CN104711300B - The preparation method of icariine - Google Patents
The preparation method of icariine Download PDFInfo
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- CN104711300B CN104711300B CN201310674836.5A CN201310674836A CN104711300B CN 104711300 B CN104711300 B CN 104711300B CN 201310674836 A CN201310674836 A CN 201310674836A CN 104711300 B CN104711300 B CN 104711300B
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- shorthorned epimedium
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- pectase
- icariine
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- OLBVDCHAEFPZOR-FMCSQSGQSA-N C[C@@H]([C@@H]([C@H]([C@H]1O)O)O)OC1OC(C(c(cc1)ccc1OC)Oc1c(CCC(C)(C)C)c(OC([C@@H]([C@H]2O)O)O[C@H](CO)[C@H]2O)cc(O)c11)C1=O Chemical compound C[C@@H]([C@@H]([C@H]([C@H]1O)O)O)OC1OC(C(c(cc1)ccc1OC)Oc1c(CCC(C)(C)C)c(OC([C@@H]([C@H]2O)O)O[C@H](CO)[C@H]2O)cc(O)c11)C1=O OLBVDCHAEFPZOR-FMCSQSGQSA-N 0.000 description 1
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Abstract
The present invention provides a kind of preparation method of icariine, this method includes that Shorthorned Epimedium P.E is carried out enzyme digestion reaction under the action of pectase, obtains icariine.The icariine that method through the invention obtains can reach 20% or more relative to the yield of general flavone, and purity is more than 99%.
Description
Technical field
The present invention relates to the preparation methods of icariine, belong to field of medicaments.
Background technology
A Kelading also known as icariine, epimedium aglucone, be extracted from Chinese medicine Herba Epimedii it is isolated main
The new effective monomer that active constituent Shorthorned Epimedium P.E is obtained through enzymatic conversion, shown in structural formula such as following formula (I)：
The preparation method of the compound is disclosed in CN101302548B.This method is using icariin as raw material, with β-grape
Glycosidase is hydrolyzed, and supernatant is obtained by filtration in the precipitation acetone solution that hydrolysate centrifuges.The supernatant is used again
Water is recrystallized, and icariine sterling is obtained.
Disclosed in the Chinese patent application No. is 201010517793.6 it is a kind of using naringinase from icariin
Icariin standard items are dissolved in alcohol solvent by the method for obtaining epimedium aglucone, this method, and shaddock is added at 40-70 DEG C
Glycosides enzyme is digested, to obtain epimedium aglucone.
A kind of preparation method of epimedium aglucone is disclosed in the Chinese patent application No. is 200910184282.4, it should
Method is extracted using Herba Epimedii as raw material by methanol, snail enzyme hydrolysis and etc. obtain epimedium aglucone crude product.More than however,
The enzymatic isolation method of icariine preparation method is all low in the presence of enzymolysis conversion ratio, the defect more than enzymolysis product impurity.
Invention content
It is an object of the present invention to provide a kind of preparation method of icariine, the excessive sheep being prepared by this method
Leaves of pulse plants element purity is high.
One aspect of the present invention provides a kind of preparation method of icariine, and this method includes by Shorthorned Epimedium P.E in fruit
Enzyme digestion reaction is carried out under the action of glue enzyme, obtains icariine.
Preferably, the pectase includes polygalacturonase and a-N- arabinofuranosidases.
Preferably, the icariin mass content in the Shorthorned Epimedium P.E is 5%-100%.
Preferably, the Shorthorned Epimedium P.E is prepared by the following method to obtain：Using Herba Epimedii as raw material, pass through ethyl alcohol
Solution extracts, and obtains Shorthorned Epimedium P.E.
Preferably, enzymolysis product enzyme digestion reaction obtained, is dissolved in weakly polar organic solvent, and filtrate is collected in filtering,
Polar solvent is added into filtrate, crystallizes.
Preferably, the weakly polar organic solvent is in ethyl acetate, acetone, dichloromethane and methyl tertiary butyl ether(MTBE)
One or more, and the polar solvent is one or more of methanol, second alcohol and water.
Most preferably, the weakly polar organic solvent is acetone, and the polar solvent is water.
Preferably, the enzyme digestion reaction includes the following steps：
A. enzymolysis product enzyme digestion reaction obtained centrifuges；
B. acetone will be added in the obtained precipitation of centrifugation；
C. distilled water will be added in filtrate that acetone is obtained by filtration again, flows back；
D. the liquid that reflux obtains is crystallized at room temperature.
Preferably, the volume ratio of the filtrate in step c and distilled water is 1-5：1, and the reflux temperature is 50-
100℃。
Preferably, Shorthorned Epimedium P.E liquid concentration is then adsorbed by macroporous resin column, then is with volumetric concentration
The ethanol water of 30%-100% is eluted, and the Shorthorned Epimedium P.E for enzyme digestion reaction is obtained.
Preferably, the mass content for being used for flavones in the Shorthorned Epimedium P.E of enzyme digestion reaction is 20%-100%.
Preferably, the quality of the Herba Epimedii and the volume ratio of ethanol solution are 1 kilogram：2-50 liters, and Extracting temperature
It is 30-100 DEG C.
Preferably, the ethanol solution is the ethanol water that volume ratio is 20-90%.
Preferably, the condition of the enzyme digestion reaction is：It is 4.0- that pH value, which is made, in Shorthorned Epimedium P.E and phosphate buffer
Pectase is added into substrate solution for 6.0 substrate solution, and the quality of pectase is 5-30 times of Shorthorned Epimedium P.E quality,
Hydrolysis temperature is 45-55 DEG C.
It is highly preferred that the quality of pectase is 10-20 times of Shorthorned Epimedium P.E quality, the pH value of substrate solution is 4.5-
5.5, hydrolysis temperature is 48-50 DEG C.
Most preferably, the quality of the pectase is 15 times of Shorthorned Epimedium P.E quality, and it is total that it is contained in substrate solution
The ethyl alcohol of the 10-15% of volume.
Preferably, the pH value of the substrate solution is adjusted by phosphate buffer.
It is highly preferred that the phosphate buffer is phosphoric acid-citrate buffer solution or disodium hydrogen phosphate-potassium dihydrogen phosphate
Buffer solution.
The beneficial effects of the present invention are：The icariine purity that the method for the present invention is prepared is very high, and content is more than
99%, by the icariine of pectin enzymatic conversion, relative to Shorthorned Epimedium P.E, the yield of icariine can reach 20%,
By-product after conversion is few, easily removes.
Description of the drawings
Fig. 1 shows the general flavones in medicinal raw material, and the general flavone obtained by step 1,2 and 3 of embodiment 1.
Fig. 2 indicates the high-efficient liquid phase chromatogram of icariine after purification.
Fig. 3 indicates the high-efficient liquid phase chromatogram that enzyme digestion reaction carries out 48 hours.
Fig. 4 indicates the high-efficient liquid phase chromatogram that enzyme digestion reaction carries out 70 hours.
Specific implementation mode
Unless otherwise stated, term herein " enzyme digestion reaction " refers to the hydrolysis under enzyme effect.
Unless otherwise stated, term herein " icariin " refers to the extract in Herba Epimedii drying cauline leaf, is
Single component has following molecular structure：
Unless otherwise stated, term herein " general flavone " refers to the Herba Epimedii extraction obtained by ethanol extraction method
Main component in object, general flavone include icariin, Epimedin A, Epimedin B, epimedin C, icariside, precious glycosides suddenly
Deng.In Chinese Pharmacopoeia first 306-308 pages computational methods for having recorded general flavone of version in 2010, according to UV-vis spectroscopy
Photometry, the absorbance at 270nm wavelength can calculate the content of general flavone.
Unless otherwise stated, trade mark of the term herein " pectase " purchased from Royal DSM company is RAPIDASE pectases
As enzyme digestion reaction enzyme, product identification 984.
Embodiment 1
The preparation of Shorthorned Epimedium P.E
Step 1：Using the Folium Epimedii 300g except stem as raw material, 600L ethyl alcohol that is broken, being 70% with volumetric concentration is rubbed
Aqueous solution extracts, and is extracted altogether at 75 DEG C 3 times.Ethanol extract is recycled to no alcohol taste, is then centrifuged the concentrate, institute
Filtrate is obtained to adsorb by macroporous resin column.
Step 2：The ethanol water for being 20% with volumetric concentration washs the macroporous resin column in step 1, and eluent discards.
Step 3：The ethanol water for being 80% with volumetric concentration carries out the macroporous resin column in washing step 2, collects this
When eluent.
The eluent concentration that three above step is obtained, obtains Shorthorned Epimedium P.E and amounts to 46g.The above three-step approach obtains
Shorthorned Epimedium P.E by high performance liquid chromatography detection flavone component therein, see Fig. 1 lower half figures.
Macroreticular resin in the present embodiment is purchased from Hebei Bao En sorbing materials Co., Ltd, model D101.
By the flavone component in high performance liquid chromatography detection medicinal material, Fig. 1 upper half figures are seen.
High performance liquid chromatography (HPLC) condition：Chromatographic column：Agela-C18 columns；Mobile phase：Acetonitrile-water is (wherein containing volume point
Number for 0.0125% trifluoroacetic acid), gradient see the table below 1, elution time 60min, flow velocity：1.0mL/min, column temperature：35
℃.UV detector Detection wavelength is respectively 254,272,320nm.
1 solvent gradient elution table of table
As a result it shows：In addition to the peak occurred when at 3 minutes is solvent peak, at 22 minutes, 24 minutes, 46 minutes and
52 minutes appearances are the peak of flavone component, by the general flavone collection of illustrative plates for the medicinal material that above method detects, are extracted with Herba Epimedii
Collection of illustrative plates (HPLC-UV) comparison of general flavone is as can be seen that after macroporous resin purification in object, and general flavone contains in Shorthorned Epimedium P.E
Amount dramatically increases, and wherein general flavone reaches 5-15% relative to the yield of Herba Epimedii raw material.
Enzyme digestion reaction prepares icariine
According to above step, epimedium herb is repeatedly extracted, obtains the pH5.2 of 55 grams of Shorthorned Epimedium P.E, 1mol/L
Disodium hydrogen phosphate-potassium phosphate buffer 0.15L, ethyl alcohol 0.22L, 660 grams of enzymes are dissolved in the water manufactured 0.7L, and pH value is
In 5L reactors, reaction temperature is digested 5.2 enzyme solutions under conditions of 48 DEG C, specific condition such as table 2：
2 enzymatic hydrolysis condition of table
| Shorthorned Epimedium P.E | Enzyme | Ethyl alcohol | Water | Buffer solution |
| 55g | 660g | 0.22L | 1.1L | 0.15L(1M) |
It is RAPIDASE pectases as enzyme digestion reaction enzyme, product identification 984 to select the trade mark of Royal DSM company.
The purifying of icariine
Reaction solution is centrifuged after reaction within 70 hours, removes supernatant, and precipitation 300mL acetone solutions filter,
Filtrate 160mL is obtained, then about 150mL distilled water is added in filtrate, 75 DEG C of reflux dissolvings are placed at room temperature for crystallization.It is small to crystallize 24
Crystallization is obtained by filtration in Shi Hou, and drying, weigh to obtain 11.5g.It precipitates crystal as icariine.Icariine is carried relative to Herba Epimedii
It is 20.9% to take the yield of object, reaches 99.5% by the purity of high-efficient liquid phase color spectral test icariine, sees Fig. 2.
Embodiment 2
Commercially available Shorthorned Epimedium P.E enzymatic isolation method prepares icariine
Shorthorned Epimedium P.E in the present embodiment is purchased from Shaanxi Jiahe plant Chemical Co., Ltd., and trade name is " excessive sheep
Leaves of pulse plants extract ", wherein the icariin for being 90% containing mass fraction.
Step 1：Enzymatic isolation method prepares icariine
By commercially available 80g Shorthorned Epimedium P.Es, wherein the icariin for being 90% containing mass fraction, is scattered in a concentration of
In the disodium hydrogen phosphate of the pH5.2 of 1mol/L-potassium phosphate buffer 2.0L, ethyl alcohol 0.6L, RAPIDASE pectase is added
1400g amounts to 1.4L in 5L reactors, and reaction temperature is digested under conditions of 50 DEG C, specific condition such as table 3：
3 enzymatic hydrolysis condition of table
It is detected by HPLC, reaction system converts 70 hours, and the conversion ratio that icariin is converted into icariine reaches
90%.
Step 2：The purifying of icariine
Reaction solution is centrifuged after reaction within 70 hours, and supernatant, precipitation 2L acetone solutions is gone to filter, then in filtrate
Middle addition about 1L distilled water, 75 DEG C of reflux dissolvings, is placed at room temperature for crystallization.After crystallization 24 hours, crystallization is obtained by filtration, dries, claims
Heavy 32.9g.It precipitates crystal as icariine.Icariine is 41.1% relative to the yield of 90% Shorthorned Epimedium P.E, is led to
Crossing high performance liquid chromatography examines the purity of icariine to reach 99.0%.
Embodiment 3
Enzymatic conversion general flavone prepares the condition optimizing of icariine
1, the investigation of pH value, reaction temperature, concentration of substrate
Select Shorthorned Epimedium P.E commercially available from 1mg or the Shorthorned Epimedium P.E obtained according to 1 method of embodiment the bottom of as
Object, in 200 μ L buffer solutions, under conditions of 7 μ L pectases and 250 μ L water that 15mg enzymes are configured to, respectively change pH value, temperature and
Concentration of substrate reacts 24 hours, and after reaction, most suitable reaction condition is found in water-saturated n-butanol extraction.Pass through thin layer
Chromatography determines most suitable reaction condition.(solvent is chloroform to thin-layer chromatographic analysis condition：Methanol：Water=76：
26：6 lower layer's solution；Color developing agent is 10% ethanol solution of sulfuric acid).
The variation range of table 4pH values
The variation range of 5 reaction temperature of table
The further investigation of reaction condition
In order to further determine substrate Shorthorned Epimedium P.E concentration and concentration of alcohol, with 15mg/ml concentration of substrate or so two
The 10mg/mL and 20mg/mL of side, ethyl alcohol volumetric concentration (10%, 15%) and different types of ion buffer solution carry out following
Experiment：
6 concentration of substrate of table, influence of the buffer solution to conversion ratio
The result shows that：When ethyl alcohol volumetric concentration is 15%, enzyme partial inactivation, therefore ethyl alcohol volumetric concentration is 10% most
Properly；As a concentration of 20mg/mL of substrate Shorthorned Epimedium P.E, conversion is incomplete, and when concentration of substrate is 15mg/mL, turn
Change is more complete, and the changing effect of acetate buffer solution is slightly poorer than phosphate buffer and phosphoric acid-citrate buffer solution.
2. summarizing
From the above results, it can be seen that when largely being converted using this pectase progress barren wort total chromocor, the concentration of substrate of selection
Can be 15mg/mL, concentration of alcohol 10%, buffer solution is disodium hydrogen phosphate-potassium phosphate buffer or phosphoric acid-lemon
Acid buffer, pH4.5, temperature control between 50-55 DEG C, and yield can reach 20% or more, obtain the purity of icariine
More than 99%.
Claims (14)
1. a kind of preparation method of icariine, this method includes digesting Shorthorned Epimedium P.E under the action of pectase
Reaction obtains icariine, and the pectase includes polygalacturonase and α-N- arabinofuranosidases, described
Reaction conditions are：The substrate solution that pH value is 4.0-6.0 is made in Shorthorned Epimedium P.E and phosphate buffer, it is molten to substrate
Pectase is added in liquid, the quality of pectase is 5-30 times of Shorthorned Epimedium P.E quality, and hydrolysis temperature is 45-55 DEG C, described
Shorthorned Epimedium P.E be the Shorthorned Epimedium P.E by using Herba Epimedii as raw material, being extracted by ethanol solution
In icariin mass content be 5%-100%.
2. according to the method described in claim 1, it is characterized in that, the enzymolysis product that enzyme digestion reaction is obtained, is dissolved in weak pole
Property organic solvent in, filtering, collect filtrate, polar solvent is added into filtrate, crystallize.
3. according to the method described in claim 2, it is characterized in that, the weakly polar organic solvent be ethyl acetate, acetone,
One or more of dichloromethane and methyl tertiary butyl ether(MTBE), and the polar solvent is methanol, one in second alcohol and water
Kind is several.
4. according to the method described in claim 3, it is characterized in that, the weakly polar organic solvent be acetone, the pole
Property solvent be water.
5. according to the method described in claim 1, it is characterized in that, this approach includes the following steps：
A. enzymolysis product enzyme digestion reaction obtained centrifuges；
B. acetone will be added in the obtained precipitation of centrifugation；
C. distilled water will be added in filtrate that acetone is obtained by filtration again, flows back；
D. the liquid that reflux obtains is crystallized at room temperature.
6. according to the method described in claim 5, it is characterized in that, the volume ratio of the filtrate and distilled water in step c is 1-5:
1, and the reflux temperature is 50-100 DEG C.
7. according to the method described in claim 1, it is characterized in that, Shorthorned Epimedium P.E liquid concentration, then passes through macropore tree
Fat adsorbs, then the ethanol water for being 30%-100% with volumetric concentration is eluted, and the Herba Epimedii for enzyme digestion reaction is obtained
Extract.
8. the method according to the description of claim 7 is characterized in that for general flavone in the Shorthorned Epimedium P.E of enzyme digestion reaction
Mass content is 20%-100%.
9. according to the method described in claim 1, it is characterized in that, the volume ratio of the Herba Epimedii and ethanol solution is 1 kilogram：
2-50 liters, and Extracting temperature is 30-100 DEG C.
10. according to the method described in claim 9, it is characterized in that, the second that it is 20-90% that the ethanol solution, which is volume ratio,
Alcohol solution.
11. according to the method described in claim 1, it is characterized in that, the quality of pectase is the 10- of Shorthorned Epimedium P.E quality
20 times, the pH value of substrate solution is 4.5-5.5, and hydrolysis temperature is 48-50 DEG C.
12. according to the method for claim 11, which is characterized in that the quality of the pectase is Shorthorned Epimedium P.E quality
15 times, the ethyl alcohol of the 10-15% containing its total volume in substrate solution.
13. according to the method for claim 12, which is characterized in that the pH value of substrate solution is carried out by phosphate buffer
It adjusts.
14. according to the method for claim 13, which is characterized in that the phosphate buffer is phosphoric acid-lemon acid buffering
Liquid or disodium hydrogen phosphate-potassium phosphate buffer.
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| CN106148454B (en) * | 2015-03-24 | 2021-01-26 | 北京珅奥基医药科技有限公司 | Preparation method of baohuoside I |
| CN109459515B (en) * | 2018-07-05 | 2021-09-17 | 广州科曼生物科技有限公司 | Herba epimedii control extract (arrow leaf) and application thereof |
| CN110699263B (en) * | 2019-10-29 | 2021-05-11 | 浙江工业大学 | Aspergillus niger YH-6 and application thereof in improving content of icaritin in epimedium |
| CN113355373A (en) * | 2021-06-29 | 2021-09-07 | 劲牌持正堂药业有限公司 | Preparation method of low polycyclic aromatic hydrocarbon icaritin |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101302548A (en) * | 2007-05-09 | 2008-11-12 | 北京珅奥基医药科技有限公司 | Preparation of icaritin |
| CN101316573A (en) * | 2005-11-30 | 2008-12-03 | 株式会社太平洋 | Cosmetic composition containing hydrolysates of icariin |
| CN103305564A (en) * | 2013-07-05 | 2013-09-18 | 西安纽赛生物科技有限公司 | Method for converting icariin to herba epimedii |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101316573A (en) * | 2005-11-30 | 2008-12-03 | 株式会社太平洋 | Cosmetic composition containing hydrolysates of icariin |
| CN101302548A (en) * | 2007-05-09 | 2008-11-12 | 北京珅奥基医药科技有限公司 | Preparation of icaritin |
| CN103305564A (en) * | 2013-07-05 | 2013-09-18 | 西安纽赛生物科技有限公司 | Method for converting icariin to herba epimedii |
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Application publication date: 20150617 Assignee: Beijing Shengnuoji Medicine Technology Co., Ltd. Assignor: Beijing Kun'aoji Medical Sci-tech Co., Ltd. Contract record no.: 2017110000017 Denomination of invention: Preparation of icaritin License type: Exclusive License Record date: 20170919 |
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