Preparation method of weakly acidic cation exchange resin and product thereof

Abstract

The invention provides a preparation method of weakly acidic cation exchange resin and a product thereof, which comprises the following steps: dispersing a microsphere matrix in a mixed solvent composed of water and an organic solvent, adding an alkaline solution and an epoxy reagent, and reacting to obtain an epoxy activated microsphere matrix; adding the obtained epoxy activated microsphere matrix into a carboxymethyl polysaccharide aqueous solution, mixing, adding an alkaline solution, sodium borohydride and 4-dimethylaminopyridine, reacting, and carrying out suction filtration and washing to obtain a carboxymethyl polysaccharide grafted microsphere matrix; and adding an alkaline solution and a halogenated acetic acid solution into the carboxymethyl polysaccharide microsphere matrix for reaction, and carrying out suction filtration and washing to finally obtain the weakly acidic cation exchange resin product. On the basis of improving the ion exchange capacity and dynamic combination loading capacity of the weakly acidic cation exchange resin product, the method has the characteristics of simple process and suitability for large-scale production, and water is mainly used as a solvent in the whole process, so that the generation of organic waste liquid is reduced.

Description

Technical Field

[0001] The invention relates to the field of biochemical separation media, and in particular to a preparation method of a weakly acidic cation exchange resin and a product thereof. Background Art

[0002] Ion exchange chromatography (IEC) is a widely used method for separation and purification of biomacromolecules. Ion exchange chromatography is a method of separation and purification achieved by exchanging charged solute molecules with exchangeable ion groups on the chromatographic medium. It can also be considered as a method of separation and purification achieved by the interaction between charged groups in biomacromolecules and the backbone of the chromatographic medium with opposite charges. It mainly relies on the interaction between charges and uses the slight difference in charge in the charged molecules for separation. According to the different types of charges carried by the functional groups of ion exchange, chromatographic media can be divided into two categories: cation exchange resins and anion exchange resins. Among them, cation exchange resins can be further divided into strong acid type and weak acid type according to the strength of the ionization ability of the groups they carry. Among them, strong acid ion exchange resins usually carry sulfonic acid groups, and weak acid cation exchange resins usually carry carboxylic acid groups and phosphate groups.

[0003] Among the weakly acidic cation exchange resins, carboxyl-type cation exchange resins are the most widely used in practice. In the prior art, carboxyl-type cation exchange resins are mainly prepared by free radical polymerization of monomers containing carboxyl groups, or by polymerization of monomers containing acrylate groups and then hydrolysis. The preparation process of the above method is simple, and the prepared weakly acidic cation exchange resin is often used in the field of water treatment. However, since the prepared carboxyl-type cation exchange resin contains a large number of carboxyl groups and unhydrolyzed ester groups, the internal structure of the resin is relatively complex and is not suitable for protein separation and purification. In the prior art, the weakly acidic cation exchange resin used for protein separation and purification is usually prepared by first preparing a microsphere matrix, and then surface modifying and grafting carboxymethyl functional groups on the microsphere matrix. The process of this method is relatively simple, and the obtained product is relatively stable, which is suitable for industrial production, but it is difficult to obtain a high protein adsorption capacity due to the steric hindrance effect.

[0004] In the prior art, grafting long-chain molecules containing functional ligands onto microsphere matrices can improve the protein adsorption capacity of ion exchange resins to a certain extent. Chinese patent CN105126936A discloses a method for preparing a weakly acidic cation chromatographic column filler exchange resin. The method uses styrene-divinylbenzene (PS-DVB) resin microspheres and maleic anhydride to perform surface pre-film physical treatment, and then conducts regular graft polymerization reaction with maleic anhydride to prepare weakly acidic cation chromatographic column filler exchange resin, which improves the ion exchange capacity, but the method is relatively complicated, has many process steps, and requires the use of a large amount of organic solvents, which is not suitable for industrial production. Chinese patent CN114989359A discloses a cation exchange chromatography medium and a method for preparing the same. The method uses 4-acryloylmorpholine and 2-acrylamido-2-methyl-N-propanesulfonic acid as surface grafting monomers, cerium sulfate as an initiator, and a grafting reaction is performed on the surface of the matrix to prepare a sulfonic acid cation exchange chromatography medium. The cation exchange chromatography medium prepared by this method has a high loading capacity, but the free radical polymerization reaction in this method is difficult to control, and the grafted monomer contains secondary amines and tertiary amines, which makes the surface charge of the cation exchange chromatography medium more complex, affecting the purification effect. Summary of the invention

[0005] Purpose of the invention: The first purpose of the present invention is to provide a method for preparing a weakly acidic cation exchange resin with a simple process and suitable for industrial production. The second purpose is to provide a weakly acidic cation exchange resin product with a high protein loading amount prepared by the method.

[0006] Technical solution: A method for preparing a weakly acidic cation exchange resin comprises the following steps:

[0007] (1) dispersing the microsphere matrix in a mixed solvent consisting of water and an organic solvent, adding an alkaline solution and an epoxy reagent, and reacting to obtain an epoxy-activated microsphere matrix;

[0008] (2) mixing the epoxy-activated microsphere matrix obtained in step (1) with a carboxymethyl polysaccharide aqueous solution, then adding an alkaline solution, sodium borohydride (NaBH4) and 4-dimethylaminopyridine (DMAP), and filtering and washing after the reaction to obtain a carboxymethyl polysaccharide-grafted microsphere matrix;

[0009] (3) adding the carboxymethyl polysaccharide grafted microsphere matrix obtained in step (2) into an alkaline solution, then dropping a halogenated acetic acid solution to react, and filtering and washing to obtain a weakly acidic cation exchange resin.

[0010] Specifically, in step (1), the microsphere matrix is ​​a hydrophilic microsphere, and the hydrophilic microsphere is one or more of agarose microspheres, dextran microspheres, chitosan microspheres, konjac microspheres, cellulose microspheres, epoxy-hydrolyzed poly(methyl methacrylate) glycidyl ester microspheres, hydrophilically modified polystyrene-divinylbenzene microspheres or polyvinyl alcohol microspheres.

[0011] Specifically, in step (1), the organic solvent is one or more of 1,4-dioxane, dimethyl sulfoxide, and acetone, and the proportion of the organic solvent in the mixed solvent is 20% to 50%.

[0012] Specifically, the alkaline solution is one or more of a NaOH solution and a KOH solution.

[0013] Specifically, in step (1), the concentration of the alkaline solution is 3 to 7 mol / L; in step (3), the concentration of the alkaline solution is 1 to 3 mol / L.

[0014] Specifically, the epoxy agent is one or more of epichlorohydrin, ethylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, 1,2-cyclohexanediol diglycidyl ether, di(2-epoxypropyl) ether, dipropylene glycol diglycidyl ether, glycerol triglycidyl ether, and pentaerythritol tetraglycidyl ether.

[0015] Specifically, in step (2), the carboxymethyl polysaccharide is one or more of carboxymethyl dextran, carboxymethyl cellulose, and carboxymethyl carboxychitosan; and the concentration of the carboxymethyl polysaccharide aqueous solution is 0.05 to 0.2 g / mL.

[0016] Specifically, the halogenated acetic acid is one or more of chloroacetic acid and bromoacetic acid, and the concentration of the halogenated acetic acid is 1 to 5 mol / L.

[0017] The invention also provides a weakly acidic cation exchange resin prepared by the method.

[0018] Beneficial effects: Compared with the prior art, the present invention has the following significant effects:

[0019] 1. The present invention reduces the steric hindrance effect on the surface of the microsphere matrix by grafting a long-chain molecule of carboxymethyl polysaccharide onto the microsphere matrix, which is beneficial to the adsorption of proteins, thereby obtaining a higher dynamic binding capacity of proteins.

[0020] 2. The process of the present invention is simple and suitable for large-scale production. In addition, water is mainly used as a solvent in the entire process, thereby reducing the generation of organic waste liquid.

[0021] 3. The present invention utilizes epoxy reagent to modify the microsphere matrix, so that the microspheres are grafted with epoxy groups for subsequent reactions, and then carboxymethyl polysaccharides are grafted through the epoxy groups. Compared with the traditional method of using free radical polymerization to graft polymer chains on the surface of microspheres, the present invention avoids the toxicity problem of free radical initiators, and the reaction process is easier to control than the free radical polymerization process.

[0022] 4. After carboxymethyl polysaccharide is grafted onto the microsphere matrix, the present invention further modifies the microsphere matrix using halogenated acetic acid. As a small molecule, halogenated acetic acid can react inside and on the surface of the microsphere matrix, so that the microsphere matrix can be grafted with more carboxymethyl groups, thereby increasing the ion exchange capacity of the weakly acidic cation exchange resin. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is a schematic diagram of the chemical structure of the weakly acidic cation exchange resin prepared in Example 5. DETAILED DESCRIPTION

[0024] The technical solution of the present invention is further described below in conjunction with preferred embodiments.

[0025] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; the reagents, materials, etc. used in the following examples, unless otherwise specified, can be obtained from commercial channels.

[0026] Example 1

[0027] (1) Add 5 mL of deionized water and 5 mL of 1,4-dioxane to a reaction bottle, then add 10 mL of PGMA microspheres (epoxy hydrolyzed poly(glycidyl methacrylate) purchased from Suzhou Saifen Technology Co., Ltd.) and 4 mL of 5 mol / L NaOH solution, control the system temperature to 30 °C, add 10 mL of epichlorohydrin, and stir for 6 h. After the reaction is completed, filter and wash with 20 mL of ethanol and 40 mL of deionized water in turn, and then filter to remove water to obtain epoxy-activated PGMA microspheres.

[0028] (2) 10 mL of the epoxy-activated PGMA microspheres obtained in step (1) and 10 mL of a 0.2 g / mL carboxymethyl dextran aqueous solution were added to a reaction flask, the system temperature was controlled to 30°C, and the mixture was stirred for 3 h. Subsequently, 1 mL of a 10 mol / L NaOH solution, 0.05 g of NaBH4, and 0.02 g of DMAP were added, and the mixture was stirred for 18 h. After the reaction was completed, the mixture was filtered and washed with 50 mL of deionized water to obtain carboxymethyl dextran-grafted PGMA microspheres.

[0029] (3) 10 mL of the carboxymethyl dextran grafted PGMA microspheres obtained in step (2) and 60 mL of 3 mol / L NaOH solution were added to the reaction bottle, the system temperature was controlled to 25°C, and then 20 mL of 3 mol / L chloroacetic acid aqueous solution was added. After the addition was completed, the temperature was raised to 60°C and the stirring reaction was continued for 4 hours. After the reaction was completed, the mixture was filtered and washed with 80 mL of deionized water until neutral to obtain a weakly acidic cation exchange resin.

[0030] Example 2

[0031] (1) 8 mL of deionized water and 2 mL of dimethyl sulfoxide were added to the reaction bottle, followed by 10 mL of PGMA microspheres (epoxy hydrolyzed poly(glycidyl methacrylate) purchased from Suzhou Saifen Technology Co., Ltd.) and 4 mL of 7 mol / L NaOH solution. The system temperature was controlled at 30 °C, and 10 mL of epichlorohydrin was added and stirred for 6 h. After the reaction was completed, the mixture was filtered and washed with 20 mL of ethanol and 40 mL of deionized water in turn, and then filtered to remove water to obtain epoxy-activated PGMA microspheres.

[0032] (2) 10 mL of the epoxy-activated PGMA microspheres obtained in step (1) and 10 mL of a 0.05 g / mL carboxymethyl dextran aqueous solution were added to a reaction flask, the system temperature was controlled to 30°C, and the mixture was stirred for 3 h. Subsequently, 1 mL of a 10 mol / L KOH solution, 0.05 g of NaBH4, and 0.02 g of DMAP were added, and the mixture was stirred for 18 h. After the reaction was completed, the mixture was filtered and washed with 50 mL of deionized water to obtain carboxymethyl dextran-grafted PGMA microspheres.

[0033] (3) 10 mL of the carboxymethyl dextran grafted PGMA microspheres obtained in step (2) and 60 mL of 1 mol / L KOH solution were added to the reaction bottle, the system temperature was controlled to 25°C, and then 20 mL of 5 mol / L chloroacetic acid aqueous solution was added. After the addition was completed, the temperature was raised to 60°C and the reaction was continued with stirring for 4 hours. After the reaction was completed, the mixture was filtered and washed with 80 mL of deionized water until neutral to obtain a weakly acidic cation exchange resin.

[0034] Example 3

[0035] (1) Add 5 mL of deionized water and 5 mL of dimethyl sulfoxide to a reaction bottle, then add 10 mL of PGMA microspheres (epoxy-hydrolyzed poly(glycidyl methacrylate), purchased from Suzhou Saifen Technology Co., Ltd.), 4 mL of 3 mol / L KOH solution, control the system temperature to 30 °C, add 10 mL of glycerol triglycidyl ether, and stir for 6 h. After the reaction is completed, filter and wash with 20 mL of ethanol and 40 mL of deionized water in turn, and then filter and remove water to obtain epoxy-activated PGMA microspheres.

[0036] (2) 10 mL of the epoxy-activated PGMA microspheres obtained in step (1) and 10 mL of a 0.10 g / mL carboxymethyl cellulose aqueous solution were added to a reaction flask, the system temperature was controlled at 30° C., and the mixture was stirred for 3 h. Subsequently, 1 mL of a 10 mol / L NaOH solution, 0.05 g of NaBH4, and 0.02 g of DMAP were added, and the mixture was stirred for 18 h. After the reaction was completed, the mixture was filtered and washed with 50 mL of deionized water to obtain carboxymethyl cellulose-grafted PGMA microspheres.

[0037] (3) 10 mL of the carboxymethyl cellulose grafted PGMA microspheres obtained in step (2) and 60 mL of 2 mol / L NaOH solution were added to the reaction bottle, the system temperature was controlled to 25° C., and then 20 mL of 1 mol / L bromoacetic acid aqueous solution was added. After the addition was complete, the temperature was raised to 60° C. and the reaction was continued with stirring for 4 h. After the reaction was completed, the mixture was filtered and washed with 80 mL of deionized water until neutral to obtain a weakly acidic cation exchange resin.

[0038] Example 4

[0039] (1) 8 mL of deionized water and 2 mL of 1,4-dioxane were added to the reaction bottle, followed by 10 mL of PGMA microspheres (epoxy hydrolyzed poly(glycidyl methacrylate) purchased from Suzhou Saifen Technology Co., Ltd.) and 4 mL of 5 mol / L NaOH solution. The system temperature was controlled at 30 °C, and 10 mL of 1,4-butanediol diglycidyl ether was added and stirred for 6 h. After the reaction was completed, the mixture was filtered and washed with 20 mL of ethanol and 40 mL of deionized water in turn, and then filtered to remove water to obtain epoxy-activated PGMA microspheres.

[0040] (2) 10 mL of the epoxy-activated PGMA microspheres obtained in step (1) and 10 mL of a 0.10 g / mL carboxymethyl chitosan aqueous solution were added to a reaction flask, the system temperature was controlled to 30°C, and stirred for 3 h, followed by the addition of 1 mL of a 10 mol / L NaOH solution, 0.05 g of NaBH4, and 0.02 g of DMAP, and continued stirring for 18 h. After the reaction was completed, the mixture was filtered and washed with 50 mL of deionized water to obtain carboxymethyl chitosan-grafted PGMA microspheres.

[0041] (3) 10 mL of the carboxymethyl chitosan grafted PGMA microspheres obtained in step (2) and 60 mL of 3 mol / L NaOH solution were added to the reaction bottle, the system temperature was controlled to 25°C, and then 20 mL of 1 mol / L bromoacetic acid aqueous solution was added. After the addition was completed, the temperature was raised to 60°C and the reaction was continued with stirring for 4 hours. After the reaction was completed, the mixture was filtered and washed with 80 mL of deionized water until neutral to obtain a weakly acidic cation exchange resin.

[0042] Example 5

[0043] The difference between this embodiment and embodiment 1 is that the microsphere matrix is ​​replaced by agarose microspheres (secondary cross-linked agarose microspheres purchased from Suzhou Saifen Technology Co., Ltd.) instead of PGMA microspheres, and the other experimental conditions and process flow are kept the same to prepare a weakly acidic cation exchange resin, whose chemical structure is as follows: Figure 1 shown.

[0044] The secondary cross-linked agarose microspheres have a high degree of cross-linking and are semi-rigid matrices. The surface of agarose microspheres has a large number of natural hydroxyl groups, which are extremely hydrophilic and have very low non-specific binding to impurities.

[0045] Example 6

[0046] The only difference between this embodiment and embodiment 3 is that the microsphere matrix is ​​replaced by agarose microspheres (secondary cross-linked agarose microspheres purchased from Suzhou Saifen Technology Co., Ltd.) instead of PGMA microspheres, and the other experimental conditions and process flow remain the same to prepare a weakly acidic cation exchange resin.

[0047] To further demonstrate the improvement effect of the present invention, the following is an explanation in combination with comparative examples and performance tests.

[0048] Comparative Example 1

[0049] The difference between this comparative example and Example 1 is that the carboxymethyl dextran grafted PGMA microspheres obtained in step (2) are used as the final product of the weakly acidic cation exchange resin, and step (3) is no longer performed. The other experimental conditions and process flow remain the same, and a weakly acidic cation exchange resin is obtained.

[0050] Comparative Example 2

[0051] 10mL PGMA microspheres (epoxy hydrolyzed polymethacrylate glycidyl ester, purchased from Suzhou Saifen Technology Co., Ltd.) and 60mL 2mol / L NaOH solution were added to the reaction bottle, the system temperature was controlled to 25°C, and then 20mL 5mol / L chloroacetic acid aqueous solution was added. After the addition was complete, the temperature was raised to 60°C and the reaction was continued for 4h. After the reaction was completed, the mixture was filtered and washed with 80mL deionized water until neutral to obtain carboxymethylated PGMA microspheres as the final product of the weakly acidic cation exchange resin of this comparative example.

[0052] The difference between this comparative example and Example 1 is that the surface of the microsphere matrix is ​​not grafted with carboxymethyl polysaccharide, but is directly modified with chloroacetic acid, and the chloroacetic acid can react with the hydroxyl groups on the surface of the microsphere matrix to obtain a carboxymethylated microsphere matrix.

[0053] Comparative Example 3

[0054] The only difference between this comparative example and comparative example 2 is that the microsphere matrix is ​​replaced by agarose microspheres (secondary cross-linked agarose microspheres, purchased from Suzhou Saifen Technology Co., Ltd.) instead of PGMA microspheres, and the other experimental conditions and process flow remain the same to prepare a weakly acidic cation exchange resin.

[0055] The weakly acidic cation exchange resins prepared in Examples 1 to 6 and Comparative Examples 1 to 3 were subjected to performance tests, including two tests, namely, ion exchange capacity and dynamic binding capacity.

[0056] 1. Determination of ion exchange capacity

[0057] Take 5mL of weakly acidic cation exchange resin sample and add it to 50mL of 0.1mol / L HCl solution and mix it evenly. Then stir the obtained mixture at 170rpm for 30min at 25℃. Remove the supernatant from the obtained sample by centrifugation to obtain the weakly acidic cation exchange resin sample again. This completes one operation. Repeat the above steps for the weakly acidic cation exchange resin sample obtained after one operation to complete two operations. After completing two operations, wash the weakly acidic cation exchange resin sample with distilled water until the pH value of the washing solution becomes neutral. Add the washed weakly acidic cation exchange resin sample to 25mL of 0.25mol / L NaOH solution and stir it at 170rpm for 3h at 25℃. Take 5mL of the supernatant of the obtained sample and titrate it with 0.01mol / L HCl solution. Use methyl orange as an indicator. The titration end point is determined by the color of the indicator changing from yellow to orange. The ion exchange capacity of the weakly acidic cation exchange resin sample is obtained by the titration experiment. The calculation formula is as follows:

[0058] C=(6.25-0.05V HCl ) / V

[0059] Where: C is the ion exchange capacity, unit is mol / L, V HCl is the volume of HCl solution used in titration, and V is the volume of the weakly acidic cation exchange resin sample used for determination.

[0060] 2. Determination of dynamic binding capacity

[0061] The instrument model used in this test is the SCG-030 protein chromatography system. The prepared weakly acidic cation exchange resin is loaded into the chromatographic column. Lysozyme is used as the test sample. The lysozyme sample volume corresponding to the volume at 10% flow-through is taken as the dynamic loading capacity of the chromatographic column. The specific experimental parameters are as follows:

[0062] Eluent: 50 mM PB, pH = 6.0;

[0063] Eluent: 50 mM PB + 1 M NaCl, pH = 6.0;

[0064] Loading solution: 50mM PB + 1mg / mL Lysozyme;

[0065] Chromatographic column: 4.6×50mm;

[0066] Loading flow rate: 1 mL / min.

[0067] The ion exchange capacity and dynamic binding capacity of the weakly acidic cation exchange resins prepared in Examples 1 to 6 and Comparative Examples 1 to 3 were tested, respectively. The test results are shown in Table 1 below.

[0068] Table 1

[0069] sample Ion exchange capacity (mol / L) Dynamic binding capacity (mg / mL) Example 1 0.18 131 Example 2 0.14 95 Example 3 0.18 115 Example 4 0.16 100 Example 5 0.21 164 Example 6 0.19 120 Comparative Example 1 0.12 89 Comparative Example 2 0.09 50 Comparative Example 3 0.10 68

[0070] It can be seen from the test results that among all the test samples, the weakly acidic cation exchange resin prepared in Example 5 has the highest ion exchange capacity and dynamic binding load, and is the optimal implementation mode; the ion exchange capacity of the weakly acidic cation exchange resins prepared in Examples 1 to 6 is greater than 0.14 mol / L, and the dynamic adsorption load of lysozyme is greater than or equal to 95 mg / mL, which is higher than all comparative examples.

[0071] The examples were compared separately. The test results of Example 1 were better than those of Example 2, indicating that the proportion of organic solvents, alkali concentration and the concentration of carboxymethyl polysaccharide have a great influence on the final product performance. The test results of Example 1 were better than those of Example 3 and Example 4, indicating that the effect of carboxymethyl dextran as a grafting group was better than that of carboxymethyl cellulose and carboxymethyl chitosan. The test results of Example 5 were the best, and the test results of Example 6 were better than those of Example 3, indicating that agarose microspheres as microsphere matrix were better than epoxide hydrolyzed PGMA microspheres.

[0072] Comparing the performance test results of Comparative Example 1 with Example 1, it is further confirmed that the haloacetic acid can modify the microsphere matrix. From the reaction mechanism, the haloacetic acid can react as a small molecule inside and on the surface of the microsphere matrix, so that the microsphere matrix can be grafted with more carboxymethyl groups, thereby increasing the ion exchange capacity and dynamic loading capacity of the weakly acidic cation exchange resin. Comparing the performance test results of Comparative Example 2 with Example 1, it is further confirmed that the carboxymethyl polysaccharide reduces the steric effect on the surface of the microsphere matrix, which is conducive to the adsorption of proteins, thereby increasing the ion exchange capacity and the dynamic binding capacity of proteins. Comparing the performance test results of Comparative Example 3 with Comparative Example 2, it is further confirmed that agarose microspheres are superior to hydrophilically modified PGMA microspheres as microsphere matrix.

Claims

1. A method for preparing a weakly acidic cation exchange resin, characterized in that: The following steps are involved: (1) dispersing the microsphere matrix in a mixed solvent consisting of water and an organic solvent, adding an alkaline solution and an epoxy reagent, and reacting to obtain an epoxy-activated microsphere matrix; (2) mixing the epoxy-activated microsphere matrix obtained in step (1) with a carboxymethyl polysaccharide aqueous solution, then adding an alkaline solution, sodium borohydride and 4-dimethylaminopyridine, and filtering and washing after the reaction to obtain a carboxymethyl polysaccharide-grafted microsphere matrix; (3) adding the carboxymethyl polysaccharide grafted microsphere matrix obtained in step (2) into an alkaline solution, then dropping a halogenated acetic acid solution to react, and filtering and washing to obtain a weakly acidic cation exchange resin.

2. The method for preparing a weakly acidic cation exchange resin according to claim 1, wherein: In step (1), the microsphere matrix is ​​a hydrophilic microsphere.

3. The method for preparing a weakly acidic cation exchange resin according to claim 2, wherein: The hydrophilic microspheres are one or more of agarose microspheres, dextran microspheres, chitosan microspheres, konjac microspheres, cellulose microspheres, epoxy-hydrolyzed poly(methacrylic glycidyl) ester microspheres, hydrophilically modified polystyrene-divinylbenzene microspheres or polyvinyl alcohol microspheres.

4. The method for preparing a weakly acidic cation exchange resin according to claim 1, wherein: The organic solvent is one or more of 1,4-dioxane, dimethyl sulfoxide, and acetone, and the volume proportion of the organic solvent in the mixed solvent is 20% to 50%.

5. The method for preparing a weakly acidic cation exchange resin according to claim 1, wherein: The alkaline solution is one or more of a NaOH solution and a KOH solution.

6. The method for preparing a weakly acidic cation exchange resin according to claim 1, wherein: In step (1), the concentration of the alkaline solution is 3 to 7 mol / L; in step (3), the concentration of the alkaline solution is 1 to 3 mol / L.

7. The method for preparing a weakly acidic cation exchange resin according to claim 1, wherein: The epoxy reagent is one or more of epichlorohydrin, ethylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, 1,2-cyclohexanediol diglycidyl ether, di(2-epoxypropyl) ether, dipropylene glycol diglycidyl ether, glycerol triglycidyl ether, and pentaerythritol tetraglycidyl ether.

8. The method for preparing a weakly acidic cation exchange resin according to claim 1, wherein: In step (2), the carboxymethyl polysaccharide is one or more of carboxymethyl dextran, carboxymethyl cellulose, and carboxymethyl carboxychitosan, and the concentration of the carboxymethyl polysaccharide aqueous solution is 0.05-0.2 g / mL.

9. The method for preparing a weakly acidic cation exchange resin according to claim 1, wherein: The halogenated acetic acid is one or more of chloroacetic acid and bromoacetic acid, and the concentration of the halogenated acetic acid is 1-5 mol / L.

10. A weakly acidic cation exchange resin prepared by the method according to any one of claims 1 to 9.

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