CN104004047A - Preparation method of glycyrrhetinic acid - Google Patents
Preparation method of glycyrrhetinic acid Download PDFInfo
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- CN104004047A CN104004047A CN201410224702.8A CN201410224702A CN104004047A CN 104004047 A CN104004047 A CN 104004047A CN 201410224702 A CN201410224702 A CN 201410224702A CN 104004047 A CN104004047 A CN 104004047A
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Abstract
The invention discloses a preparation method of glycyrrhetinic acid. The method comprises the step of performing reaction on acetyl glycyrrhetinic acid to remove acetyl in the presence of alkali under microwave conditions, thus obtaining glycyrrhetinic acid. The method disclosed by the invention is used for shortening the deacetylation reaction time and improving the conversion rate by adopting a microwave-assisted technology; a product prepared by adopting the method is good in chroma, high in purity and low in cost; each index of the product can reach European and Japanese pharmacopoeia standard requirements; the preparation method disclosed by the invention is suitable for large-scale production of raw material medicaments namely glycyrrhetinic acid, and can be used for reducing the dose of reagents, shortening the production time, greatly reducing the energy consumption, reducing the pollution to the environment, and saving a great number of cost.
Description
Technical field
The present invention relates to a kind of preparation method of glycyrrhetinic acid, belong to medical material medicine technical field.
Background technology
Radix Glycyrrhizae is China's traditional Chinese medicine material, and applicating history is long, is famous at home and abroad.As far back as the Warring States Period, just there is the record that utilizes Radix Glycyrrhizae to cure the disease, apart from modern existing more than 2500 year.Eastern Han Dynasty's " legendary god of farming's book on Chinese herbal medicine " claims that Radix Glycyrrhizae is " lantern " and " close sweet ", classifies as top grade.Chinese materia medica is thought: Radix Glycyrrhizae taste is sweet, flat, is to invigorate the spleen and benefit qi, cough-relieving happiness disease, relieving spasm to stop pain, coordinating the actions of various ingredients in a prescription, the good medicine of removing toxic substances.U.S. FDA is classified Radix Glycyrrhizae extract as safety non-toxic material.
The hydrolysis of Radix Glycyrrhizae main component Potenlini is sloughed two molecule glucose aldehydic acid and has been deformed into glycyrrhetinic acid.Glycyrrhetinic acid mainly contains in the application of pharmaceutical industries: have the effect of adrenocortical hormone sample and can be used for treating go down disease (Addison's disease) have diuretic properties of adrenal cortex; Antisepsis and anti-inflammation antitumor action can be made into anti-inflammatory antianaphylaxis preparation and is used for the treatment of rheumatic arthritis asthma supersensitivity and occupational dermatitis Yan Bi larynx section's inflammation and ulcer etc.In recent years research shows, glycyrrhetinic acid has certain anti-cancer and antitumous effect, can suppress information transmission and the genetic expression of former cancer cells.Glycyrrhetinic acid also has the effect of anti-virus infection, and to the virus of carinogenicity, as hepatitis virus, the infection of Epstein-Barr virus and virus of AIDS all has restraining effect.
At present, both at home and abroad the method for relevant glycyrrhetinic acid conversion mainly contains chemical method and microbial method, and microbial method transformation time is long, and efficiency is low is unfavorable for large production.Chemical process, normally taking high-purity liquorice hydrochlorate or Potenlini as raw material, through sulphuric acid hydrolysis, is filtered, and hydrolysis time is long, low conversion rate, and slagging-off is difficult, cannot obtain high purity product.
Along with the development of microwave technology, microwave-assisted extracts the extraction of be widely used natural compounds and bioactive ingredients.Microwave technology has high-recovery, highly selective, rapid heating, be easy to temperature control and low solvent consumption, equipment size is less, the use of pollution-free energy source, reduce the pollution of refuse and product, can rapid extraction to heat-sensitive substance, reduce its thermolysis effect, reduce the generation of by product, the series of advantages such as leaching process is capable of fast starting, and process is simple.
Be in the application for a patent for invention of " preparation method of glycyrrhetinic acid " in application number CN101838303A, denomination of invention, Yu Fang etc. are also applied to microwave technology the preparation of glycyrrhetinic acid.But it is raw materials used is Potenlini or glycyrrhetate, relates to the hypertoxic solvents such as chloroform in preparation process, and institute's glycyrrhetinic acid content in crude product that obtains is lower, is difficult to further improve content to reach European standard again.
Be in the patent of invention of " a kind of preparation method of glycyrrhetinic acid " in application number CN101817867B, denomination of invention; Gao Ying etc. utilize chemical process that Potenlini or glycyrrhetate are converted into acetyl glycyrrhetinic acid; then further deacetylation obtains glycyrrhetinic acid; this method transformation efficiency is high; but transformation time is longer, deacetylation needs 3-6h.
Summary of the invention
The object of this invention is to provide a kind of preparation method of glycyrrhetinic acid, the present invention, taking acetyl glycyrrhetinic acid as raw material, introduces microwave-assisted and prepares glycyrrhetinic acid, has greatly shortened the reaction times, has reduced energy consumption, can be applicable to scale operation; The prepared glycyrrhetinic acid of the inventive method can reach the standard of Europe and Japanese Pharmacopoeia.
The preparation method of a kind of glycyrrhetinic acid provided by the invention, comprises the steps:
Under the condition of microwave condition and alkali existence, acetyl glycyrrhetinic acid, through reaction deacetylate, obtains described glycyrrhetinic acid.
In above-mentioned preparation method, described alkali can be sodium hydroxide and/or potassium hydroxide;
Described deacetylation can be carried out in the aqueous solution of described alkali;
The consumption of the aqueous solution of described alkali can be: described in every 1g, acetyl glycyrrhetinic acid needs the aqueous solution of alkali described in 1～10mL, and acetyl glycyrrhetinic acid can need the aqueous solution of alkali described in 1～4mL, 1mL, 2mL, 3mL or 4mL described in concrete every 1g;
The volumetric molar concentration of the aqueous solution of described alkali can be 0.1～5mol/L, specifically can be 0.1～4mol/L, 2mol/L～5mol/L, 2mol/L, 4mol/L or 5mol/L.
In above-mentioned preparation method, the power of described microwave condition can be 100～700W, specifically can be 100W, 300W, 500W or 700W;
The time of described reaction can be 5～60min, specifically can be 20min.
Above-mentioned preparation method also comprises the step of described glycyrrhetinic acid being carried out in aqueous ethanolic solution to recrystallization.
In the step of above-mentioned preparation method's recrystallization: the consumption of described aqueous ethanolic solution is: described in every 1g, glycyrrhetinic acid needs aqueous ethanolic solution described in 10～20mL, glycyrrhetinic acid needs aqueous ethanolic solution described in 10mL, 15mL or 20mL described in concrete every 1g;
The volume fraction of described aqueous ethanolic solution can be 80%～95%, specifically can be 80%, 90% or 95%;
The number of times of described recrystallization can be 3～5 times, specifically can be 3 times, 4 times or 5 times.
The present invention has the following advantages:
1, this employing microwave-assisted technology of the inventive method has shortened the deacetylation time, has improved transformation efficiency;
2, product colourity is good, and purity is high, and cost is low, and indices all can reach Europe and Japanese Pharmacopoeia standard-required;
3, this preparation method is applicable to the scale operation of bulk drug glycyrrhetinic acid, has reduced the usage quantity of reagent, has shortened the production time, and energy consumption reduces greatly, and the pollution of environment is reduced, and can save great amount of cost.
Embodiment
The experimental technique using in following embodiment if no special instructions, is ordinary method.
Material, reagent etc. used in following embodiment, if no special instructions, all can obtain from commercial channels.
In following embodiment, the HPLC content of acetyl glycyrrhetinic acid and glycyrrhetinic acid is all to detect as follows: operating basis is according to two annex VI D of Chinese Pharmacopoeia version in 2010.
With octadecylsilane chemically bonded silica be weighting agent, methyl alcohol-0.01mol/L phosphoric acid solution (80: 20) is moving phase; Detection wavelength is 252nm.Sample dissolves with anhydrous methanol, and constant volume shakes up; The accurate 20ul that draws, injects high performance liquid chromatograph respectively, records color atlas, calculates by area normalization method.
The preparation of embodiment 1, glycyrrhetinic acid
Take 20.3g acetyl glycyrrhetinic acid raw material, HPLC content is 55%; Adding concentration by 1: 1 (w/v) is the NaOH solution (20.3mL) of 5mol/L; Put into microwave reactor and react 20min, microwave power is 100W; After having reacted, be down to 25 DEG C, filter, washing filter cake, removes salt; Filter cake obtains crude product glycyrrhetinic acid 17.8g after drying; Add 20 times of amount (being 406mL) 80% aqueous ethanolic solutions (v/v) to dissolve crude product glycyrrhetinic acid, recrystallization 5 times, crystallization obtains fine work glycyrrhetinic acid 16.1g after drying, HPLC content is 98.45%, total impurities peak is no more than 2%, single contaminant peak is no more than 0.7%, meets European Pharmacopoeia standard completely.
The preparation of embodiment 2, glycyrrhetinic acid
Take 20.5g acetyl glycyrrhetinic acid raw material, HPLC content is 63%; Adding concentration by 1: 2 (w/v) is the KOH solution (41mL) of 4mol/L; Put into microwave reactor and react 20min, microwave power is 300W; After having reacted, be down to 25 DEG C, filter, washing filter cake, removes salt; Filter cake obtains crude product glycyrrhetinic acid 18.6g after drying; Add 10 times of amount (being 205mL) 90% aqueous ethanolic solutions (v/v) to dissolve crude product glycyrrhetinic acid, recrystallization 4 times, crystallization obtains fine work glycyrrhetinic acid 16.4g after drying, and HPLC content is 98.21%.Total impurities peak is no more than 2%, and single contaminant peak is no more than 0.7%, meets European Pharmacopoeia standard completely.
The preparation of embodiment 3, glycyrrhetinic acid
Take 20.4g acetyl glycyrrhetinic acid raw material, HPLC content is 71%; Adding concentration by 1: 4 (w/v) is the NaOH solution (91.6mL) of 2mol/L; Put into microwave reactor and react 20min, microwave power is 500W; After having reacted, be down to 25 DEG C, filter, washing filter cake, removes salt; Filter cake obtains crude product glycyrrhetinic acid 18.1g after drying; Add 10 times of amount (being 204mL) 95% aqueous ethanolic solutions (v/v) to dissolve crude product glycyrrhetinic acid, recrystallization 3 times, crystallization obtains fine work glycyrrhetinic acid 16.8g after drying, and HPLC content is 98.35%.Total impurities peak is no more than 2%, and single contaminant peak is no more than 0.7%, meets European Pharmacopoeia standard completely.
The preparation of embodiment 4, glycyrrhetinic acid
Take 20.6 acetyl glycyrrhetinic acid raw materials, HPLC content is 82%; Adding concentration by 1: 3 (w/v) is the KOH solution (61.8mL) of 4mol/L; Put into microwave reactor and react 20min, microwave power is 700W; After having reacted, be down to 25 DEG C, filter, washing filter cake, removes salt; Filter cake obtains crude product glycyrrhetinic acid 19.0g after drying; Add 15 times of amount (being 309mL) 90% aqueous ethanolic solutions (v/v) to dissolve crude product glycyrrhetinic acid, recrystallization 3 times, crystallization obtains fine work glycyrrhetinic acid 17.2g after drying, and HPLC content is 98.13%.Total impurities peak is no more than 2%, and single contaminant peak is no more than 0.7%, meets European Pharmacopoeia standard completely.
Claims (5)
1. a preparation method for glycyrrhetinic acid, comprises the steps:
Under the condition of microwave condition and alkali existence, acetyl glycyrrhetinic acid, through reaction deacetylate, obtains described glycyrrhetinic acid.
2. preparation method according to claim 1, is characterized in that: described alkali is sodium hydroxide and/or potassium hydroxide;
Described deacetylation is carried out in the aqueous solution of described alkali;
The consumption of the aqueous solution of described alkali is: the aqueous solution of alkali described in acetyl glycyrrhetinic acid needs 1～10mL described in every 1g;
The volumetric molar concentration of the aqueous solution of described alkali is 0.1～5mol/L.
3. preparation method according to claim 1 and 2, is characterized in that: the power of described microwave condition is 100～700W;
The time of described reaction is 5～60min.
4. according to the preparation method described in claim 1-4 any one, it is characterized in that: described method also comprises the step of described glycyrrhetinic acid being carried out in aqueous ethanolic solution to recrystallization.
5. preparation method according to claim 4, is characterized in that: the consumption of described aqueous ethanolic solution is: aqueous ethanolic solution described in glycyrrhetinic acid needs 10～20mL described in every 1g.
The volume fraction of described aqueous ethanolic solution is 80%～95%;
The number of times of described recrystallization is 3～5 times.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106543261A (en) * | 2016-10-27 | 2017-03-29 | 深圳市新阳唯康科技有限公司 | A kind of enoxolone crystal-form substances and preparation method thereof |
| CN106565817A (en) * | 2016-11-09 | 2017-04-19 | 深圳市新阳唯康科技有限公司 | Amorphous glycyrrhetinic acid and preparation method thereof |
| CN106632575A (en) * | 2016-12-20 | 2017-05-10 | 深圳市新阳唯康科技有限公司 | Novel glycyrrhetinic acid crystal form and preparation method thereof |
| CN107058443A (en) * | 2017-06-07 | 2017-08-18 | 江苏天晟药业股份有限公司 | A kind of preparation method of enoxolone |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106543261A (en) * | 2016-10-27 | 2017-03-29 | 深圳市新阳唯康科技有限公司 | A kind of enoxolone crystal-form substances and preparation method thereof |
| CN106565817A (en) * | 2016-11-09 | 2017-04-19 | 深圳市新阳唯康科技有限公司 | Amorphous glycyrrhetinic acid and preparation method thereof |
| CN106632575A (en) * | 2016-12-20 | 2017-05-10 | 深圳市新阳唯康科技有限公司 | Novel glycyrrhetinic acid crystal form and preparation method thereof |
| CN107058443A (en) * | 2017-06-07 | 2017-08-18 | 江苏天晟药业股份有限公司 | A kind of preparation method of enoxolone |
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