A kind of synthesis method of high-purity magnesium isoglycyrrhizinate

Abstract

The present invention relates to a method for synthesizing high-purity magnesium isoglycyrrhizinate, and belongs to the field of drug synthesis. It uses diammonium glycyrrhizinate as a starting material, and obtains magnesium isoglycyrrhizinate through esterification, hydrolysis and salt formation. The preparation process of magnesium isoglycyrrhizinate of the present invention has achieved a major technical breakthrough, and its impurity control level is significantly better than the current pharmacopoeia standard. Compared with commercially available products (single impurity <1.0%, total impurities <3.0%), the present invention achieves single impurity content control below 0.1% and total impurity content below 1.0% through process optimization, and the reduction rate reaches 90% and 83% or more respectively. This breakthrough effectively solves the safety hazards such as allergic reactions and phlebitis that may be caused by impurities in intravenous drugs, so that the purity of the product reaches the international advanced level, meets the strict requirements of EMA and FDA on impurities in injections, and provides reliable guarantee for clinical safe drug use.

Description

Technical Field

[0001] The invention relates to a method for synthesizing high-purity magnesium isoglycyrrhizinate, and belongs to the field of drug synthesis. Background Art

[0002] As an excellent liver cell protector, magnesium isoglycyrrhizinate plays a key role in the medical field. It combines multiple functions such as anti-inflammatory, liver cell membrane protection and liver function improvement. It belongs to the 4th generation of glycyrrhizic acid drugs and is currently the only drug that is clearly identified as suitable for the treatment of acute drug-induced liver injury.

[0003] Many efficacy tests have fully confirmed its remarkable therapeutic effect. When dealing with the acute liver injury scenario induced by D-galactosamine in rats, magnesium isoglycyrrhizinate showed excellent prevention and treatment capabilities, which can effectively prevent the rise of animal serum transaminases, minimize liver cell degeneration and necrosis, and inhibit the infiltration of inflammatory cells, thus building a solid protective barrier for liver cells. Faced with the problem of chronic liver injury in rats caused by carbon tetrachloride, the drug also performed exceptionally well, significantly improving the liver function of damaged rats, accurately reducing NO levels, effectively alleviating the degree of inflammatory activity in liver tissue, curbing the process of fibrosis, and helping liver function gradually return to normal.

[0004] Moreover, magnesium isoglycyrrhizinate can also provide strong protection against Gal / FCA-induced immune liver damage in mice. It reduces the levels of serum transaminase and plasma NO, alleviates the damage to liver tissue, and significantly improves the survival rate of mice, bringing new hope for the treatment of liver immune diseases.

[0005] In summary, magnesium isoglycyrrhizinate, with its outstanding efficacy, provides a reliable drug option for the treatment of various liver damage-related diseases and has extremely high clinical application value. Magnesium isoglycyrrhizinate mainly works through intravenous administration in clinical treatment, so the quality control of magnesium isoglycyrrhizinate is particularly important. The presence of drug impurities may have a negative impact on the safety and efficacy of the drug. Especially in the case of intravenous administration, impurities enter the blood circulation system, which may cause a series of adverse reactions, such as allergic reactions, infusion reactions, etc., which seriously threaten the health of patients.

[0006] At present, magnesium isoglycyrrhizinate has not been included in the pharmacopoeias of various countries, but its quality standards are gradually being improved. Studies have shown that the purity of magnesium isoglycyrrhizinate must reach more than 98%, the content of individual impurities must be controlled below 0.1%, and the total impurity content must be less than 1.0% to meet the requirements of clinical application (Liu Mengjun, Quality Research on Magnesium Isoglycyrrhizinate API, Nanjing University of Chinese Medicine, Master's Thesis June 2020). At present, there are relevant literature reports on magnesium isoglycyrrhizinate, such as: CN1169826C first reported the synthesis method of magnesium isoglycyrrhizinate, which uses monoammonium glycyrrhizinate as the starting material, and prepares magnesium isoglycyrrhizinate through configuration transformation, esterification, hydrolysis and salt formation. This method has the problem that the configuration transformation is difficult to be completely transformed and the reaction becomes more complicated over time, and the product purity is difficult to reach a high level, and the reaction requires four steps, which is costly.

[0007] CN104861031A reports a method for synthesizing magnesium isoglycyrrhizinate: magnesium isoglycyrrhizinate is prepared by using glycyrrhizic acid as a starting material through isomerization, esterification, hydrolysis and salification. The esterification step of the method requires the use of HMCM-49 as a catalyst, which is expensive and has not been commercialized, limiting its industrial production.

[0008] CN116693594A reports a method for synthesizing magnesium isoglycyrrhizinate: using methyl isoglycyrrhizinate as a starting material to obtain magnesium isoglycyrrhizinate through hydrolysis and salification. The methyl isoglycyrrhizinate raw material used in this method is not very accessible, and since all refining is done in the last step, the purity of methyl isoglycyrrhizinate is very demanding. The last step uses a high boiling point solvent, n-butanol, and the final product has a risk of exceeding the residue limit. The patent states that the purity of the product prepared by the patent method is above 99%, but it does not mention whether the single impurity can be controlled below 0.1%.

[0009] CN117567545A reports a method for synthesizing magnesium isoglycyrrhizinate: glycyrrhizic acid is used as the starting material, and magnesium isoglycyrrhizinate is prepared by ultraviolet irradiation isomerization, esterification, hydrolysis and salification. However, the method has the following problems: a. The power of a single-wavelength ultraviolet lamp is limited during industrial mass production. If a higher-power mercury lamp is used, then the control of the wavelength will be a major problem. b. It is still necessary to concentrate high-boiling n-butanol, and the problem of difficulty in crystallization after adding glacial acetic acid is difficult if the concentration is not complete. At the same time, there is a problem that the possibility of residual finished product using a high-boiling point solvent in the penultimate step is relatively high. c. The patent states that the purity of the product prepared by the patent method is above 99%, but it does not mention whether the single impurity can be controlled below 0.1%.

[0010] CN117946204A reports a method for synthesizing isoglycyrrhizic acid salt: using monoammonium glycyrrhizinate as the starting material, isomerization, esterification, hydrolysis and salt formation are carried out at high temperature and high pressure to prepare isoglycyrrhizic acid salt. However, the method has the following problems: a. High temperature and high pressure limit its industrial application. b. The process uses high boiling point solvents such as n-butanol and dioxane, and the possibility of residual product residue is relatively high. The purity of the product is more than 0.1%.

[0011] In the literature currently reported, magnesium isoglycyrrhizinate is prepared from glycyrrhizic acid, monoammonium glycyrrhizinate or diammonium glycyrrhizinate as starting materials through a series of reactions (such as isomerization, esterification, hydrolysis and salt formation). The conversion rate of the isomerization step is low and the reaction is relatively complex. The isomerization step is then purified by esterification, resulting in a low overall yield of the isomerization and esterification steps, which in turn affects the purity of the product. The purity of the current commercially available product fails to meet the quality requirement of less than 0.1% of single impurities. Summary of the invention

[0012] The invention provides a method for synthesizing high-purity magnesium isoglycyrrhizinate, which can significantly reduce the impurity content of the magnesium isoglycyrrhizinate, greatly improve the safety of intravenous administration of the magnesium isoglycyrrhizinate, has fewer reaction steps and is low in cost.

[0013] The present invention provides a method for synthesizing high-purity magnesium isoglycyrrhizinate, which uses diammonium glycyrrhizinate as a starting material, and obtains magnesium isoglycyrrhizinate through esterification, hydrolysis and salt formation. The synthesis route is:

[0014] .

[0015] It includes the following steps:

[0016] a. Synthesis of dimethyl glycyrrhizinate: using diammonium glycyrrhizinate as the starting material, esterification reaction and purification with acetic acid solution to obtain dimethyl glycyrrhizinate;

[0017] b. Synthesis of isoglycyrrhizic acid: the dimethyl glycyrrhizinate prepared in step a is hydrolyzed, the pH value is adjusted, and n-butanol, acetic acid or glacial acetic acid is added for crystallization and purification to obtain isoglycyrrhizic acid;

[0018] c. Synthesis of magnesium isoglycyrrhizinate: react the isoglycyrrhizic acid prepared in step b to form a salt, cool and crystallize to obtain magnesium isoglycyrrhizinate.

[0019] Wherein, the solvent for the esterification reaction in step a is: methanol, dichloromethane, DMF, triethylamine, one or a mixed solvent of two or more; the acylating agent for the esterification reaction is: acetyl chloride, oxalyl chloride or concentrated sulfuric acid; the concentration of the acetic acid solution is 50%-85%.

[0020] Preferably, the solvent for the esterification reaction in step a is methanol; the acylating agent for the esterification reaction is acetyl chloride; the concentration of the acetic acid solution is 75%; it comprises the following steps:

[0021] Take diammonium glycyrrhizinate and add methanol, stir and cool to 0-5°C, add acetyl chloride dropwise, return to room temperature and continue stirring and reacting for 2 hours; add water dropwise, filter after adding, add methanol and water to the filter cake, stir at room temperature, filter, and obtain crude dimethyl glycyrrhizinate;

[0022] The crude dimethyl glycyrrhizinate was then added with 75% acetic acid, slurried at 25° C. for 20 hours, and filtered to obtain dimethyl glycyrrhizinate.

[0023] Wherein, the hydrolysis solvent described in step b is sodium hydroxide or potassium hydroxide solution; the crystallization solvent is 50-90% acetic acid; the hydrolysis temperature is 45-85°C; the pH value is adjusted to 1-5; and the crystallization temperature is 0°C-50°C.

[0024] Preferably, the hydrolysis solvent in step b is a sodium hydroxide solution, the amount of sodium hydroxide used is 5 to 8 times the molar amount of dimethyl glycyrrhizinate, and the amount of water used is 1 to 6 times the molar amount of dimethyl glycyrrhizinate; it comprises the following steps:

[0025] Add sodium hydroxide and water to dimethyl glycyrrhizinate, heat to 70-80℃, react for 1 hour, cool to below 10℃, adjust pH to 2-3 with concentrated hydrochloric acid; add glacial acetic acid, stir and heat to 80℃ to dissolve, cool naturally to 10℃ to crystallize for 2 hours, filter, add 85% acetic acid to the filter cake, stir and heat to 80℃ to dissolve, cool naturally to 10℃ to crystallize for 2 hours, filter to obtain isoglycyrrhizic acid.

[0026] Wherein, the solvent for the salt-forming reaction in step c is: acetone aqueous solution, isopropanol aqueous solution, ethanol; the magnesium salt for the salt-forming reaction includes basic magnesium carbonate or magnesium carbonate.

[0027] Preferably, the reaction solvent is acetone and water; the volume ratio of acetone to water is 0.5:1 to 5:1; the total amount of acetone and water is 5 to 10 times the amount of isoglycyrrhizic acid.

[0028] Wherein, the volume ratio of acetone to water is 1:1. The crystallization temperature in step c is 5°C to 25°C.

[0029] The beneficial effects of the present invention are:

[0030] a. An innovative purification scheme for dimethyl glycyrrhizinate was proposed for the first time. By pre-positioning the impurity purification step, the production cost was effectively reduced from the source, greatly improving the production efficiency.

[0031] b. In terms of the hydrolysis step, compared with the existing technology, the present invention does not need to concentrate the high boiling point solvent, effectively avoiding the adverse effects on crystallization caused by incomplete solvent concentration. After the entire reaction process is completed, acetic acid solution can be directly added for crystallization. The operation process is simple and convenient, which not only greatly shortens the production cycle, but also significantly reduces energy consumption, which is in line with the green and efficient production concept.

[0032] c. The total reaction yield of this synthesis method can reach 40% or above. The process operation flow is simple and clear, with high stability and repeatability, which can ensure the stability and controllability of product quality, and can achieve a single impurity content of the product below 0.1%, fully meeting the production requirements of high-quality products.

[0033] The preparation process of magnesium isoglycyrrhizinate of the present invention has achieved a major technological breakthrough, and its impurity control level is significantly better than the current pharmacopoeia standard. Compared with commercially available products (single impurity <1.0%, total impurities <3.0%), the present invention achieves single impurity content control below 0.1% and total impurity content below 1.0% through process optimization, with a reduction of 90% and 83% respectively. This breakthrough effectively solves the safety hazards such as allergic reactions and phlebitis that may be caused by impurities in intravenous drugs, so that the product purity reaches the international advanced level, meets the strict requirements of EMA and FDA for impurities in injections, and provides reliable protection for clinical safe drug use. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The HPLC spectrum of dimethyl glycyrrhizinate in Example 1;

[0035] Figure 2 is the HPLC spectrum of isoglycyrrhizic acid in Example 1;

[0036] Figure 3 is the HPLC spectrum of magnesium isoglycyrrhizinate in Example 1;

[0037] Figure 4 The HPLC spectrum of dimethyl glycyrrhizinate in Example 2;

[0038] Figure 5 The HPLC spectrum of isoglycyrrhizic acid in Example 2;

[0039] Figure 6 The HPLC spectrum of magnesium isoglycyrrhizinate in Example 2;

[0040] Figure 7 The HPLC spectrum of dimethyl glycyrrhizinate in Example 3;

[0041] Figure 8 The HPLC spectrum of isoglycyrrhizic acid in Example 3;

[0042] Fig. 9 The HPLC spectrum of magnesium isoglycyrrhizinate in Example 3. DETAILED DESCRIPTION

[0043] All features disclosed in this specification, except mutually exclusive features and / or steps, can be combined in any way. Below will be explained in conjunction with embodiment to the scheme of the present invention. It will be appreciated by those skilled in the art that the following examples are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. In the embodiment, if no specific technology or condition is indicated, it is carried out according to the technology or condition described in the document in this area or according to the product specification. The reagents used or the instrument that do not indicate the manufacturer are all conventional products that can be obtained by commercial purchase.

[0044] The scheme of the present invention will be explained below in conjunction with the embodiments. It will be appreciated by those skilled in the art that the following embodiments are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. Where specific techniques or conditions are not indicated in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used are not indicated by the manufacturer and are all conventional products that can be obtained commercially.

[0045] Example 1 Synthesis method of magnesium isoglycyrrhizinate of the present invention

[0046] 1. Synthesis of dimethyl glycyrrhizinate

[0047]

[0048] Weigh 200g (0.233mol) of diammonium glycyrrhizinate and add 1200mL of methanol. Stir and cool to 0~5℃. Add 83mL (1.167mol) of acetyl chloride dropwise. After adding, return to room temperature and continue stirring and reacting for 2 hours. Add 50mL of water dropwise. After adding, filter. Add 1000mL of methanol and 200mL of water to the filter cake. Stir at room temperature for 30 minutes and filter to obtain 140g of crude dimethyl glycyrrhizinate. The yield is 75.49%.

[0049] The crude product of dimethyl glycyrrhizinate was added to 700 mL of 75% acetic acid, slurried at 25°C for 20 hours, and filtered to obtain 106 g of dimethyl glycyrrhizinate. The yield was 85.71%. HPLC analysis Figure 1 And the data in Table 1 (the detection method was detected according to the method published in the literature (Liu Mengjun, Determination of related substances in magnesium isoglycyrrhizinate raw materials by high performance liquid chromatography, 2020, CNKI: SUN: ZXYZ.0.2020-04-017)).

[0050] Table 1 HPLC chromatographic data of dimethyl glycyrrhizinate

[0051]

[0052] Refer to the previous steps and run with the following parameters:

[0053] Table 2 Investigation of different proportions of acetic acid concentration

[0054]

[0055] From the above table, it can be seen that within the investigated acetic acid concentration range, the product purity increases with the increase of acetic acid concentration. Considering the economic efficiency and the subsequent purification effect, the optimal acetic acid concentration in this step is 75% (mass ratio).

[0056] Table 3 Investigation of different beating temperatures

[0057]

[0058] From the above table, it can be seen that within the temperature range investigated, the purity of the product increases with the increase in temperature, but the yield is significantly affected. Considering the economy and the subsequent purification effect, the acetic acid beating temperature in this step is preferably 20°C ± 5°C.

[0059] 2. Synthesis of Isoglycyrrhizic Acid

[0060]

[0061] Take 106g (0.120mol) of dimethyl glycyrrhizinate, add 29.41g (0.735mol) of sodium hydroxide and 212mL of water, heat to 70-80℃ for reaction for 1 hour, cool to below 10℃, adjust pH to 2-3 with concentrated hydrochloric acid. Add 1500mL of glacial acetic acid, stir and heat to 80℃ to dissolve, cool to 10℃ naturally to crystallize for 2 hours, filter, add 530mL of 85% acetic acid to the filter cake, stir and heat to 80℃ to dissolve, cool to 10℃ naturally to crystallize for 2 hours, filter, and obtain 94g of isoglycyrrhizic acid. Yield 91.70%. HPLC see Figure 2 And the data in Table 4.

[0062] Table 4 HPLC chromatographic data of isoglycyrrhizic acid

[0063]

[0064] Run with the following parameters:

[0065] Table 5 Investigation of acetic acid concentration

[0066]

[0067] It can be seen from the above table that within the investigated acetic acid concentration range, the purity of the product increases with the increase of acetic acid concentration, but the yield is affected. Considering the economic efficiency and the subsequent purification effect, the acetic acid concentration in this step is preferably 85% (mass ratio).

[0068] Table 6 Investigation of the dosage of 85% acetic acid

[0069]

[0070] From the above table, it can be seen that within the range of acetic acid dosage investigated, as the acetic acid dosage increases, the product quality is improved, but the yield is affected to a certain extent. Considering the economic efficiency and the subsequent purification effect, the acetic acid dosage in this step is preferably 5 times.

[0071] 3. Synthesis of Magnesium Isoglycyrrhizinate

[0072]

[0073] Take 82 g (0.1 mol) of isoglycyrrhizic acid, add 410 mL of acetone and 410 mL of water, stir to dissolve, then add 7.1 g (0.05 mol) of basic magnesium carbonate, heat to reflux for 1 hour, cool to about 10 ° C for crystallization for 2 hours, filter, and obtain 69.7 g of magnesium isoglycyrrhizinate, with a yield of 76.29%. The maximum single impurity is 0.069%, and the purity is 99.828%. HPLC see Figure 3 and the data in Table 7.

[0074] Table 7 HPLC chromatographic data of magnesium isoglycyrrhizinate

[0075]

[0076] Run with the following parameters:

[0077] Table 8 Study on the ratio of acetone and water

[0078]

[0079] From the above table, it can be seen that within the investigated ratio range of acetone to purified water, as the amount of acetone increases, the product quality decreases, and the yield is relatively less affected. Considering the economy and the subsequent purification effect, the ratio of acetone to purified water in this step is preferably 1:1 (volume ratio).

[0080] Embodiment 2 Synthesis method of magnesium isoglycyrrhizinate of the present invention

[0081] 1. Synthesis of dimethyl glycyrrhizinate

[0082] Weigh 200g (0.233mol) of diammonium glycyrrhizinate, add 1000mL of dichloromethane, then add 3mL of DMF, 130mL (0.932mol) of triethylamine, and 200mL of methanol, stir and cool to 0~5℃, add 60mL (0.7mol) of oxalyl chloride dropwise, return to room temperature and continue stirring for 5 hours. Add 500mL of water, stir, separate the organic layer, wash with 500mL of sodium bicarbonate aqueous solution, wash with 500mL of saturated salt water, separate the organic layer, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to obtain 137g of crude dimethyl glycyrrhizinate. The yield is 68.98%.

[0083] Add 500 mL of 80% acetic acid to the crude product of dimethyl glycyrrhizinate, stir and heat to 80°C to dissolve, cool naturally to crystallize, and filter to obtain 95 g of dimethyl glycyrrhizinate. The yield is 69.34%. HPLC Figure 4 And Table 9 data.

[0084] Table 9 HPLC chromatogram data of dimethyl glycyrrhizinate

[0085]

[0086] 2. Synthesis of Isoglycyrrhizic Acid

[0087] Take 60g (0.07mol) of dimethyl glycyrrhizinate, add 11.76g (0.21mol) of potassium hydroxide and 300mL of water, react at room temperature for 4 hours, cool to below 10°C, and adjust the pH to 2-3 with concentrated sulfuric acid. Add 200mL of n-butanol to extract, separate the organic layer, concentrate to dryness, add 200mL of 90% glacial acetic acid to the residue, stir and heat to reflux, cool naturally to 0°C for crystallization for 3 hours, filter, and obtain 49.9g of isoglycyrrhizic acid. The yield is 86.00%. HPLC see Figure 5 And the data in Table 10.

[0088] Table 10 HPLC chromatogram data of isoglycyrrhizic acid

[0089]

[0090] 3. Synthesis of Magnesium Isoglycyrrhizinate

[0091] Take 40 g (0.049 mol) of isoglycyrrhizic acid, add 280 mL of isopropanol and 120 mL of water, stir and dissolve, then add 7.1 g (0.05 mol) of basic magnesium carbonate, heat and reflux for 30 minutes, cool to 5 ° C for crystallization for 4 hours, filter, and obtain 32.58 g of crude magnesium isoglycyrrhizinate, with a yield of 72.52%. The maximum single impurity is 0.27%, and the purity is 99.335%. HPLC see Figure 6 And the data in Table 11.

[0092] Table 11 Magnesium isoglycyrrhizinate HPLC chromatogram data

[0093]

[0094] Embodiment 3 Synthesis method of magnesium isoglycyrrhizinate of the present invention

[0095] 1. Synthesis of dimethyl glycyrrhizinate

[0096] Weigh 100 g (0.117 mol) of diammonium glycyrrhizinate, add 500 mL of methanol, dropwise add 10 mL of concentrated sulfuric acid, heat under reflux for 8 hours, return to room temperature, filter, and obtain 63 g of crude dimethyl glycyrrhizinate. The yield is 63.50%.

[0097] The crude product of dimethyl glycyrrhizinate was added with 120 mL of 85% acetic acid, stirred, heated and refluxed until the solution was clear, cooled and crystallized naturally, and filtered to obtain 52 g of dimethyl glycyrrhizinate. The yield was 82.54%. HPLC analysis Figure 7 And Table 12 data.

[0098] Table 12 HPLC chromatogram data of dimethyl glycyrrhizinate

[0099]

[0100] 2. Synthesis of Isoglycyrrhizic Acid

[0101] Take 50g (0.059mol) of dimethyl glycyrrhizinate, add 7.08g (0.177mol) of sodium hydroxide and 100mL of water, reflux for 30 minutes, reduce the temperature to below 10℃, adjust the pH to 4-5 with 2mol of hydrochloric acid. Add 300mL of acetone, filter, and obtain 37g of isoglycyrrhizic acid. The yield is 76.52%. HPLC Figure 8 And the data in Table 13.

[0102] Table 13 HPLC chromatogram data of isoglycyrrhizic acid

[0103]

[0104] 3. Synthesis of Magnesium Isoglycyrrhizinate

[0105] Take 30 g (0.036 mol) of isoglycyrrhizic acid, add 210 mL of ethanol and 90 mL of water, stir and dissolve, then add 6.07 g (0.072 mol) of magnesium carbonate, heat and reflux for 30 minutes, cool to about 25 ° C for crystallization for 8 hours, filter, and obtain 24.83 g of crude magnesium isoglycyrrhizinate, with a yield of 75.24%, a maximum single impurity of 0.125%, and a purity of 99.846%. HPLC results show Fig. 9 And the data in Table 14.

[0106] Table 14 Magnesium isoglycyrrhizinate HPLC chromatogram data

[0107]

[0108] In summary, Examples 1-3 can all achieve the synthesis of magnesium isoglycyrrhizinate, with simple synthesis steps, strong raw material accessibility, and low cost. The concentration, dosage, ratio, beating temperature and time of acetic acid in the synthesis step of isoglycyrrhizic acid are investigated, and the ratio of acetone and water in the synthesis step of magnesium isoglycyrrhizinate is investigated. Among them, Example 1 is the optimal synthesis route of the present invention. The magnesium isoglycyrrhizinate prepared according to the optimal synthesis route of the present invention not only reduces the cost under the premise of satisfying the yield, but also the maximum single impurity content can be controlled below 0.1%. Therefore, a breakthrough has been made, which provides safety for the intravenous clinical use of magnesium isoglycyrrhizinate.

Claims

1. A method for synthesizing high-purity magnesium isoglycyrrhizinate, characterized in that: It uses diammonium glycyrrhizinate as the starting material, and iso-glycyrrhizic acid magnesium is obtained through esterification, hydrolysis and salt formation. The synthetic route is: ； It includes the following steps: a. Synthesis of dimethyl glycyrrhizinate: using diammonium glycyrrhizinate as the starting material, esterifying it with acetic acid solution and purifying it, to obtain dimethyl glycyrrhizinate; the solvent for the esterification reaction in step a is: methanol, dichloromethane, DMF, triethylamine or a mixed solvent of two or more; the acylating agent for the esterification reaction is: acetyl chloride, oxalyl chloride or concentrated sulfuric acid; the concentration of the acetic acid solution is 50%-85%; b. Synthesis of isoglycyrrhizic acid: the dimethyl glycyrrhizinate prepared in step a is hydrolyzed, the pH value is adjusted, and n-butanol, acetic acid or glacial acetic acid is added for crystallization and purification to obtain isoglycyrrhizic acid; The hydrolysis solvent in step b is sodium hydroxide or potassium hydroxide solution; the crystallization solvent is 50-90% acetic acid; the hydrolysis temperature is 45-85°C; the pH value is adjusted to 1-5; the crystallization temperature is 0°C-50°C; c. Synthesis of magnesium isoglycyrrhizinate: subjecting the isoglycyrrhizic acid prepared in step b to a salt-forming reaction, cooling and crystallizing to obtain magnesium isoglycyrrhizinate; the solvent for the salt-forming reaction in step c is: an acetone aqueous solution, an isopropanol aqueous solution, or ethanol; the magnesium salt in the salt-forming reaction includes basic magnesium carbonate or magnesium carbonate; and the crystallization temperature in step c is 5° C. to 25° C.

2. The method for synthesizing high-purity magnesium isoglycyrrhizinate according to claim 1, wherein: The solvent for the esterification reaction in step a is methanol; the acylating agent for the esterification reaction is acetyl chloride; the concentration of the acetic acid solution is 75%; it comprises the following steps: Take diammonium glycyrrhizinate and add methanol, stir and cool to 0-5°C, add acetyl chloride dropwise, return to room temperature and continue stirring and reacting for 2 hours; add water dropwise, filter after adding, add methanol and water to the filter cake, stir at room temperature, filter, and obtain crude dimethyl glycyrrhizinate; The crude dimethyl glycyrrhizinate was then added with 75% acetic acid, slurried at 25° C. for 20 hours, and filtered to obtain dimethyl glycyrrhizinate.

3. The method for synthesizing high-purity magnesium isoglycyrrhizinate according to claim 1, wherein: The hydrolysis solvent in step b is a sodium hydroxide solution, the amount of sodium hydroxide used is 5 to 8 times the molar amount of dimethyl glycyrrhizinate, and the amount of water used is 1 to 6 times the molar amount of dimethyl glycyrrhizinate; it comprises the following steps: Add sodium hydroxide and water to dimethyl glycyrrhizinate, heat to 70-80℃, react for 1 hour, cool to below 10℃, adjust pH to 2-3 with concentrated hydrochloric acid; add glacial acetic acid, stir and heat to 80℃ to dissolve, cool naturally to 10℃ to crystallize for 2 hours, filter, add 85% acetic acid to the filter cake, stir and heat to 80℃ to dissolve, cool naturally to 10℃ to crystallize for 2 hours, filter to obtain isoglycyrrhizic acid.

4. The method for synthesizing high-purity magnesium isoglycyrrhizinate according to claim 1, wherein: The reaction solvents described in step c are acetone and water; the volume ratio of acetone to water is 0.5:1 to 5:1; the total amount of acetone and water is 5 to 10 times the amount of isoglycyrrhizic acid feed.

5. The method for synthesizing high-purity magnesium isoglycyrrhizinate according to claim 4, characterized in that: The volume ratio of acetone to water is 1:1.

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