A method for isomerizing glycyrrhizic acid and a method for preparing magnesium isoglycyrrhizinate

Abstract

The present invention belongs to the field of biopharmaceutical technology and relates to methods for preparing pharmaceutical intermediates, specifically methods for isomerizing glycyrrhizic acid and preparing magnesium isoglycyrrhizate. The isomerization method is characterized by rapid reaction, simple operation, and suitability for industrial production by irradiating an aqueous solution of glycyrrhizic acid with ultraviolet light for at least 2 hours at a temperature of 50 to 90°C.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine and relates to a preparation method of a pharmaceutical intermediate, and specifically relates to an isomerization method of glycyrrhizic acid and a preparation method of magnesium isoglycyrrhizinate. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance 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 those skilled in the art.

[0003] Magnesium isoglycyrrhizinate injection can be used to treat chronic viral hepatitis and acute drug-induced liver injury, and improve abnormal liver function. Glycyrrhizic acid is an important raw material for magnesium isoglycyrrhizinate. The two have the same molecular weight, differing only in the conformation of H at position 18. Magnesium isoglycyrrhizinate is obtained by isomerizing glycyrrhizic acid to obtain isoglycyrrhizic acid, which is then purified through a series of purifications to obtain the magnesium salt. According to literature reports, isoglycyrrhizic acid is currently mainly obtained by isomerizing glycyrrhizic acid in a sodium hydroxide solution. The reaction takes 24 hours, and post-reaction treatment requires a large amount of hydrochloric acid for neutralization. This method has a long conversion time, low conversion rate, and a high waste liquid. Therefore, it is necessary to develop a highly efficient isomerization method. Summary of the Invention

[0004] In order to solve the deficiencies of the prior art, the present invention aims to provide a method for isomerizing glycyrrhizic acid and a method for preparing magnesium isoglycyrrhizinate. The isomerization method of glycyrrhizic acid provided by the present invention has fast reaction, simple operation, and is suitable for industrial production.

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

[0006] In one aspect, the present invention provides a method for isomerizing glycyrrhizic acid, comprising: irradiating an aqueous solution of glycyrrhizic acid with ultraviolet light at a temperature of 50 to 90° C. for at least 2 hours to obtain the product.

[0007] The present invention unexpectedly discovered through experiments that, under heating conditions, when water is used as a solvent, ultraviolet light is used to irradiate glycyrrhizic acid, which can cause the 18-position H of glycyrrhizic acid to flip, thereby forming isoglycyrrhizic acid.

[0008] In some embodiments, the reaction temperature is 80-90° C. Studies have shown that under these conditions, the isomerization conversion rate of glycyrrhizic acid is improved.

[0009] In some embodiments, the ultraviolet wavelength of the ultraviolet light irradiation is 300-365 nm. Studies have shown that under such conditions, the isomerization conversion rate of glycyrrhizic acid is improved.

[0010] When the reaction temperature is 80-90° C. and the ultraviolet wavelength is 300-365 nm, the conversion rate of glycyrrhizic acid is higher.

[0011] In some embodiments, the reaction time is 4 to 6 hours.

[0012] In some embodiments, the reaction is followed by cooling, crystallization, filtration, and drying.

[0013] The purpose of preparing isoglycyrrhizic acid by isomerization of glycyrrhizic acid is to prepare magnesium isoglycyrrhizate. After research, it was found that the purity of magnesium isoglycyrrhizic acid prepared by the current preparation process of magnesium isoglycyrrhizic acid is relatively low, generally about 97%, and it is difficult to reach more than 99%. After further research, it was found that the factors affecting the purity of magnesium isoglycyrrhizic acid are related to the conversion rate of glycyrrhizic acid isomerization. When the conversion rate of glycyrrhizic acid isomerization is high, the impurities are low and the purity of magnesium isoglycyrrhizic acid is high.

[0014] Therefore, on the other hand, the present invention provides a method for preparing magnesium isoglycyrrhizate, comprising: irradiating an aqueous glycyrrhizic acid solution with ultraviolet light having a wavelength of 300 to 365 nm at a temperature of 80 to 90° C. for a reaction of 4 to 6 hours to obtain isoglycyrrhizic acid, subjecting the isoglycyrrhizic acid to an esterification reaction to obtain methyl isoglycyrrhizate, hydrolyzing the methyl isoglycyrrhizic acid to obtain refined isoglycyrrhizic acid, and reacting the refined isoglycyrrhizic acid with a magnesium salt to obtain magnesium isoglycyrrhizate.

[0015] The method of the present invention performs ultraviolet irradiation under the conditions of a temperature of 80-90° C. and a wavelength of 300-365 nm, thereby achieving a higher conversion rate of glycyrrhizic acid isomerization and greatly reducing the impurity content, thereby reducing the impurity content generated by side reactions caused by impurities during the esterification reaction and the hydrolysis reaction, and further improving the purity of magnesium isoglycyrrhizate.

[0016] In some embodiments, after the ultraviolet light irradiation reaction, the temperature is lowered, the crystals are filtered, and then dried.

[0017] In some embodiments, the esterification reaction is carried out by adding isoglycyrrhizic acid to methanol and then adding acetyl chloride to react.

[0018] In some embodiments, the process of hydrolyzing methyl isoglycyrrhizate to obtain refined isoglycyrrhizic acid is as follows: adding methyl isoglycyrrhizic acid to an aqueous solution of an alkali metal hydroxide (e.g., sodium hydroxide) and heating to 70-90°C for reaction; after the reaction, adding an acid solution (e.g., hydrochloric acid) to adjust the pH to acidic (pH 1-3); then extracting with n-butanol; concentrating after extraction; and then recrystallizing with an aqueous acetic acid solution to obtain refined isoglycyrrhizic acid.

[0019] In one or more embodiments, the volume concentration of the acetic acid aqueous solution is 85-95%.

[0020] The magnesium salt of the present invention is a compound whose cation is a magnesium ion, especially an alkaline compound whose cation is a magnesium ion, such as magnesium carbonate, magnesium hydroxide, basic magnesium carbonate, etc. In some embodiments, refined isoglycyrrhizic acid and magnesium salt are added to a solvent, heated under reflux for reaction, cooled for crystallization after the reaction, filtered, and dried to obtain refined isoglycyrrhizic acid.

[0021] The beneficial effects of the present invention are:

[0022] The invention can isomerize glycyrrhizic acid by ultraviolet irradiation by adjusting the temperature and the solvent system, has simple operation, easy control of conditions, low cost, little pollution and is easy for industrial production.

[0023] The invention greatly reduces the impurities generated by the isomerization of glycyrrhizic acid under the process conditions of better isomerization conversion rate. The purity of the magnesium isoglycyrrhizinate prepared thereby is greater than or equal to 99%, which can meet the standard of raw materials for preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] The accompanying drawings, 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.

[0025] Figure 1 HPLC chromatogram of glycyrrhizic acid, a raw material used in the present invention;

[0026] Figure 2 This is a high performance liquid chromatogram of isoglycyrrhizic acid prepared in Comparative Example 1 of the present invention;

[0027] Figure 3 This is a high performance liquid chromatogram of isoglycyrrhizic acid prepared in Comparative Example 2 of the present invention;

[0028] Figure 4 This is a high performance liquid chromatogram of isoglycyrrhizic acid prepared in Comparative Example 3 of the present invention;

[0029] Figure 5 This is a high performance liquid chromatogram of isoglycyrrhizic acid prepared in Comparative Example 4 of the present invention;

[0030] Figure 6 This is a high performance liquid chromatogram of magnesium isoglycyrrhizinate prepared in Example 1 of the present invention;

[0031] Figure 7 This is a high performance liquid chromatogram of magnesium isoglycyrrhizinate prepared in Example 2 of the present invention;

[0032] Figure 8 This is a high performance liquid chromatogram of magnesium isoglycyrrhizinate prepared in Example 3 of the present invention;

[0033] Figure 9 This is a high performance liquid chromatogram of magnesium isoglycyrrhizinate prepared in Example 4 of the present invention;

[0034] Figure 10 This is the HPLC chromatogram of the reference substance of the marketed preparation of magnesium isoglycyrrhizinate; DETAILED DESCRIPTION

[0035] 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 with reference to specific embodiments and comparative examples.

[0036] Comparative Example 1: Sodium hydroxide isomerization method

[0037] Glycyrrhizic acid (Source: Shaanxi Fujie Pharmaceutical Co., Ltd., content: 75.1%, the same below. The spectrum is as follows Figure 1 20.0g of the product (shown) was added to a 250ml reaction flask, 10.0g of sodium hydroxide and 190ml of water were added, and the mixture was heated to about 80°C for 24 hours. The mixture was cooled and 25.0g of concentrated hydrochloric acid was added dropwise to adjust the pH to 1-3. Filtering and drying gave 15.7g of isoglycyrrhizic acid, with a yield of 78.5% and a content of 58.2%. Figure 2 shown.

[0038] Comparative Example 2: Experiment without UV irradiation

[0039] 20.0 g of glycyrrhizic acid was added to a 500 ml reaction flask, 200 ml of water was added, and the temperature was raised to 70-80 ° C for 4 hours. The product was crystallized, filtered, and dried to obtain 17.2 g of the product with a yield of 86.0%. There was no isoglycyrrhizic acid in the product. Figure 3 shown.

[0040] Comparative Example 3: UV irradiation experiment under low temperature conditions

[0041] Put 20.0g of glycyrrhizic acid into a 500ml light container, add 200mL of water, turn on the ultraviolet lamp, 500W, wavelength 300nm, control the temperature to 25℃ and irradiate for 4 hours. Cool down, crystallize, filter and dry to obtain 17.4g of product with a yield of 87.0%. There is no isoglycyrrhizic acid in the product. Figure 4 shown.

[0042] Comparative Example 4: UV irradiation in polar organic solvents

[0043] Put 20.0g of glycyrrhizic acid into a 500ml light container, add 200mL of isopropyl alcohol, heat to about 80℃, turn on the ultraviolet lamp, 500W, wavelength 300nm, and irradiate for 4 hours. Cool down, crystallize, filter, and dry to obtain 13.8g of product with a yield of 69.0%. There is no isoglycyrrhizic acid in the product. Figure 5 shown.

[0044] Example 1: Isomerization of the method of the present invention

[0045] 20.0g of glycyrrhizic acid was placed in a 500ml light container, 200ml of water was added, and the mixture was heated to about 80℃. A 500W ultraviolet lamp with a wavelength of 300nm was turned on and the reaction was allowed to proceed for 4 hours. The mixture was cooled, crystallized, filtered, and dried to obtain 16.5g of isoglycyrrhizic acid intermediate with a yield of 82.5% and a content of 65.5%. Figure 6 shown.

[0046] Example 2: Isomerization of the present invention

[0047] 20.0g of glycyrrhizic acid was placed in a 500ml light container, 200ml of water was added, and the mixture was heated to about 80°C. A 500W ultraviolet lamp with a wavelength of 365nm was turned on and the reaction was allowed to proceed for 4 hours. The mixture was cooled, crystallized, filtered, and dried to obtain 17.2g of isoglycyrrhizic acid intermediate with a yield of 86.0% and a content of 63.9%. Figure 7 shown.

[0048] Example 3: Isomerization of the present invention

[0049] 20.0g of glycyrrhizic acid was placed in a 500ml light container, 200mL of water was added, and the mixture was heated to about 80°C. A 500W ultraviolet lamp with a wavelength of 365nm was turned on and the reaction was allowed to proceed for 6 hours. The mixture was cooled, crystallized, filtered, and dried to obtain 16.8g of isoglycyrrhizic acid intermediate with a yield of 84.0% and a content of 64.8%. Figure 8 shown.

[0050] As can be seen from Example 1, the sodium hydroxide solution isomerization method requires a long reaction time and requires a large amount of hydrochloric acid for post-reaction neutralization. The ultraviolet irradiation method of Examples 2-3 has a short reaction time and is easy to operate.

[0051] pass Figures 2 to 8 and Figure 10 The comparison shows that the products obtained in Comparative Examples 2 to 4 are not isoglycyrrhizic acid, while the products obtained in Comparative Example 1 and Examples 1 to 3 are isoglycyrrhizic acid.

[0052] Example 4: Synthesis of Magnesium Isoglycyrrhizate

[0053] 15.0 g of the isoglycyrrhizic acid intermediate sample obtained in Example 3 was placed in a reaction flask, and 150 ml of methanol was added. 4.0 g of acetyl chloride was added under stirring at room temperature and stirred for 1 hour. Filtration afforded 4.8 g of methyl isoglycyrrhizate, with a yield of 50.3%.

[0054] Place 4.5 g of methyl isoglycyrrhizate in a reaction flask, add 15.0 g of a 10% (mass percent) aqueous sodium hydroxide solution, and heat to 80°C with stirring for 2 hours. Cool to room temperature and add 10% (mass percent) dilute hydrochloric acid to adjust the pH to 2. Add 20 ml of n-butanol and extract three times. Combine the n-butanol and concentrate under reduced pressure to obtain a residue. Dissolve in 15 ml of a 90% (volume percent) aqueous acetic acid solution, then cool and crystallize. Filter and air-dry at 60°C to obtain 3.8 g of purified isoglycyrrhizic acid (85.9% yield).

[0055] 3.5g of purified isoglycyrrhizic acid was added to a reaction flask, 5ml of water, 20ml of isopropanol, and 0.8g of basic magnesium carbonate were added, and the mixture was stirred and heated to reflux for 2 hours. The mixture was cooled and crystallized, filtered, and dried at 60℃ with forced air to obtain 3.5g of magnesium isoglycyrrhizate with a yield of 89.4% and a content of 99.6%. Figure 9 shown.

[0056] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention.

Claims

1. A method for isomerizing glycyrrhizic acid, characterized in that: The glycyrrhizic acid aqueous solution is irradiated with ultraviolet light to react for at least 2 hours to obtain; The reaction temperature is 80~90℃; The ultraviolet wavelength of ultraviolet light irradiation is 300~365nm.

2. The isomerization method of glycyrrhizic acid according to claim 1, wherein The reaction time is 4~6 h.

3. The isomerization method of glycyrrhizic acid according to claim 1, wherein: After the reaction, the temperature was lowered, the crystals were filtered and dried.

4. A method for preparing magnesium isoglycyrrhizinate, characterized in that: Under the condition of temperature of 80-90°C, an aqueous solution of glycyrrhizic acid is irradiated with ultraviolet light of wavelength of 300-365 nm for reaction for 4-6 hours to obtain isoglycyrrhizic acid, which is then subjected to esterification reaction to obtain methyl isoglycyrrhizate, which is then hydrolyzed to obtain refined isoglycyrrhizic acid, and the refined isoglycyrrhizic acid is reacted with magnesium salt to obtain magnesium isoglycyrrhizate.

5. The method for preparing magnesium isoglycyrrhizinate according to claim 4, wherein: After the reaction is irradiated with ultraviolet light, the temperature is lowered, the crystals are filtered and dried.

6. The method for preparing magnesium isoglycyrrhizinate according to claim 4, wherein: The process of the esterification reaction is as follows: isoglycyrrhizic acid is added to methanol, and then acetyl chloride is added to react.

7. The method for preparing magnesium isoglycyrrhizinate as claimed in claim 4, wherein The process of hydrolyzing glycyrrhizic acid methyl ester to obtain refined isoglycyrrhizic acid is as follows: adding isoglycyrrhizic acid methyl ester to an aqueous solution of alkali metal hydroxide and heating to 70-90°C for reaction; after the reaction, adding an acid solution to adjust the pH to acidic; then extracting with n-butanol; concentrating after extraction; and then recrystallizing with an aqueous solution of acetic acid to obtain refined isoglycyrrhizic acid.

8. The method for preparing magnesium isoglycyrrhizinate according to claim 7, wherein: The volume concentration of the acetic acid aqueous solution is 85~95%.

9. The method for preparing magnesium isoglycyrrhizinate according to claim 4, wherein: The purified isoglycyrrhizic acid and magnesium salt are added to a solvent, heated under reflux for reaction, cooled for crystallization after the reaction, filtered, and dried to obtain purified magnesium isoglycyrrhizate.

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