An adsorption resin and its preparation method and application in cephalosporin C extraction

Abstract

The present invention provides an adsorption resin and a preparation method thereof and an application thereof in the extraction of cephalosporin C, comprising: S1: dissolving a dispersant in water to obtain an aqueous phase; mixing a monomer, a porogen, a crosslinking agent and an initiator to obtain an oil phase; adding the oil phase to the aqueous phase to perform a polymerization reaction to obtain a copolymer matrix; S2: performing a post-crosslinking reaction on the copolymer matrix and an additional crosslinking agent in the presence of a catalyst to obtain a post-crosslinked macroporous adsorption resin; S3: performing halogen modification on the post-crosslinked macroporous adsorption resin, and controlling the halogen content of the halogen-modified macroporous adsorption resin within a range of 6% to 12% to obtain an adsorption resin. The present invention solves the problem that the selectivity, adsorption capacity and anti-pollution performance of the existing macroporous adsorption resin cannot be taken into account in the process of extracting cephalosporin C.

Description

Technical Field

[0001] The present invention belongs to the technical fields of chemical engineering and antibiotics, and relates to a novel polymer adsorbent material, and particularly to a novel adsorption resin having a specific adsorption effect on cephalosporin C, and a preparation method and application thereof. Background Art

[0002] Cephalosporin is a broad-spectrum semi-synthetic antibiotic with a β-lactam ring, and shows broad-spectrum antibacterial activity against Gram-positive bacteria, Gram-negative bacteria and spirochetes. Cephalosporin has the advantages of strong bactericidal power, low toxicity, few allergic reactions, and being more stable to acid and β-lactamase than penicillin, so it is widely used in the clinical and pharmaceutical fields. Cephalosporin C is a key intermediate for preparing cephalosporin antibiotics. The production of cephalosporin C in China accounts for more than 80% of the world's total output, and the output of cephalosporin C has been continuously increasing in recent years.

[0003] Cephalosporin C is generally first produced by fermentation, and then extracted and separated by methods such as ion exchange method, solvent extraction method, complex salt precipitation method, membrane separation method, resin adsorption method, etc. Since the free molecule of cephalosporin C is acidic, when the ion exchange method is used to adsorb and separate cephalosporin C, only an anion exchange resin can be used for extraction. However, strong basic anion exchange resins have the problem of difficult desorption and are not suitable for the extraction of cephalosporin C. Therefore, it is most common to use weakly basic ion exchange resins to adsorb cephalosporin C, but there are also problems such as poor selectivity and low yield. The solvent extraction method mainly adds an acyl chloride to the fermentation broth to mask the basicity of its side-chain amino group, making the amino group of cephalosporin C become an N-acylated derivative, controlling the pH of the solution to be acidic, and then extracting with a solvent such as dichloromethane. The cephalosporin C obtained by this method has a high yield and good quality, but the loss of the solvent and the acylating reagent is too large, resulting in a high cost. Therefore, this method is not widely used. The complex salt precipitation method is mainly based on the fact that cephalosporin C can form a precipitate with divalent metals such as Cu 2+ and Zn 2+ to form a precipitate, and this precipitate belongs to a poorly soluble complex salt crystal. This method is simple to operate and has a high yield. However, the selectivity of cephalosporin C heavy metal salting out crystallization is poor, and the cephalosporin C needs to reach an extremely high concentration when the crystal precipitates. Therefore, this method is usually combined with other methods to further improve the purity of cephalosporin C.

[0004] With the development of macroporous adsorbents, the separation of cephalosporin C by adsorption has been widely used at home and abroad. Its advantage is that the high specific surface area of ​​macroporous adsorbents has a large adsorption capacity for cephalosporin C, and cephalosporin C can be selectively adsorbed through van der Waals force, while inorganic ions and other polar impurities in the fermentation broth are not adsorbed by macroporous adsorbents through salting out, which will improve the quality and yield of cephalosporin C products at the same time. As a kind of macroporous adsorbent, adsorption resin plays a pivotal role in the adsorption and separation process of cephalosporin C. For example, patent document CN101288841 provides a macroporous adsorption resin for cephalosporin C extraction and a preparation method thereof, that is, a macroporous adsorption resin matrix with polar groups is prepared by adjusting the amount of porogen and adding polar monomers to change the pore size distribution and specific surface area of ​​the resin by using a traditional suspension polymerization method, and then a Friedel-Crafts alkylation reaction is carried out under the condition of Lewis acid as a catalyst, and finally a macroporous adsorption resin with selective adsorption for cephalosporin C is obtained. As the market requirements for product purity increase, the selectivity of this resin for cephalosporin C is too poor, and the purity of the obtained product is too low, which can no longer meet the market demand. For example, patent document CN104844744A also provides a resin with specific adsorption for cephalosporin C and its preparation method, that is, an aromatic alkylating agent is used in the Friedel-Crafts alkylation reaction to perform additional cross-linking on the macroporous adsorption matrix, thereby improving the adsorption of the resin to cephalosporin C. This patent document simply increases the density of benzene rings in the resin skeleton structure and improves the selectivity of the resin to cephalosporin C through the π-π conjugation effect. Although the selectivity and adsorption amount are improved, the resin has poor anti-pollution performance. In actual use, the operating cycle is too short, resulting in increased production costs. Therefore, it is necessary to develop a new adsorption resin with large adsorption capacity for cephalosporin C, high selectivity, good anti-pollution performance and stable performance for the extraction and separation of cephalosporin C. SUMMARY OF THE INVENTION

[0005] The purpose of the present invention is to provide an adsorption resin and a preparation method thereof and an application thereof in the extraction of cephalosporin C, so as to solve the problem that the selectivity, adsorption capacity and anti-pollution performance of the existing macroporous adsorption resin cannot be taken into account in the extraction process of cephalosporin C.

[0006] The present invention is achieved through the following technical solutions:

[0007] A method for preparing an adsorption resin, comprising:

[0008] S1: dissolving the dispersant in water to obtain a water phase; mixing the monomer, porogen, crosslinking agent and initiator to obtain an oil phase; adding the oil phase to the water phase to perform a polymerization reaction to obtain a copolymer matrix;

[0009] S2: Carry out a post-crosslinking reaction on the copolymer matrix and an additional crosslinking agent in the presence of a catalyst to obtain a post-crosslinked macroporous adsorption resin;

[0010] S3: Carry out halogenation modification on the post-crosslinked macroporous adsorption resin, and control the halogen content after halogenation modification within the range of 6% - 12% to obtain an adsorption resin.

[0011] Preferably, in S1, the monomer is one or more of divinylbenzene, styrene, ethylstyrene, and vinyl acrylate; the mass ratio of the monomer, porogen, and initiator is 100:(125 - 175):(0.5 - 1).

[0012] Preferably, S2 is specifically: Mix the copolymer matrix and the additional crosslinking agent, add a solvent for swelling. After swelling for 3 - 5 hours, add a catalyst and react at 55 - 65°C for 3 - 10 hours, then add a catalyst and react at 80 - 100°C for 8 - 12 hours. After the reaction ends, boil the resin beads to recover the solvent, wash with water until neutral to obtain a post-crosslinked macroporous adsorption resin.

[0013] Preferably, in S2, the additional crosslinking agent is one or more of 4,4'-dichloromethyl biphenyl, dichlorobenzyl, and p-xylylene dichloride; the mass ratio of the copolymer matrix to the additional crosslinking agent is 100:(5 - 25), and the mass ratio of the copolymer matrix to the catalyst is 100:(10 - 25).

[0014] Preferably, S3 is specifically: Add the post-crosslinked macroporous adsorption resin to water and place it in an ice-water bath. While stirring, dropwise add HX acid to adjust the pH to 1 - 4, then add an oxidizing agent and react for 5 - 10 hours. Then, take a sample to detect the halogen content in the resin. If the halogen content is lower than 6%, supplement the oxidizing agent or HX acid and continue the reaction. After the halogen content meets 6% - 12%, wash with water until neutral and discharge.

[0015] Preferably, S3 is specifically: Add the post-crosslinked macroporous adsorption resin to water and place it in an ice-water bath. While stirring, dropwise add an acid to adjust the pH to between 1 - 2, then add an alkali metal halide, stir to dissolve, then add an oxidizing agent and react for 5 - 10 hours. Then, take a sample to detect the halogen content in the resin. If the halogen content is lower than 6%, supplement the oxidizing agent or alkali metal halide and continue the reaction. After the halogen content meets 6% - 12%, wash with water until neutral and discharge.

[0016] Furthermore, the oxidizing agent is a hydrogen peroxide solution, and the volume fraction of the hydrogen peroxide solution is 20% - 26%.

[0017] Furthermore, the HX acid is hydrochloric acid or hydrobromic acid, and the alkali metal halide is potassium bromide, sodium bromide, potassium chloride, or sodium chloride.

[0018] An adsorption resin obtained by using the described preparation method.

[0019] Application of the described adsorption resin in cephalosporin C extraction.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] The present invention prepares a resin matrix by suspension polymerization and then performs post-crosslinking on the resin matrix. Post-crosslinking can increase the specific surface area of the resin, thereby improving the resin adsorption capacity. However, after post-crosslinking, the micropores of the resin increase, resulting in low anti-pollution ability. Therefore, the present invention performs halogenation modification on the post-crosslinked adsorption resin. Halogenation modification reduces the crosslinking degree of the resin and simultaneously makes the resin backbone structure contain a certain amount of halogen elements; after the halogenation reaction, the crosslinking degree of the macroporous adsorption resin decreases, and the number of micropores inside the resin decreases. The fewer the micropores, the easier the resin is to be desorbed during the desorption process, and the better the regeneration performance, and its anti-pollution performance is stronger. Finally, it achieves the improvement of resin performance and the enhancement of resin anti-pollution ability. The halogen content must be controlled within the range of 6% - 12%. If the halogen content is too low, the modification of the resin is not thorough enough, and the anti-pollution performance of the resin cannot be improved; if the halogen content is too high, the pore structure of the resin is severely damaged during the halogenation reaction in a strong acid environment, thereby reducing the adsorption capacity of the resin.

[0022] The adsorption resin prepared by the present invention has the advantages of high selectivity, large adsorption capacity for cephalosporin C, and high purity of the cephalosporin finished product. It has the advantages of good anti-pollution performance, easy desorption, stable operation, and long service life during the extraction process of cephalosporin C, and can be used for the efficient extraction of cephalosporin C from cephalosporin fermentation broth. It solves the problem that the selectivity, adsorption capacity, and anti-pollution ability cannot be taken into account simultaneously in the prior art during the extraction process of cephalosporin C. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 It is the pore size distribution diagram of Example 3 and Comparative Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0024] To further understand the present invention, the present invention will be described below in conjunction with embodiments. These descriptions are only to further explain the features and advantages of the present invention and are not intended to limit the claims of the present invention.

[0025] The preparation method of the adsorption resin of the present invention is by suspension polymerization, and specifically includes the following steps:

[0026] S1: Add a dispersant to deionized water, heat and dissolve it to prepare an aqueous phase; then mix monomers, porogens, crosslinking agents and initiators, stir evenly as the oil phase; add the oil phase to the prepared aqueous solution, let it stand for layering, and adjust the stirring speed to control the particle size after the oil phase and aqueous phase are completely layered, react at 75-95 °C for 8-12 hours; after the reaction, wash the surface of the resin with hot water to remove the dispersant, remove the porogen inside the resin, and finally wash with water and dry to obtain a copolymer matrix.

[0027] S2: Add the copolymer matrix prepared in step S1 and an additional crosslinking agent to a reaction kettle, and add a certain amount of solvent for swelling. After swelling for 3-5 hours, add a catalyst and react at 55-65 °C for 3-10 hours, and finally add a catalyst and react at 80-100 °C for 8-12 hours. After the reaction, boil the beads to recover the solvent,

[0028] wash with water until neutral, and finally obtain a post-crosslinked macroporous adsorption resin.

[0029] S3: Carry out halogenation modification on the post-crosslinked macroporous adsorption resin obtained in step S2 to obtain an adsorption resin.

[0030] In step S1, the dispersant is one or more of polyvinyl alcohol, sodium carboxymethyl cellulose, hydroxyethyl cellulose and lignin. The type and specific dosage of the dispersant should be determined in combination with the dosage of monomers and porogens.

[0031] In step S1, the monomers are one or more of divinylbenzene, styrene, ethylstyrene, vinyl acrylate; the initiator is benzoyl peroxide; the porogen is any one or more of toluene, xylene, C 7 ~C 12 saturated alkanes, methyl isobutyl carbinol, methylcyclohexane, dichloroethane.

[0032] The mass-volume ratio of the dispersant to the aqueous phase in step S1 is (0.5-1.5):100, the mass ratio of the total amount of monomers, porogens and initiators is 100:(125-175):(0.5-1), the mass ratio of the copolymer matrix to the additional crosslinking agent in step S2 is 100:(5-25), and the mass ratio of the copolymer matrix to the catalyst is 100:(10-25).

[0033] In step S2, the additional crosslinking agent is one or more of 4,4'-dichloromethylbiphenyl, dichlorobenzyl, p-phenylenedichloride and other benzyl chlorides.

[0034] In step S2, the solvent is dichloroethane or 1,1,2-trichloroethane.

[0035] In step S2, the catalyst is anhydrous ferric chloride or anhydrous zinc chloride.

[0036] Step S3 specifically is: adding the post-crosslinked macroporous adsorption resin obtained in step S2 into a reaction kettle containing deionized water, placing it in an ice-water bath, while stirring, dropping HX acid, adjusting the pH to 1-4, then slowly dropping a hydrogen peroxide solution, reacting for 5-10 hours, sampling, detecting the halogenated content in the resin by the Volhard method. When the halogenated content is low, add more hydrogen peroxide solution or acid. After the halogen content is qualified, wash it with water until neutral and then discharge.

[0037] Alternatively, step S3 specifically is: adding the post-crosslinked macroporous adsorption resin obtained in step S2 into a reaction kettle containing deionized water, placing it in an ice-water bath, while stirring, dropping an acid to adjust the pH to between 1-2, then adding an alkali metal halide, stirring until completely dissolved, then slowly dropping a hydrogen peroxide solution, reacting for 5-10 hours, sampling, detecting the halogenated content in the resin by the Volhard method. When the halogenated content is low, add more hydrogen peroxide solution or acid. After the halogen content is qualified, wash it with water until neutral and then discharge.

[0038] The reaction in step S3 mainly generates halogen elements (such as Cl 2 、Br 2 etc.) by dropping sulfuric acid or HX acid (where X is a halogen atom) under the action of the oxidant hydrogen peroxide. The generated halogen elements have high activity and undergo substitution reactions on the resin skeleton, reducing the crosslinking degree of the resin, and at the same time making the resin skeleton structure contain a certain amount of halogen elements; after the halogenation reaction, the crosslinking degree of the macroporous adsorption resin decreases, the number of micropores inside the resin decreases, the fewer the micropores, the easier the resin is to be desorbed during the desorption process, the better the regeneration performance, and the stronger its anti-pollution performance, ultimately achieving the improvement of the resin performance and the enhancement of the anti-pollution property of the resin.

[0039] In step S3, the volume fraction of the hydrogen peroxide solution is 20%-26%, and the mass percentage of halogen measured by the Volhard method must be controlled within the range of 6%-12%. If the halogen content is too low, the modification of the resin is not thorough enough, and the anti-pollution performance of the resin cannot be improved; if the halogenated content is too high, the pore structure of the resin is damaged greatly during the halogenation reaction in a strong acid environment, thus reducing the adsorption capacity of the resin.

[0040] The adsorption resin of the present invention has the advantages of high selectivity, large adsorption capacity for cephalosporin C, and high purity of the cephalosporin finished product, and has the advantages of good anti-pollution performance, easy desorption, stable operation, and long service life during the extraction process of cephalosporin C. It can be used for efficiently extracting cephalosporin C from cephalosporin fermentation broth.

[0041] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the attached tables in the embodiments of the present invention. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. Usually, the components of the present invention described and shown in the attached tables here can be arranged and designed in various different configurations. Therefore, the following detailed description of the embodiments of the present invention provided in the attached tables is not intended to limit the scope of the claimed present invention, but merely represents the selected embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts fall within the scope of protection of the present invention.

[0042] Example 1

[0043] A novel adsorption resin for cephalosporin C extraction and its preparation method

[0044] Add 500 ml of water and 7.5 g of sodium carboxymethylcellulose to a 1000 ml three-necked flask equipped with stirring, and stir until completely dissolved to prepare an aqueous phase; weigh 20 g of divinylbenzene with a content of 80%, 80 g of styrene, 175 g of toluene, and 1 g of benzoyl peroxide, mix them evenly to prepare an oil phase, add the oil phase mixture to the three-necked flask, let it stand for layer separation, adjust the stirring speed to control the droplet size, then keep stirring at a constant speed and slowly heat up to 75 °C for reaction for 3 hours and 80 °C for reaction for 9 hours. After the reaction is completed, wash the residual dispersant on the resin surface with hot water, then extract the pore-forming agent inside the resin with methylal, wash with water, dry until the water content ≤ 2%, and screen out the copolymer matrix between 0.2 and 0.6 mm.

[0045] Weigh 50 g of the copolymer matrix and 12.5 g of 4,4'-dichloromethylbiphenyl, add 400 ml of dichloroethane, stir and swell at room temperature for 3 hours, then add 5 g of anhydrous ferric chloride, and heat up to 55 °C for reaction for 6 hours; finally add 7.5 g of anhydrous ferric chloride and react at 80 °C for 8 hours. After the reaction is completed, add water to the system, heat up to the azeotropic point of water and dichloroethane, recover dichloroethane, wash the resin with water until neutral, and finally obtain a yellowish-brown opaque macroporous adsorption resin.

[0046] Add the yellowish-brown opaque macroporous adsorption resin to a reaction kettle containing deionized water, add 25 g of potassium bromide, place it in an ice-water bath, adjust the pH to 1.0 with concentrated sulfuric acid solution, then slowly dropwise add 10 ml of 26% hydrogen peroxide solution, after reacting for 5 hours, use the Volhard method to detect that the chlorine content in the resin is 11.95%, and finally wash with water until neutral and discharge.

[0047] Example 2

[0048] A novel adsorption resin for cephalosporin C extraction and its preparation method

[0049] Add 500 ml of water and 2.5 g of hydroxyethyl cellulose into a 1000 ml three-necked flask equipped with stirring, and stir until completely dissolved to prepare an aqueous phase; weigh 100 g of divinylbenzene with a content of 63%, 110 g of toluene, 15 g of n-heptane and 0.5 g of benzoyl peroxide, mix them evenly to prepare an oil phase, add the oil phase mixture into the three-necked flask, let it stand and separate layers, adjust the stirring speed to control the droplet size, then keep stirring at a constant speed and slowly heat up to 75 °C for reaction for 3 hours, 80 °C for reaction for 3 hours, and 85 °C for reaction for 6 hours. After the reaction is completed, wash the residual dispersant on the resin surface with hot water, then extract the pore-forming agent inside the resin with methylal, wash with water, dry until the water content ≤ 2%, and screen out the copolymer matrix between 0.2 and 0.6 mm.

[0050] Weigh 50 g of the copolymer matrix and 2.5 g of p-xylylene dichloride, add 300 ml of 1,1,2-trichloroethane, stir and swell at room temperature for 5 hours, then add 2.5 g of anhydrous ferric chloride, heat up to 55 °C and react for 3 hours; finally add 2.5 g of anhydrous ferric chloride and react at 100 °C for 12 hours. After the reaction is completed, add water to the system, heat up to the azeotropic point of water and 1,1,2-trichloroethane, recover dichloroethane, wash the resin with water until neutral, and finally obtain a yellow opaque macroporous adsorption resin.

[0051] Add the yellow opaque macroporous adsorption resin into a reaction kettle containing deionized water, place it in an ice-water bath, add 30% hydrochloric acid solution to adjust the pH to 4.0, then slowly dropwise add 15 ml of 20% hydrogen peroxide solution, after reacting for 10 hours, use the Volhard method to detect that the chlorine content in the resin is 8.16%, and finally wash with water until neutral, and discharge the material.

[0052] Example 3

[0053] A novel adsorption resin for cephalosporin C extraction and its preparation method

[0054] Add 500 ml of water, 3 g of polyvinyl alcohol and 2 g of sodium carboxymethylcellulose into a 1000 ml three-necked flask equipped with stirring, and stir until completely dissolved to prepare an aqueous phase; weigh 100 g of divinylbenzene with a content of 80%, 100 g of toluene, 50 g of methylcyclohexane and 1.0 g of benzoyl peroxide, mix them evenly to prepare an oil phase, add the oil phase mixture into the three-necked flask, let it stand and separate layers, adjust the stirring speed to make it into uniform droplets of a certain size, then keep stirring at a constant speed and slowly heat up to 80 °C for reaction for 6 hours, 85 °C for reaction for 6 hours. After the reaction is completed, wash the residual dispersant on the resin surface, then extract the pore-forming agent with methylal, wash with water, dry until the water content ≤ 2%, and screen out the copolymer matrix between 0.2 and 0.6 mm.

[0055] Weigh 50 g of copolymer matrix and 7.5 g of 4,4'-dichloromethylbiphenyl, add 350 ml of dichloroethane, stir and swell at room temperature for 3 hours, then add 5 g of anhydrous ferric chloride, raise the temperature to 60 °C and react for 10 hours; finally add 7.5 g of anhydrous ferric chloride and react at 80 °C for 10 hours. After the reaction, add water to the system, heat to the azeotropic point of water and dichloroethane, recover dichloroethane, wash the resin with water until neutral, and finally obtain a yellow opaque macroporous adsorption resin.

[0056] Add the yellow opaque macroporous adsorption resin to a reaction kettle containing deionized water, place it in an ice-water bath, adjust the pH to between 1 and 2 with hydrobromic acid solution, stir until completely dissolved, then slowly dropwise add 10 ml of 26% hydrogen peroxide solution, after reacting for 10 hours, use the Volhard method to detect that the bromine content in the resin is 6.35%, and finally wash with water until neutral and discharge.

[0057] Comparative Example 1 (without halogenation modification)

[0058] Add 500 ml of water, 3 g of polyvinyl alcohol, and 2 g of sodium carboxymethylcellulose to a 1000 ml three-necked flask equipped with stirring, stir until completely dissolved to prepare an aqueous phase; weigh 100 g of 80% divinylbenzene, 100 g of toluene, 50 g of methylcyclohexane, and 1.0 g of benzoyl peroxide, mix them evenly to prepare an oil phase, add the oil phase mixture to the three-necked flask, let it stand and separate layers, adjust the stirring speed to make it into uniform droplets of a certain size, then keep stirring at a constant speed and slowly raise the temperature to 80 °C and react for 6 hours, and react at 85 °C for 6 hours. After the reaction, wash the residual dispersant on the resin surface, then extract the pore-forming agent with methylal, wash with water, dry until the water content ≤ 2%, and screen out the copolymer matrix between 0.2 and 0.6 mm.

[0059] Weigh 50 g of copolymer matrix and 7.5 g of 4,4'-dichloromethylbiphenyl, add 350 ml of dichloroethane, stir and swell at room temperature for 3 hours, then add 5 g of anhydrous ferric chloride, raise the temperature to 60 °C and react for 10 hours; finally add 7.5 g of anhydrous ferric chloride and react at 80 °C for 10 hours. After the reaction, add water to the system, heat to the azeotropic point of water and dichloroethane, recover dichloroethane, wash the resin with water until neutral, and finally obtain a yellow opaque macroporous adsorption resin.

[0060] Comparative Example 2 (without additional crosslinking and halogenation modification)

[0061] Add 500 ml of water, 3 g of polyvinyl alcohol, and 2 g of sodium carboxymethyl cellulose to a 1000-ml three-necked flask equipped with stirring, and stir until completely dissolved to prepare an aqueous phase; weigh 100 g of divinylbenzene with a content of 80%, 100 g of toluene, 50 g of methylcyclohexane, and 1.0 g of benzoyl peroxide, mix them evenly to prepare an oil phase, add the oil phase mixture to the three-necked flask, let it stand for layering, adjust the stirring speed to make it into uniform droplets of a certain size, then keep stirring at a constant speed and slowly heat up to 80 °C for reaction for 6 hours and 85 °C for reaction for 6 hours. After the reaction is completed, wash away the dispersant remaining on the resin surface, then extract the pore-forming agent with methylal, wash with water, dry until the water content is ≤2%, and screen out the copolymer matrix between 0.2 and 0.6 mm.

[0062] Weigh 50 g of the copolymer matrix, add 350 ml of dichloroethane, stir and swell at room temperature for 3 hours, then add 5 g of anhydrous ferric chloride, heat up to 60 °C and react for 10 hours; finally add 7.5 g of anhydrous ferric chloride and react at 80 °C for 10 hours. After the reaction is completed, add water to the system, heat up to the azeotropic point of water and dichloroethane, recover dichloroethane, wash the resin with water until neutral, and finally obtain a yellow opaque macroporous adsorption resin.

[0063] Comparative Example 3 (Excessive halogenation reaction modification)

[0064] Add 500 ml of water, 3 g of polyvinyl alcohol, and 2 g of sodium carboxymethyl cellulose to a 1000-ml three-necked flask equipped with stirring, and stir until completely dissolved to prepare an aqueous phase; weigh 100 g of divinylbenzene with a content of 80%, 100 g of toluene, 50 g of methylcyclohexane, and 1.0 g of benzoyl peroxide, mix them evenly to prepare an oil phase, add the oil phase mixture to the three-necked flask, let it stand for layering, adjust the stirring speed to make it into uniform droplets of a certain size, then keep stirring at a constant speed and slowly heat up to 80 °C for reaction for 6 hours and 85 °C for reaction for 6 hours. After the reaction is completed, wash away the dispersant remaining on the resin surface, then extract the pore-forming agent with methylal, wash with water, dry until the water content is ≤2%, and screen out the copolymer matrix between 0.2 and 0.6 mm.

[0065] Weigh 50 g of the copolymer matrix and 7.5 g of 4,4'-dichloromethylbiphenyl, add 350 ml of dichloroethane, stir and swell at room temperature for 3 hours, then add 5 g of anhydrous ferric chloride, heat up to 60 °C and react for 10 hours; finally add 7.5 g of anhydrous ferric chloride and react at 80 °C for 10 hours. After the reaction is completed, add water to the system, heat up to the azeotropic point of water and dichloroethane, recover dichloroethane, wash the resin with water until neutral, and finally obtain a yellow opaque macroporous adsorption resin.

[0066] Add yellow opaque macroporous adsorption resin into a reaction kettle containing deionized water, place it in an ice-water bath, slowly dropwise add an excessive amount of hydrobromic acid solution, keep the system in a strong acid environment, then slowly dropwise add 50 ml of 26% hydrogen peroxide solution. After reacting for 20 hours, detect the bromine content in the resin by the Volhard method, which is 17.95%. Finally, wash it with water until neutral and discharge the material.

[0067] The pore structure parameters of the resin prepared in the present invention are detected by a specific surface area and pore size analyzer. The results are shown in Table 1. After additional cross-linking of the resin, the specific surface area of the resin has been improved to a certain extent. However, at the same time, the number of micropores inside the resin ( the following small pores) also increases significantly. After appropriate improvement by halogenation reaction, the number of micropores inside the resin significantly decreases; while without additional cross-linking reaction or excessive improvement by halogenation reaction, the specific surface area of the resin is relatively low. Next, the extraction effect of the resin prepared under different process conditions on cephalosporin C will be verified by specific adsorption experiments.

[0068] The pore structure parameters of the adsorption resin prepared in the above examples are shown in Table 1:

[0069] Table 1: Pore structure parameters of the adsorption resin in each example

[0070]

[0071] Verification of the adsorption of cephalosporin C

[0072] Experimental method:

[0073] S1: Take the cephalosporin C fermentation broth with a titer of about 10,000, and adjust the pH between 2.5 and 3.0.

[0074] S2: Take 100 ml of wet resin of the adsorption resins prepared in Example 1, Example 2, Example 3, Comparative Example 1, Comparative Example 2, and Comparative Example 3 respectively and load them into a resin column. Soak them with 2 BV (BV is the volume of the resin) of alkaline alcohol solution for 3 hours, wash them clean with production water and then acidify, acid wash until the pH is between 2.6 and 2.8, and then feed at a flow rate of 1 BV / h. After feeding, wash with 3 BV of pure water to remove impurities, and then desorb with 2% sodium bicarbonate solution at a desorption flow rate of 0.5 BV / h; collect the adsorption mixture, desorption solution, and top water mixture, and determine the titer by high performance liquid chromatography. Finally, calculate the adsorption capacity, desorption rate, and product purity, etc.

[0075] S3: After regenerating the resin after the first cycle of desorption with acid and alkali, conduct the next cycle of adsorption experiment, repeat three cycles, and finally test the content of each component.

[0076] The extraction effect of the resin prepared by the present invention on cephalosporin C is shown in Table 2. It can be seen from the results that the adsorption capacity for cephalosporin C is above 60 g / L, the desorption rate is above 95%, and the purity of cephalosporin C is above 98%. Through comparison, it is found that although the resin obtained by the additional cross-linking method has a large adsorption capacity for cephalosporin C, after several operation cycles, the adsorption capacity gradually decreases. Combining with Figure 1 the pore size distribution, it can be known that after additional cross-linking, there are more micropores inside the resin. After this part of the pores adsorb cephalosporin C, it is very difficult to desorb it, resulting in pore blockage, reducing the anti-pollution performance of the resin and shortening the service life of the resin; while after appropriate halogenation reaction improvement, the number of micropores inside the resin significantly decreases. Therefore, the adsorption capacity of the resin for cephalosporin C remains stable. After the resin after additional cross-linking is improved by halogenation, the number of micropores significantly decreases, mainly because during the halogenation reaction, the generated Cl 2 or Br 2 undergoes a substitution reaction on the benzene ring, resulting in a decrease in the cross-linking degree inside the resin, thereby causing a decrease in the number of micropores inside the resin; after the cross-linking degree is damaged, the freedom degree of the resin skeleton increases, and it is more inclined to stretch towards the region with more macropores and less steric hindrance, thereby causing a decrease in the number of macropores inside the resin, the overall pore size becomes smaller, and the distribution is more concentrated. After the halogenation reaction, the overall pore channel distribution is more concentrated, which also ensures that while the number of micropores in the resin decreases, its specific surface area does not decrease but increases instead. In the actual experimental process, it is specifically manifested that the number of effective pores for adsorbing cephalosporin C increases, mainly the number of pores between 12 and 18 nm significantly increases. Through a large number of experiments, it is summarized that this part of the pores has better selectivity for cephalosporin through the size screening effect. Therefore, the adsorption capacity for cephalosporin C also increases, and after three cycles of adsorption and desorption experiments, the resin maintains a stable adsorption and desorption effect.

[0077] In order to more clearly illustrate the practical effect of the present invention, on the basis of Example 3, the processes were adjusted to prepare resin samples under different conditions, that is, the polystyrene matrix in Example 3 was prepared by three processes: no halogenation reaction, no additional crosslinking and halogenation reaction, and excessive halogenation reaction. The resin samples were verified in the extraction process of cephalosporin C. The results are shown in Table 3. Although the resin without halogenation improvement has a higher adsorption capacity, its anti-pollution performance is poor. After three cycles of adsorption experiments, the adsorption capacity decreased by more than 20%; compared with Example 3, the resin without additional crosslinking and halogenation improvement has a significantly lower adsorption capacity for cephalosporin C in the first cycle than Example 3, and in the later experimental process, the adsorption capacity also decreased rapidly, showing not only a low adsorption capacity for cephalosporin C, but also a good adsorption capacity for cephalosporin C. Moreover, the anti-pollution performance is also poor, mainly because no additional cross-linking reaction is carried out, the specific surface area of ​​the resin is low, and the adsorption capacity of cephalosporin C is also low. At the same time, no halogenation improvement is carried out, and the anti-pollution ability of the resin is also reduced; previous experiments have proved that the halogenation reaction improvement has a certain improvement on the anti-pollution performance of the resin, but at the same time, the pore structure of the resin is also greatly damaged. In order to compare with the present invention, a destructive test was carried out on Example 3, which greatly improved the halogenation degree of the resin (halogen content is 17.95%). From the structure of the resin itself, it can be found that excessive halogenation improvement of the resin is mainly manifested in a significant reduction in the specific surface area of ​​the resin, and in the process of cephalosporin C extraction, it is mainly reflected in the greatly reduced adsorption amount of cephalosporin C. The anti-pollution performance of the resin has also been improved to a certain extent. After three cycles of operation, the adsorption amount of the resin remains stable. Therefore, excessive halogenation modification still cannot solve the need to meet both adsorption amount and anti-pollution performance.

[0078] In summary, after additional cross-linking and appropriate halogenation reaction improvement, the resin prepared by the present invention has significantly improved anti-pollution performance while maintaining a stable resin adsorption capacity, and the overall extraction effect of cephalosporin C is also stable, thus solving the problem of the prior art that selectivity, adsorption capacity and anti-pollution performance cannot be taken into account in the process of cephalosporin C extraction.

[0079] Table 2: Cephalosporin C adsorption experimental data

[0080]

[0081] Table 3: Comparative test data of cephalosporin C adsorption

[0082]

[0083] Note: Deacetyl cephalosporin C (DCPC) and deacetyloxy cephalosporin C (DOCPC) are the two main impurities in cephalosporin C (CPC) fermentation broth.

[0084] The above content is only for explaining the technical idea of the present invention and cannot be used to limit the protection scope of the present invention. Any modification made on the basis of the technical solution in accordance with the technical idea proposed by the present invention falls within the protection scope of the claims of the present invention.

Claims

1. A method for preparing an adsorption resin, characterized in that: include: S1: dissolving a dispersant in water to obtain a water phase; mixing a monomer, a porogen, a crosslinking agent and an initiator to obtain an oil phase; adding the oil phase to the water phase to perform a polymerization reaction to obtain a copolymer matrix; S2: post-crosslinking the copolymer matrix and the additional crosslinking agent in the presence of a catalyst to obtain a post-crosslinked macroporous adsorption resin; S3: halogen-modifying the post-crosslinked macroporous adsorption resin, wherein the halogen content of the halogen-modified resin is controlled within a range of 6% to 12%, to obtain an adsorption resin; S2 is specifically as follows: the copolymer matrix is ​​mixed with the additional crosslinking agent, and a solvent is added to swell the mixture. After swelling for 3 to 5 hours, a catalyst is added to react at 55 to 65° C. for 3 to 10 hours, and then a catalyst is added to react at 80 to 100° C. for 8 to 12 hours. After the reaction is completed, the pellets are boiled to recover the solvent, and the pellets are washed with water until neutral to obtain a post-crosslinked macroporous adsorption resin; the additional crosslinking agent is one or more of 4,4'-dichloromethylbiphenyl, dichlorobenzyl and dichloroterephthalene; the mass ratio of the copolymer matrix to the additional crosslinking agent is 100:(5 to 25), and the mass ratio of the copolymer matrix to the catalyst is 100:(10 to 25); S3 is specifically as follows: adding the post-crosslinked macroporous adsorption resin into water and placing it in an ice water bath, adding HX acid dropwise while stirring, adjusting the pH to 1-4, and then adding an oxidant. After reacting for 5-10 hours, sampling is performed to detect the halogen content in the resin. If the halogen content is less than 6%, the oxidant or HX acid is added to continue the reaction. After the halogen content reaches 6%-12%, the material is washed with water until it is neutral. Alternatively, S3 is specifically as follows: adding a post-crosslinked macroporous adsorption resin to water and placing it in an ice water bath, adding acid dropwise while stirring, adjusting the pH to between 1 and 2, then adding an alkali metal halide, stirring to dissolve, and then adding an oxidant. After reacting for 5 to 10 hours, sampling is performed to detect the halogen content in the resin. If the halogen content is less than 6%, additional oxidant or alkali metal halide is added to continue the reaction. After the halogen content reaches 6% to 12%, the material is washed with water until it is neutral.

2. The method for preparing the adsorption resin according to claim 1, characterized in that: In S1, the monomer is one or more of divinylbenzene, styrene, ethyl styrene and vinyl acrylate; the mass ratio of the monomer, the porogen and the initiator is 100: (125-175): (0.5-1).

3. The method for preparing the adsorption resin according to claim 1, characterized in that: The oxidant is a hydrogen peroxide solution, and the volume fraction of the hydrogen peroxide solution is 20%~26%.

4. The method for preparing an adsorption resin according to claim 1, characterized in that: The HX acid is hydrochloric acid or hydrobromic acid, and the alkali metal halide is potassium bromide, sodium bromide, potassium chloride or sodium chloride.

5. The adsorption resin obtained by the preparation method according to any one of claims 1 to 4.

6. Use of the adsorption resin according to claim 5 in the extraction of cephalosporin C.

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