Modified polystyrene resin as well as preparation method and application thereof

Abstract

The invention discloses modified polystyrene resin as well as a preparation method and application thereof, and belongs to the technical field of medicine purification. The modified polystyrene resin contains phenolic hydroxyl groups and sulfonic acid groups at the same time, electrostatic interaction and hydrogen-bond interaction can be generated on pyridine, the two actions are complementary, and pyridine molecules in different protonation states can be captured; moreover, a benzene ring of the modified polystyrene resin can be combined with an aromatic ring of pyridine through pi-pi stacking, and the introduction of a sulfonic acid group and a phenolic hydroxyl group further polarizes an electron cloud of the benzene ring of polystyrene, so that the conjugation effect can be enhanced, and the bonding strength of the benzene ring and the aromatic ring of pyridine is improved. The modified polystyrene resin prepared by the method has nanoscale pores and ultrahigh specific surface area, can form a'pore capture-group immobilization 'synergistic path when pyridine is adsorbed, and can effectively remove residual pyridine in a reaction system.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug purification, and particularly relates to a modified polystyrene resin, a preparation method thereof and an application thereof. Background Art

[0002] Diosmin is a natural flavonoid with venous affinity. This drug can rapidly relieve symptoms during acute hemorrhoid attacks, can relieve symptoms in patients with chronic hemorrhoids, can prevent the recurrence of acute hemorrhoids, and can significantly reduce bleeding after hemorrhoid resection. It can also be used for chronic venous insufficiency, such as varicose veins, leg ulcers, etc.

[0003] Since the content of diosmin in natural plants is very low, diosmin is now chemically synthesized from hesperidin extracted from Fructus Aurantii Immaturus. The current production process generally uses hesperidin as the raw material, pyridine as the solvent, and iodine for heating dehydrogenation reaction, followed by vacuum concentration. The crude product obtained after adding water and filtering is then subjected to refined purification treatment to remove the residual pyridine in diosmin so that it meets the requirement of ≤200 ppm in the pharmacopoeia. The refined purification operation is as follows:

[0004] The crude product is dissolved in water and sodium hydroxide, and then hydrochloric acid is added for crystallization and filtration. The purpose of this step is to change the crystal form of the crude product to facilitate the treatment in the next step, and at the same time, a part of pyridine can be removed;

[0005] The filtered crystals are added with water and sodium carbonate, heated and stirred for a certain time and then filtered. Most of the pyridine is removed by utilizing the property that pyridine is soluble in sodium carbonate solution while diosmin is insoluble;

[0006] The filtered crystals are dissolved in water and sodium hydroxide, finely filtered, and then hydrochloric acid is added for crystallization and filtration;

[0007] The filtered crystals are dried, pulverized and sieved to obtain diosmin.

[0008] The pyridine residue in this kind of operation is 30 - 150 ppm, which can meet the requirement of ≤200 ppm, but the production steps are numerous, the operation is cumbersome, and a large amount of time, water, electricity and steam energy are consumed. Therefore, it is necessary to develop a method for rapidly removing the pyridine residue in diosmin. Summary of the Invention

[0009] In view of the above-mentioned prior art, the present invention provides a modified polystyrene resin, a preparation method thereof and an application thereof to solve the technical problem of difficult removal of pyridine in the existing diosmin.

[0010] In order to achieve the above object, the technical solution adopted by the present invention is to provide a preparation method of a modified polystyrene resin, comprising the following steps:

[0011] S1: Pretreat the polystyrene chloride beads to obtain pretreated polystyrene chloride beads;

[0012] S2: Immerse the pretreated polystyrene chloride beads in 1,2 - dichloroethane, let it stand at room temperature for swelling for 6 - 10 h, then add phenol and iron salt, mix well and reflux at 55 - 65 °C for 16 - 24 h. Collect the product, wash and dry it to obtain Intermediate One.

[0013] S3: Immerse Intermediate One in 1,2 - dichloroethane, let it stand at room temperature for swelling for 6 - 10 h, then add methylal and iron salt, mix well and reflux at 90 - 100 °C for 16 - 24 h. Collect the product, wash and dry it to obtain Intermediate Two.

[0014] S4: Immerse Intermediate Two in 1,2 - dichloroethane, let it stand at 40 - 50 °C for swelling for 4 - 6 h; then add concentrated sulfuric acid, stir and react at 30 - 40 °C for 6 - 8 h. Collect the product, wash and dry it to obtain the product.

[0015] Based on the above - mentioned technical solution, the present invention can be further improved as follows.

[0016] Further, the pretreatment method of the polystyrene chloride beads is: Use 95% ethanol solution as the extraction reagent to perform Soxhlet extraction on the polystyrene chloride beads for 6 h, then air - dry naturally, and then dry at 50 °C to constant weight.

[0017] Further, the iron salt is ferric chloride.

[0018] Further, in S2, the swelling time is 8 h; the mass ratio of the added phenol, iron salt to the pretreated polystyrene chloride beads is 15:8:20; the reflux reaction temperature is 60 °C, and the reflux reaction time is 18 h.

[0019] Further, in S3, the swelling time is 8 h; the mass ratio of the added methylal, iron salt to Intermediate One is 22:8:35; the reflux reaction temperature is 95 °C, and the reflux reaction time is 18 h.

[0020] Further, the method of washing and drying the product in S2 and S3 is: Disperse the collected product in hydrochloric acid - acetone solution, stir for 6 h, then extract with anhydrous ethanol for 8 h, then wash with water until there is no ethanol smell, and then dry at 40 °C to constant weight.

[0021] Further, the volume concentration of the concentrated sulfuric acid is 98%; the liquid - to - solid ratio of the added concentrated sulfuric acid to Intermediate Two is 30 mL:1 g.

[0022] The present invention discloses a modified polystyrene resin, which is prepared by the above - mentioned preparation method.

[0023] The present invention also discloses the application of the above-mentioned modified polystyrene resin, specifically using the modified polystyrene resin to prepare high-purity diosmin.

[0024] Furthermore, the preparation of high-purity diosmin includes the following steps:

[0025] (1) Mix hesperidin, pyridine and iodine in a ratio of 1 g: 5 - 8 mL: 4 - 6 g, stir and react at 80 - 100 °C for 8 - 16 h, and then concentrate under reduced pressure until the volume no longer changes;

[0026] (2) Disperse the concentrate obtained in step (1) in water, stir for 10 - 20 min, and then filter to obtain the crude product; then dissolve the crude product in a sodium hydroxide solution with a concentration of 10 - 15 wt% to obtain the liquid to be treated;

[0027] (3) Load 100 g of the modified polystyrene resin into a chromatography column to obtain an adsorption column;

[0028] (4) Load the liquid to be treated into the adsorption column, flow out at a speed of 1 BV, collect the effluent and filter it precisely; then adjust the pH value of the precise filtrate to 6 and crystallize at room temperature; then filter, wash with water and dry to obtain the product.

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

[0030] 1. When preparing the modified polystyrene resin in the present invention, phenolic hydroxyl groups are first introduced into polystyrene. When purifying the crude diosmin product, the introduced phenolic hydroxyl groups can combine with the nitrogen atoms of pyridine through hydrogen bonds, thereby "capturing" and fixing pyridine, and effectively removing pyridine in the diosmin preparation system.

[0031] 2. The modified polystyrene resin in the present invention is further sulfonated after introducing phenolic hydroxyl groups. Sulfonation can introduce sulfonic acid groups into the polystyrene resin. The sulfonic acid group (-SO 3 H) has strong acidity, and after dissociation, it generates a negatively charged sulfonate (-SO 3 - ). Under acidic conditions (pH < 7), it can electrostatically adsorb protonated pyridine (the cation formed by the combination of pyridine nitrogen atoms and H + ) to achieve the purpose of fixing and removing pyridine.

[0032] 3. The modified polystyrene resin of the present invention contains both phenolic hydroxyl groups and sulfonic acid groups, wherein the sulfonic acid groups can generate electrostatic interactions with protonated pyridine, and the phenolic hydroxyl groups can generate hydrogen bonds with non-protonated pyridine. The electrostatic interactions and hydrogen bonds complement each other and can capture pyridine molecules in different protonation states. Moreover, the benzene ring of the modified polystyrene resin can be combined with the aromatic ring of pyridine through π-π stacking, and the introduction of sulfonic acid groups and phenolic hydroxyl groups further polarizes the electron cloud of the polystyrene benzene ring, which can strengthen the conjugation effect and enhance the bonding strength between the benzene ring and the aromatic ring of pyridine.

[0033] 4. The modified polystyrene resin prepared by the present invention has nanoscale pores and ultra-high specific surface area, providing diffusion channels and physical adsorption sites for pyridine molecules; the sulfonic acid group and phenolic hydroxyl group anchor the pyridine molecules through chemical reactions; that is, when the modified polystyrene in the present invention adsorbs pyridine, it can form a synergistic path of "pore capture-group fixation", which can effectively remove residual pyridine in the reaction system. DETAILED DESCRIPTION

[0034] The specific implementation modes of the present invention are described in detail below with reference to the embodiments.

[0035] Embodiment 1:

[0036] A modified polystyrene resin is prepared by the following steps:

[0037] S1: Put polystyrene chloride balls (Qiyue Biotechnology) into a small cloth bag, and put the small cloth bag into a Soxhlet extractor; extract in 95% (v / v) ethanol solution for 6 hours. After the extraction, take out the resin in the bag and air dry it for two hours, then transfer it to a vacuum drying oven and dry it at 50°C until the weight remains unchanged, thereby obtaining pretreated polystyrene chloride balls;

[0038] S2: Immerse the pretreated polystyrene chloride ball in 1,2-dichloroethane, let it stand at room temperature to swell for 8 hours, then add phenol and ferric chloride, the mass ratio of the added phenol and ferric chloride to the pretreated polystyrene chloride ball is 15:8:20; stir well and reflux at 60°C for 18 hours, collect the product, disperse the collected product in a hydrochloric acid acetone solution, stir for 6 hours, then extract with anhydrous ethanol for 8 hours, wash with water until there is no ethanol smell, and then dry at 40°C to constant weight to obtain intermediate 1;

[0039] S3: Immerse the intermediate 1 in 1,2-dichloroethane, let it stand at room temperature to swell for 8 hours, then add methylal and ferric chloride, the mass ratio of the added methylal and ferric chloride to the intermediate 1 is 22:8:35; mix well and reflux at 95°C for 18 hours, collect the product, disperse the collected product in a hydrochloric acid acetone solution, stir for 6 hours, then extract with anhydrous ethanol for 8 hours, wash with water until there is no ethanol smell, and then dry at 40°C to constant weight to obtain intermediate 2;

[0040] S4: Immerse the intermediate 2 in 1,2-dichloroethane and allow to swell at 45°C for 5 hours; then add concentrated sulfuric acid with a volume concentration of 98%, and the liquid-to-solid ratio of the added concentrated sulfuric acid to the intermediate 2 is 30mL:1g; stir the reaction at 35°C for 7 hours, collect the product, wash the product with a concentrated sulfuric acid-ethanol mixed solution (1:1), and then gradually reduce the volume ratio of concentrated sulfuric acid to ethanol for gradient washing; finally wash with distilled water until neutral, extract with ethanol for 8 hours, and then dry at 40°C to constant weight to obtain modified polystyrene resin.

[0041] Embodiment 2:

[0042] A modified polystyrene resin is prepared by the following steps:

[0043] S1: Put polystyrene chloride balls (Qiyue Biotechnology) into a small cloth bag, and put the small cloth bag into a Soxhlet extractor; extract in 95% (v / v) ethanol solution for 6 hours. After the extraction, take out the resin in the bag and air dry it for two hours, then transfer it to a vacuum drying oven and dry it at 50°C until the weight remains unchanged, thereby obtaining pretreated polystyrene chloride balls;

[0044] S2: Immerse the pretreated polystyrene chloride ball in 1,2-dichloroethane, let it stand at room temperature for 6 hours to swell, then add phenol and ferric chloride, the mass ratio of the added phenol and ferric chloride to the pretreated polystyrene chloride ball is 15:8:20; mix well and reflux at 55°C for 24 hours, collect the product, disperse the collected product in a hydrochloric acid acetone solution, stir for 6 hours, then extract with anhydrous ethanol for 8 hours, wash with water until there is no ethanol smell, and then dry at 40°C to constant weight to obtain intermediate 1;

[0045] S3: Immerse the intermediate 1 in 1,2-dichloroethane, let it stand at room temperature to swell for 6 hours, then add methylal and ferric chloride, the mass ratio of the added methylal and ferric chloride to the intermediate 1 is 22:8:35; mix well and reflux at 90°C for 24 hours, collect the product, disperse the collected product in a hydrochloric acid acetone solution, stir for 6 hours, then extract with anhydrous ethanol for 8 hours, wash with water until there is no ethanol smell, and then dry at 40°C to constant weight to obtain intermediate 2;

[0046] S4: Immerse the intermediate 2 in 1,2-dichloroethane and allow to swell at 40°C for 6 hours; then add concentrated sulfuric acid with a volume concentration of 98%, and the liquid-to-solid ratio of the added concentrated sulfuric acid to the intermediate 2 is 30mL:1g; stir the reaction at 30°C for 8 hours, collect the product, wash the product with a concentrated sulfuric acid-ethanol mixed solution (1:1), and then gradually reduce the volume ratio of concentrated sulfuric acid to ethanol for gradient washing; finally wash with distilled water until neutral, extract with ethanol for 8 hours, and then dry at 40°C to constant weight to obtain the modified polystyrene resin.

[0047] Embodiment 3:

[0048] A modified polystyrene resin is prepared by the following steps:

[0049] S1: Put polystyrene chloride balls (Qiyue Biotechnology) into a small cloth bag, and put the small cloth bag into a Soxhlet extractor; extract in 95% (v / v) ethanol solution for 6 hours. After the extraction, take out the resin in the bag and air dry it for two hours, then transfer it to a vacuum drying oven and dry it at 50°C until the weight remains unchanged, thereby obtaining pretreated polystyrene chloride balls;

[0050] S2: Immerse the pretreated polystyrene chloride balls in 1,2-dichloroethane, let it stand at room temperature to swell for 10 hours, then add phenol and ferric chloride, the mass ratio of the added phenol and ferric chloride to the pretreated polystyrene chloride balls is 15:8:20; mix well and reflux at 65°C for 16 hours, collect the product, disperse the collected product in a hydrochloric acid acetone solution, stir for 6 hours, then extract with anhydrous ethanol for 8 hours, wash with water until there is no ethanol smell, and then dry at 40°C to constant weight to obtain intermediate 1;

[0051] S3: Immerse the intermediate 1 in 1,2-dichloroethane, let it stand at room temperature to swell for 10 hours, then add methylal and ferric chloride, the mass ratio of the added methylal and ferric chloride to the intermediate 1 is 22:8:35; mix well and reflux at 100°C for 16 hours, collect the product, disperse the collected product in a hydrochloric acid acetone solution, stir for 6 hours, then extract with anhydrous ethanol for 8 hours, wash with water until there is no ethanol smell, and then dry at 40°C to constant weight to obtain intermediate 2;

[0052] S4: Immerse the intermediate 2 in 1,2-dichloroethane and allow to swell at 50°C for 4 hours; then add concentrated sulfuric acid with a volume concentration of 98%, and the liquid-to-solid ratio of the added concentrated sulfuric acid to the intermediate 2 is 30mL:1g; stir the reaction at 40°C for 6 hours, collect the product, wash the product with a concentrated sulfuric acid-ethanol mixed solution (1:1), and then gradually reduce the volume ratio of concentrated sulfuric acid to ethanol for gradient washing; finally wash with distilled water until neutral, extract with ethanol for 8 hours, and then dry at 40°C to constant weight to obtain modified polystyrene resin.

[0053] Comparative Example 1:

[0054] A modified polystyrene resin is prepared by the following steps:

[0055] S1: Put polystyrene chloride balls (Qiyue Biotechnology) into a small cloth bag, and put the small cloth bag into a Soxhlet extractor; extract in 95% (v / v) ethanol solution for 6 hours. After the extraction, take out the resin in the bag and air dry it for two hours, then transfer it to a vacuum drying oven and dry it at 50°C until the weight remains unchanged, thereby obtaining pretreated polystyrene chloride balls;

[0056] S2: Immerse the pretreated polystyrene chloride ball in 1,2-dichloroethane, let it stand at room temperature to swell for 8 hours, then add phenol and ferric chloride, the mass ratio of the added phenol and ferric chloride to the pretreated polystyrene chloride ball is 15:8:20; stir well and reflux at 60°C for 18 hours, collect the product, disperse the collected product in a hydrochloric acid acetone solution, stir for 6 hours, then extract with anhydrous ethanol for 8 hours, wash with water until there is no ethanol smell, and then dry at 40°C to constant weight to obtain intermediate 1;

[0057] S3: Immerse the intermediate 1 in 1,2-dichloroethane, let it stand at room temperature to swell for 8 hours, then add methylal and ferric chloride, the mass ratio of the added methylal and ferric chloride to the intermediate 1 is 22:8:35; after mixing well, reflux at 95°C for 18 hours, collect the products, disperse the collected products in a hydrochloric acid acetone solution, stir for 6 hours, then extract with anhydrous ethanol for 8 hours, wash with water until there is no ethanol smell, and then dry at 40°C to constant weight to obtain modified polystyrene resin.

[0058] Comparative Example 2:

[0059] A modified polystyrene resin is prepared by the following steps:

[0060] S1: Put polystyrene chloride balls (Qiyue Biotechnology) into a small cloth bag, and put the small cloth bag into a Soxhlet extractor; extract in 95% (v / v) ethanol solution for 6 hours. After the extraction, take out the resin in the bag and air dry it for two hours, then transfer it to a vacuum drying oven and dry it at 50°C until the weight remains unchanged, thereby obtaining pretreated polystyrene chloride balls;

[0061] S2: Immerse the pretreated polystyrene chloride beads in 1,2-dichloroethane and let them stand and swell at 45 °C for 5 h; then add concentrated sulfuric acid with a volume concentration of 98%, and the liquid ratio of the added concentrated sulfuric acid to the pretreated polystyrene chloride beads is 30 mL:1 g; stir and react at 35 °C for 7 h, collect the product, wash the product with a concentrated sulfuric acid-ethanol mixed solution (1:1), then gradually reduce the volume ratio of concentrated sulfuric acid to ethanol for gradient washing; finally wash with distilled water until neutral, then extract with ethanol for 8 h, and then dry at 40 °C to constant weight to obtain the modified polystyrene resin.

[0062] Comparative Example 3:

[0063] Directly use commercially available polystyrene chloride beads as the pyridine adsorption material.

[0064] Experimental Example:

[0065] Use the modified polystyrene resins prepared in the above examples and comparative examples to prepare high-purity diosmin. The specific method is as follows:

[0066] (1) Add 100 g of hesperidin and 40 g of iodine to 500 mL of pyridine, stir and react at 80 °C for 16 h, and then concentrate under reduced pressure until the volume no longer changes;

[0067] (2) Disperse the concentrate obtained in step (1) in 300 mL of water, stir for 15 min, and then filter to obtain the crude product; then dissolve the crude product in a sodium hydroxide solution with a concentration of 12 wt% to obtain the liquid to be treated;

[0068] (3) Load 100 g of the modified polystyrene resin into a chromatography column to obtain an adsorption column;

[0069] (4) Load the liquid to be treated into the adsorption column, let it flow out at a speed of 1 BV, collect the effluent and filter it precisely; then adjust the pH value of the precise filtrate to 6 and crystallize at room temperature; then filter, wash with water and dry to obtain high-purity diosmin.

[0070] The pyridine content of the liquid to be treated prepared in the experimental example was measured by liquid chromatography, and the result was 2827.6 ppm. The pyridine content in the diosmin purified by using the modified polystyrene resins in the above examples and comparative examples was detected by gas chromatography, and the results are shown in Table 1.

[0071] Table 1 Pyridine content in diosmin

[0072]

[0073] As can be seen from Table 1, the modified polystyrene resin prepared by the preparation method in the present invention (Examples 1 to 3) can effectively remove pyridine in the diosmin preparation system to obtain high-purity diosmin. Moreover, the diosmin purification method in the present invention is simple and does not require multiple dissolution and crystallization operations, greatly simplifying the preparation process of high-purity diosmin.

[0074] Although the specific implementation manners of the present invention have been described in detail in conjunction with the embodiments, it should not be construed as a limitation on the protection scope of this patent. Within the scope described in the claims, various modifications and deformations that can be made by those skilled in the art without creative efforts still fall within the protection scope of this patent.

Claims

1. A method for preparing a modified polystyrene resin, characterized in that: The following steps are involved: S1: pretreating the polystyrene chlorine balls to obtain pretreated polystyrene chlorine balls; S2: Immerse the pretreated polystyrene chloride ball in 1,2-dichloroethane, let it stand at room temperature to swell for 6-10 hours, then add phenol and iron salt, mix well, reflux at 55-65°C for 16-24 hours, collect the product, wash and dry it to obtain intermediate 1; S3: immerse the intermediate 1 in 1,2-dichloroethane, let it stand at room temperature to swell for 6-10 hours, then add methylal and iron salt, mix well, reflux at 90-100°C for 16-24 hours, collect the product, wash and dry it, and obtain the intermediate 2; S4: Immerse the intermediate II in 1,2-dichloroethane and allow to swell at 40-50°C for 4-6 hours; then add concentrated sulfuric acid and stir the reaction at 30-40°C for 6-8 hours. Collect the product, wash it and dry it to obtain the product.

2. The preparation method according to claim 1, characterized in that: The pretreatment method of the polystyrene chloride ball is: using 95% ethanol solution as an extraction reagent to perform Soxhlet extraction on the polystyrene chloride ball for 6 hours, then air-drying naturally, and then drying at 50°C to constant weight.

3. The preparation method according to claim 1, characterized in that: The iron salt is ferric chloride.

4. The preparation method according to claim 3, characterized in that: The swelling time in S2 is 8 hours; the mass ratio of the added phenol and iron salt to the pretreated polystyrene chloride balls is 15:8:20; the reflux reaction temperature is 60° C., and the reflux reaction time is 18 hours.

5. The preparation method according to claim 3, characterized in that: The swelling time in S3 is 8 hours; the mass ratio of the added methylal and iron salt to the intermediate 1 is 22:8:35; the reflux reaction temperature is 95° C., and the reflux reaction time is 18 hours.

6. The preparation method according to claim 4 or 5, characterized in that: The washing and drying methods of the products in S2 and S3 are as follows: the collected products are dispersed in a hydrochloric acid acetone solution, stirred for 6 h, then extracted with anhydrous ethanol for 8 h, then washed with water until there is no ethanol smell, and then dried at 40°C to constant weight.

7. The preparation method according to claim 1, characterized in that: The volume concentration of the concentrated sulfuric acid is 98%; the liquid-to-material ratio of the added concentrated sulfuric acid to the intermediate 2 is 30 mL:1 g.

8. A modified polystyrene resin, characterized in that: The preparation method is described in any one of claims 1 to 7.

9. The use of the modified polystyrene resin according to claim 8, characterized in that: The modified polystyrene resin is used to prepare high-purity diosmin.

10. The use according to claim 9, characterized in that: The preparation of the high-purity diosmin comprises the following steps: (1) Hesperidin, pyridine and iodine were mixed in a ratio of 1 g: 5-8 mL: 4-6 g, stirred at 80-100° C. for 8-16 h, and then concentrated under reduced pressure until the volume no longer changed; (2) dispersing the concentrate obtained in step (1) in water, stirring for 10 to 20 minutes, and then filtering to obtain a crude product; then dissolving the crude product in a sodium hydroxide solution with a concentration of 10 to 15 wt% to obtain a liquid to be treated; (3) loading 100 g of modified polystyrene resin into a chromatography column to obtain an adsorption column; (4) The liquid to be treated is loaded into an adsorption column, and flows out at a rate of 1 BV. The effluent is collected and finely filtered; the pH value of the fine filtrate is then adjusted to 6, and crystallization is performed at room temperature; it is then filtered, washed with water, and dried to obtain the product.

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