A polystyrene resin microsphere for pyridine adsorption, its preparation method and application

Abstract

This invention discloses a polystyrene resin microsphere for pyridine adsorption, its preparation method, and its application, belonging to the field of drug purification technology. The resin microspheres prepared in this invention possess excellent pore structure, providing more adsorption sites while shortening the diffusion path of pyridine molecules, thus facilitating the adsorption and removal of pyridine from solution. The prepared resin microspheres also contain phenolic hydroxyl groups and sulfonic acid groups, which can generate electrostatic and hydrogen bonding interactions with pyridine. These two interactions are complementary, enabling the capture of pyridine molecules in different protonated states. Furthermore, through silanization modification, not only can the active sites of the resin microspheres be further enhanced, but the breakage or swelling of the resin microspheres during the adsorption-desorption cycle can also be prevented, thereby ensuring the pyridine removal effect. When adsorbing pyridine, the resin microspheres prepared in this invention can form a synergistic pathway of "pore trapping-group fixation," effectively removing residual pyridine from the reaction system.

Description

Technical Field

[0001] This invention belongs to the field of drug purification technology, specifically relating to a polystyrene resin microsphere for pyridine adsorption, its preparation method, and its application. Background Technology

[0002] Diosmin, also known as geraniol, is a natural flavonoid glycoside compound that was first used as a therapeutic agent in 1969. Its molecular formula is C0. 28 H 32 O 15 It has a relative molecular weight of 608.54 and is a grayish-yellow to yellow powder or crystalline powder, odorless. Diosmin does not have a specific melting point range, but it usually melts and decomposes at a temperature of 277℃~278℃. Diosmin is soluble in dimethyl sulfoxide, insoluble in water, methanol or ethanol, very slightly soluble in 0.1 mol / L sodium hydroxide, and practically insoluble in 0.1 mol / L hydrochloric acid solution. The structure of diosmin consists of the 7-hydroxyl group of geraniol and rutin linked at the 1-position of glucose, as shown below:

[0003]

[0004] Diosmin can improve venous tone, protect microcirculation, and increase capillary resistance, maintaining high capillary permeability, thereby promoting lymphatic circulation and relieving local inflammation. Clinically, it is often used for hemorrhoids and venous return disorders in the limbs.

[0005] Because the content of diosmin in natural plants is very low and cannot meet the needs of modern medicine, pharmaceutical diosmin is now obtained through chemical synthesis using hesperidin as a raw material. The traditional method involves mixing hesperidin, iodine, and pyridine in an alkaline solvent and heating to react and synthesize diosmin. However, iodine is a particulate solid, making it difficult to mix evenly with hesperidin, resulting in low reaction consistency, slow reaction rate, and increased side reactions and impurities as the reaction time increases, leading to lower product yield. Furthermore, pyridine, as a reaction solvent, is difficult to remove in post-processing, usually requiring significant time for cleaning, resulting in a long process cycle. The final cleaning effect is often unsatisfactory, with high pyridine residue in the product affecting the purity of the filter cake and reducing safety. Especially in large-scale industrial production, the problem of low cleaning uniformity arises, with some products not being completely cleaned, affecting not only purity but also posing a health risk. Summary of the Invention

[0006] In view of the above-mentioned prior art, the present invention provides a method for preparing polystyrene resin microspheres for pyridine adsorption, so as to solve the technical problem of difficult removal of pyridine from diosmin.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is to provide a method for preparing polystyrene resin microspheres for pyridine adsorption, characterized by comprising the following steps:

[0008] S1: The first dispersant, the first initiator and styrene are co-dissolved in ethanol and reacted at 65~75℃ for 12~16h. The product is then collected and dried to obtain polystyrene seed pellets.

[0009] S2: Disperse the second dispersant, swelling agent and polystyrene seed balls in water and allow them to swell at room temperature for 1-3 hours; then add the second initiator, styrene, acrylic acid, divinylbenzene and crosslinking agent, and react at 75-85°C for 16-20 hours. Collect the product and dry it to obtain resin microspheres.

[0010] S3: Immerse the resin microspheres in 1,2-dichloroethane and allow them to swell at room temperature for 6-10 hours. Then add phenol and iron salt, mix well, and reflux at 55-65°C for 16-24 hours. Collect the product, wash and dry it to obtain intermediate one.

[0011] S4: Immerse intermediate one in 1,2-dichloroethane and allow it to swell at room temperature for 6-10 hours. Then add methyl acetal and iron salt, mix well, and reflux at 90-100℃ for 16-24 hours. Collect the product, wash and dry it to obtain intermediate two.

[0012] S5: Immerse intermediate II in 1,2-dichloroethane and allow it 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 and dry it to obtain intermediate III.

[0013] S6: The intermediate is tripeed in a solvent, a silicon source precursor and a catalyst are added, and the mixture is reacted at room temperature for 5-10 hours to obtain a mixed gel; then the mixed gel is dried to obtain the final product.

[0014] Based on the above technical solution, the present invention can be further improved as follows.

[0015] Furthermore, the pretreatment method for polystyrene chloroform is as follows: the first dispersant is PVP, PVA or HPC; the first initiator is AIBN, ABVN or BPO; the mass ratio of the first dispersant, the first initiator and styrene in S1 is 5~7:0.5~2:100.

[0016] Furthermore, the second dispersant is sodium dodecyl sulfate; the swelling agent is phthalate; the crosslinking agent is HEC or PVA; the second initiator is BPO; the ratio of the second dispersant, swelling agent, polystyrene seed pellets, second initiator, styrene, acrylic acid, divinylbenzene and crosslinking agent in S2 is 2~5g:1~3mL:10~20g:1~3g:100mL:40~50mL:20~30mL:5~10g.

[0017] Furthermore, the mass ratio of phenol and iron salt to resin microspheres added in S3 is 15:8:20; the reflux reaction temperature is 60℃, and the reflux reaction time is 18h; the iron salt is ferric chloride.

[0018] Furthermore, the mass ratio of methyl acetal and iron salt added in S4 to intermediate one is 22:8:35; the reflux reaction temperature is 95℃, and the reflux reaction time is 18h; the iron salt is ferric chloride.

[0019] Furthermore, the volume concentration of concentrated sulfuric acid in S5 is 98%; the liquid-to-solid ratio of the added concentrated sulfuric acid to intermediate II is 30 mL: 1 g.

[0020] Furthermore, the silicon source precursor is tetraethyl orthosilicate; the catalyst is ammonia water with a mass concentration of 25%; the ratio of tetraethyl orthosilicate, ammonia water and intermediate III is 3~5mL:3~5mL:5g.

[0021] Furthermore, the drying temperature in S6 is 100~120℃, and the drying time is 3~5h.

[0022] This invention discloses a polystyrene resin microsphere for pyridine adsorption, which is prepared by the above-described preparation method.

[0023] This invention also discloses the application of the above-mentioned polystyrene resin microspheres for pyridine adsorption in the preparation of high-purity diosmin. The preparation of high-purity diosmin includes the following steps:

[0024] (1) Mix hesperidin, pyridine and iodine in a ratio of 1g:5~8mL:4~6g, stir and react at 80~100℃ for 8~16h, and then concentrate under reduced pressure until the volume no longer changes;

[0025] (2) Disperse the concentrate obtained in step (1) in water, stir for 10-20 min, then filter to obtain crude product; then dissolve the crude product in a sodium hydroxide solution with a concentration of 10-15 wt% to obtain the solution to be treated;

[0026] (3) 100g of polystyrene resin microspheres for pyridine adsorption were loaded into a chromatography column to obtain an adsorption column;

[0027] (4) Load the liquid to be treated into the adsorption column and elute at a rate of 1 BV. Collect the eluent and filter it finely. Then adjust the pH of the fine filtrate to 6 and crystallize it at room temperature. Then filter it, wash it with water and dry it to obtain the final product.

[0028] The beneficial effects of this invention are:

[0029] 1. This invention prepares resin microspheres by first preparing polystyrene seed spheres, then mixing the polystyrene seed spheres with a swelling agent, functional monomers (styrene, acrylic acid, divinylbenzene), and a crosslinking agent to undergo a crosslinking reaction. The swelling agent penetrates into the interior of the polystyrene seed spheres, causing the polymer chains to expand and form temporary pores. During subsequent polymerization, the swelling agent is removed, leaving a nanoscale porous structure. The crosslinking agent forms a rigid three-dimensional network during the graft polymerization stage, preventing the collapse of the nanoscale pores. The resulting resin microspheres have an excellent pore structure, providing more adsorption sites while shortening the diffusion path of pyridine molecules, thus facilitating the adsorption and removal of pyridine from solution. Furthermore, the polymeric monomers used in the preparation of the resin microspheres include acrylic acid and divinylbenzene, which can introduce active groups (such as -COOH) into the resin microspheres. This allows the resin microspheres to bind with pyridine molecules through hydrogen bonds and π-π stacking, thereby enhancing the adsorption effect of the polymerized microspheres on pyridine.

[0030] 2. In this invention, phenolic hydroxyl groups are introduced into the resin microspheres. When purifying the crude diosmin product, the introduced phenolic hydroxyl groups can bind to the nitrogen atoms of pyridine through hydrogen bonds, thereby "capturing" and fixing pyridine, which can effectively remove pyridine from the diosmin preparation system.

[0031] 3. The resin microspheres in this invention undergo sulfonation treatment after the introduction of phenolic hydroxyl groups. Sulfonation treatment can introduce sulfonic acid groups into polystyrene resin. Sulfonic acid groups (-SO3H) are strongly acidic and, upon dissociation, generate negatively charged sulfonate ions (-SO3). - Under acidic conditions (pH < 7), it can electrostatically adsorb protonated pyridine (pyridine nitrogen atom bound to H). + The formed cations achieve the purpose of pyridine fixation and removal.

[0032] 4. The polystyrene resin microspheres for pyridine adsorption in this invention simultaneously contain phenolic hydroxyl groups and sulfonic acid groups. The sulfonic acid groups can generate electrostatic interactions with protonated pyridine, while the phenolic hydroxyl groups can generate hydrogen bonds with unprotonated pyridine. These electrostatic and hydrogen bonding interactions are complementary, enabling the capture of pyridine molecules in different protonated states. Furthermore, the benzene ring of the modified polystyrene resin can bond with the aromatic ring of pyridine through π-π stacking, and the introduction of sulfonic acid and phenolic hydroxyl groups further polarizes the electron cloud of the polystyrene benzene ring, enhancing the conjugation effect and increasing the bonding strength between the benzene ring and the pyridine aromatic ring.

[0033] 5. In this invention, after grafting phenolic hydroxyl groups and sulfonic acid groups onto the resin microspheres, a post-treatment is further performed. The post-treatment involves reacting the grafted resin microspheres with a silicon source precursor and a catalyst. Under the action of the catalyst, the silicon source precursor undergoes hydrolysis and condensation reactions to generate SiO2 sol particles. These particles are adsorbed onto the surface of the resin microspheres through hydrogen bonds and chemical bonds, and further condense to form a three-dimensional network structure. Ultimately, a porous SiO2 shell is formed on the resin surface or nanopores are embedded inside the resin, thereby further increasing the specific surface area of ​​the resin microspheres and thus increasing the number of adsorption active sites. Furthermore, SiO2 has high hardness and chemical stability, which can prevent the resin microspheres from breaking or swelling during the adsorption-desorption cycle, thereby ensuring the removal effect of pyridine.

[0034] 6. The modified polystyrene resin prepared in this invention possesses nanoscale pores and an ultra-high specific surface area, providing diffusion channels and physical adsorption sites for pyridine molecules; the sulfonic acid groups and phenolic hydroxyl groups anchor pyridine molecules through chemical action; that is, when the modified polystyrene in this invention adsorbs pyridine, it can form a synergistic pathway of "pore trapping-group immobilization," effectively removing residual pyridine from the reaction system. Detailed Implementation

[0035] The specific embodiments of the present invention will be described in detail below with reference to examples.

[0036] Example 1:

[0037] A polystyrene resin microsphere for pyridine adsorption is prepared by the following steps:

[0038] S1: PVP (polyvinylpyrrolidone), AIBN (azobisisobutyronitrile), and styrene were co-dissolved in ethanol at a mass ratio of 6:1:100, with a volume ratio of styrene to ethanol of 1:3; the reaction was carried out at 70°C for 14 hours, and then the product was collected, washed with water three times, and air-dried to obtain polystyrene seed pellets.

[0039] S2: Sodium dodecyl sulfate, phthalate, and polystyrene seed pellets were dispersed in water and swollen at room temperature for 2 hours; then BPO (benzoyl peroxide), styrene, acrylic acid, divinylbenzene, and HEC (hydroxyethyl cellulose) were added, and the mixture was reacted at 80°C for 18 hours. The product was then collected, washed three times with water, and air-dried to obtain resin microspheres. The ratio of sodium dodecyl sulfate, phthalate, polystyrene seed pellets, BPO, styrene, acrylic acid, divinylbenzene, and HEC was 3g:2mL:15g:2g:100mL:45mL:25mL:8g.

[0040] S3: Immerse the resin microspheres in 1,2-dichloroethane and allow them to swell at room temperature for 8 hours. Then add phenol and ferric chloride, with a mass ratio of phenol, ferric chloride and resin microspheres of 15:8:20. After mixing, reflux the reaction at 60°C for 18 hours. Collect the product and disperse it in acetone hydrochloride solution. Stir for 6 hours, then extract with anhydrous ethanol for 8 hours. Wash with water until there is no ethanol odor, and then dry at 40°C to constant weight to obtain intermediate one.

[0041] S4: Immerse intermediate one in 1,2-dichloroethane and allow it to swell at room temperature for 8 hours. Then add methyl acetal and ferric chloride in a mass ratio of 22:8:35 to intermediate one. After mixing, reflux at 95°C for 18 hours. Collect the product and disperse it in acetone hydrochloride solution. Stir for 6 hours, then extract with anhydrous ethanol for 8 hours. Wash with water until there is no ethanol odor, and then dry at 40°C to constant weight to obtain intermediate two.

[0042] S5: Immerse intermediate II in 1,2-dichloroethane and allow it to swell at 45°C for 5 hours; then add concentrated sulfuric acid with a volume concentration of 98%, with a liquid-to-solid ratio of 30 mL:1 g; stir the reaction at 35°C for 7 hours, collect the product, wash the product with a concentrated sulfuric acid-ethanol mixture (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, then extract with ethanol for 8 hours, and then dry at 40°C to constant weight to obtain intermediate III;

[0043] S6: Disperse intermediate three in water, add tetraethyl orthosilicate and ammonia water with a mass concentration of 25%, react at room temperature for 8 hours to obtain a mixed gel. The ratio of tetraethyl orthosilicate, ammonia water and intermediate three is 4 mL: 4 mL: 5 g. Then dry at 110 °C for 4 hours to obtain polystyrene resin microspheres for pyridine adsorption.

[0044] Example 2:

[0045] A polystyrene resin microsphere for pyridine adsorption is prepared by the following steps:

[0046] S1: PVA (polyvinyl alcohol), ABVN (azobisisoheptanenitrile), and styrene were co-dissolved in ethanol at a mass ratio of 5:0.5:100, with a volume ratio of styrene to ethanol of 1:3; the reaction was carried out at 65°C for 16 hours, and the product was collected, washed three times with water, and then air-dried to obtain polystyrene seed pellets.

[0047] S2: Sodium dodecyl sulfate, phthalate, and polystyrene seed pellets were dispersed in water and swollen at room temperature for 1 hour; then BPO (benzoyl peroxide), styrene, acrylic acid, divinylbenzene, and PVA (polyvinyl alcohol) were added, and the mixture was reacted at 75°C for 20 hours. The product was then collected, washed three times with water, and air-dried to obtain resin microspheres. The ratio of sodium dodecyl sulfate, phthalate, polystyrene seed pellets, BPO, styrene, acrylic acid, divinylbenzene, and PVA was 2g:1mL:10g:1g:100mL:40mL:20mL:5g.

[0048] S3: Immerse the resin microspheres in 1,2-dichloroethane and allow them to swell at room temperature for 6 hours. Then add phenol and ferric chloride, with a mass ratio of phenol, ferric chloride and resin microspheres of 15:8:20. After mixing, reflux the reaction at 55°C for 24 hours. Collect the product and disperse it in acetone hydrochloride solution. Stir for 6 hours, then extract with anhydrous ethanol for 8 hours. Wash with water until there is no ethanol odor, and then dry at 40°C to constant weight to obtain intermediate one.

[0049] S4: Immerse intermediate one in 1,2-dichloroethane and allow it to swell at room temperature for 6 hours. Then add methyl acetal and ferric chloride in a mass ratio of 22:8:35 to intermediate one. After mixing, reflux at 90°C for 24 hours. Collect the product and disperse it in acetone hydrochloride solution. Stir for 6 hours, then extract with anhydrous ethanol for 8 hours. Wash with water until there is no ethanol odor, and then dry at 40°C to constant weight to obtain intermediate two.

[0050] S5: Immerse intermediate II in 1,2-dichloroethane and allow it to swell at 40°C for 6 hours; then add concentrated sulfuric acid with a volume concentration of 98%, with a liquid-to-solid ratio of 30 mL:1 g; stir the reaction at 30°C for 8 hours, collect the product, wash the product with a concentrated sulfuric acid-ethanol mixture (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, then extract with ethanol for 8 hours, and then dry at 40°C to constant weight to obtain intermediate III;

[0051] S6: Disperse intermediate three in water, add tetraethyl orthosilicate and ammonia water with a mass concentration of 25%, react at room temperature for 5 hours to obtain a mixed gel. The ratio of tetraethyl orthosilicate, ammonia water and intermediate three is 3 mL: 3 mL: 5 g. Then dry at 100 °C for 5 hours to obtain polystyrene resin microspheres for pyridine adsorption.

[0052] Example 3:

[0053] A polystyrene resin microsphere for pyridine adsorption is prepared by the following steps:

[0054] S1: HPC (hydroxypropyl cellulose), BPO (benzoyl peroxide) and styrene were co-dissolved in ethanol at a mass ratio of 7:2:100, and the volume ratio of styrene to ethanol was 1:3; the reaction was carried out at 75°C for 12 hours, and then the product was collected, washed with water 3 times and air-dried to obtain polystyrene seed pellets.

[0055] S2: Sodium dodecyl sulfate, phthalate, and polystyrene seed pellets were dispersed in water and swollen at room temperature for 3 hours; then BPO (benzoyl peroxide), styrene, acrylic acid, divinylbenzene, and HEC (hydroxyethyl cellulose) were added, and the mixture was reacted at 85°C for 16 hours. The product was then collected, washed three times with water, and air-dried to obtain resin microspheres. The ratio of sodium dodecyl sulfate, phthalate, polystyrene seed pellets, BPO, styrene, acrylic acid, divinylbenzene, and HEC was 5g:3mL:20g:3g:100mL:50mL:30mL:10g.

[0056] S3: Immerse the resin microspheres in 1,2-dichloroethane and allow them to swell at room temperature for 10 hours. Then add phenol and ferric chloride, with a mass ratio of phenol, ferric chloride and resin microspheres of 15:8:20. After mixing, reflux the reaction at 65°C for 16 hours. Collect the product and disperse it in acetone hydrochloride solution. Stir for 6 hours, then extract with anhydrous ethanol for 8 hours. Wash with water until there is no ethanol odor, and then dry at 40°C to constant weight to obtain intermediate one.

[0057] S4: Immerse intermediate one in 1,2-dichloroethane and allow it to swell at room temperature for 10 hours. Then add methyl acetal and ferric chloride in a mass ratio of 22:8:35 to intermediate one. After mixing, reflux at 100°C for 16 hours. Collect the product and disperse it in acetone hydrochloride solution. Stir for 6 hours, then extract with anhydrous ethanol for 8 hours. Wash with water until there is no ethanol odor, and then dry at 40°C to constant weight to obtain intermediate two.

[0058] S5: Immerse intermediate II in 1,2-dichloroethane and allow it to swell at 50°C for 4 hours; then add concentrated sulfuric acid with a volume concentration of 98%, with a liquid-to-solid ratio of 30 mL:1 g; stir the reaction at 40°C for 6 hours, collect the product, wash the product with a concentrated sulfuric acid-ethanol mixture (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, then extract with ethanol for 8 hours, and then dry at 40°C to constant weight to obtain intermediate III;

[0059] S6: Disperse intermediate three in water, add tetraethyl orthosilicate and ammonia water with a mass concentration of 25%, react at room temperature for 10 h to obtain a mixed gel. The ratio of tetraethyl orthosilicate, ammonia water and intermediate three is 5 mL: 5 mL: 5 g. Then dry at 120 °C for 3 h to obtain polystyrene resin microspheres for pyridine adsorption.

[0060] Comparative Example 1:

[0061] A polystyrene resin microsphere for pyridine adsorption is prepared by the following steps:

[0062] S1: Place polystyrene chlorinated polystyrene 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 extraction, remove the resin from the cloth bag and air dry it naturally for two hours, then transfer it to a vacuum drying oven and dry it at 50°C until the weight remains unchanged to obtain pretreated polystyrene chlorinated polystyrene balls.

[0063] S2: The pretreated polystyrene chloride spheres were immersed in 1,2-dichloroethane and allowed to swell at room temperature for 8 hours. Then, phenol and ferric chloride were added, with a mass ratio of phenol, ferric chloride and pretreated polystyrene chloride spheres of 15:8:20. After mixing, the mixture was refluxed at 60°C for 18 hours. The product was collected and dispersed in acetone hydrochloride solution. The mixture was stirred for 6 hours and then extracted with anhydrous ethanol for 8 hours. The mixture was washed with water until there was no ethanol odor and then dried at 40°C to constant weight to obtain intermediate one.

[0064] S3: Immerse intermediate one in 1,2-dichloroethane and allow it to swell at room temperature for 8 hours. Then add methyl acetal and ferric chloride in a mass ratio of 22:8:35 to intermediate one. After mixing, reflux at 95°C for 18 hours. Collect the product and disperse it in acetone hydrochloride solution. Stir for 6 hours, then extract with anhydrous ethanol for 8 hours. Wash with water until there is no ethanol odor, and then dry at 40°C to constant weight to obtain intermediate two.

[0065] S4: Immerse intermediate II in 1,2-dichloroethane and allow it to swell at 45°C for 5 hours; then add concentrated sulfuric acid with a volume concentration of 98%, with a liquid-to-solid ratio of 30 mL:1 g; stir the reaction at 35°C for 7 hours, collect the product, wash the product with a concentrated sulfuric acid-ethanol mixture (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, then extract with ethanol for 8 hours, and then dry at 40°C to constant weight to obtain intermediate III;

[0066] S5: Disperse intermediate three in water, add tetraethyl orthosilicate and ammonia water with a mass concentration of 25%, react at room temperature for 8 hours to obtain a mixed gel. The ratio of tetraethyl orthosilicate, ammonia water and intermediate three is 4 mL: 4 mL: 5 g. Then dry at 110 °C for 4 hours to obtain polystyrene resin microspheres for pyridine adsorption.

[0067] Comparative Example 2:

[0068] A polystyrene resin microsphere for pyridine adsorption is prepared by the following steps:

[0069] S1: PVP (polyvinylpyrrolidone), AIBN (azobisisobutyronitrile), and styrene were co-dissolved in ethanol at a mass ratio of 6:1:100, with a volume ratio of styrene to ethanol of 1:3; the reaction was carried out at 70°C for 14 hours, and then the product was collected, washed with water three times, and air-dried to obtain polystyrene seed pellets.

[0070] S2: Sodium dodecyl sulfate, phthalate, and polystyrene seed pellets were dispersed in water and swollen at room temperature for 2 hours; then BPO (benzoyl peroxide), styrene, acrylic acid, divinylbenzene, and HEC (hydroxyethyl cellulose) were added, and the mixture was reacted at 80°C for 18 hours. The product was then collected, washed three times with water, and air-dried to obtain resin microspheres. The ratio of sodium dodecyl sulfate, phthalate, polystyrene seed pellets, BPO, styrene, acrylic acid, divinylbenzene, and HEC was 3g:2mL:15g:2g:100mL:45mL:25mL:8g.

[0071] S3: The resin microspheres were immersed in 1,2-dichloroethane and allowed to swell at room temperature for 8 hours. Then, methyl acetal and ferric chloride were added, with the mass ratio of methyl acetal and ferric chloride to intermediate one being 22:8:35. After mixing, the mixture was refluxed at 95°C for 18 hours. The product was collected and dispersed in acetone hydrochloride solution. The mixture was stirred for 6 hours and then extracted with anhydrous ethanol for 8 hours. The mixture was then washed with water until there was no ethanol odor and dried at 40°C to constant weight to obtain intermediate one.

[0072] S4: Immerse intermediate one in 1,2-dichloroethane and allow it to swell at 45°C for 5 hours; then add concentrated sulfuric acid with a volume concentration of 98%, with a liquid-to-solid ratio of 30 mL:1 g to intermediate two; stir the reaction at 35°C for 7 hours, collect the product, wash the product with a concentrated sulfuric acid-ethanol mixture (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, then extract with ethanol for 8 hours, and then dry at 40°C to constant weight to obtain intermediate two;

[0073] S5: Disperse the intermediate in water, add tetraethyl orthosilicate and 25% ammonia, and react at room temperature for 8 hours to obtain a mixed gel. The ratio of tetraethyl orthosilicate, ammonia and intermediate three is 4 mL:4 mL:5 g. Then dry at 110 °C for 4 hours to obtain polystyrene resin microspheres for pyridine adsorption.

[0074] Comparative Example 3:

[0075] A polystyrene resin microsphere for pyridine adsorption is prepared by the following steps:

[0076] S1: PVP (polyvinylpyrrolidone), AIBN (azobisisobutyronitrile), and styrene were co-dissolved in ethanol at a mass ratio of 6:1:100, with a volume ratio of styrene to ethanol of 1:3; the reaction was carried out at 70°C for 14 hours, and then the product was collected, washed with water three times, and air-dried to obtain polystyrene seed pellets.

[0077] S2: Sodium dodecyl sulfate, phthalate, and polystyrene seed pellets were dispersed in water and swollen at room temperature for 2 hours; then BPO (benzoyl peroxide), styrene, acrylic acid, divinylbenzene, and HEC (hydroxyethyl cellulose) were added, and the mixture was reacted at 80°C for 18 hours. The product was then collected, washed three times with water, and air-dried to obtain resin microspheres. The ratio of sodium dodecyl sulfate, phthalate, polystyrene seed pellets, BPO, styrene, acrylic acid, divinylbenzene, and HEC was 3g:2mL:15g:2g:100mL:45mL:25mL:8g.

[0078] S3: Immerse the resin microspheres in 1,2-dichloroethane and allow them to swell at room temperature for 8 hours. Then add phenol and ferric chloride, with a mass ratio of phenol, ferric chloride and resin microspheres of 15:8:20. After mixing, reflux the reaction at 60°C for 18 hours. Collect the product and disperse it in acetone hydrochloride solution. Stir for 6 hours, then extract with anhydrous ethanol for 8 hours. Wash with water until there is no ethanol odor, and then dry at 40°C to constant weight to obtain intermediate one.

[0079] S4: Immerse intermediate one in 1,2-dichloroethane and allow it to swell at 45°C for 5 hours; then add concentrated sulfuric acid with a volume concentration of 98%, with a liquid-to-solid ratio of 30 mL:1 g to intermediate two; stir the reaction at 35°C for 7 hours, collect the product, wash the product with a concentrated sulfuric acid-ethanol mixture (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, then extract with ethanol for 8 hours, and then dry at 40°C to constant weight to obtain intermediate two;

[0080] S5: Disperse the intermediate in water, add tetraethyl orthosilicate and 25% ammonia, and react at room temperature for 8 hours to obtain a mixed gel. The ratio of tetraethyl orthosilicate, ammonia and intermediate three is 4 mL:4 mL:5 g. Then dry at 110 °C for 4 hours to obtain polystyrene resin microspheres for pyridine adsorption.

[0081] Comparative Example 4:

[0082] A polystyrene resin microsphere for pyridine adsorption is prepared by the following steps:

[0083] S1: PVP (polyvinylpyrrolidone), AIBN (azobisisobutyronitrile), and styrene were co-dissolved in ethanol at a mass ratio of 6:1:100, with a volume ratio of styrene to ethanol of 1:3; the reaction was carried out at 70°C for 14 hours, and then the product was collected, washed with water three times, and air-dried to obtain polystyrene seed pellets.

[0084] S2: Sodium dodecyl sulfate, phthalate, and polystyrene seed pellets were dispersed in water and swollen at room temperature for 2 hours; then BPO (benzoyl peroxide), styrene, acrylic acid, divinylbenzene, and HEC (hydroxyethyl cellulose) were added, and the mixture was reacted at 80°C for 18 hours. The product was then collected, washed three times with water, and air-dried to obtain resin microspheres. The ratio of sodium dodecyl sulfate, phthalate, polystyrene seed pellets, BPO, styrene, acrylic acid, divinylbenzene, and HEC was 3g:2mL:15g:2g:100mL:45mL:25mL:8g.

[0085] S3: Immerse the resin microspheres in 1,2-dichloroethane and allow them to swell at room temperature for 8 hours. Then add phenol and ferric chloride, with a mass ratio of phenol, ferric chloride and resin microspheres of 15:8:20. After mixing, reflux the reaction at 60°C for 18 hours. Collect the product and disperse it in acetone hydrochloride solution. Stir for 6 hours, then extract with anhydrous ethanol for 8 hours. Wash with water until there is no ethanol odor, and then dry at 40°C to constant weight to obtain intermediate one.

[0086] S4: Immerse intermediate one in 1,2-dichloroethane and allow it to swell at room temperature for 8 hours. Then add methyl acetal and ferric chloride in a mass ratio of 22:8:35 to intermediate one. After mixing, reflux at 95°C for 18 hours. Collect the product and disperse it in acetone hydrochloride solution. Stir for 6 hours, then extract with anhydrous ethanol for 8 hours. Wash with water until there is no ethanol odor, and then dry at 40°C to constant weight to obtain intermediate two.

[0087] S5: Immerse intermediate II in 1,2-dichloroethane and allow it to swell at 45°C for 5 hours; then add concentrated sulfuric acid with a volume concentration of 98%, with a liquid-to-solid ratio of 30 mL:1 g; stir the reaction at 35°C for 7 hours, collect the product, wash the product with a concentrated sulfuric acid-ethanol mixture (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, then extract with ethanol for 8 hours, and then dry at 40°C to constant weight to obtain polystyrene resin microspheres for pyridine adsorption.

[0088] Comparative Example 5:

[0089] Commercially available polystyrene chloride spheres were used directly as the pyridine adsorbent.

[0090] Experimental example:

[0091] The modified polystyrene resins prepared in the above embodiments and comparative examples were used to prepare high-purity diosmin, and the specific methods are as follows:

[0092] (1) Add 100g of hesperidin and 40g of iodine to 500mL of pyridine, stir at 80℃ for 16h, and then concentrate under reduced pressure until the volume no longer changes.

[0093] (2) Disperse the concentrate obtained in step (1) in 300 mL of water, stir for 15 min, and then filter to obtain crude product; then dissolve the crude product in a 12 wt% sodium hydroxide solution to obtain the solution to be treated.

[0094] (3) 100g of modified polystyrene resin was packed into a chromatography column to obtain an adsorption column;

[0095] (4) The liquid to be treated is loaded into the adsorption column and effluent is flowed out at a rate of 1 BV. The effluent is collected and filtered. Then the pH of the filtrate is adjusted to 6 and crystallized at room temperature. After filtration, it is washed with water and dried to obtain high-purity diosmin.

[0096] The pyridine content of the solution prepared in the experimental example was determined by liquid chromatography, and the result was 2827.6 ppm. The pyridine content of diosmin purified by the modified polystyrene resin in the above examples and comparative examples was detected by gas chromatography, and the results are shown in Table 1.

[0097] Table 1. Pyridine content in diosmin

[0098]

[0099] As can be seen from Table 1, the polystyrene resin microspheres for pyridine adsorption prepared by the preparation method of the present invention (Examples 1-3) can effectively remove pyridine from the diosmin preparation system and obtain high-purity diosmin. Furthermore, the diosmin purification method in the present invention is simple and does not require multiple dissolution and crystallization operations, which greatly simplifies the preparation process of high-purity diosmin.

[0100] Although specific embodiments of the present invention have been described in detail with reference to examples, they should not be construed as limiting the scope of protection of this patent. Various modifications and variations that can be made by those skilled in the art without inventive effort within the scope described in the claims are still within the scope of protection of this patent.

Claims

1. A method for preparing polystyrene resin microspheres for pyridine adsorption, characterized by, It comprises the following steps: S1: the first dispersant, the first initiator and styrene are co-dissolved in ethanol, and the reaction is carried out at 65-75℃ for 12-16h, then the product is collected and dried, and the polystyrene seed ball is obtained; S2: the second dispersant, the swelling agent and the polystyrene seed ball are dispersed in water, and the swelling is carried out at room temperature for 1-3h; then the second initiator, styrene, acrylic acid, divinylbenzene and crosslinking agent are added, and the reaction is carried out at 75-85℃ for 16-20h, then the product is collected and dried, and the resin microspheres are obtained; the second dispersant is sodium dodecyl sulfate; the swelling agent is phthalate; the crosslinking agent is HEC or PVA; the second initiator is BPO; the mass ratio of the second dispersant, the swelling agent, the polystyrene seed ball, the second initiator, styrene, acrylic acid, divinylbenzene and the crosslinking agent is 2-5g:1-3mL:10-20g:1-3g:100mL:40-50mL:20-30mL:5-10g; S3: the resin microspheres are immersed in 1,2-dichloroethane, and the swelling is carried out at room temperature for 6-10h, then phenol and iron salt are added, and after stirring, the reflux reaction is carried out at 55-65℃ for 16-24h, then the product is collected and washed and dried, and the intermediate one is obtained; S4: the intermediate one is immersed in 1,2-dichloroethane, and the swelling is carried out at room temperature for 6-10h, then methylal and iron salt are added, and after stirring, the reflux reaction is carried out at 90-100℃ for 16-24h, then the product is collected and washed and dried, and the intermediate two is obtained; S5: the intermediate two is immersed in 1,2-dichloroethane, and the swelling is carried out at 40-50℃ for 4-6h; then concentrated sulfuric acid is added, and the stirring reaction is carried out at 30-40℃ for 6-8h, then the product is collected and washed and dried, and the intermediate three is obtained; S6: the intermediate three is dispersed in a solvent, and a silicon source precursor and a catalyst are added, and the reaction is carried out at room temperature for 5-10h, and the mixed gel is obtained; then the mixed gel is dried, and the product is obtained; the silicon source precursor is tetraethyl orthosilicate; the catalyst is ammonia water with a mass concentration of 25%; the mass ratio of the silicon source precursor, the ammonia water and the intermediate three is 3-5mL:3-5mL:5g.

2. The method of claim 1, wherein: The first dispersant is PVP, PVA or HPC; the first initiator is AIBN, ABVN or BPO; the mass ratio of the first dispersant, the first initiator and styrene in S1 is 5-7:0.5-2:

100.

3. The method of claim 1, wherein: The mass ratio of the phenol and the iron salt added in S3 to the resin microspheres is 15:8:20; the reflux reaction temperature is 60℃, and the reflux reaction time is 18h; the iron salt is ferric chloride.

4. The method of claim 1, wherein: The mass ratio of the methylal and the iron salt added in S4 to the intermediate one is 22:8:35; the reflux reaction temperature is 95℃, and the reflux reaction time is 18h; the iron salt is ferric chloride.

5. The method of claim 1, wherein: The volume concentration of the concentrated sulfuric acid in S5 is 98%; the liquid material ratio of the concentrated sulfuric acid added to the intermediate two is 30mL:1g.

6. The method of claim 1, wherein: The drying temperature in S6 is 100-120℃, and the drying time is 3-5h.

7. Polystyrene resin microspheres for pyridine adsorption, characterized by: The preparation method is prepared by any one of claims 1-6.

8. Use of polystyrene resin microspheres for pyridine adsorption according to claim 7 for the preparation of high purity diosmin, characterized in that, The preparation of the high-purity dioxydendron includes the following steps: (1) mixing hesperidin, pyridine and iodine in a ratio of 1 g: 5-8 mL: 4-6 g, stirring and reacting at 80-100 ℃ for 8-16 h, and then concentrating under reduced pressure until the volume no longer changes; (2) dispersing the concentrate obtained in step (1) in water, stirring for 10-20 min, then filtering to obtain a crude product; dissolving the crude product in a 10-15 wt% sodium hydroxide solution to obtain a treatment liquid; (3) loading 100 g of polystyrene resin microspheres for pyridine adsorption into a chromatographic column to obtain an adsorption column; (4) loading the treatment liquid into the adsorption column, flowing out at a speed of 1 BV, collecting the effluent and performing precision filtration; then adjusting the pH value of the precision filtrate to 6, and performing crystallization at room temperature; then filtering, and then washing with water and drying to obtain.

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