A kind of purification method of glycyrrhizic acid

Abstract

The invention belongs to the field of biomedicine technology, relates to the refining of pharmaceutical intermediates, and specifically to a method for purifying glycyrrhizic acid, wherein a metal salt solution is dripped into an organic solution of a crude glycyrrhizic acid product, the metal salt solution is dripped and crystallized simultaneously during the process, and the first filtration is performed after crystallization, water is added to the filter cake filtered for the first time to dissolve, and then a complex reagent is added to react and precipitate, and then a second filtration is performed, and acid is added to the filtrate filtered for the second time to adjust the pH to acidity, precipitate solids, separate the precipitated solids, and dry them; wherein the metal salt is a zinc salt, an iron salt and / or a ferrous salt, and the complex reagent is pyridine, 2-picoline and / or 4-picoline. The purification method provided by the present invention obtains a purity of glycyrrhizic acid of ≥95%, and the magnesium isoglycyrrhizinate further synthesized by using the glycyrrhizic acid of this purity as a raw material has a purity of ≥99%.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, relates to the purification of pharmaceutical intermediates, and specifically relates to a method for purifying glycyrrhizic acid. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Magnesium isoglycyrrhizinate injection can be used for the treatment of chronic viral hepatitis and acute drug-induced liver injury, and improves abnormal liver function. Glycyrrhizic acid is an important raw material for magnesium isoglycyrrhizinate, and the two have the same molecular weight, with only a conformational difference in the 18th position H. Magnesium isoglycyrrhizinate is a product obtained by isomerizing glycyrrhizic acid to obtain isoglycyrrhizic acid, and then a series of purifications are finally made into magnesium salts. At present, the crude glycyrrhizic acid content is generally about 40%. According to the inventor's research, the conventional refining or purification methods of glycyrrhizic acid currently include soaking method, ammonia extraction method and resin method. The content of glycyrrhizic acid refined or purified by these methods is generally about 70%, so the content of commercially available glycyrrhizic acid is generally 60-80%, and the product quality of different companies varies greatly, and there are many impurities, which makes it difficult to purify magnesium isoglycyrrhizic acid. Therefore, it is necessary to develop a purification (refining) method for obtaining high-purity glycyrrhizic acid. Summary of the invention

[0004] In order to solve the deficiencies of the prior art, the purpose of the present invention is to provide a method for purifying glycyrrhizic acid. The purification method provided by the present invention obtains glycyrrhizic acid with a purity of ≥95%. The purity of magnesium isoglycyrrhizinate further synthesized using glycyrrhizic acid of this purity as a raw material has a purity of ≥99%.

[0005] In order to achieve the above object, the technical solution of the present invention is:

[0006] On the one hand, a method for purifying glycyrrhizic acid comprises the steps of dripping a metal salt solution into an organic solution of a crude glycyrrhizic acid product, crystallizing during the process of dripping the metal salt solution, performing a first filtration after crystallization, adding water to the filter cake of the first filtration to dissolve it, adding a complex reagent to react and generate a precipitate, then performing a second filtration, adding acid to the filtrate of the second filtration to adjust the pH to acidic, precipitating a solid, separating the precipitated solid, and drying the obtained product;

[0007] Wherein, the metal salt is zinc salt, iron salt and / or ferrous salt, and the complex reagent is pyridine, 2-methylpyridine and / or 4-methylpyridine.

[0008] The invention firstly adopts an organic solvent to dissolve glycyrrhizic acid in a crude glycyrrhizic acid product by heating and refluxing, then drops zinc salt, iron salt and / or ferrous salt to make the metal ions therein complex with the glycyrrhizic acid to generate a precipitated complex, adds water to dissolve the complex, adopts pyridine, 2-methylpyridine and / or 4-methylpyridine to carry out a replacement reaction on the ligand in the complex, so that the complex after the reaction is precipitated and the glycyrrhizic acid is replaced and freed in water, and then the aqueous solution is adjusted to be acidic to precipitate the glycyrrhizic acid.

[0009] Based on the above method, the selection of metal salts and complex reagents is the key to obtaining high-purity glycyrrhizic acid. Studies have shown that the purity of the glycyrrhizic acid obtained by complexing with zinc salts, iron salts and / or ferrous salts and then replacing with pyridine, 2-methylpyridine and / or 4-methylpyridine is ≥95%.

[0010] Since the glycyrrhizic acid prepared by the present invention has high purity, the purity of the magnesium isoglycyrrhizinate prepared therefrom is ≥99%, which can meet the standard of raw materials for preparations. Therefore, on the other hand, a method for preparing magnesium isoglycyrrhizic acid is provided, wherein the glycyrrhizic acid obtained by the above-mentioned glycyrrhizic acid purification method is used as a raw material, an isomerization reaction is performed to obtain isoglycyrrhizic acid, and the isoglycyrrhizic acid is reacted with a magnesium source to obtain magnesium isoglycyrrhizic acid.

[0011] The beneficial effects of the present invention are:

[0012] The invention firstly carries out a complex reaction with a metal salt to convert glycyrrhizic acid into a metal complex, and separates the metal complex from impurities in a crude glycyrrhizic acid product by virtue of the low solubility of the metal complex in an organic solvent; then, the glycyrrhizic acid in the metal complex is replaced by the freeing of a complex reagent, and the glycyrrhizic acid is further purified by virtue of the low solubility of the complex in water after the replacement; and then, the glycyrrhizic acid is precipitated by virtue of the low solubility of glycyrrhizic acid under acidic conditions, thereby greatly improving the purity of the glycyrrhizic acid. Experiments show that, after the key selection of the metal salt and the complex reagent, the purity of the prepared glycyrrhizic acid can reach 100%.

[0013] ≥95%. The purification method of the present invention has easy controllable conditions, low cost and is easy for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0015] Figure 1 This is a high performance liquid chromatogram of glycyrrhizic acid prepared in Example 1 of the present invention;

[0016] Figure 2 This is a high performance liquid chromatogram of glycyrrhizic acid prepared in Example 2 of the present invention;

[0017] Figure 3 This is a high performance liquid chromatogram of glycyrrhizic acid prepared in Example 3 of the present invention;

[0018] Figure 4 This is a high performance liquid chromatogram of glycyrrhizic acid prepared in Example 4 of the present invention;

[0019] Figure 5 This is a high performance liquid chromatogram of glycyrrhizic acid prepared in Example 5 of the present invention;

[0020] Figure 6 This is a high performance liquid chromatogram of glycyrrhizic acid prepared in Example 6 of the present invention;

[0021] Figure 7 The high performance liquid chromatogram of magnesium isoglycyrrhizinate prepared in Example 7 of the present invention. DETAILED DESCRIPTION

[0022] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0023] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprising" and / or "including" are used in this specification, it indicates the presence of features, steps, operations, devices, components and / or combinations thereof.

[0024] In view of the low purity of glycyrrhizic acid obtained by the existing conventional glycyrrhizic acid purification method, the present invention provides a method for purifying glycyrrhizic acid.

[0025] A typical embodiment of the present invention provides a method for purifying glycyrrhizic acid, wherein a metal salt solution is dripped into an organic solution of a crude glycyrrhizic acid product, crystallization occurs during the process of dripping the metal salt solution, a first filtration is performed after crystallization, water is added to the filter cake of the first filtration to dissolve, a complex reagent is added to react to produce a precipitate, and then a second filtration is performed, acid is added to the filtrate of the second filtration to adjust the pH to acidic, a solid is precipitated, and the precipitated solid is separated and dried to obtain the product;

[0026] Wherein, the metal salt is zinc salt, iron salt and / or ferrous salt, and the complex reagent is pyridine, 2-methylpyridine and / or 4-methylpyridine.

[0027] The zinc salt described in the present invention is a compound whose cation is a zinc ion, such as zinc chloride, zinc nitrate, etc.

[0028] The iron salt described in the present invention is a compound whose cation is a zinc ion, such as ferric chloride, ferric nitrate, etc.

[0029] The ferrous salt described in the present invention is a compound whose cation is a ferrous ion, such as ferrous chloride, ferrous nitrate, and the like.

[0030] In some embodiments, the crude glycyrrhizic acid is added to an organic solvent for extraction, and then pre-filtered, the pre-filtered filtrate is collected and a metal salt solution is added dropwise. The extraction method is more conducive to improving the yield of glycyrrhizic acid. When the extraction condition is heated under reflux, the yield of glycyrrhizic acid is higher.

[0031] In one or more embodiments, the addition ratio of glycyrrhizic acid to organic solvent is 1:15-20, g / mL.

[0032] In some embodiments, the organic solvent in the organic solution of crude glycyrrhizic acid is ethanol or acetone.

[0033] In some embodiments, the solvent of the metal salt solution is ethanol.

[0034] In some embodiments, the mass ratio of the metal salt to the crude glycyrrhizic acid is 0.2-0.3:1.

[0035] In some embodiments, the ratio of metal salt to complex reagent is 1:1-3, g / mL.

[0036] In some embodiments, the acid adjusts the pH to 1.0 to 3.0, preferably 1.5 to 2.5.

[0037] In some embodiments, hydrochloric acid is used to adjust the pH.

[0038] In some embodiments, the precipitated solid is filtered for a third time, and the solid after the third filtration is dried. The drying is carried out by forced air drying at a drying temperature of 50-60°C.

[0039] Another embodiment of the present invention provides a method for preparing magnesium isoglycyrrhizinate, wherein the glycyrrhizic acid obtained by the above-mentioned glycyrrhizic acid purification method is used as a raw material, an isomerization reaction is performed to obtain isoglycyrrhizic acid, and the isoglycyrrhizic acid is reacted with a magnesium source to obtain magnesium isoglycyrrhizinate.

[0040] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.

[0041] Example 1: Conventional method solvent purification and refining of glycyrrhizic acid

[0042] Put 50.0g of crude glycyrrhizic acid (content: 68.5%, the same below) into a 1L reaction bottle, add 800mL of 95% ethanol, heat to reflux and extract for 1 hour. Filter, add 20mL of 36% concentrated hydrochloric acid to the filtrate to precipitate solid. Filter, add ethanol to dissolve the filter cake, add ammonia water to adjust pH=8, precipitate solid, filter to obtain glycyrrhizic acid ammonium salt. Add 20% glacial acetic acid aqueous solution to dissolve and crystallize, filter and dry to obtain glycyrrhizic acid, 44.2g, yield 88.4%, content: 75.4%, as Figure 1 shown.

[0043] Example 2: Resin purification of glycyrrhizic acid using conventional methods

[0044] Put 50.0g of crude glycyrrhizic acid into a 1L reaction bottle, add 800mL of water, heat to about 80℃, dissolve and extract for 1 hour, and filter. Add 20mL of hydrochloric acid to the filtrate for crystallization, filter. Add 150mL of ethanol to dissolve, pass through macroporous adsorption resin D101, elute with 1L of water, and collect the eluate. Concentrate under reduced pressure to 200mL, add 36% concentrated hydrochloric acid to adjust pH=2, precipitate solid, filter and dry to obtain 32.5g of glycyrrhizic acid, with a yield of 65.0% and a content of 77.1%. Figure 2 shown.

[0045] Example 3: Purification of glycyrrhizic acid by the method of the present invention

[0046] Put 50.0g of crude glycyrrhizic acid into a 1L reaction bottle, add 800mL of ethanol, heat under reflux to dissolve and extract. Filter, add 10.0g of zinc chloride in ethanol solution dropwise to the filtrate, and crystallize during the dropwise addition. Filter, add 400mL of water to dissolve the filter cake, add 15mL of pyridine to free it, and precipitate. Filter and collect the filtrate. Add 36% concentrated hydrochloric acid to the filtrate to adjust the pH to 2, crystallize and filter. White solid powder, 55℃ air drying to obtain 22.5g of glycyrrhizic acid, yield 45.0%, content: 96.4%, such as Figure 3 shown.

[0047] Example 4: Purification of glycyrrhizic acid by the method of the present invention

[0048] Put 50.0g of crude glycyrrhizic acid into a 1L reaction bottle, add 800mL of acetone, and heat under reflux to dissolve and extract. Filter, add 15.0g of ferric chloride ethanol solution dropwise to the filtrate, and crystallize during the dropwise addition. Filter, add 400mL of water to dissolve the filter cake, add 20mL of pyridine to free it, and precipitate. Filter and collect the filtrate. Add 36% concentrated hydrochloric acid to the filtrate to adjust the pH to 2, crystallize and filter. White solid powder, 55℃ air drying to obtain 24.5g of glycyrrhizic acid, yield 49.0%, content: 97.5%, such as Figure 4 shown.

[0049] Example 5: Purification of glycyrrhizic acid by the method of the present invention

[0050] Put 50.0g of crude glycyrrhizic acid into a 1L reaction bottle, add 800mL of acetone, heat under reflux to dissolve and extract. Filter, add 15.0g of ferrous chloride ethanol solution dropwise to the filtrate, and crystallize during the dropwise addition. Filter, add 400mL of water to dissolve the filter cake, add 25mL of 2-methylpyridine to free it, and precipitate. Filter and collect the filtrate. Add 36% concentrated hydrochloric acid to the filtrate to adjust the pH to 2, crystallize and filter. White solid powder, 55℃ air drying to obtain 25.2g of glycyrrhizic acid, yield 50.4%, content: 98.3%, such as Figure 5 shown.

[0051] Example 6: Purification of glycyrrhizic acid by the method of the present invention

[0052] Put 50.0g of crude glycyrrhizic acid into a 1L reaction bottle, add 800mL of acetone, and heat under reflux to dissolve and extract. Filter, add 15.0g of zinc chloride in ethanol solution dropwise to the filtrate, and crystallize during the dropwise addition. Filter, add 400mL of water to dissolve the filter cake, add 25mL of 4-methylpyridine to free it, and precipitate. Filter and collect the filtrate. Add 36% concentrated hydrochloric acid to the filtrate to adjust the pH to about 2 for crystallization and filtration. White solid powder, 55°C air drying to obtain 26.2g of glycyrrhizic acid, yield 52.4%, content: 97.9%, such as Figure 6 shown.

[0053] It can be seen from the above Examples 1 to 2 that the purity of glycyrrhizic acid obtained by conventional purification methods is only about 70%, while the purity of glycyrrhizic acid obtained by Examples 2 to 4 representing the purification method of the present invention is all above 95%, and the purity is significantly improved.

[0054] Example 7: Synthesis of Magnesium Isoglycyrrhizinate

[0055] 20.0 g of the glycyrrhizic acid sample obtained in Example 6 was put into a reaction flask, 50.0 g of a 10% sodium hydroxide aqueous solution was added, and the mixture was heated under reflux for 8 hours. The reaction solution was cooled to room temperature, and 36% concentrated hydrochloric acid was added to adjust the pH to 3 for crystallization. The filter cake was filtered and dried at 60° C. to obtain 12.5 g of isomerized glycyrrhizic acid, with a yield of 62.5%.

[0056] 12.5 g of sample was put into a reaction bottle, and 125 ml of methanol was added. 5.0 g of acetyl chloride was added under stirring at room temperature and stirred for 1 hour. 6.5 g of methyl isoglycyrrhizinate was obtained by filtration, with a yield of 51.1%.

[0057] Put 6.5g of methyl isoglycyrrhizinate into a reaction bottle, add 19.5g of 10% sodium hydroxide aqueous solution, stir and heat to 80℃ for 2 hours. Cool to room temperature and add 10% dilute hydrochloric acid to adjust pH=3. Add 20ml of n-butanol and extract 3 times. Combine n-butanol and concentrate under reduced pressure to obtain residue. Add 15ml of 90% acetic acid aqueous solution to dissolve and cool to crystallize. Filter and dry at 60℃ to obtain 5.5g of refined isoglycyrrhizic acid with a yield of 86.1%.

[0058] 5.0 g of refined isoglycyrrhizic acid was put into a reaction bottle, and 5 ml of water, 20 ml of isopropanol, and 1.0 g of magnesium carbonate were added. The mixture was stirred and heated to reflux for 2 hours. The mixture was cooled and crystallized, filtered, and dried with air at 60°C to obtain 5.1 g of magnesium isoglycyrrhizinate with a yield of 91.2%. Figure 7 shown.

[0059] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for purifying glycyrrhizic acid, characterized in that: The crude glycyrrhizic acid is added to an organic solvent for heating and refluxing extraction, and pre-filtered after extraction, the pre-filtered filtrate is collected and a metal salt solution is added dropwise, crystallization occurs during the process of adding the metal salt solution dropwise, and a first filtration is performed after crystallization, water is added to the filter cake of the first filtration to dissolve, and then a complex reagent is added to react to produce a precipitate, and then a second filtration is performed, and an acid is added to the filtrate of the second filtration to adjust the pH to acidic, and a solid is precipitated, and the precipitated solid is separated and dried to obtain the product; The organic solvent in the organic solution of crude glycyrrhizic acid is ethanol or acetone, the solvent of the metal salt solution is ethanol, the metal salt is zinc salt, iron salt and / or ferrous salt, the complex reagent is pyridine, 2-methylpyridine and / or 4-methylpyridine, and the pH is adjusted to 1.5-2.5 by acid.

2. The method for purifying glycyrrhizic acid as claimed in claim 1, characterized in that: The addition ratio of glycyrrhizic acid to organic solvent is 1:15-20, g / mL.

3. The method for purifying glycyrrhizic acid according to claim 1, characterized in that: The mass ratio of the metal salt to the crude glycyrrhizic acid is 0.2-0.3:

1.

4. The method for purifying glycyrrhizic acid according to claim 1, wherein: The ratio of metal salt to complex reagent is 1:1-3, g / mL.

5. The method for purifying glycyrrhizic acid according to claim 1, characterized in that: The precipitated solid was filtered for the third time, and the solid after the third filtration was dried.

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