CN101817867B - Method for preparing glycyrrhetinic acid - Google Patents
Method for preparing glycyrrhetinic acid Download PDFInfo
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- CN101817867B CN101817867B CN 201010183738 CN201010183738A CN101817867B CN 101817867 B CN101817867 B CN 101817867B CN 201010183738 CN201010183738 CN 201010183738 CN 201010183738 A CN201010183738 A CN 201010183738A CN 101817867 B CN101817867 B CN 101817867B
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Abstract
The invention provides a method for preparing glycyrrhetinic acid, which comprises the followings steps of: dissolving glycyrrihizic acid powder with an organic solvent, and extracting and purifying to obtain an extract; in acetic acid, performing catalytic hydrolysis of mineral acid and acetylation to obtain acetyl glycyrrhetinic acid; adding water or alcohol into the acetyl glycyrrhetinic acid, and hydrolyzing under the catalysis of alkali to obtain crude glycyrrhetinic acid; dissolving with an organic solvent, adding active carbon for refluxing and decoloring, and crystallizing to obtain the glycyrrhetinic acid of which the purity is over 97 percent (by a neutralization process); and further crystallizing for multiple times with the organic solvent to obtain the glycyrrhetinic acid with the purity over 98 percent (HPLC). In the method, the glycyrrihizic acid powder is used as a raw material, so the raw material range is widened; the production is carried out under normal pressure, pressure containers are not needed, and the requirement on equipment is low; and the process is easily controlled, the process technology is simplified, and the production cost is low.
Description
Technical field
The invention belongs to the medical material technical field, be specifically related to a kind of preparation method of bulk drug glycyrrhetinic acid.
Background technology
Glycyrrhetinic acid is one of deep processing series product of Radix Glycyrrhizae extract.Radix Glycyrrhizae is a conventional Chinese medicine, is widely used in fields such as medicine, tobacco, food.Its main effective constituent Potenlini has thyroliberin appearance effect, can be used for detoxifcation, anti-inflammatory, antibechic, antitumor etc.The aglycon of Potenlini is a glycyrrhetinic acid, in human body, Potenlini through the hydrochloric acid in gastric juice hydrolysis or in liver β～glycuronidase be decomposed to form glycyrrhetinic acid.The pharmacological action of Potenlini comes down to the effect of glycyrrhetinic acid.Pharmacological research is in recent years found; The medicine of Potenlini and Enoxolone derivative has anti-inflammatory, antiulcer agent, antianaphylaxis, antiviral, reducing blood-fat, antibechic, effect such as relieving asthma, eliminate the phlegm, and also can be used for preventing and treating diseases such as viral hepatitis, hyperlipidemia and cancer.China is the leading exporter of Radix Glycyrrhizae, carries out deep processing and the comprehensive utilization of Radix Glycyrrhizae, and is significant.
The method that in the past prepared glycyrrhetinic acid is a raw material with Glycyrrhizinic acid monopotassium salt or ammonium salt normally, and through adding ore deposit acid, pressurized hydrolysis just can obtain glycyrrhetinic acid.The glycyrrhetinic acid purity that this method obtains is relatively poor, and is difficult with the recrystallization method purifying; Production process needs pressure vessel, and is high to equipment requirements; If hydrolysising condition is controlled bad, be easy to take place the isomerization reaction of glycyrrhetinic acid.For example, 18 β～H glycyrrhetinic acid, 18 α～H glycyrrhetinic acid, 18 β～H glycyrrhetinic acid methyl esters, glycyrrhetinic acid dewatered product and methyl esters thereof etc. have been detected after the bibliographical information hydrolysis.In addition, prepare glycyrrhetinic acid with Glycyrrhizinic acid monopotassium salt or ammonium salt hydrolysis, raw materials cost is higher.People adopt the thick glycyrrhetinic acid of dissolved in chloroform more, through equipment and higher aluminum oxide or the polymeric amide adsorption chromatography column chromatography for separation of technical requirements, just can make pure glycyrrhetinic acid, and Technology is complicated, and turnout also is restricted.
Developed enzymatic hydrolysis process afterwards, promptly Potenlini obtains pure glycyrrhetinic acid through enzymic hydrolysis.Although enzyme hydrolysis method can obtain pure glycyrrhetinic acid, preparation condition and Technology are complicated, and cost is higher, are difficult for realizing industriallization.
Summary of the invention
The object of the present invention is to provide that a kind of raw material range is able to expand, Technology is simplified, process is controlled easily, the preparation method of glycyrrhetinic acid with low cost.
For realizing above-mentioned purpose, the technical scheme that the present invention takes is:
A kind of preparation method of glycyrrhetinic acid utilizes the Potenlini powder to be raw material, under normal pressure, produces pure glycyrrhetinic acid, and it may further comprise the steps:
1. with the Potenlini powder with 6～30 times of hydrophilic organic solvent dissolutions, extracted 1～5 hour under room temperature to the 50 ℃ condition, filter; Filtrating concentrates, and reclaims organic solvent and obtains extract, obtains water ratio 80～100 ℃ of following dryings and is not more than 20% dry extract; In dry extract, add 2～5 times of mass percent concentrations and be in 60～90% the acetic acid, add 0.05～0.3 mole ore deposit acid as catalyzer by per 100 gram dry extract, hydrolysis and acetylize under the normal pressure; Temperature is controlled at 85～110 ℃, reacts 1～4 hour, to hydrolysis and acetylize completion; Be cooled to room temperature, filter organic solvent washing; Water washing, dry under 80～100 ℃, obtain the acetyl glycyrrhetinic acid;
2. the water or the alcohol that in the acetyl glycyrrhetinic acid that obtains, add 10～18 times of amounts add alkali control pH in 12～14 scopes, and room temperature is reduced in atmospheric pressure reflux hydrolysis 3～6 hours; Hydrolyzed solution adds acidifying pH to 4～6, filters, and the washing filter cake is removed inorganic salt; 80～100 ℃ down dry, obtain thick glycyrrhetinic acid, with it with 10～30 times of organic solvent dissolutions; Add gac by 10～40% of thick glycyrrhetinic acid weight and carry out reflux decolour, filter, after filtrating is reclaimed organic solvent; Separate out solid, filter, obtain glycyrrhetinic acid; Measure its purity with neutralisation and reach more than 97%, behind the organic solvent recrystallization, obtain HPLC mensuration purity and reach the glycyrrhetinic acid more than 98% again.
Described hydrophilic organic solvent particular methanol, ethanol, propyl alcohol, Virahol or acetone.
Described ore deposit acid catalyst preferably sulfuric acid, hydrochloric acid or phosphoric acid.
Described washing is with organic solvent particular methanol, ethanol, propyl alcohol, Virahol, acetone or acetic acid.
The preparation method of glycyrrhetinic acid provided by the invention utilizes the Potenlini powder to be raw material, has expanded raw material range; Normal pressure is produced down, need not pressure vessel, and equipment requirements is reduced; Process is controlled easily, and Technology is simplified, and production cost is low, obtains glycyrrhetinic acid purity and reaches more than 97% (neutralisation).Further can obtain for several times the above glycyrrhetinic acid of purity 98% (HPLC) with the organic solvent recrystallization.In the high-pressure liquid chromatography, the total impurities peak is less than 2%, and single impurity peaks is no more than 0.7%.This product meets the European Pharmacopoeia standard fully.
Embodiment
Embodiment 1
Extracting liquorice acid powder (the about 25%HPLC of the content of Potenlini) 140g; Add 1120ml 95% edible ethanol; 40 ℃ were extracted 3 hours, removed by filter insoluble impurities, and the filtrating distillation is reclaimed ethanol and obtained extract; Extract is put 100 ℃ of dryings in the water-bath, obtains water ratio and is not more than 20% 118g dry extract; With getting 100g after the dry extract pulverizing, add 70% Glacial acetic acid min. 99.5 300ml, add vitriol oil 7ml, hydrolysis and acetylize under the normal pressure; Be warming up to 98～103 ℃, reacted 2 hours, to hydrolysis and acetylize completion, be cooled to room temperature; The solids that filtration is separated out with 250ml 65% acetic acid washing leaching cake, is used the 200ml washing with alcohol again, washes with 300ml at last; Dry under 100 ℃, obtain acetyl glycyrrhetinic acid bullion 20.21g, purity 88.2% (HPLC).Get acetyl glycyrrhetinic acid 20g, add 300ml water, hydro-oxidation sodium 5g adjusts pH to 13, atmospheric pressure reflux hydrolysis 4 hours; Reduce to room temperature,, filter, use the pure water washing leaching cake with hcl acidifying pH to 5.2; Remove inorganic salt, dry under 100 ℃, obtain 17.8g glycyrrhetinic acid bullion, purity 92.9% (HPLC); Again the glycyrrhetinic acid bullion being used the 214ml concentration of volume percent is 95% dissolve with ethanol, carries out reflux decolour by 25% (4.45g) the adding gac of glycyrrhetinic acid bullion weight, and the reflux decolour after-filtration is behind the filtrate recycling ethanol; Separate out solid, filter and obtain glycyrrhetinic acid 16.4g, purity 98.2% (neutralisation).Be further purified, with 95% ethyl alcohol recrystallization three times, obtaining purity is the glycyrrhetinic acid product of 98% (HPLC), and the total impurities peak is no more than 2%, and single impurity peaks is no more than 0.7%, meets the European Pharmacopoeia standard fully.
Embodiment 2
Extracting liquorice acid powder (the about 25%HPLC of the content of Potenlini) 140g adds 980ml methyl alcohol, extracts 1.5 hours under the room temperature; Remove by filter insoluble impurities, methyl alcohol is reclaimed in the filtrating distillation, obtains extract; Extract is put 80 ℃ of dryings in the water-bath, obtains water ratio and is not more than 20% 120g dry extract; With getting 100g after the dry extract pulverizing, add 60% Glacial acetic acid min. 99.5 500ml, add concentrated hydrochloric acid 24ml, be warming up to 85～90 ℃ of hydrolysis and acetylize; Reacted 4 hours, and to hydrolysis and acetylize completion, be cooled to room temperature, filter and separate out solids; With 250ml 65% acetic acid washing leaching cake, use the 200ml methanol wash again, wash with 300ml at last; Dry under 80 ℃, obtain acetyl glycyrrhetinic acid bullion 20.38g, purity 87.0% (HPLC).
Get acetyl glycyrrhetinic acid 20g, add 200ml methyl alcohol, hydro-oxidation sodium 5g (water dissolution of 10ml) adjusts pH to 13, atmospheric pressure reflux hydrolysis 3 hours; Reduce to room temperature,, filter, use the pure water washing leaching cake with hcl acidifying pH to 5.0; Remove inorganic salt, dry under 80 ℃, obtain 17.8g glycyrrhetinic acid bullion, purity 92.9% (HPLC); Again the glycyrrhetinic acid bullion is used the 178ml dissolve with methanol, add gac 7.12g reflux decolour, the reflux decolour after-filtration is after filtrating is reclaimed methyl alcohol; Separate out solid, filter and obtain glycyrrhetinic acid 16.4g, purity 98.0% (neutralisation).Be further purified, with recrystallizing methanol three times, obtaining purity is the glycyrrhetinic acid product of 98% (HPLC), and the total impurities peak is less than 2%, and single impurity peaks is no more than 0.7%.Product meets the European Pharmacopoeia standard fully.
Embodiment 3
Extracting liquorice acid powder (the about 25%HPLC of the content of Potenlini) 140g adds 4200ml acetone, extracts 5 hours down at 50 ℃; Remove by filter insoluble impurities; The filtrating distillation is reclaimed ethanol and is obtained extract, and extract obtains water ratio and is not more than 20% 110g dry extract 90 ℃ of dryings; With getting 100g after the dry extract pulverizing, add 85% Glacial acetic acid min. 99.5 200ml, add phosphatase 24 .2ml, be warming up to 95～98 ℃; Hydrolysis and acetylize under the normal pressure were reacted 3 hours, to hydrolysis and acetylize completion, were cooled to room temperature; Solids is separated out in filtration, with 250ml 65% acetic acid washing leaching cake, uses the 200ml washing with acetone again, washes with 300ml at last; Dry under 90 ℃, obtain acetyl glycyrrhetinic acid bullion 20.3g, purity 91.2% (HPLC).
Get acetyl glycyrrhetinic acid 20g, add 360ml water, hydro-oxidation sodium 5g adjusts pH to 12, atmospheric pressure reflux hydrolysis 6 hours; Reduce to room temperature,, filter, use the pure water washing leaching cake with hcl acidifying pH to 4.5; Remove inorganic salt, dry under 90 ℃, obtain 17.7g glycyrrhetinic acid bullion, purity 92.9% (neutralisation); Again the glycyrrhetinic acid bullion is used the 530ml acetone solution, add the 1.8g gac, reflux decolouring, reflux decolour after-filtration; Filtrating is separated out solid after reclaiming methyl alcohol, filters to obtain glycyrrhetinic acid 16.4g, purity 98.5% (neutralisation).Be further purified, with acetone recrystallization three times, obtaining purity is the glycyrrhetinic acid product of 98% (HPLC), and the total impurities peak is no more than 2%, and single impurity peaks is no more than 0.7%.This product meets the European Pharmacopoeia standard fully.
Embodiment 4
The difference of embodiment 4 and embodiment 1 only is the corresponding propyl alcohol that replaces with of organic solvent ethanol.
Embodiment 5
The difference of embodiment 5 and embodiment 1 only is the corresponding Virahol that replaces with of organic solvent ethanol.
Claims (3)
1. the preparation method of a glycyrrhetinic acid is characterized in that: utilize the Potenlini powder to be raw material, under normal pressure, produce pure glycyrrhetinic acid, it may further comprise the steps:
1. with the Potenlini powder with 6～30 times of hydrophilic organic solvent dissolutions, extracted 1～5 hour under room temperature to the 50 ℃ condition, filter; Filtrating concentrate to be reclaimed organic solvent and is obtained extract, obtains water ratio 80～100 ℃ of following dryings and is not more than 20% dry extract, in dry extract, adds 2～5 times of mass percent concentrations and is in 60～90% the acetic acid; The ore deposit acid of pressing 0.05～0.3 mole of per 100 gram dry extract adding is as catalyzer, and described ore deposit acid catalyst is selected sulfuric acid, hydrochloric acid or phosphoric acid for use, hydrolysis and acetylize under the normal pressure; Temperature is controlled at 85～110 ℃, reacts 1～4 hour, to hydrolysis and acetylize completion; Be cooled to room temperature, filter organic solvent washing; Water washing, dry under 80～100 ℃, obtain the acetyl glycyrrhetinic acid;
2. the water or the alcohol that in the acetyl glycyrrhetinic acid that obtains, add 10～18 times of amounts add alkali control pH in 12～14 scopes, and room temperature is reduced in atmospheric pressure reflux hydrolysis 3～6 hours; Hydrolyzed solution adds acidifying pH to 4～6, filters, and the washing filter cake is removed inorganic salt; 80～100 ℃ down dry, obtain thick glycyrrhetinic acid, with it with 10～30 times of organic solvent dissolutions; 10～40% gacs that add thick glycyrrhetinic acid weight carry out reflux decolour, filter, after filtrating is reclaimed organic solvent; Separate out solid, filter, obtain glycyrrhetinic acid; Measure its purity with neutralisation and reach more than 97%, behind the organic solvent recrystallization, obtain HPLC mensuration purity and reach the glycyrrhetinic acid more than 98% again.
2. the preparation method of glycyrrhetinic acid according to claim 1 is characterized in that: described hydrophilic organic solvent particular methanol, ethanol, propyl alcohol, Virahol or acetone.
3. the preparation method of glycyrrhetinic acid according to claim 1, it is characterized in that: described washing is with organic solvent particular methanol, ethanol, propyl alcohol, Virahol, acetone or acetic acid.
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Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103588849A (en) * | 2012-08-14 | 2014-02-19 | 江苏汉邦科技有限公司 | Preparation method for glycyrrhetinic acid |
| CN104004047A (en) * | 2014-05-27 | 2014-08-27 | 普凡生生物科技(北京)有限公司 | Preparation method of glycyrrhetinic acid |
| CN104004046A (en) * | 2014-05-27 | 2014-08-27 | 普凡生生物科技(北京)有限公司 | Preparation method of acetyl glycyrrhetinic acid |
| CN104497093A (en) * | 2014-11-25 | 2015-04-08 | 普凡生生物科技(北京)有限公司 | Glycyrrhetinic acid preparation method |
| CN104861030A (en) * | 2015-03-01 | 2015-08-26 | 李玉山 | Method for preparing glycyrrhetinic acid through dual phase hydrolysis method |
| CN104829681A (en) * | 2015-05-08 | 2015-08-12 | 江苏天晟药业有限公司 | Method for purifying glycyrrhetinic acid |
| CN105669823A (en) * | 2016-03-04 | 2016-06-15 | 南京大学 | Piperazine-framework-containing glycyrrhetinic acid derivatives, and preparation method and application thereof |
| 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 |
| CN106749485A (en) * | 2016-11-25 | 2017-05-31 | 深圳市新阳唯康科技有限公司 | A kind of enoxolone novel crystal forms 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 |
| CN110090469A (en) * | 2019-04-26 | 2019-08-06 | 青岛农业大学 | A method of extraction purification glycyrrhizin and enoxolone from Radix Glycyrrhizae |
| CN110283225B (en) * | 2019-07-29 | 2021-02-02 | 洛阳蓝斯利科技有限公司 | Preparation method of 24-hydroxy-glycyrrhetinic acid |
| CN111620924A (en) * | 2020-06-04 | 2020-09-04 | 华中农业大学 | Drug design method based on natural product, pentacyclic triterpenoid compound, preparation method and application thereof |
| CN114196723A (en) * | 2021-12-30 | 2022-03-18 | 淮安兄弟生物科技有限公司 | Preparation method of glycyrrhetinic acid |
| CN114507269A (en) * | 2022-03-07 | 2022-05-17 | 新疆富沃药业有限公司 | Preparation method of acetyl glycyrrhetinic acid |
| CN115772205A (en) * | 2022-11-18 | 2023-03-10 | 江苏天晟药业股份有限公司 | Green preparation process of stearyl alcohol glycyrrhetinate |
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