CN110818765A - Method for isomerizing cis-glycyrrhizic acid - Google Patents
Method for isomerizing cis-glycyrrhizic acid Download PDFInfo
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- CN110818765A CN110818765A CN201810892437.9A CN201810892437A CN110818765A CN 110818765 A CN110818765 A CN 110818765A CN 201810892437 A CN201810892437 A CN 201810892437A CN 110818765 A CN110818765 A CN 110818765A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/09—Geometrical isomers
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Abstract
The method for converting cis-glycyrrhizic acid into trans-glycyrrhizic acid by using commercially available glycyrrhizic acid as an initial raw material under the condition of alkali water with a certain concentration can ensure that the conversion rate of converting the cis-glycyrrhizic acid into the trans-glycyrrhizic acid is high, the generated impurities are small, the amount of alkali required by reaction is small, the generated three wastes are small, and the process has the characteristics of good reproducibility, simplicity in operation, greenness and environmental friendliness, and high purity of the obtained product, and is suitable for industrial mass production.
Description
Technical Field
The invention belongs to the field of chemical synthesis, relates to glycyrrhizic acid, and particularly relates to a preparation method of trans-glycyrrhizic acid.
Background
Trans-glycyrrhizic acid, also known as 18 α -glycyrrhizic acid and iso-glycyrrhizic acid 18 β -glycyrrhizic acid (cis-glycyrrhizic acid) is an epimer of 18 α -glycyrrhizic acid trans-glycyrrhizic acid has a lower polarity than cis-glycyrrhizic acid, α - β -isomer has the same structure, the difference is that the configuration of hydrogen at C18 position is different, i.e. trans and cis, respectively, and the structure is as follows:
trans-glycyrrhizic acid
Cis-glycyrrhizic acid.
The glycyrrhizic acid preparation is a third-generation glycyrrhizic acid preparation which is developed in the year 1994 and is ganlixin, is a mixed preparation of α -body and β -body, and has better effect on improving liver function than the first two generations.
The trans-magnesium glycyrrhetate is a medicament developed by great day fine, is approved in 9 months in 2005 and is marketed in 2006, and the trans-magnesium glycyrrhetate injection is colorless clear liquid, mainly comprises the magnesium isoglycyrrhetate, and the chemical name of the magnesium isoglycyrrhetate is 18 α, 20 β -carboxyl-11-oxo-n-oleanane-12-alkene-3 β -yl-2-O- β -D-glucopyranosyl aldonic acid- α -D-glucopyranosyl aldonic acid magnesium tetrahydrate, so that the magnesium isoglycyrrhetate is suitable for chronic viral hepatitis and improving abnormal liver function.
Research shows that trans-glycyrrhizic acid has the characteristics of lower polarity, better absorption, more reasonable distribution in vivo, stronger liver targeting and anti-inflammatory effects, weaker inhibition capability on kidney 11 β -HSD and the like, so the development of the trans-glycyrrhizic acid with low toxic and side effects has positive significance, and in natural glycyrrhizic acid, cis-glycyrrhizic acid is used as a main component, the content of the trans-glycyrrhizic acid is low, so the natural glycyrrhizic acid C18-H needs to be isomerized.
The prior art at present: one is natural glycyrrhizic acid isomerizing under the action of strong inorganic base to obtain cis-trans isomer mixture, which is further esterified or acylated to obtain trans-glycyrrhizic acid.
Patent CN1615886A discloses a method for synthesizing trans-glycyrrhizic acid:
the method has low yield, large generated impurities, unconverted cis-isomer and difficult recovery.
At present, the application of trans-glycyrrhizic acid is continuously expanded, and how to prepare high-purity trans-glycyrrhizic acid is an important work.
Disclosure of Invention
Therefore, the technical problem to be solved by the invention is to disclose a method for converting cis-glycyrrhizic acid into trans-glycyrrhizic acid, and provide a production process of trans-glycyrrhizic acid, which has high yield and less generated impurities and is suitable for industrial production.
The technical route of the invention is as follows:
trans-glycyrrhizic acid is prepared by isomerizing cis-glycyrrhizic acid in a mixed solvent under the action of organic base, dioxane or tetrahydrofuran is used as a solvent, a reaction system can perform layered reaction, strong base is in a water layer, and a product can be distributed to an organic layer. And crystallizing and refining the obtained trans-glycyrrhizic acid crude product to obtain high-purity trans-glycyrrhizic acid.
The molecular weight of trans-glycyrrhizic acid is: 822.9; the structure is as follows:
the specific object of the invention is achieved by:
a method for preparing trans-glycyrrhizic acid from cis-glycyrrhizic acid comprises the following steps:
(1) isomerization of cis-glycyrrhizic acid in organic base
Dissolving commercially available cis-glycyrrhizic acid in dioxane, adding sodium alkoxide for reflux reaction for 18-24h, cooling to 0 ℃, performing acid neutralization reaction until the pH value is 3-4, extracting with methyltetrahydrofuran, and volatilizing the solvent under reduced pressure to obtain a trans-glycyrrhizic acid crude product.
(2) Refining trans-glycyrrhizic acid crystal
Dissolving the obtained trans-glycyrrhizic acid crude product in a certain volume of acetone: heating and dissolving in ethanol (5: 5) solvent (W/V = g/5 ml), cooling to 0 deg.C, stirring, crystallizing, filtering, and washing filter cake with ethanol to obtain high-purity trans-glycyrrhizic acid.
Detailed Description
Example 1
Preparing a trans-glycyrrhizic acid crude product:
dissolving 50g (0.0607 mol) of glycyrrhizic acid in 500mL of dioxane, adding 5g (0.0925 mol) of sodium methoxide solid, stirring, heating to reflux reaction for 18h, stopping the reaction, concentrating under reduced pressure to specific gravity of 1.0-1.1, adding 500mL of purified water, adjusting pH to 3-4 with hydrochloric acid (4 mol/L), extracting with methyltetrahydrofuran for 3 times, combining organic layers, washing with purified water for 2 times, and volatilizing solvent under reduced pressure to obtain 45g of crude trans-glycyrrhizic acid with yield of 90%. (C18, acetonitrile-phosphate buffer (80: 20) as mobile phase, detection wavelength 250).
Purity by HPLC check and cis-trans ratio
And (3) refining a crude product:
dissolving 45g of trans-glycyrrhizic acid in 250ml of acetone: heating in ethanol (5: 5) solvent to reflux, stopping heating, stirring at room temperature for crystallization for 8h, cooling to 0 deg.C, stirring for 1h, filtering, washing with ethanol for 1 time to obtain white solid 38.5g, yield 85.5%.
Purity by HPLC check and cis-trans ratio
Example 2
Preparing a trans-glycyrrhizic acid crude product:
dissolving 75g (0.091 mol) of glycyrrhizic acid in 800mL of dioxane, adding 8g (0.118 mol) of sodium ethoxide solid, stirring, heating to reflux reaction for 18h, stopping the reaction, concentrating under reduced pressure to the specific gravity of 1.0-1.1, adding 1000mL of purified water, adjusting the pH value to 3-4 with hydrochloric acid (4 mol/L), extracting with methyltetrahydrofuran for 3 times, combining organic layers, washing with purified water for 2 times, and volatilizing the solvent under reduced pressure to obtain 61.8g of crude trans-glycyrrhizic acid, wherein the yield is 82.4%. (C18, acetonitrile-phosphate buffer (80: 20) as mobile phase, detection wavelength 250).
Purity by HPLC check and cis-trans ratio
And (3) refining a crude product:
dissolving 60g of trans-glycyrrhizic acid in 300ml of acetone: heating in ethanol (5: 5) solvent to reflux, stopping heating, stirring at room temperature for crystallization for 8h, cooling to 0 deg.C, stirring for 1h, filtering, washing with ethanol for 1 time to obtain white solid 50g, yield 83.3%.
Purity by HPLC check and cis-trans ratio
。
Claims (4)
1. A method for isomerizing cis-glycyrrhizic acid by using cis-glycyrrhizic acid as a raw material comprises the following steps:
(1) isomerizing, neutralizing, extracting and spin-drying cis-glycyrrhizic acid in organic alkali;
(2) and (5) refining trans-glycyrrhizic acid crystals.
2. The method for isomerizing cis-glycyrrhizic acid according to claim 1, wherein the solvent used in step (1) is one of dioxane and tetrahydrofuran, the organic base is one of sodium methoxide, sodium ethoxide, sodium hydride and potassium tert-butoxide, the reaction is carried out for 18-24h, the concentration under reduced pressure is carried out, water is added, the temperature is cooled to 0 ℃, the neutralization reaction is carried out with 4mol/L hydrochloric acid until the pH value is 3-4, the organic solvent is used for extraction, and the solvent is volatilized to obtain the trans-glycyrrhizic acid crude product.
3. The method for isomerizing cis-glycyrrhizic acid according to claim 1, wherein the extraction solvent used in the step (1) is one of methyltetrahydrofuran and ethyl acetate-ethanol (7: 3), and the solvent temperature is evaporated under reduced pressure to 40 ℃.
4. A method for isomerizing cis-glycyrrhizic acid according to claim 1, wherein the crystallizing solvent used in step (2) is acetone: ethanol (5: 5), mass/volume = g/5ml, refluxing and dissolving at 55-60 deg.C, cooling to 0 deg.C, stirring, crystallizing, filtering, washing filter cake with small amount of ethanol, and vacuum drying at 50-60 deg.C.
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| CN201810892437.9A CN110818765A (en) | 2018-08-07 | 2018-08-07 | Method for isomerizing cis-glycyrrhizic acid |
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| CN201810892437.9A CN110818765A (en) | 2018-08-07 | 2018-08-07 | Method for isomerizing cis-glycyrrhizic acid |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114605488A (en) * | 2020-12-03 | 2022-06-10 | 中国科学院大连化学物理研究所 | Method for purifying glycyrrhizic acid by using preparative chromatography technology |
| CN115677813A (en) * | 2021-03-25 | 2023-02-03 | 河北中医学院 | Application of compound in TMEM16A agonist |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1752096A (en) * | 2004-09-21 | 2006-03-29 | 杭州民生药业集团有限公司 | Method of preparing 18 alpha type glycyrrhizic acid and its salt using non homogeneous phase reaction |
| CN102584928A (en) * | 2011-12-02 | 2012-07-18 | 杭州市第六人民医院 | Preparation method for trans-glycyrrhizic acid |
| CN104861029A (en) * | 2015-01-30 | 2015-08-26 | 李玉山 | Preparation method of ammonium 18alpha,beta-H-glycyrrhetate and hydrate thereof |
| CN106380506A (en) * | 2016-08-29 | 2017-02-08 | 江苏天晟药业股份有限公司 | Preparation method of 18 alpha type diammonium glycyrrhizinate |
-
2018
- 2018-08-07 CN CN201810892437.9A patent/CN110818765A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1752096A (en) * | 2004-09-21 | 2006-03-29 | 杭州民生药业集团有限公司 | Method of preparing 18 alpha type glycyrrhizic acid and its salt using non homogeneous phase reaction |
| CN102584928A (en) * | 2011-12-02 | 2012-07-18 | 杭州市第六人民医院 | Preparation method for trans-glycyrrhizic acid |
| CN104861029A (en) * | 2015-01-30 | 2015-08-26 | 李玉山 | Preparation method of ammonium 18alpha,beta-H-glycyrrhetate and hydrate thereof |
| CN106380506A (en) * | 2016-08-29 | 2017-02-08 | 江苏天晟药业股份有限公司 | Preparation method of 18 alpha type diammonium glycyrrhizinate |
Non-Patent Citations (2)
| Title |
|---|
| L. A. BALTINA, JR.等: "SYNTHESIS AND ANTIVIRAL ACTIVITY OF 18a-GLYCYRRHIZIC ACID AND ITS ESTERS", 《PHARMACEUTICAL CHEMISTRY JOURNAL》 * |
| 李立威等: "18α-H-甘草酸二铵的制备", 《中国现代应用药学杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114605488A (en) * | 2020-12-03 | 2022-06-10 | 中国科学院大连化学物理研究所 | Method for purifying glycyrrhizic acid by using preparative chromatography technology |
| CN115677813A (en) * | 2021-03-25 | 2023-02-03 | 河北中医学院 | Application of compound in TMEM16A agonist |
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