CN100522985C - Method of preparing 18 alpha type glycyrrhizic acid and its salt using non homogeneous phase reaction - Google Patents
Method of preparing 18 alpha type glycyrrhizic acid and its salt using non homogeneous phase reaction Download PDFInfo
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- CN100522985C CN100522985C CN 200410083052 CN200410083052A CN100522985C CN 100522985 C CN100522985 C CN 100522985C CN 200410083052 CN200410083052 CN 200410083052 CN 200410083052 A CN200410083052 A CN 200410083052A CN 100522985 C CN100522985 C CN 100522985C
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- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 title claims abstract description 27
- 238000006243 chemical reaction Methods 0.000 title claims abstract description 23
- 235000019410 glycyrrhizin Nutrition 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 title claims description 16
- 150000003839 salts Chemical class 0.000 title abstract description 10
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 title abstract description 5
- 229960004949 glycyrrhizic acid Drugs 0.000 title abstract description 5
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 title abstract description 4
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 title abstract description 4
- 239000001685 glycyrrhizic acid Substances 0.000 title abstract description 4
- 239000013078 crystal Substances 0.000 claims abstract description 14
- 239000012071 phase Substances 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000012074 organic phase Substances 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 14
- 229960000583 acetic acid Drugs 0.000 claims description 7
- 239000012362 glacial acetic acid Substances 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 239000008346 aqueous phase Substances 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 3
- 238000012546 transfer Methods 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- 150000001298 alcohols Chemical class 0.000 claims 2
- 235000021050 feed intake Nutrition 0.000 claims 2
- 230000003197 catalytic effect Effects 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 claims 1
- 238000013517 stratification Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- LPLVUJXQOOQHMX-IOHDZAKGSA-N (2s,3s,4s,5r,6r)-6-[(2s,3r,4s,5s,6s)-2-[[(3s,4ar,6ar,6bs,8as,11s,12as,14ar,14bs)-11-carboxy-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-2,3,4a,5,6,7,8,9,10,12,12a,14a-dodecahydro-1h-picen-3-yl]oxy]-6-carboxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-c Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-IOHDZAKGSA-N 0.000 abstract 3
- 238000010521 absorption reaction Methods 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ILRKKHJEINIICQ-OOFFSTKBSA-N Monoammonium glycyrrhizinate Chemical compound N.O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O ILRKKHJEINIICQ-OOFFSTKBSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000126 substance Chemical group 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000003822 preparative gas chromatography Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- -1 salt compounds Chemical class 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 description 1
- 244000303040 Glycyrrhiza glabra Species 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- SPPIIOPGDLITJE-VLQRKCJKSA-N diazanium;(2s,3s,4s,5r,6s)-6-[[(3s,4ar,6ar,6bs,8as,11s,12ar,14ar,14bs)-11-carboxylato-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-2,3,4a,5,6,7,8,9,10,12,12a,14a-dodecahydro-1h-picen-3-yl]oxy]-5-[(2r,3r,4s,5s,6s)-6-carboxy-3,4,5-trihydroxyoxan-2-yl]oxy-3,4-dihy Chemical compound N.N.O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O SPPIIOPGDLITJE-VLQRKCJKSA-N 0.000 description 1
- 229960003720 enoxolone Drugs 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 150000002500 ions Chemical group 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 235000011477 liquorice Nutrition 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 150000002966 pentacyclic triterpenoids Chemical group 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
A process for preparing 18 alpha-glycyrrhizic acid and its salt from 18 beta-glycyrrhizic acid and its salt by heterogeneous reaction features that as the solubilities of said two salts of glycyrrhizic acid are difference and the salt of 18 alpha-glycyrrhizic acid has higher solubility in organic solvent, the organic solvent and water are used to form a heterogeneous reaction system and the resultant of the transform reaction in water phase can be continuously transferred into organic phase, resulting in high transform rate. After said reaction is finished, the organic phase is separated from water phase and the organic phase is then acidified and recrystallized to obtain high-purity crystal of 18 alpha-glycyrrhizic acid.
Description
Technical field
The present invention relates to be used for 18 alpha type glycyrrhizic acids of medicine and the preparation method and the processing condition of salt compounds thereof, 18 alpha type glycyrrhizic acids and the salt thereof of indication is characterized in that it is a pentacyclic triterpenoid, and chemical structure is:
Its chemical name is: 18 α, the salt that the positive volatile oil of 20 β carboxyl-11-oxo-12-alkene-3 β base-2-O-β-D-glucopyranoside aldehydic acid base-α-D-glucopyranoside aldehydic acid or itself and ammonium or other metal ion form.
Technical background
Potenlini is the effective constituent of natural drug Radix Glycyrrhizae.Because it is Radix Glycyrrhizae is to know for people and widely used natural drug a kind of morning, quite deep to its effective constituent Potenlini and salt compounds research thereof.Known in Radix Glycyrrhizae to contain 18 α types and two kinds of epimers of 18 β types, but the Potenlini overwhelming majority that exists in the Radix Glycyrrhizae is 18 beta comfigurations that the epimer of 18 α types only is present in the Radix Glycyrrhizae with trace.And the result of a large amount of biochemistry and pharmacological research and clinical application has proved, the Potenlini of 18 α types or the effect of its salt at aspects such as anti-inflammatories more are better than 18 beta comfigurations, except that anti-inflammatory action, 18 alpha type glycyrrhizic acids have wide biological activity at aspect such as anticancer, antiviral, and this but is that 18 β type isomer are unexistent.
18 α types and 18 β type Potenlinis are epimer each other, the position difference of hydrogen atom on 18 the chiral carbon atom only between two isomer.Between two kinds of epimers, physico-chemical property and spectral quality (IR) are all very similar, but both uv-absorption maximum wavelengths exist certain difference.The maximum absorption wavelength of 18 alpha type glycyrrhizic acid salt in water is 252nm, and the maximum absorption wavelength of 18 β type glycyrrhetates is 257nm.On chromatographic separation, two isomer liquid chromatography (HPLC) behaviors are identical, but utilize gas chromatography (GC) can make it to separate and carry out assay.
Directly extract not only cost height of 18 alpha type glycyrrhizic acid salt from natural product, output is little, is difficult to satisfy needs pharmaceutically, therefore adopts chemical process, and the epimer that the glycyrrhetate of 18 β types is converted into 18 α types is significant.
A large amount of documents and materials and patented technologies show, former study all concentrates on so that Potenlini or its glucoside unit---glycyrrhetinic acid is a parent nucleus, method by chemosynthesis or base group modification is prepared into various derivatives, and these derivatives are in the action effect and the structure activity relationship of anti-inflammatory, all many-sides such as antiviral, and method and the technology of extracting purifying 18 β type Potenlinis in addition from natural phant also have been subjected to paying attention to widely.For example, " separation and refining method of Potenlini ", number of patent application: 88101932; " separation and refining method of high-purity liquorice acid crystal ", number of patent application: 85104970.Wu Ximing, king's pendant etc. are in " new compound Isoglycyrrhiza acid salt and the production method thereof " of CN1381462A in the patent No., the characteristic easy according to 18 alpha type glycyrrhizic acids (Isoglycyrrhiza acid) and methyl alcohol formation methyl esters is separated out, invented from the mixture of 18 β types and 18 alpha type glycyrrhizic acids separation and purification and gone out the method for highly purified Isoglycyrrhiza acid, obtained highly purified Isoglycyrrhiza acid with this.
Summary of the invention
The present invention is conceived to the difference of 18 alpha type glycyrrhizic acid salt and the solubility property of 18 β type glycyrrhetates in organic solvents such as alcohol, ether and water.Adopt heterogeneous reaction system, make the 18 alpha type glycyrrhizic acid salt that under the catalysis of aqueous phase highly basic, generate constantly transfer to organic phase, make aqueous phase 18 alpha type glycyrrhizic acid salt keep low concentration always, impel the reaction of commentaries on classics structure constantly to carry out to generating 18 alpha type glycyrrhizic acid salt directions, thereby realize 18 natural β type glycyrrhetates constantly to the conversion of 18 α type isomer, and therefore obtain to change the higher transformation efficiency of structure reaction than homogeneous phase.
After changeing structure reaction end, only need simply organic phase to be separated with water (18 residual β type glycyrrhetate solution), it is 2～3 that organic phase is acidified to pH with Glacial acetic acid or other acidic substance, can obtain highly purified 18 alpha type glycyrrhizic acid crystal at 5 ℃ of following recrystallizations.
Inhomogeneous reaction of the present invention, than with alkali as catalyzer with the homogeneous system of water as reaction medium, not only improved the transformation efficiency of 18 β types greatly, and made 18 natural β type glycyrrhetates in reaction process, separate automatically with product 18 alpha type glycyrrhizic acid salt to 18 α type isomer.Simplified the separation and the purifying process that change the reacted product of structure greatly, the more important thing is avoided product extract and purge process in virose material and solvent such as use methyl alcohol, guaranteed safety that product is medicinal and harmless.
Embodiment
Below by embodiment the present invention is described further:
Embodiment 1.
20g monoammonium glycyrrhizinate (or Potenlini transfers PH=4.0 to obtain monoammonium glycyrrhizinate with ammonia soln) is dissolved in the 100ml20%KOH aqueous solution, adds the KOH ethanolic soln of 400ml 20% again.Pour into after the mixing in the reactor, react down at 100 ℃ and refluxed 36 hours.Stop the stirring system after reaction finishes and be divided into two-phase.Inclining the clear and bright solution in upper strata, adds Glacial acetic acid, regulates pH value to 3.0, at 5 ℃ of following recrystallizations, filters and obtains crystal, and 50 ℃ of vacuum-dryings obtain crystal 14.4g, and yield is 72%.
UV scanning in 190nm～400nm scope, the maximum absorption wavelength of product is 252.21nm
With 18 alpha type glycyrrhizic acids of purity 〉=98% in contrast, the vapor-phase chromatography detected result shows that the content of 18 alpha type glycyrrhizic acids in the product has reached 92.6%
Above-mentioned Potenlini crystal is dissolved with strong aqua, again with Glacial acetic acid instead drip to PH be 6.2.Place crystallization, obtain 18 alpha type glycyrrhizic acids, two ammoniums.
The content that the content assaying method of diammonium glycyrrhizinate (the UV method is an object of reference with the niacinamide) is measured product is 99.5%
Ultimate analysis measured value (%) theoretical value (%)
C 58.31 58.86
H 8.011 7.998
N 3.290 3.200
Embodiment 2.
The 20g monoammonium glycyrrhizinate is dissolved in the 100ml 20%KOH aqueous solution, adds the 400ml propyl carbinol again, pour into after the mixing in the reactor, react down at 90 ℃ and refluxed 48 hours.Stop the stirring system after reaction finishes and be divided into two-phase.Inclining the upper strata clear soln, adds Glacial acetic acid, regulates pH value to 3.0, at 5 ℃ of following recrystallizations, filters and obtains 18 alpha type glycyrrhizic acid crystal, and 50 ℃ of vacuum-dryings obtain crystal 11.6g, and yield is 55.3%.
Maximum absorption wavelength is 252.68nm
With 18 alpha type glycyrrhizic acids of purity 〉=98% in contrast, gas chromatographic detection shows that the content of 18 alpha type glycyrrhizic acids in the product has reached 94.9%
Embodiment 3.
The 10g monoammonium glycyrrhizinate is dissolved in the 100ml 20%KOH aqueous solution, adds the 400ml dioxane again.Pour into after the mixing in the reactor, react down at 90 ℃ and refluxed 48 hours.Stop the stirring system after reaction finishes and be divided into two-phase.Inclining the clear and bright solution in upper strata, adds Glacial acetic acid, regulates pH value to 3.0, is placed to crystallization under 5 ℃, filters and obtains 0 ℃ of vacuum-drying of crystal 5, obtains crystal 4 .2g, and yield is 42%.
Maximum absorption wavelength is 252.78nm
With 18 alpha type glycyrrhizic acids of purity 〉=98% in contrast, gas chromatographic detection shows that the content of 18 alpha type glycyrrhizic acids in the product has reached 95.1%
Embodiment 4.
The 20g monoammonium glycyrrhizinate is dissolved in the 100ml 20%KOH aqueous solution, adds the KOH ethanolic soln of 400ml20% again.Pour into after the mixing in the reactor, react down at 50 ℃ and refluxed 48 hours.Stop the stirring system after reaction finishes and be divided into two-phase.Inclining the clear and bright solution in upper strata, adds Glacial acetic acid, regulates pH value to 3.0, is placed to crystallization under 5 ℃, filters and obtains 0 ℃ of vacuum-drying of crystal 5, obtains crystal 3 .7g, and yield is 18.5%.
The maximum absorption wavelength that uv scan must this crystal gets the aqueous solution is 252.16nm
With 18 alpha type glycyrrhizic acids of purity 〉=98% in contrast, the vapor-phase chromatography detected result shows that the content of 18 alpha type glycyrrhizic acids in the product has reached 90.8%.
Claims (5)
1, a kind of method for preparing 18 alpha type glycyrrhizic acids from 18 β type glycyrrhetates, it is characterized in that according to two kinds of differences of the glycyrrhetate solubility property of isomorphism type not, use alcohols or ether organic solvent and water to form heterogeneous reaction system, utilize 18 alpha type glycyrrhizic acid salt bigger characteristic of solubleness in alcohols or ether organic solvent, make and constantly transfer to organic phase with the catalytic commentaries on classics structure of highly basic reaction product 18 alpha type glycyrrhizic acid salt at aqueous phase, make aqueous phase 18 alpha type glycyrrhizic acid salt remain low concentration, constantly carry out with the commentaries on classics structure reaction that impels glycyrrhetate towards the direction of 18 alpha type glycyrrhizic acid salt, reaction finishes the back two phase stratification, incline and upper solution, add Glacial acetic acid or hydrochloric acid, the 18 alpha type glycyrrhizic acid salt that reaction is generated change into 18 α Potenlinis, and to make it in concentration be that crystallization obtains 18 α Potenlini crystal in 20%～100% the ethanolic soln.
2, method according to claim 1 is characterized in that: described 18 β glycyrrhetates feed intake concentration between 5%～30%, and the alkaline concentration range is between 5%～25%, and temperature of reaction is between 50 ℃～100 ℃.
3, method according to claim 2 is characterized in that: described 18 β glycyrrhetates feed intake concentration between 15%～20%, and alkaline concentration is between 15%～20%, and temperature of reaction is between 90 ℃～100 ℃.
4, method according to claim 1 is characterized in that: described ethanolic soln is an aqueous ethanolic solution, and its concentration is 60%～80%.
5, method according to claim 4 is characterized in that: described aqueous ethanolic solution concentration is 65%～75%.
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| CN101440116B (en) * | 2008-09-25 | 2012-06-06 | 杭州市第六人民医院 | Glycyrrhizin, preparation and use thereof |
| CN101928325A (en) * | 2010-08-27 | 2010-12-29 | 江苏天晟药业有限公司 | Method for preparing natural 18-alpha glycyrrhizinic acid |
| CN110818765A (en) * | 2018-08-07 | 2020-02-21 | 重庆圣华曦药业股份有限公司 | Method for isomerizing cis-glycyrrhizic acid |
| CN111057124B (en) * | 2019-12-31 | 2022-02-11 | 中国医药健康产业股份有限公司 | Impurity removing method for glycyrrhetate |
| CN111675652A (en) * | 2020-05-13 | 2020-09-18 | 深圳市萱嘉生物科技有限公司 | Chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate, and preparation method and application thereof |
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Non-Patent Citations (2)
| Title |
|---|
| 甘草酸、甘草次酸的提取分离及应用概况. 范云鸽等.天然产物研究与开发，第8卷第4期. 1996 |
| 甘草酸、甘草次酸的提取分离及应用概况. 范云鸽等.天然产物研究与开发，第8卷第4期. 1996 * |
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