silibinin increase sharply (Fig. 1) in the blood plasma as seen from the figure, these data show, the silibinin sodium succinate is after entering blood, rapidly it is decomposed into silibinin, thus the performance liver protection function, for clinically use offers theoretical foundation.
Description of drawings:
Fig. 1: the pharmacokinetic curve of silibinin in the blood plasma of silibinin sodium succinate injection back
Claims (1)
1. the preparation method of a silybin bis-bias succinate is characterized in that with the Succinic anhydried being esterifying agent, is catalyzer with the triethylamine, is solvent with the methylene dichloride, makes silybin bis-bias succinate by the starting raw material silibinin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008101380407A CN101302212B (en) | 2008-07-04 | 2008-07-04 | Preparation and use of silybum marianum di-partial succinate and salt thereof |
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| CN2008101380407A CN101302212B (en) | 2008-07-04 | 2008-07-04 | Preparation and use of silybum marianum di-partial succinate and salt thereof |
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| Publication Number | Publication Date |
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| CN101302212A CN101302212A (en) | 2008-11-12 |
| CN101302212B true CN101302212B (en) | 2010-11-03 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105037337A (en) * | 2015-06-29 | 2015-11-11 | 中国科学院理化技术研究所 | Silybin ether derivative and synthesis method and application thereof |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102406636A (en) * | 2011-10-28 | 2012-04-11 | 西安安健药业有限公司 | Pharmaceutical composition for treating liver disease |
| CN103193768B (en) * | 2013-02-22 | 2016-03-30 | 西安安健药业有限公司 | The silybin bis-bias succinate isomer for the treatment of hepatopathy |
| CN103172622B (en) * | 2013-02-22 | 2015-11-04 | 西安安健药业有限公司 | The active isomer of silybin bis-bias succinate |
| CN103113359B (en) * | 2013-02-22 | 2016-01-06 | 西安安健药业有限公司 | Silybin bis-bias succinate and pharmaceutical salts thereof |
| CN111925394A (en) * | 2020-09-25 | 2020-11-13 | 嘉兴金派特生物科技有限公司 | Silybin derivative or pharmaceutically acceptable salt thereof, and preparation method and application thereof |
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2008
- 2008-07-04 CN CN2008101380407A patent/CN101302212B/en active Active
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105037337A (en) * | 2015-06-29 | 2015-11-11 | 中国科学院理化技术研究所 | Silybin ether derivative and synthesis method and application thereof |
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