Synthesis method and application of amino functional group-containing resin

Abstract

The invention discloses a synthesis method of resin containing amino functional groups, and belongs to the technical field of adsorption resin. The synthesis method comprises the following steps: (1) preparing a water phase; (2) preparing an oil phase; (3) polymerization: slowly adding the oil phase into the water phase to prepare resin white balls; (4) extracting a pore-foaming agent; (5) dibromoethane grafting: adding NaH into the fully swelled resin in tetrahydrofuran, stirring at 0 DEG C until the reaction is complete, and adding 1, 2-dibromoethane for grafting reaction; and (6) amino functionalization: adding ammonia water and ethidene diamine into the resin which is fully swelled by absolute ethyl alcohol, and fully reacting to obtain amino-containing resin. The specific surface area of the synthesized resin is 450-600m < 2 > / g, the single particle strength is greater than 6N, the bilirubin at a long distance can be effectively captured, and the bilirubin adsorption capacity of the resin is 35.0-45.0 mg / g.

Description

Technical Field

[0001] This invention belongs to the field of adsorption resin technology, specifically relating to amino-containing bilirubin adsorption resin. Background Technology

[0002] Bilirubin is a metabolic byproduct produced by the breakdown of aging red blood cells in the human body. Excessive accumulation can be toxic to organs and tissues, leading to serious conditions such as liver failure and neonatal jaundice. The clearance of bilirubin mainly relies on the synergistic action of the liver, intestines, and kidneys, and is also influenced by the body's metabolic state.

[0003] Under normal circumstances, the liver is the core organ for clearing bilirubin, and the intestines and kidneys also participate in the final excretion. If there is an abnormality in the body, bilirubin will accumulate in the body and cause jaundice. Common causes include: excessive production, liver processing disorders, and obstructed excretion. Therefore, there is an urgent need for efficient auxiliary clearance methods.

[0004] Bilirubin is lipid-soluble and readily binds to albumin, making it difficult to remove effectively with conventional hemodialysis. Adsorption technology uses physical or chemical interactions (such as hydrophobic binding, electrostatic attraction, and specific binding) between the adsorbent and bilirubin to "capture" and remove it from the blood.

[0005] Commonly used adsorbents include activated carbon and resins, but existing adsorbents or adsorption methods have many drawbacks. For example, activated carbon has high adsorption efficiency but poor biocompatibility, and carbon particle shedding can easily cause thrombosis; although resins can remove bilirubin, they disrupt electrolyte balance and cause severe platelet loss; drugs and conventional hemodialysis have limited bilirubin removal rates, especially for conjugated bilirubin. Therefore, there is an urgent need to develop an adsorbent material with good bilirubin adsorption properties and few side effects. Summary of the Invention

[0006] To address the aforementioned problems, this invention provides a method for synthesizing a resin containing amino functional groups and its application. The resin synthesized by this invention has a specific surface area of ​​450-600 m². 2 With a single particle strength greater than 6N, the resin of this invention can effectively capture bilirubin from a relatively long distance. The bilirubin adsorption capacity of the resin is 35.0-45.0 mg / g.

[0007] A method for synthesizing resins containing amino functional groups includes the following steps: (1) Preparation of aqueous phase: After adding water to the reactor and heating, add polyvinyl alcohol and stir until completely dissolved. Add magnesium sulfate and sodium carbonate and continue stirring until completely dissolved for later use. Add 25-35 grams of polyvinyl alcohol, 25-35 grams of magnesium sulfate, and 55-65 grams of sodium carbonate per liter of water to the aqueous phase.

[0008] (2) Preparation of oil phase: Divinylbenzene, hydroxyethyl methacrylate, styrene, dichlorohexane, toluene and dodecyl peroxide are mixed evenly to form the oil phase; The mass ratio of divinylbenzene, hydroxyethyl methacrylate, styrene, dichlorohexane, toluene, and dodecyl peroxide in the oil phase is 8-12:12-18:3-8:12-18:25-35:1.

[0009] (3) Polymerization: Slowly add the oil phase to the aqueous phase, stir until constant, and continue stirring at a constant speed for 10 min; raise the temperature from 45℃ to 78℃ at a rate of 5℃ / 10 min, and after the resin has set for 3 h, continue to raise the temperature from 78℃ to 85℃ at a rate of 5℃ / 10 min, keep it at the temperature for 2 hours, and continue to raise the temperature from 85℃ to 95℃ at a rate of 5℃ / 10 min, keep it at the temperature for 6 h, and then take it out. The mass ratio of the aqueous phase to the oil phase is 3-4:1.

[0010] (4) Extraction of porogen: Dry the above-synthesized resin to a moisture content of less than 10%, and sieve the resin with a particle size of 0.5-1.25 mm using a sieve separator; put the sieved resin into a container, add ethyl acetate, the amount of ethyl acetate should cover the resin, heat to 50°C, turn on the stirring, extract for 4 hours, then replace with new ethyl acetate and continue extraction, repeat 6 times to complete the extraction of porogen. (5) Under ice-melting conditions, the resin from which the porogen was extracted was added to tetrahydrofuran to fully swell, and NaH was added. The mixture was stirred at 0°C until the reaction was complete. 1,2-dibromoethane was added, and the mixture was reacted at room temperature for 24 hours under dry conditions. After the reaction was completed, the resin was filtered out and washed with tetrahydrofuran. Then it was extracted with anhydrous ethanol for 23 hours. In this step, the mass ratio of resin to tetrahydrofuran is 3:4-6, and the amounts of NaH and 1,2-dibromoethane added are both 45%-55% of the resin mass in this step.

[0011] (6) After the above-extracted resin is fully swollen with anhydrous ethanol, ammonia and ethylenediamine are added and reacted at 65°C for 24 hours. The resin is washed with water, and then the organic solvents and impurities outside the resin skeleton are extracted with anhydrous ethanol. The ethanol is washed away with purified water to obtain the resin containing amino groups. In this step, the resin and ethylenediamine have the same mass, and the amount of ammonia added is 50% of the mass of ethylenediamine.

[0012] The present invention also provides the application of the resin synthesized above in bilirubin adsorption.

[0013] The ammonia water used in this invention is conventional ammonia water with a concentration of 25%-28%.

[0014] The divinylbenzene raw material used in this invention has a divinylbenzene mass percentage of 80%, the hydroxyethyl methacrylate raw material has a hydroxyethyl methacrylate mass percentage of 99%, the styrene raw material has a styrene mass percentage of 99%, the dichloroethane raw material has a dichloroethane mass percentage of 99%, the toluene raw material has a toluene mass percentage of 99%, and the dodecyl peroxide raw material has a dodecyl peroxide mass percentage of 90%.

[0015] Compared with the prior art, the present invention has the following advantages: 1. The polymerization process utilizes two benign porogens, dichloroethane and toluene, to create pores. This results in a larger resin specific surface area, a longer resin phase separation time, longer polymer chains, and a more uniform pore structure, which is beneficial for bilirubin adsorption. The use of benign porogens also results in relatively smaller resin pores, preventing the adsorption of beneficial proteins (albumin). Additionally, the use of dodecyl peroxide extends the resin setting time, increasing resin strength. The synthesized resin has a specific surface area of ​​450-600 m². 2 / g, single particle strength greater than 6N.

[0016] 2. 1,2-Dibromoethane is selected as the linker arm. One end of the dibromoethane is grafted onto the resin skeleton, and the other end is combined with an amino group. This is equivalent to an amino-containing arm growing on the resin skeleton, which allows the functional group (amino group) to extend and effectively capture bilirubin at a greater distance.

[0017] 3. The resin of this invention mainly uses amino adsorption. The selected molecules containing two amino groups can combine with the grafted 1,2-dibromoethane on the one hand, and contribute functional amino groups on the other hand. The bilirubin adsorption capacity of this invention is 35.0-45.0 mg / g. Detailed Implementation

[0018] The present invention will be further illustrated by specific embodiments below. However, those skilled in the art should know that the specific embodiments of the present invention do not limit the present invention in any way, and any equivalent substitutions made on the basis of the present invention fall within the protection scope of the present invention. Example 1

[0019] 1. Polymerization: Place a 1000ml three-necked flask in a water bath, add a stirrer, add 500ml of purified water and 15g of polyvinyl alcohol to the three-necked flask, turn on the stirrer and heat to 45℃. After the polyvinyl alcohol is completely dissolved, add 15g of magnesium sulfate and 30g of sodium carbonate respectively, and continue stirring until it is completely dissolved and ready for use.

[0020] Oil phase preparation: Take 20g divinylbenzene (80%), 30g hydroxyethyl methacrylate (99%), 10g styrene (99%), 30g dichloroethane (99%), 60g toluene (99%), and 2g dodecyl peroxide (90%) and add them to beakers and mix thoroughly.

[0021] Slowly add the oil phase to the aqueous phase and stir until it reaches a constant temperature. Continue stirring at a constant speed for 10 minutes. Increase the temperature from 45°C to 78°C at a rate of 5°C / 10 minutes. After the resin has set for 3 hours, continue to increase the temperature from 78°C to 85°C at a rate of 5°C / 10 minutes and hold for 2 hours. Continue to increase the temperature from 85°C to 95°C at a rate of 5°C / 10 minutes and hold for 6 hours before removing the resin.

[0022] 2. Extraction of porogen: Dry the synthesized resin to a moisture content of less than 10%, and sieve the resin with a particle size of 0.5-1.25 mm using a sieve separator; put the sieved resin into a three-necked flask, add ethyl acetate (enough to cover the resin), heat to 50°C, start stirring, and extract for 4 hours. Then replace with fresh ethyl acetate and continue extraction. Repeat 6 times to complete the extraction of porogen.

[0023] Table 1. Resin Indicators for White Balls

[0024] 3. Grafting with 1,2-dibromoethane: Under ice-melting conditions, 30g of resin from which the porogen was extracted was added to 50g of tetrahydrofuran, along with 15g of NaH. The mixture was stirred at 0℃ for 2 hours until fully mixed and the reaction was complete. Then, 15g of 1,2-dibromoethane was added, and the mixture was reacted at room temperature under dry conditions for 24 hours. After the reaction was complete, the resin was filtered out, and the organic matter inside the resin was washed with tetrahydrofuran. The resin was then extracted with anhydrous ethanol for 23 hours until all organic solvents and impurities outside the resin skeleton were completely extracted.

[0025] Table 2 Properties of the resin after dibromoethane grafting

[0026] 4. Amin functionalization: After fully swelling 30g of the extracted resin with anhydrous ethanol, add 15g of ammonia and 30g of ethylenediamine, and react at 65℃ for 24 hours. Wash the resin with water until neutral.

[0027] Table 3 Resin properties after amino functionalization

[0028] The resin bilirubin adsorption experiment prepared in this embodiment a test solution Prepare bovine plasma with a total bilirubin content of 10 mg / mL.

[0029] b. Determination of the concentrations of total bilirubin and total protein The concentration of total bilirubin was determined using a registered in vitro diagnostic kit and related methods.

[0030] c. Preparation of plasma Preparation of bovine plasma: Take fresh anticoagulated bovine plasma, add bilirubin, and prepare bovine plasma with a total bilirubin concentration of 10 mg / mL for later use.

[0031] d Adsorption process Measure 1g of adsorbent (dry resin prepared in this example), place it in an Erlenmeyer flask, add 10mL of bilirubin plasma, place it in a constant temperature water bath shaker, adjust the temperature to 37℃±1℃, and the shaking frequency to 80 times / min~100 times / min. During the shaking adsorption process, pay attention to protection from light. After shaking adsorption for 2 hours, take out the Erlenmeyer flask, let it stand at room temperature, take a sample for concentration determination, and repeat the experiment 4 times.

[0032] e-calculation The adsorption capacity of the adsorbent for bilirubin is calculated using the following formula: C=(C0-C t )×10 In the formula: C – Bilirubin adsorption capacity; unit: mg; CO—Concentration of bilirubin in plasma before adsorption; unit: mg / ml; C t — The concentration of bilirubin in the plasma after adsorption; the unit is mg / ml.

[0033] f test results

[0034] Example 2

[0035] 1. Polymerization: Place a 1000ml three-necked flask in a water bath, add a stirrer, add 500ml of purified water and 13g of polyvinyl alcohol to the three-necked flask, turn on the stirrer and heat to 45℃. After the polyvinyl alcohol is completely dissolved, add 13g of magnesium sulfate and 28g of sodium carbonate respectively, and continue stirring until it is completely dissolved and ready for use.

[0036] Oil phase preparation: Take 16g divinylbenzene (80%), 36g hydroxyethyl methacrylate (99%), 16g styrene (99%), 24g dichloroethane (99%), 70g toluene (99%), and 2g dodecyl peroxide (90%) and add them to beakers and mix thoroughly.

[0037] Slowly add the oil phase to the aqueous phase and stir until it reaches a constant temperature. Continue stirring at a constant speed for 10 minutes. Increase the temperature from 45°C to 78°C at a rate of 5°C / 10 minutes. After the resin has set for 3 hours, continue to increase the temperature from 78°C to 85°C at a rate of 5°C / 10 minutes and hold for 2 hours. Continue to increase the temperature from 85°C to 95°C at a rate of 5°C / 10 minutes and hold for 6 hours before removing the resin.

[0038] 2. Extraction of porogen: Dry the synthesized resin to a moisture content of less than 10%, and sieve the resin with a particle size of 0.5-1.25 mm using a sieve separator; put the sieved resin into a three-necked flask, add ethyl acetate (enough to cover the resin), heat to 50°C, start stirring, and extract for 4 hours. Then replace with fresh ethyl acetate and continue extraction. Repeat 6 times to complete the extraction of porogen.

[0039] Table 4. Resin Indicators for White Balls

[0040] 3. Grafting with 1,2-dibromoethane: Under ice-melting conditions, 30g of resin from which the porogen was extracted was added to 40g of tetrahydrofuran, along with 14g of NaH. The mixture was stirred at 0℃ for 2 hours until fully mixed and the reaction was complete. Then, 14g of 1,2-dibromoethane was added, and the mixture was reacted at room temperature under dry conditions for 24 hours. After the reaction was complete, the resin was filtered out, and the organic matter inside the resin was washed with tetrahydrofuran. The resin was then extracted with anhydrous ethanol for 23 hours until all organic solvents and impurities outside the resin skeleton were completely extracted.

[0041] Table 5 Properties of the resin after dibromoethane grafting

[0042] 4. Amin functionalization: After fully swelling 30g of the extracted resin with anhydrous ethanol, add 15g of ammonia and 30g of ethylenediamine, and react at 65℃ for 24 hours. Wash the resin with water until neutral.

[0043] Table 6. Resin properties after amino functionalization Example 3

[0044] 1. Polymerization: Place a 1000ml three-necked flask in a water bath, add a stirrer, add 500ml of purified water and 17g of polyvinyl alcohol to the three-necked flask, turn on the stirrer and heat to 45℃. After the polyvinyl alcohol is completely dissolved, add 17g of magnesium sulfate and 32g of sodium carbonate respectively, and continue stirring until it is completely dissolved and ready for use.

[0045] Oil phase preparation: Take 24g divinylbenzene (80%), 24g hydroxyethyl methacrylate (99%), 6g styrene (99%), 36g dichloroethane (99%), 50g toluene (99%), and 2g dodecyl peroxide (90%) and add them to beakers and mix thoroughly.

[0046] Slowly add the oil phase to the aqueous phase and stir until it reaches a constant temperature. Continue stirring at a constant speed for 10 minutes. Increase the temperature from 45°C to 78°C at a rate of 5°C / 10 minutes. After the resin has set for 3 hours, continue to increase the temperature from 78°C to 85°C at a rate of 5°C / 10 minutes and hold for 2 hours. Continue to increase the temperature from 85°C to 95°C at a rate of 5°C / 10 minutes and hold for 6 hours before removing the resin.

[0047] 2. Extraction of porogen: Dry the synthesized resin to a moisture content of less than 10%, and sieve the resin with a particle size of 0.5-1.25 mm using a sieve separator; put the sieved resin into a three-necked flask, add ethyl acetate (enough to cover the resin), heat to 50°C, start stirring, and extract for 4 hours. Then replace with fresh ethyl acetate and continue extraction. Repeat 6 times to complete the extraction of porogen.

[0048] Table 7. Resin Indicators for White Balls

[0049] 3. Grafting with 1,2-dibromoethane: Under ice-melting conditions, 30g of resin from which the porogen was extracted was added to 60g of tetrahydrofuran, along with 16g of NaH. The mixture was stirred at 0℃ for 2 hours until fully mixed and the reaction was complete. Then, 16g of 1,2-dibromoethane was added, and the mixture was reacted at room temperature under dry conditions for 24 hours. After the reaction was complete, the resin was filtered out, and the organic matter inside the resin was washed with tetrahydrofuran. The resin was then extracted with anhydrous ethanol for 23 hours until all organic solvents and impurities outside the resin skeleton were completely extracted.

[0050] Table 8. Properties of the resin after dibromoethane grafting

[0051] 4. Amin functionalization: After fully swelling 30g of the extracted resin with anhydrous ethanol, add 15g of ammonia and 30g of ethylenediamine, and react at 65℃ for 24 hours. Wash the resin with water until neutral.

[0052] Table 9. Resin properties after amino functionalization

Claims

1. A method for synthesizing a resin containing amino functional groups, characterized in that, Includes the following steps: (1) Preparation of aqueous phase: After adding water to the reactor and heating, add polyvinyl alcohol and stir until completely dissolved. Add magnesium sulfate and sodium carbonate and continue stirring until completely dissolved for later use. (2) Preparation of oil phase: Divinylbenzene, hydroxyethyl methacrylate, styrene, dichlorohexane, toluene and dodecyl peroxide are mixed evenly to form the oil phase; (3) Polymerization: Slowly add the oil phase to the aqueous phase, stir until constant, and continue stirring at a constant speed for 10 min; raise the temperature from 45℃ to 78℃ at a rate of 5℃ / 10 min, and after the resin has set for 3 h, continue to raise the temperature from 78℃ to 85℃ at a rate of 5℃ / 10 min, keep it at the temperature for 2 hours, and continue to raise the temperature from 85℃ to 95℃ at a rate of 5℃ / 10 min, keep it at the temperature for 6 h, and then take it out. (4) Extraction of pore-forming agents; (5) Under ice-melting conditions, the resin from which the porogen was extracted was added to tetrahydrofuran to fully swell, and NaH was added. The mixture was stirred at 0°C until the reaction was complete. 1,2-dibromoethane was added, and the mixture was reacted at room temperature for 24 hours under dry conditions. After the reaction was completed, the resin was filtered out and washed with tetrahydrofuran. Then it was extracted with anhydrous ethanol for 23 hours. (6) After the above-extracted resin is fully swollen with anhydrous ethanol, ammonia and ethylenediamine are added and reacted at 65°C for 24 hours. The resin is washed with water, and then the organic solvents and impurities outside the resin skeleton are extracted with anhydrous ethanol. The ethanol is washed away with purified water to obtain the resin containing amino groups.

2. The method for synthesizing the resin containing amino functional groups according to claim 1, characterized in that: Add 25-35 grams of polyvinyl alcohol, 25-35 grams of magnesium sulfate, and 55-65 grams of sodium carbonate per liter of water to the aqueous phase.

3. The method for synthesizing the resin containing amino functional groups according to claim 1, characterized in that: The mass ratio of divinylbenzene, hydroxyethyl methacrylate, styrene, dichlorohexane, toluene, and dodecyl peroxide in the oil phase is 8-12:12-18:3-8:12-18:25-35:

1.

4. The method for synthesizing the resin containing amino functional groups according to claim 1, characterized in that: In step (3), the mass ratio of the aqueous phase to the oil phase is 3-4:

1.

5. The method for synthesizing the resin containing amino functional groups according to claim 1, characterized in that: In step (5), the mass ratio of the resin to tetrahydrofuran is 3:4-6, and the amount of NaH and 1,2-dibromoethane added is 45%-55% of the mass of the resin in this step.

6. The method for synthesizing the resin containing amino functional groups according to claim 1, characterized in that: In step (6), the resin and ethylenediamine have the same mass, and the amount of ammonia added is 50% of the mass of ethylenediamine.

7. The application of the resin synthesized by any one of the synthesis methods of claims 1-6 in bilirubin adsorption.

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