Preparation method of dipotassium glycyrrhizinate for deeply removing heavy metals based on chelate resin

Abstract

The invention relates to the field of chemistry, and provides a preparation method of dipotassium glycyrrhizinate for deeply removing heavy metals based on chelate resin, which comprises the following steps: adding mono-ammonium glycyrrhizinate into an alkaline purified water solution, stirring, and adjusting the pH value to 7.5-8.5 to obtain a solution; enabling the obtained solution to pass through a mixed resin column, flushing the mixed resin column, combining effluent, concentrating and drying to obtain dipotassium glycyrrhizinate; wherein the mixed resin in the mixed resin is a composition of cation exchange resin and novel chelating resin. The preparation method disclosed by the invention is simple and reasonable in process, green and environment-friendly, and the cation exchange resin and the novel chelating resin are used in the preparation process to promote the purification of the dipotassium glycyrrhizinate, so that the content of residual alcohol in the obtained dipotassium glycyrrhizinate is less than or equal to 500mg / kg, the content of residual ammonia is less than or equal to 40mg / kg, and the contents of lead, cadmium, arsenic and mercury are less than or equal to 0.2 mg / kg.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of chemistry, and particularly relates to a preparation method of glycyrrhizin dipotassium salt with deep removal of heavy metals based on chelating resin. BACKGROUND

[0002] As an important natural product, glycyrrhizin dipotassium salt has significant biological activity and pharmacological effect, and is widely used in the fields of medicine, food, cosmetics and the like. However, in the preparation process of glycyrrhizin dipotassium salt, the raw material glycyrrhizin monopotassium salt contains alcohol, ammonia and heavy metal ions (such as lead, cadmium, mercury and the like), which seriously affects the quality and safety of the product.

[0003] Chinese patent CN 107722102 B discloses a preparation method of glycyrrhizin dipotassium salt with low residual alcohol and low residual ammonia. The method uses glycyrrhizin monopotassium salt as raw material, uses pure water as solvent in the preparation process, adds a certain amount of potassium hydroxide (or potassium carbonate), dissolves the glycyrrhizin monopotassium salt in the alkaline pure water, and then converts the glycyrrhizin dipotassium salt through a hydrogen type strong acid cation exchange resin. The preparation method is simple and reasonable, green and environmentally friendly, and reduces the residual alcohol and ammonia in the glycyrrhizin dipotassium salt prepared by the original production process. However, the removal of heavy metal ions is very limited.

[0004] Therefore, it is urgent to develop a preparation method of glycyrrhizin dipotassium salt with deep removal of heavy metals based on chelating resin, which effectively removes the heavy metal ions in the glycyrrhizin dipotassium salt under the condition of low residual alcohol and low residual ammonia, and further improves the purity and safety of the glycyrrhizin dipotassium salt. SUMMARY

[0005] In view of the existing technical problems, the purpose of the present application is to provide a preparation method of glycyrrhizin dipotassium salt with deep removal of heavy metals based on chelating resin. The preparation method is simple and reasonable, green and environmentally friendly. In the preparation process, the cation exchange resin and the new chelating resin are used together to promote the purification of the glycyrrhizin dipotassium salt. The residual alcohol content in the obtained glycyrrhizin dipotassium salt is ≤500 mg / kg, the residual ammonia content is ≤40 mg / kg, and the contents of lead, cadmium, arsenic and mercury are all ≤0.2 mg / kg.

[0006] In order to achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows:

[0007] The present application provides a preparation method of glycyrrhizin dipotassium salt with deep removal of heavy metals based on chelating resin, comprising the following steps:

[0008] S1. Adding glycyrrhizin monopotassium salt into an alkaline pure water solution, stirring, adjusting the pH to 7.5-8.5, and obtaining a solution;

[0009] S2. passing the solution obtained in step S1 through a mixed resin column, washing the mixed resin column, combining the effluent, and concentrating and drying to obtain glycyrrhizin di-potassium salt; wherein the mixed resin in the mixed resin column is a combination of cation exchange resin and a novel chelating resin.

[0010] The reaction mechanism and action of the present application are as follows:

[0011] 1. In the present application, glycyrrhizin mono-ammonium salt is added to an alkaline aqueous solution to fully dissolve it. At this time, the glycyrrhizin mono-ammonium salt is converted into glycyrrhizin tri-potassium salt, and the potassium ion replaces the ammonium ion in the product, so that most of the ammonium ion escapes from the solution in the form of ammonia gas. Then, the present application slowly passes the glycyrrhizin tri-potassium salt solution through a mixed resin column for treatment, so that the glycyrrhizin tri-potassium salt is converted into glycyrrhizin di-potassium salt, and the small amount of residual ammonium ion and heavy metal ion in the solution are further removed by ion exchange and coordination with the mixed resin column. It can be seen that the preparation method of the present application is simple and reasonable, and pure water is used as the solvent in the preparation process, without using organic solvents. The present application is not only green, environmentally friendly and safe, but also makes the residual amount of alcohol and ammonia in the glycyrrhizin di-potassium salt extremely low, further improving the quality of the glycyrrhizin di-potassium salt.

[0012] 2. In the present application, first, the porosity and specific surface area of the aminomethyl polystyrene resin are increased by swelling in N,N-dimethylformamide, so as to improve the efficiency of subsequent reactions and the adsorption capacity of the resin. Then, the methoxycarbonyl group is introduced by reaction with methyl acrylate, and then the N-aminoethyl piperazine is successfully grafted on the resin 1, so as to improve the chelating capacity of the resin for heavy metal ions. Finally, the 5-chloro-1,3,4-thiadiazole-2-amine is grafted on the resin 2 to form a group with strong chelating capacity. The synergistic effect of the thiazole group and the amino group improves the chelating capacity of the resin for heavy metal ions, so as to efficiently remove heavy metals, and the content of lead, cadmium, arsenic and mercury in the glycyrrhizin di-potassium salt is ≤0.2 mg / kg.

[0013] In some embodiments, the alkaline substance in the alkaline pure water solution in step S1 is potassium hydroxide or potassium carbonate.

[0014] In some embodiments, the temperature of the stirring in step S1 is 40-60℃.

[0015] In some embodiments, the flow rate of the solution through the mixed resin column in step S2 is 0.5-1.5 BV / h, and the temperature is 25-40℃.

[0016] In some embodiments, the ratio of the amount of glycyrrhizin mono-ammonium salt to the amount of mixed resin is 1 g:(1.5-3.5) mL.

[0017] In some embodiments, the cation exchange resin is a hydrogen form strongly acidic cation exchange resin.

[0018] Preferably, the hydrogen form strongly acidic cation exchange resin is any one of Amberlite D001, Lewatit C100E resin and Rohm & Haas SP112 resin.

[0019] In some embodiments, the volume ratio of the cation exchange resin to the novel chelating resin is (2-4):1.

[0020] In some embodiments, the preparation method of the novel chelating resin comprises the following steps:

[0021] Q1. The aminomethyl polystyrene resin is washed with aqueous ethanol solution for 3-4 times, suction filtered, taken out and placed in N,N-dimethylformamide, sealed, stirred and swelled for 10-15 h, filtered to obtain a pretreated resin;

[0022] Q2. The pretreated resin obtained in step Q1, methanol and methyl acrylate are mixed, reacted at room temperature for 18-30 h, filtered under reduced pressure, extracted with anhydrous ethanol for 7-10 h, washed with aqueous ethanol solution and dried to obtain resin 1;

[0023] Q3. Resin 1 obtained in step Q2, methanol and N-aminoethylpiperazine are mixed, reacted at room temperature for 18-30 h, filtered under reduced pressure, washed with aqueous ethanol solution and dried to obtain resin 2;

[0024] Q4. Resin 2 obtained in step Q3, toluene and 5-chloro-1,3,4-thiadiazol-2-amine are mixed, inert gas is introduced, a catalyst is added, heated to 65-100℃ and reacted for 5-8 h, washed, dried to obtain a novel chelating resin.

[0025] In some embodiments, the mass ratio of the pretreated resin to methyl acrylate in step Q2 is 1:(3.5-4.5).

[0026] In some embodiments, the mass ratio of resin 1 to N-aminoethylpiperazine in step Q3 is 1:(1.6-2.2).

[0027] In some embodiments, the mass ratio of resin 2 to 5-chloro-1,3,4-thiadiazol-2-amine in step Q4 is 1:(2.2-2.8).

[0028] In some embodiments, the glycyrrhizin di-potassium salt obtained by any one of the above preparation methods has a residual alcohol content ≤500 mg / kg, a residual ammonia content ≤40 mg / kg, and a lead, cadmium, arsenic and mercury content each ≤0.2 mg / kg.

[0029] Compared with the prior art, the present application has the following advantages:

[0030] 1. The preparation method of the present application is simple and reasonable, green and environmentally friendly. Cation exchange resin and a new type of chelating resin are used in the preparation process to promote the purification of glycyrrhizin dipotassium salt, so that the residual alcohol content in the obtained glycyrrhizin dipotassium salt is ≤500 mg / kg, the residual ammonia content is ≤40 mg / kg, and the lead, cadmium, arsenic and mercury contents are all ≤0.2 mg / kg.

[0031] 2. The present application synthesizes a new type of chelating resin, forms a group with strong chelating ability, and the thiazole group and amino group act simultaneously to produce a synergistic effect, thereby improving the chelating ability of the resin to heavy metal ions, and efficiently removing heavy metals in the preparation process of glycyrrhizin dipotassium salt. DETAILED DESCRIPTION

[0032] The present application will be described below in conjunction with specific embodiments. It should be noted that the following examples are examples of the present application and are only used to illustrate the present application, but not to limit the present application. Other combinations and various modifications within the concept of the present application can be made without departing from the spirit or scope of the present application.

[0033] Glycyrrhizin dipotassium salt was prepared according to the ratio and method of each raw material specified in the following examples and comparative examples.

[0034] In order to facilitate the implementation of the present application by those skilled in the art, the manufacturers of some raw materials in the examples and comparative examples are described as follows:

[0035] Hydrogen type strong acid cation exchange resin: Plante C100E resin, purchased from Bengbu Sanyi Technology Co., Ltd.;

[0036] Aminomethyl polystyrene resin: purchased from Tishir (Shanghai) Chemical Industry Development Co., Ltd.;

[0037] Chelating resin: Plante S930 resin, purchased from Shanghai Kaiping Resin Co., Ltd.;

[0038] Other raw materials are not specially mentioned and can be purchased from the market.

[0039] Preparation Example 1

[0040] The preparation method of the new type of chelating resin column A comprises the following steps:

[0041] Q1. The aminomethyl polystyrene resin is washed with 50% ethanol aqueous solution for 4 times, and the filtered for 3 min. 40 g of the filtered aminomethyl polystyrene resin is taken out and placed in 200 mL of N,N-dimethylformamide, sealed with plastic wrap, stirred and swelled for 12 h, and filtered to obtain the pretreated resin;

[0042] Q2. Mix 20 g of the pretreated resin obtained in step Q1, 200 mL of methanol and 80 g of methyl acrylate, and react at room temperature for 24 h, filter under reduced pressure, extract with anhydrous ethanol for 8 h, wash with a 50% by mass aqueous ethanol solution until the resin is neutral, and dry under vacuum at 70°C for 12 h to obtain resin 1;

[0043] Q3. Mix 15 g of resin 1 obtained in step Q2, 150 mL of methanol and 28.5 g of N-aminoethylpiperazine, and react at room temperature for 24 h, filter under reduced pressure, wash with a 20% by mass aqueous ethanol solution until the resin is neutral, and dry under vacuum at 70°C for 12 h to obtain resin 2;

[0044] Q4. Mix 12 g of resin 2 obtained in step Q3, 120 mL of toluene and 30 g of 5-chloro-1,3,4-thiadiazol-2-amine, introduce nitrogen, add 0.6 g of sodium hydroxide, heat to 80°C and react for 6.5 h, sequentially wash with toluene and deionized water each once, wash with a mixed solution of acetone and diethyl ether (volume ratio of acetone to diethyl ether is 1:1) once, and dry under vacuum at 70°C for 12 h to obtain novel chelating resin A.

[0045] Preparation Example 2

[0046] The preparation method of novel chelating resin B is the same as that in Preparation Example 1, except that the amount of N-aminoethylpiperazine added in step Q3 is 22.5 g.

[0047] Preparation Example 3

[0048] The preparation method of novel chelating resin C is the same as that in Preparation Example 1, except that the amount of 5-chloro-1,3,4-thiadiazol-2-amine added in step Q4 is 25.2 g.

[0049] Example 1

[0050] A preparation method of glycyrrhizin di-potassium salt based on deep removal of heavy metals by chelating resin, comprising the following steps:

[0051] S1. Dissolve 480 g of potassium hydroxide in 2000 mL of pure water to obtain an alkaline pure aqueous solution, add 400 g of glycyrrhizin mono-ammonium salt to the alkaline pure aqueous solution, heat to 50°C and stir for 45 min, and adjust the pH to 8.0 to obtain a solution;

[0052] S2. The solution obtained in step S1 is passed through a mixed resin column (volume of mixed resin 1000 mL) at a flow rate of 1 BV / h and a temperature of 35°C, and then 2000 mL of pure water at 35°C is used to flush the mixed resin column, the effluent is combined, the pH is adjusted to 6.5 using a 20 wt% aqueous potassium hydroxide solution, and the solution is concentrated under reduced pressure to 800 mL, and then spray dried at an inlet air temperature of 125°C to obtain glycyrrhizin dipotassium salt; wherein,

[0053] The mixed resin in the mixed resin column is a combination of hydrogen type strong acid cation exchange resin and novel chelating resin A, and the volume ratio of hydrogen type strong acid cation exchange resin and novel chelating resin A is 3:1.

[0054] Example 2

[0055] A preparation method of glycyrrhizin dipotassium salt based on deep removal of heavy metals by chelating resin, comprising the following steps:

[0056] S1. 480 g of potassium hydroxide is dissolved in 2000 mL of pure water to obtain an alkaline pure water solution, 400 g of glycyrrhizin monopotassium salt is added to the alkaline pure water solution, heated to 40°C and stirred for 60 min, the pH is adjusted to 7.5 to obtain a solution;

[0057] S2. The solution obtained in step S1 is passed through a mixed resin column (volume of mixed resin 1000 mL) at a flow rate of 0.5 BV / h and a temperature of 25°C, and then 2000 mL of pure water at 25°C is used to flush the mixed resin column, the effluent is combined, the pH is adjusted to 6.5 using a 20 wt% aqueous potassium hydroxide solution, and the solution is concentrated under reduced pressure to 800 mL, and then spray dried at an inlet air temperature of 125°C to obtain glycyrrhizin dipotassium salt; wherein,

[0058] The mixed resin in the mixed resin column is a combination of hydrogen type strong acid cation exchange resin and novel chelating resin A, and the volume ratio of hydrogen type strong acid cation exchange resin and novel chelating resin A is 2:1.

[0059] Example 3

[0060] A preparation method of glycyrrhizin dipotassium salt based on deep removal of heavy metals by chelating resin, comprising the following steps:

[0061] S1. 480 g of potassium hydroxide is dissolved in 2000 mL of pure water to obtain an alkaline pure water solution, 400 g of glycyrrhizin monopotassium salt is added to the alkaline pure water solution, heated to 60°C and stirred for 30 min, the pH is adjusted to 8.5 to obtain a solution;

[0062] S2. The solution obtained in step S1 was passed through a mixed resin column (volume of mixed resin 1000 mL) at a flow rate of 1.5 BV / h and a temperature of 40°C, and the mixed resin column was then rinsed with 2000 mL of pure water at 40°C. The effluent was combined and the pH was adjusted to 6.5 with 20 wt% aqueous potassium hydroxide solution. The solution was concentrated under reduced pressure to 800 mL and spray dried to obtain glycyrrhizin dipotassium salt; wherein,

[0063] The mixed resin in the mixed resin column is a combination of hydrogen type strong acid cation exchange resin and novel chelating resin A, and the volume ratio of hydrogen type strong acid cation exchange resin to novel chelating resin A is 4:1.

[0064] Example 4

[0065] A method for preparing glycyrrhizin dipotassium salt based on deep removal of heavy metals by chelating resin is the same as in Example 1, except that in step S2, an equal amount of novel chelating resin B is used instead of novel chelating resin A.

[0066] Example 5

[0067] A method for preparing glycyrrhizin dipotassium salt based on deep removal of heavy metals by chelating resin is the same as in Example 1, except that in step S2, an equal amount of novel chelating resin C is used instead of novel chelating resin A.

[0068] Example 6

[0069] A method for preparing glycyrrhizin dipotassium salt based on deep removal of heavy metals by chelating resin is the same as in Example 1, except that in step S2, the volume ratio of hydrogen type strong acid cation exchange resin to novel chelating resin A is 1.5:1.

[0070] Comparative Example 1

[0071] A method for preparing glycyrrhizin dipotassium salt based on deep removal of heavy metals by chelating resin is the same as in Example 1, except that in step S2, an equal amount of commercially available chelating resin is used instead of novel chelating resin A.

[0072] Effect evaluation:

[0073] The glycyrrhizin dipotassium salt prepared in Examples 1-6 and Comparative Example 1 above was tested and analyzed, and the specific results are shown in Table 1.

[0074] Performance test:

[0075] (1) The residual ethanol content, i.e. residual alcohol content, was measured by gas chromatography;

[0076] (2) The ammonia ions in the sample were separated and quantitatively analyzed by ion chromatography, and the residual ammonia content was measured.

[0077] (3) The total content of heavy metals (lead, cadmium, arsenic, mercury) was determined according to the method described in the Chinese Pharmacopoeia 2020 edition four general rules 2321.

[0078] Table 1

[0079] No. Residual alcohol mg / kg Residual amine mg / kg Heavy metals mg / kg Example 1 432 32 0.71 Example 2 484 36 0.70 Example 3 426 30 0.78 Example 4 434 32 0.84 Example 5 432 32 0.98 Example 6 438 42 0.69 Comparative Example 1 434 32 1.24

[0080] From the results in Table 1, it can be seen that the residual alcohol content of glycyrrhizin acid dipotassium salt obtained in Examples 1-3 is ≤500 mg / kg, the residual ammonia content is ≤40 mg / kg, the total content of heavy metals (lead, cadmium, arsenic, mercury) is ≤0.8 mg / kg, and the content of lead, cadmium, arsenic and mercury is all ≤0.2 mg / kg.

[0081] Compared with Example 1, in the preparation of the new chelating resin, Example 4 changes the mass ratio of resin 1 and N-aminoethylpiperazine, the amino group is reduced, Example 5 changes the mass ratio of resin 2 and 5-chloro-1,3,4-thiadiazole-2-amine, the thiazole group is reduced, and the synergistic effect is weakened, so that the chelating ability of the resin to heavy metal ions is reduced. In Comparative Example 1, the same amount of commercially available chelating resin is used to replace the new chelating resin A, the chelating group is reduced, and the chelating ability to heavy metal ions is reduced. The above will cause the content of heavy metals in the product to increase.

[0082] Compared with Example 1, Example 6 changes the volume ratio of both cation exchange resin and new chelating resin, although it does not affect the efficient removal of heavy metals, but the content of ammonia exceeds the standard.

[0083] The above is only the preferred embodiment of the present application, and does not limit the application in any form. Although the above application is disclosed as a preferred embodiment, it does not limit the application. Any skilled person in the art can make some changes or modifications to the above disclosed technical content without departing from the scope of the technical solution of the application, and the equivalent embodiments are also equivalent. Any simple modification, equivalent change and modification of the above embodiments according to the technical essence of the present application are still within the scope of the technical solution.

Claims

1. A method for preparing dipotassium glycyrrhizate for deep removal of heavy metals using a chelating resin, characterized in that: The following steps are included: S1. Glycyrrhizic acid monoammonium salt was added to a purified alkaline aqueous solution, stirred, and the pH was adjusted to 7.5 to 8.5 to obtain a solution; S2. Passing the solution obtained in step S1 through a mixed resin column, washing the mixed resin column, combining the effluent, concentrating and drying to obtain dipotassium glycyrrhizate; wherein the mixed resin in the mixed resin column is a combination of a cation exchange resin and a novel chelating resin.

2. The method for preparing dipotassium glycyrrhizate based on deep removal of heavy metals by chelating resin according to claim 1, wherein: The alkaline substance in the alkaline purified aqueous solution in step S1 is potassium hydroxide or potassium carbonate.

3. The method for preparing dipotassium glycyrrhizate based on deep removal of heavy metals by chelating resin according to claim 1, wherein: The stirring temperature in step S1 is 40-60°C.

4. The method for preparing dipotassium glycyrrhizate based on deep removal of heavy metals by chelating resin according to claim 1, wherein: In step S2, the solution passes through the mixed resin column at a flow rate of 0.5 to 1.5 BV / h and a temperature of 25 to 40°C.

5. The method for preparing dipotassium glycyrrhizate based on deep removal of heavy metals by chelating resin according to claim 1, wherein: The cation exchange resin is a hydrogen-type strongly acidic cation exchange resin.

6. The method for preparing dipotassium glycyrrhizate based on deep removal of heavy metals by chelating resin according to claim 1, wherein: The volume ratio of the cation exchange resin to the novel chelating resin is (2-4):

1.

7. The method for preparing dipotassium glycyrrhizate based on deep removal of heavy metals by chelating resin according to claim 1, wherein: The preparation method of the novel chelating resin comprises the following steps: Q1. The aminomethyl polystyrene resin was washed 3-4 times with an ethanol aqueous solution, filtered, removed and placed in N, N-dimethylformamide, sealed, stirred and swelled for 10-15h, and filtered to obtain a pretreated resin; Q2. The pretreated resin obtained in step Q1, methanol and methyl acrylate were mixed and reacted at room temperature for 18-30h, filtered under reduced pressure, extracted with anhydrous ethanol for 7-10h, then washed with an ethanol aqueous solution and dried to obtain resin 1; Q3. The resin 1 obtained in step Q2, methanol, and N-aminoethylpiperazine were mixed and reacted at room temperature for 18-30h, filtered under reduced pressure, washed with aqueous ethanol, and dried to obtain resin 2; Q4. The resin 2 obtained in step Q3, toluene, and 5-chloro-1,3,4-thiadiazole-2-amine are mixed, an inert gas is introduced, a catalyst is added, the mixture is heated to 65-100°C and reacted for 5-8h, washed, and dried to obtain a novel chelating resin.

8. The method for preparing dipotassium glycyrrhizate based on deep removal of heavy metals by chelating resin according to claim 7, wherein: The mass ratio of resin 1 to N-aminoethylpiperazine in step Q3 is 1:(1.6-2.2).

9. The method for preparing dipotassium glycyrrhizate for deep removal of heavy metals based on chelating resin according to claim 7, wherein: The mass ratio of the resin 2 and 5-chloro-1,3,4-thiadiazole-2-amine in step Q4 is 1:(2.2-2.8).

10. The method for preparing dipotassium glycyrrhizate for deep removal of heavy metals based on chelating resin according to any one of claims 1 to 9, characterized in that: The dipotassium glycyrrhizate obtained by the preparation method has a residual alcohol content of ≤500 mg / kg, a residual ammonia content of ≤40 mg / kg, and lead, cadmium, arsenic and mercury contents of ≤0.2 mg / kg.