CN110283225B - Preparation method of 24-hydroxy-glycyrrhetinic acid - Google Patents
Preparation method of 24-hydroxy-glycyrrhetinic acid Download PDFInfo
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- CN110283225B CN110283225B CN201910688309.7A CN201910688309A CN110283225B CN 110283225 B CN110283225 B CN 110283225B CN 201910688309 A CN201910688309 A CN 201910688309A CN 110283225 B CN110283225 B CN 110283225B
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Abstract
The invention discloses a preparation method of 24-hydroxy-glycyrrhetinic acid, relates to the field of pharmaceutical chemicals, and provides a method for extracting 24-hydroxy-glycyrrhetinic acid from glycyrrhizin, which has the advantages of simple extraction process, strong operability, high yield of effective substances, full utilization of resources and the like.
Description
Technical Field
The invention relates to the field of pharmaceutical chemicals, and particularly relates to a preparation method of 24-hydroxy-glycyrrhetinic acid.
Background
It is known that glycyrrhetinic acid is a metabolite of glycyrrhizic acid in vivo, and has anti-inflammatory, anti-immune, and liver protecting effects. The glycyrrhetinic acid and derivatives thereof in the market mostly take (18 beta, 20 beta) glycyrrhetinic acid as the main component, and the research on 24-hydroxy-glycyrrhetinic acid is not reported. In fact, the 24-hydroxy-glycyrrhetinic acid has better water solubility, is more beneficial to absorption, and improves the bioavailability, thereby having better anti-hepatitis and anti-virus effects, smaller toxic and side effects and better application prospect. Therefore, providing a method for preparing 24-hydroxy-glycyrrhetinic acid has become a long-standing technical demand of those skilled in the art.
Disclosure of Invention
In order to overcome the defects in the background technology, the invention provides a preparation method of 24-hydroxy-glycyrrhetinic acid, 24-hydroxy glycyrrhetinic acid is extracted from glycyrrhizin, and the prepared 24-hydroxy glycyrrhetinic acid has better pharmacological activity and absorption efficiency compared with glycyrrhetinic acid.
In order to achieve the above purpose, the invention adopts the following technical scheme:
a preparation method of 24-hydroxy-glycyrrhetinic acid specifically comprises the following steps:
firstly, stirring and extracting glycyrrhizin in a solvent at normal temperature for 1-2 hours, wherein the ratio of glycyrrhizin to solvent is 1: 8-1: 10, stopping stirring after extraction to obtain a mixture, filtering the mixture to remove insoluble substances, retaining filtrate, repeatedly extracting the mixture for multiple times, combining the filtrates obtained each time, and concentrating the combined filtrates at 60-70 ℃ under reduced pressure to obtain thick paste;
and secondly, adding water which is 5-8 times of the weight of the thick paste into the thick paste, then adding ammonia water to dissolve the water to obtain a solution, extracting the obtained solution by using acetone, ether and petroleum ether in sequence at a ratio of 1:1, repeatedly extracting each solvent for 2-3 times, concentrating the extracted water phase at 50-70 ℃ under reduced pressure until the solid content is 30-50%, pumping the concentrated solution into a storage tank before concentration, cleaning the tower body, setting the upper limit temperature and the lower limit temperature of an outlet of a hot blast stove, opening a heating device, starting drying the tower body, drying the tower body after 30min, starting a high-pressure pump piston to lubricate water when the inlet air temperature reaches the temperature required by production of 160-170 ℃, starting the high-pressure pump to pressurize to 10-15MPa, controlling the temperature in the tower to be 100-110 ℃, and opening a feed valve when the outlet air temperature reaches 80-95 ℃, thus obtaining spray powder of the concentrated solution at a discharge port.
Thirdly, adding water into the spray powder obtained in the previous step to prepare a 3-5% solution, purifying the solution by using macroporous resin, washing the solution by using 3-5 column volumes of water after the sample loading is finished, eluting the solution by using 30-80% ethanol or methanol after the water washing, and concentrating the eluent at 50-70 ℃ under reduced pressure to form thick paste, wherein the volume of the macroporous resin is 3-10 times of the feeding amount, and the sample loading speed is 1-2 BV/h;
and fourthly, adding a sulfuric acid aqueous solution with the weight 6-10 times that of the thick paste obtained in the previous step, stirring and reacting at the temperature of 70-100 ℃ until the reaction is complete, cooling after the reaction is complete, separating out 24-hydroxy-glycyrrhetinic acid at the moment because the 24-hydroxy-glycyrrhetinic acid is insoluble in water, cooling to room temperature, carrying out suction filtration, washing with deionized water until the pH value is unchanged, drying the solid at the temperature of 40-60 ℃, and obtaining the dried solid, namely 24-hydroxy-glycyrrhetinic acid.
In the preparation method of 24-hydroxy-glycyrrhetinic acid, the solvent in the first step is one or the combination of two or more of ethyl acetate, n-butanol or propanol.
In the preparation method of 24-hydroxy-glycyrrhetinic acid, the solvent is preferably ethyl acetate.
In the preparation method of 24-hydroxy-glycyrrhetinic acid, the material-to-liquid ratio of glycyrrhizin to solvent is preferably 1: 8.
in the preparation method of 24-hydroxy-glycyrrhetinic acid, the pH of the solution in the second step is 7.5-9.
In the preparation method of 24-hydroxy-glycyrrhetinic acid, the type of the macroporous resin in the third step is any one of HPD-400, HPD-500, HPD-600, D101 and D1300.
In the preparation method of 24-hydroxy-glycyrrhetinic acid, the model of the macroporous resin is preferably D101 type resin.
In the preparation method of 24-hydroxy-glycyrrhetinic acid, the concentration of sulfuric acid in the sulfuric acid aqueous solution in the fourth step is 6-8%.
By adopting the technical scheme, the invention has the following advantages:
the method for extracting 24-hydroxy glycyrrhetinic acid from glycyrrhizin has the advantages of simple extraction process, strong operability, high effective substance yield, full utilization of resources and the like, and compared with glycyrrhetinic acid, the prepared 24-hydroxy glycyrrhetinic acid has better pharmacological activity, absorption efficiency and the like, and is suitable for large-scale popularization and application.
Detailed Description
The present invention will be explained in more detail by the following examples, which are not intended to limit the invention;
the preparation method of 24-hydroxy-glycyrrhetinic acid specifically comprises the following steps:
firstly, stirring and extracting glycyrrhizin in a solvent at normal temperature for 1-2 hours, wherein the ratio of glycyrrhizin to solvent is 1: 8-1: 10, and in specific implementation, the material-liquid ratio is preferably 1: 8, stopping stirring after extraction to obtain a mixture, filtering the mixture to remove insoluble substances, retaining filtrate, repeatedly extracting the mixture for multiple times, combining the filtrates obtained each time, and concentrating the combined filtrates at 60-70 ℃ under reduced pressure to obtain thick paste; when the solvent is one or a combination of two or more of ethyl acetate, n-butanol or propanol, the solvent is preferably ethyl acetate;
step two, adding water which is 5-8 times of the weight of the thick paste into the thick paste, then adding ammonia water to dissolve the water to obtain a solution, wherein the pH value of the solution is 7.5-9, sequentially extracting the obtained solution with acetone, diethyl ether and petroleum ether at a ratio of 1:1, repeatedly extracting each solvent for 2-3 times, concentrating a water phase at 50-70 ℃ under reduced pressure after extraction until the solid content is 30-50%, pumping the concentrated solution into a storage tank before concentration, setting the upper and lower limit temperatures of an outlet of a hot blast stove after cleaning the tower body, opening a heating device, starting drying the tower body, drying the tower body after 30min, when the inlet air temperature reaches the temperature of 160-170 ℃ required by production, starting a high-pressure pump piston to lubricate water, starting the high-pressure pump to pressurize to 10-15MPa, controlling the temperature in the tower to be 100-110 ℃, when the air outlet temperature reaches 80-95 ℃, the feed valve is opened, and the spray powder of the concentrated solution is obtained at the discharge hole.
Thirdly, adding water into the spray powder obtained in the previous step to prepare a 3-5% solution, purifying the solution by using macroporous resin, wherein the type of the macroporous resin is HPD-400, HPD-500, HPD-600, D101 or D1300, in specific implementation, the type of the macroporous resin is preferably D101 type resin, the volume of the macroporous resin is 3-10 times of the feeding amount, the sample loading speed is 1-2 BV/h, after sample loading is finished, washing by using 3-5 column volumes of water, eluting by using 30-80% ethanol or methanol, and concentrating the eluent at 50-70 ℃ under reduced pressure to form thick paste;
and fourthly, adding a sulfuric acid aqueous solution with the weight 6-10 times that of the thick paste obtained in the previous step, wherein the sulfuric acid concentration in the sulfuric acid aqueous solution is 6% -8%, stirring and reacting at the temperature of 70-100 ℃ until the reaction is complete, cooling after the reaction is complete, separating out 24-hydroxy-glycyrrhetinic acid because the 24-hydroxy-glycyrrhetinic acid is insoluble in water, cooling to room temperature, carrying out suction filtration, washing with deionized water until the pH value is unchanged, drying the solid at the temperature of 40-60 ℃, and obtaining the dried solid which is the 24-hydroxy-glycyrrhetinic acid.
It should be noted that various devices related to the present invention, such as stirring devices, extraction devices, etc., are not the main point of protection of the present invention, and the above-mentioned various devices can be purchased and used directly from the market, so the present invention does not give a full description of the information of the structure, model, etc. of the devices.
The specific embodiment of the invention is as follows:
example one:
firstly, taking 5kg of glycyrrhizin, extracting with 40L of ethyl acetate, stirring and extracting for 1 hour, stopping stirring after 1 hour, filtering to remove about 2.03kg of insoluble substances, recording the filtrate as filtrate 1, extracting the insoluble substances with 40L of ethyl acetate, stirring and extracting for 1 hour, closing stirring after 1 hour, filtering to remove about 1.88kg of insoluble substances, taking the filtrate as filtrate 2, combining the filtrate 1 and the filtrate 2 into filtrate 3, and concentrating the filtrate 3 extracting solution to 8L of thick paste at 65 ℃;
adding 48L of water into the concentrated thick paste, adding ammonia water, stirring for dissolving, measuring the pH of the solution to be 8.5 after dissolving, adding acetone into the solution, stirring for 20min, standing for liquid separation, recovering an acetone phase, extracting the water phase with acetone again, extracting the water phase with diethyl ether and petroleum ether in sequence after extraction, extracting each solvent twice, concentrating the water phase at 60 ℃ under reduced pressure until the solid content is 40%, and spraying at 130 ℃ to obtain 1.10kg of spray powder;
and (3) adding water into the spray powder obtained in the previous step, stirring until the spray powder is dissolved, separating the solution by using D101 type macroporous resin, wherein the column volume is 8L, after the column is loaded, washing 24L with water to remove impurities with large polarity, eluting with 40L30% ethanol until no 24-hydroxy-glycyrrhizic acid exists, collecting eluent, and concentrating the eluent under reduced pressure to 2L to obtain thick paste.
And (3) adding the prepared sulfuric acid aqueous solution with the concentration of 8% into the thick paste obtained in the previous step, stirring and reacting for 8 hours at 100 ℃, standing and cooling to room temperature after stirring is finished, separating out substances, performing suction filtration, washing the solid with deionized water until the pH value is unchanged, taking out the solid, drying at 50 ℃, and drying the solid to obtain 20-hydroxy-glycyrrhetinic acid, so as to obtain 0.6kg of solid powder.
Example two:
firstly, taking 5kg of glycyrrhizin, extracting with 50L of n-butyl alcohol, stirring and extracting for 1.5 hours, turning off stirring after 1.5 hours, filtering to remove about 1.89kg of insoluble substances, recording filtrate as filtrate 1, extracting the insoluble substances with 50L of n-butyl alcohol, stirring and extracting for 1 hour, turning off stirring after 1 hour, filtering to remove about 1.76kg of insoluble substances, mixing filtrate 2 with filtrate 1 to obtain filtrate 3, and concentrating the filtrate 3 extract to 8L of thick paste under reduced pressure at 65 ℃;
adding 48L of water into the thick paste, adding ammonia water, stirring for dissolving, measuring the pH of the solution to be 8.5 after dissolving, adding acetone into the solution, stirring for 20min, standing for liquid separation, recovering an acetone phase, extracting the water phase with acetone again, extracting the water phase with diethyl ether and petroleum ether in sequence after extraction, extracting each solvent twice, concentrating the water phase at 60 ℃ under reduced pressure until the solid content is 40%, and spraying at 130 ℃ to obtain 0.95kg of spray powder;
adding 27.5L of water into the spray powder, stirring until the water is dissolved, separating the solution by using HPD-600 type macroporous resin, wherein the column volume is 8L, after the column is loaded, washing 24L of water to remove impurities with large polarity, eluting by using 40L of 30% ethanol until no 24-hydroxy-glycyrrhizic acid exists, collecting eluent, and concentrating the eluent under reduced pressure to form 2L thick paste;
and adding 6.4L of prepared 6% sulfuric acid aqueous solution into the thick paste, stirring and reacting for 5 hours at 100 ℃, standing and cooling to room temperature after stirring is finished, separating out substances, performing suction filtration, washing the solid with deionized water until the pH value is unchanged, taking out the solid, drying at 50 ℃, and obtaining the dried solid, namely 20-hydroxy-glycyrrhetinic acid, so as to obtain 0.69kg of solid powder.
The present invention is not described in detail in the prior art.
The embodiments selected for the purpose of disclosing the invention, are presently considered to be suitable, it being understood, however, that the invention is intended to cover all variations and modifications of the embodiments which fall within the spirit and scope of the invention.
Claims (4)
1. A preparation method of 24-hydroxy-glycyrrhetinic acid is characterized by comprising the following steps: the preparation method specifically comprises the following steps:
firstly, stirring and extracting glycyrrhizin in a solvent at normal temperature for 1-2 hours, wherein the ratio of glycyrrhizin to solvent is 1: 8-1: 10, wherein the solvent is one or a combination of two or more of ethyl acetate, n-butanol or propanol, stirring is stopped after extraction is finished to obtain a mixture, the mixture is filtered to remove insoluble substances, filtrate is reserved, then the mixture is extracted repeatedly for multiple times, the filtrates obtained each time are combined, and the combined filtrate is concentrated under reduced pressure at 60-70 ℃ to form thick paste;
secondly, adding water which is 5-8 times of the weight of the thick paste into the thick paste, then adding ammonia water to dissolve to obtain a solution, the pH value of the solution is 7.5-9, the obtained solution is sequentially extracted by acetone, ether and petroleum ether at a ratio of 1:1, each solvent is repeatedly extracted for 2-3 times, the water phase is decompressed and concentrated at 50-70 ℃ after extraction until the solid content is 30-50%, the concentrated solution is pumped into a storage tank before concentration, the upper limit temperature and the lower limit temperature of an outlet of a hot blast stove are set after a tower body is cleaned, a heating device is opened, the tower body is dried after 30min, when the inlet air temperature reaches the temperature of 160-170 ℃ required by production, starting a high-pressure pump piston to lubricate water, starting the high-pressure pump to pressurize to 10-15MPa, controlling the temperature in the tower to be 100-110 ℃, when the air outlet temperature reaches 80-95 ℃, opening a feed valve, and obtaining spray powder of the concentrated solution at a discharge hole;
thirdly, adding water into the spray powder obtained in the previous step to prepare a 3-5% solution, purifying the solution by using macroporous resin, wherein the type of the macroporous resin is any one of HPD-400, HPD-500, HPD-600, D101 and D1300, the volume of the macroporous resin is 3-10 times of the feeding amount, the sampling speed is 1-2 BV/h, after sampling is finished, washing the solution by using 3-5 column volumes of water, eluting the solution by using 30-80% ethanol or methanol, and concentrating the eluent to thick paste at 50-70 ℃ under reduced pressure;
and fourthly, adding a sulfuric acid aqueous solution with the weight 6-10 times that of the thick paste obtained in the previous step, wherein the sulfuric acid concentration in the sulfuric acid aqueous solution is 6% -8%, stirring and reacting at the temperature of 70-100 ℃ until the reaction is complete, cooling after the reaction is complete, separating out 24-hydroxy-glycyrrhetinic acid because the 24-hydroxy-glycyrrhetinic acid is insoluble in water, cooling to room temperature, carrying out suction filtration, washing with deionized water until the pH value is unchanged, drying the solid at the temperature of 40-60 ℃, and obtaining the dried solid which is the 24-hydroxy-glycyrrhetinic acid.
2. The method for preparing 24-hydroxy-glycyrrhetinic acid according to claim 1, characterized in that: in the first step, the ratio of glycyrrhizin to solvent is preferably 1: 8.
3. the method for preparing 24-hydroxy-glycyrrhetinic acid according to claim 1, characterized in that: the solvent in the first step is preferably ethyl acetate.
4. The method for preparing 24-hydroxy-glycyrrhetinic acid according to claim 1, characterized in that: the model of the macroporous resin in the third step is preferably D101 type resin.
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| CN111171106A (en) * | 2020-02-19 | 2020-05-19 | 洛阳蓝斯利科技有限公司 | Preparation method of 24-hydroxystearyl glycyrrhetinate |
| CN113913489A (en) * | 2021-11-24 | 2022-01-11 | 洛阳蓝斯利科技有限公司 | Preparation method of monoglucuronic acid 24-hydroxy-glycyrrhetinic acid |
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| CN101817867A (en) * | 2010-05-27 | 2010-09-01 | 高颖 | Method for preparing glycyrrhetinic acid |
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| CN104250279A (en) * | 2013-06-28 | 2014-12-31 | 江苏天晟药业有限公司 | Preparation method of 24-hydroxyglycyrrhizic acid |
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| CN1563073A (en) * | 2004-04-06 | 2005-01-12 | 南开大学 | Method for preparing enoxolone |
| CN101817867A (en) * | 2010-05-27 | 2010-09-01 | 高颖 | Method for preparing glycyrrhetinic acid |
| CN102653550A (en) * | 2011-03-01 | 2012-09-05 | 广西壮族自治区药用植物园 | Preparation and application of glycyrrhetinic acid |
| CN103588849A (en) * | 2012-08-14 | 2014-02-19 | 江苏汉邦科技有限公司 | Preparation method for glycyrrhetinic acid |
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Non-Patent Citations (1)
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