CN113018506A - Composite polyacrylamide hydrogel and preparation method thereof - Google Patents

Abstract

The invention discloses a composite polyacrylamide hydrogel which comprises the following raw materials in parts by weight: 100 portions of acrylamide, 0.2 to 1 portion of antibacterial agent, 0.05 to 1 portion of cross-linking agent, 290 portions of deionized water, 0.1 to 0.5 portion of initiator and 0.1 to 0.5 portion of catalyst; is prepared by the following steps: adding acrylamide and deionized water into a round-bottom flask, stirring for dissolving, then adding a cross-linking agent into a reaction kettle, increasing the rotating speed to 300-plus-500 r/min, placing the round-bottom flask into an ice-water bath, introducing nitrogen for 5min, adding an initiator, a catalyst and an antibacterial agent, stirring for 5min, sucking into an injector, sealing in an environment at 4 ℃ for 48h to form hydrogel, placing the product into distilled water for dialysis for 48h, and changing water once every 12h to obtain the composite polyacrylamide hydrogel.

Description

Composite polyacrylamide hydrogel and preparation method thereof

Technical Field

The invention belongs to the technical field of hydrogel preparation, and particularly relates to a composite polyacrylamide hydrogel and a preparation method thereof.

Background

The hydrogel is a structural gel with a three-dimensional network structure, has strong hydrophilicity and water absorption, can quickly swell in water, contains a large amount of water, can be divided into natural hydrogel and synthetic hydrogel, such as chitosan hydrogel, sodium alginate hydrogel, polyacrylic acid hydrogel, polyacrylamide hydrogel and the like, and can be obtained by chemical crosslinking or physical crosslinking, and the hydrogel has high water absorption and high water retention characteristics, so that the hydrogel has important application in aspects of cosmetic masks, medical drug carriers, tissue engineering and the like.

The Chinese patent application CN109513039A discloses an antibacterial hydrogel dressing containing imidazole bromide, wherein antibacterial components of the imidazole bromide and acrylamide are uniformly dispersed in a hydrophilic polymer monomer solution containing hydroxyl to form a carrier system, and then the carrier system is heated and repeatedly frozen-thawed, so that the imidazole bromide is tightly combined with matrix macromolecules through chemical bonds. Chinese patent applications CN109550073A and CN109481727A disclose that the antibacterial hydrogel dressing is prepared by dispersing chlorine dioxide or tungsten disulfide in sodium alginate solution, and then mixing the sodium chloride or tungsten disulfide with acrylamide, a cross-linking agent and an initiator to form a gel, and the antibacterial hydrogel dressing has an antibacterial effect only under specific illumination. The patent discloses that organic synthetic drugs or inorganic metal compounds are selected as antibacterial agents, although the antibacterial effect is good, the antibacterial effect has certain potential safety hazard, hydrogel has good load performance, mechanical property and the like, and multiple materials are required to be combined into a composite gel carrier, so that the manufacturing cost is high, and the process is complex.

Disclosure of Invention

The invention aims to provide a composite polyacrylamide hydrogel and a preparation method thereof.

The technical problems to be solved by the invention are as follows:

in the prior art, the hydrogel material has low strength, poor toughness and potential safety hazard.

The purpose of the invention can be realized by the following technical scheme:

the composite polyacrylamide hydrogel comprises the following raw materials in parts by weight: 100 portions of acrylamide, 0.2 to 1 portion of antibacterial agent, 0.05 to 1 portion of cross-linking agent, 290 portions of deionized water, 0.1 to 0.5 portion of initiator and 0.1 to 0.5 portion of catalyst;

the composite polyacrylamide hydrogel is prepared by the following steps:

adding acrylamide and deionized water into a round-bottom flask, stirring and dissolving at the rotating speed of 60r/min, then adding a cross-linking agent into a reaction kettle, increasing the rotating speed to 300-500r/min, placing the round-bottom flask into an ice-water bath, introducing nitrogen for 5min, adding an initiator, a catalyst and an antibacterial agent, stirring for 5min, sucking into an injector, sealing in an environment at 4 ℃ for 48h to form hydrogel, then placing the product into distilled water for dialysis for 48h, and changing water once every 12h to obtain the composite polyacrylamide hydrogel.

Further, the antibacterial agent is prepared by the following steps:

step A1, adding dodecyl dimethyl tertiary amine and isopropanol into a beaker, stirring and reacting at the rotating speed of 60-100r/min for 10min at room temperature, heating to 30-50 ℃, adding epoxy chloropropane into the beaker, controlling the reaction temperature to be 70-90 ℃, stirring and reacting at the rotating speed of 120r/min for 7-9h, after the reaction is finished, carrying out reduced pressure rotary evaporation at 0.09MPa and 85 ℃ to remove the isopropanol, cooling to room temperature, dissolving with acetone, putting into a refrigerator at 5 ℃ for 3-5h, taking out, carrying out suction filtration, and drying a filter cake for 12h at 30-40 ℃ to obtain an intermediate 1;

the reaction process is as follows:

step A2, adding sulfadiazine and absolute ethyl alcohol into a three-neck flask, stirring for 10min under an ice bath condition, adding triethylamine into the three-neck flask, controlling the reaction temperature to be 40 ℃, stirring and reacting for 5min at a rotating speed of 100r/min, adding oxalyl chloride, continuously stirring and reacting for 2-4h, after the reaction is finished, dropwise adding a sodium hydroxide solution with the mass fraction of 1% into the three-neck flask until precipitation is separated out, stopping dropwise adding, and then filtering, washing and drying to obtain an intermediate 2;

the reaction process is as follows:

step A3, adding potassium carbonate and dimethylformamide into a round-bottom flask, stirring for 40min at room temperature, adding 4-methyl-2-nitroaniline and 2-chloropropane, stirring at the rotation speed of 100r/min for reaction for 24h, after the reaction is finished, adding deionized water into the round-bottom flask, extracting for 3 times by using ethyl acetate under the condition of ice-water bath, combining organic phases, drying by using anhydrous sodium sulfate, and purifying by using silica gel column chromatography to obtain an intermediate 3;

the reaction process is as follows:

step A4, sequentially adding an intermediate 3, ethanol and deionized water into a three-neck flask, heating to reflux, dropwise adding a sodium hydrosulfite aqueous solution with the mass fraction of 20% into the three-neck flask by using a constant-pressure dropping funnel, controlling the dropwise adding speed to be 1-3 drops/second, after the dropwise adding is finished, refluxing and stirring for 30min, stopping heating, cooling the solution to room temperature, extracting for 3 times by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, evaporating and concentrating to obtain an intermediate 4, adding the intermediate 4, tetrahydrofuran and carbonyldiimidazole into a reaction kettle, and stirring for 2-4h at the room temperature and the rotation speed of 100-150r/min to obtain an intermediate 5;

the reaction process is as follows:

step A5, adding the intermediate 5 and dichloromethane into a reaction kettle, stirring and dissolving, adding triethylamine, dropwise adding a dichloromethane solution of the intermediate 2 into the reaction kettle through a constant-pressure dropping funnel at the temperature of 0-5 ℃, after dropwise adding, heating to room temperature, reacting for 2 hours at the rotation speed of 100 plus materials at 200r/min, washing for 3 times with saturated sodium bicarbonate, water and saturated saline water respectively, finally drying through anhydrous sodium sulfate, and carrying out silica gel column chromatography to obtain an intermediate 6;

the reaction process is as follows:

step A6, adding the intermediate 6 and dimethyl sulfoxide into a three-neck flask, heating to 80-100 ℃, adding potassium permanganate and 17% by mass of hydrochloric acid solution into the three-neck flask, stirring and reacting for 20-40min under the condition that the rotation speed is 100 plus 200r/min, filtering, transferring filtrate into a reaction kettle to obtain an intermediate 7 solution, then adding the intermediate 1 into the reaction kettle, dropwise adding concentrated sulfuric acid into the reaction kettle through a constant-pressure dropping funnel, finishing dropwise adding within 5min, heating to 40-50 ℃, keeping the temperature and stirring for reacting for 2-4h, adding deionized water after the reaction is finished, extracting for 3 times with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, and purifying by silica gel column chromatography to obtain the antibacterial agent.

The reaction process is as follows:

further, the amount ratio of the dodecyl dimethyl tertiary amine, the isopropanol and the epichlorohydrin in the step A1 is 0.1 mol: 100-200mL, 0.1 mol; in the step A2, the dosage ratio of sulfadiazine, absolute ethyl alcohol, triethylamine and oxalyl chloride is 0.1 mol: 180-220 mL: 5mL of: 0.1 mol; in the step A3, the using amount ratio of potassium carbonate, dimethylformamide, 4-methyl-2-nitroaniline, 2-chloropropane and deionized water is 4 g: 20mL of: 1.68 g: 2.04 g: 50 mL; in the step A4, the using ratio of the intermediate 3, ethanol, deionized water and the aqueous solution of sodium hydrosulfite is 8 mmol: 10mL of: 30mL of: 20mL, the dosage ratio of the intermediate 4, the tetrahydrofuran and the carbonyldiimidazole is 1 g: 15-20 mL: 0.5 g; the dosage ratio of the dichloromethane solution of the intermediate 5, the dichloromethane, the triethylamine and the intermediate 2 in the step A5 is 1 mmol: 20mL of: 300 mu L of: 3-5 mL; dichloromethane solution of intermediate 1 from intermediate 1 and dichloromethane as 1 g: 3-5mL of the mixture; in the step A6, the dosage ratio of the intermediate 6, dimethyl sulfoxide, potassium permanganate and 17% by mass of hydrochloric acid solution is 1 g: 20-30 mL:0.1 g: 1-3mL, wherein the dosage ratio of the intermediate 6, the intermediate 1 and concentrated sulfuric acid is 0.1 mol: 0.1 mol: 0.1mL of concentrated sulfuric acid, and the mass fraction of the concentrated sulfuric acid is 95%.

Further, the eluent in the silica gel column chromatography process in the step A3 is formed by mixing petroleum ether and ethyl acetate according to the volume ratio of 6:1, and the eluent in the silica gel column chromatography process in the step A5 and the step A6 is formed by mixing petroleum ether and ethyl acetate according to the volume ratio of 7: 1.

Further, the preparation method of the cross-linking agent is as follows:

adding cystamine dihydrochloride and deionized water into a four-neck flask, cooling to 0-5 ℃ in an ice-water bath, simultaneously dropwise adding a dichloromethane solution of acryloyl chloride with the concentration of 0.01mol/mL and a sodium hydroxide solution with the concentration of 0.01mol/mL into the four-neck flask, stirring for 1h under the condition of the rotation speed of 100-5 ℃, stirring for reaction for 2h, filtering, extracting filtrate with dichloromethane, drying for 24h with anhydrous sodium sulfate, removing a dichloromethane solvent by rotary evaporation, and finally performing reaction on ethyl acetate and heptane in a volume ratio of 1: 2, recrystallizing in a solvent to obtain the cross-linking agent.

Further, the dosage ratio of the cystamine dihydrochloride, the deionized water, the methylene chloride solution of the acryloyl chloride and the sodium hydroxide aqueous solution is 11.5 g: 50mL of: 10mL of: 20 mL.

Further, the initiator is ammonium persulfate.

Further, the catalyst is tetramethylethylenediamine.

Further, a preparation method of the composite polyacrylamide hydrogel comprises the following steps:

adding acrylamide and deionized water into a round-bottom flask, stirring and dissolving at the rotating speed of 60r/min, then adding a cross-linking agent into a reaction kettle, increasing the rotating speed to 300-500r/min, placing the round-bottom flask into an ice-water bath, introducing nitrogen for 5min, adding an initiator, a catalyst and an antibacterial agent, stirring for 5min, sucking into an injector, sealing in an environment at 4 ℃ for 48h to form hydrogel, then placing the product into distilled water for dialysis for 48h, and changing water once every 12h to obtain the composite polyacrylamide hydrogel.

The invention has the beneficial effects that:

the invention takes acrylamide, an antibacterial agent, a cross-linking agent, deionized water, an initiator and a catalyst as raw materials to prepare the composite polyacrylamide hydrogel, wherein the cross-linking agent is cystamine dihydrochloride and acryloyl chloride which are subjected to chemical reaction to obtain cross-linked molecules containing-C-C-S-S-C-long hydrophobic groups, the cross-linked molecules have larger molecular distance and are easier to mutually interpenetrate compared with the common cross-linking agent, and the formed structural entanglement is more complex, so the movement of molecular chains in the stretching or compressing process is relatively more difficult, the movement of the molecular chains can generate selective slippage and disentanglement to keep certain structural integrity, in addition, disulfide bonds have self-repairing performance, the mechanical performance of the hydrogel can be further improved, dodecyl dimethyl tertiary amine is taken as an initiator to generate ring-opening reaction with epoxy chloropropane in isopropanol solution, obtaining a quaternary ammonium salt intermediate 1 containing an alkyl long chain and alcoholic hydroxyl, carrying out chemical reaction on sulfadiazine serving as an initiator and oxalyl chloride in absolute ethyl alcohol to obtain an intermediate 2 with an acyl chloride structure, further carrying out reaction on 4-methyl-2-nitroaniline serving as a substrate and 2-chloropropane to obtain an intermediate 3, carrying out reduction reaction on the intermediate 3 in a sodium hydrosulfite aqueous solution to obtain an intermediate 4, further forming an intermediate 5 containing an imidazolone structure on the intermediate 4 under the action of a carbonyldiimidazole condensing agent, carrying out elimination reaction on secondary amine on the intermediate 5 and the intermediate 2 to obtain an intermediate 6, oxidizing benzyl of the intermediate 6 into carboxyl by acidic potassium permanganate to obtain an intermediate 7, and finally carrying out esterification reaction on the intermediate 1 and the intermediate 7 under the catalytic action of concentrated sulfuric acid to obtain an antibacterial agent, the antibacterial agent contains alkyl long chains of quaternary ammonium salt, an imidazolone structure, sulfanilamide and other antibacterial groups, can endow hydrogel with excellent antibacterial and anti-inflammatory performances, contains a benzene ring and a diazacyclo structure, has high stability, is not easy to volatilize, contains secondary amine and tertiary amine groups, can interact with polar base materials and non-polar base materials, and enhances the adhesive performance of the hydrogel.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1

The antibacterial agent is prepared by the following steps:

step A1, adding 0.1mol of dodecyl dimethyl tertiary amine and 100mL of isopropanol into a beaker, stirring and reacting at the rotating speed of 60r/min for 10min at room temperature, heating to 30 ℃, adding 0.1mol of epoxy chloropropane into the beaker, controlling the reaction temperature to be 70 ℃, stirring and reacting at the rotating speed of 120r/min for 7h, after the reaction is finished, carrying out reduced pressure rotary evaporation at the temperature of 0.09MPa and 85 ℃ to remove the isopropanol, cooling to room temperature, dissolving with acetone, putting into a refrigerator at the temperature of 5 ℃ for 3h, taking out, carrying out suction filtration, and drying a filter cake at the temperature of 30 ℃ for 12h to obtain an intermediate 1;

step A2, adding 0.1mol of sulfadiazine and 180mL of absolute ethyl alcohol into a three-neck flask, stirring for 10min under an ice bath condition, adding 5mL of triethylamine into the three-neck flask, then controlling the reaction temperature to be 40 ℃, stirring and reacting for 5min at the rotating speed of 100r/min, adding 0.1mol of oxalyl chloride, continuing stirring and reacting for 2h, after the reaction is finished, dropwise adding a sodium hydroxide solution with the mass fraction of 1% into the three-neck flask until precipitation is separated out, stopping dropwise adding, and then filtering, washing and drying to obtain an intermediate 2;

step A3, adding 4g of potassium carbonate and 20mL of dimethylformamide into a round-bottom flask, stirring for 40min at room temperature, adding 1.68g of 4-methyl-2-nitroaniline and 2.04g of 2-chloropropane, stirring at the rotating speed of 100r/min for reaction for 24h, after the reaction is finished, adding 50mL of deionized water into the round-bottom flask, extracting for 3 times by using ethyl acetate under the condition of ice-water bath, combining organic phases, drying by using anhydrous sodium sulfate, and purifying by using silica gel column chromatography to obtain an intermediate 3;

step A4, sequentially adding 8mmol of intermediate 3, 10mL of ethanol and 30mL of deionized water into a three-neck flask, heating to reflux, dropwise adding 20mL of sodium hydrosulfite aqueous solution with the mass fraction of 20% into the three-neck flask by using a constant-pressure dropping funnel, controlling the dropwise adding speed to be 1 drop/second, after the dropwise adding is finished, stopping heating after refluxing and stirring for 30min, cooling the solution to room temperature, extracting for 3 times by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, and performing evaporation concentration to obtain an intermediate 4, adding 1g of intermediate 4, 15mL of tetrahydrofuran and 0.5g of carbonyldiimidazole into a reaction kettle, stirring for 2h at the rotation speed of 100r/min under the room temperature condition, and obtaining an intermediate 5;

step A5, adding 1mmol of intermediate 5 and 20mL of dichloromethane into a reaction kettle, stirring and dissolving, then adding 300 mu L of triethylamine, dropwise adding 3mL of dichloromethane solution of intermediate 2 into the reaction kettle through a constant-pressure dropping funnel at the temperature of 0 ℃, after dropwise adding, heating to room temperature, reacting for 2 hours at the rotation speed of 100r/min, washing 3 times with saturated sodium bicarbonate, water and saturated saline water respectively, finally drying through anhydrous sodium sulfate, and carrying out silica gel column chromatography to obtain an intermediate 6;

step A6, adding 1g of intermediate 6 and 20mL of dimethyl sulfoxide into a three-neck flask, heating to 80 ℃, adding 0.1g of potassium permanganate and 1mL of hydrochloric acid solution with the mass fraction of 17% into the three-neck flask, stirring and reacting for 20min at the rotation speed of 100r/min, filtering, transferring filtrate into a reaction kettle to obtain an intermediate 7 solution, then adding the intermediate 1 with the same molar weight as the intermediate 6 into the reaction kettle, dropwise adding 1mL of concentrated sulfuric acid into the reaction kettle through a constant-pressure dropping funnel, finishing dropwise adding within 5min, heating to 40 ℃, keeping the temperature and stirring for reacting for 2h, adding deionized water after the reaction is finished, extracting for 3 times with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, and purifying by silica gel column chromatography to obtain the antibacterial agent.

Example 2

The antibacterial agent is prepared by the following steps:

step A1, adding 0.1mol of dodecyl dimethyl tertiary amine and 150mL of isopropanol into a beaker, stirring and reacting at the rotation speed of 80r/min for 10min at room temperature, heating to 40 ℃, adding 0.1mol of epoxy chloropropane into the beaker, controlling the reaction temperature of 80 ℃, stirring and reacting at the rotation speed of 120r/min for 8h, carrying out reduced pressure rotary evaporation at the temperature of 0.09MPa and 85 ℃ after the reaction is finished to remove the isopropanol, cooling to room temperature, dissolving with acetone, putting into a refrigerator at the temperature of 5 ℃ for 4h, taking out, carrying out suction filtration, and drying a filter cake for 12h at the temperature of 35 ℃ to obtain an intermediate 1;

step A2, adding 0.1mol of sulfadiazine and 200mL of absolute ethyl alcohol into a three-neck flask, stirring for 10min under an ice bath condition, adding 5mL of triethylamine into the three-neck flask, then controlling the reaction temperature to be 40 ℃, stirring and reacting for 5min at the rotating speed of 100r/min, adding 0.1mol of oxalyl chloride, continuing stirring and reacting for 3h, after the reaction is finished, dropwise adding a sodium hydroxide solution with the mass fraction of 1% into the three-neck flask until precipitation is separated out, stopping dropwise adding, and then filtering, washing and drying to obtain an intermediate 2;

step A3, adding 4g of potassium carbonate and 20mL of dimethylformamide into a round-bottom flask, stirring for 40min at room temperature, adding 1.68g of 4-methyl-2-nitroaniline and 2.04g of 2-chloropropane, stirring at the rotating speed of 100r/min for reaction for 24h, after the reaction is finished, adding 50mL of deionized water into the round-bottom flask, extracting for 3 times by using ethyl acetate under the condition of ice-water bath, combining organic phases, drying by using anhydrous sodium sulfate, and purifying by using silica gel column chromatography to obtain an intermediate 3;

step A4, sequentially adding 8mmol of intermediate 3, 10mL of ethanol and 30mL of deionized water into a three-neck flask, heating to reflux, dropwise adding 20mL of sodium hydrosulfite aqueous solution with the mass fraction of 20% into the three-neck flask by using a constant-pressure dropping funnel, controlling the dropwise adding speed to be 2 drops/second, after the dropwise adding is finished, stopping heating after refluxing and stirring for 30min, cooling the solution to room temperature, extracting for 3 times by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, evaporating and concentrating to obtain an intermediate 4, adding 1g of intermediate 4, 18mL of tetrahydrofuran and 0.5g of carbonyldiimidazole into a reaction kettle, and stirring for 3h at the rotating speed of 120r/min under the room temperature condition to obtain an intermediate 5;

step A5, adding 1mmol of intermediate 5 and 20mL of dichloromethane into a reaction kettle, stirring and dissolving, then adding 300 mu L of triethylamine, dropwise adding 4mL of dichloromethane solution of intermediate 2 into the reaction kettle through a constant pressure dropping funnel at the temperature of 3 ℃, after dropwise adding, heating to room temperature, reacting for 2 hours at the rotation speed of 150r/min, washing 3 times with saturated sodium bicarbonate, water and saturated saline water respectively, finally drying through anhydrous sodium sulfate, and carrying out silica gel column chromatography to obtain an intermediate 6;

step A6, adding 1g of intermediate 6 and 25mL of dimethyl sulfoxide into a three-neck flask, heating to 90 ℃, adding 0.1g of potassium permanganate and 2mL of hydrochloric acid solution with the mass fraction of 17% into the three-neck flask, stirring and reacting for 30min under the condition of the rotation speed of 150r/min, filtering, transferring filtrate into a reaction kettle to obtain an intermediate 7 solution, then adding the intermediate 1 with the same molar weight as the intermediate 6 into the reaction kettle, dropwise adding concentrated sulfuric acid into the reaction kettle through a constant-pressure dropping funnel, finishing dropwise adding within 5min, heating to 45 ℃, keeping warm and stirring for reaction for 3h, adding deionized water after the reaction is finished, extracting for 3 times with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, and purifying with silica gel column chromatography to obtain the antibacterial agent.

Example 3

The antibacterial agent is prepared by the following steps:

step A1, adding 0.1mol of dodecyl dimethyl tertiary amine and 200mL of isopropanol into a beaker, stirring and reacting at the rotation speed of 100r/min for 10min at room temperature, heating to 50 ℃, adding 0.1mol of epoxy chloropropane into the beaker, controlling the reaction temperature to 90 ℃, stirring and reacting at the rotation speed of 120r/min for 9h, after the reaction is finished, carrying out reduced pressure rotary evaporation at the temperature of 0.09MPa and 85 ℃ to remove the isopropanol, cooling to room temperature, dissolving with acetone, putting into a refrigerator at the temperature of 5 ℃ for 5h, taking out, carrying out suction filtration, and drying a filter cake for 12h at the temperature of 40 ℃ to obtain an intermediate 1;

step A2, adding 0.1mol of sulfadiazine and 220mL of absolute ethyl alcohol into a three-neck flask, stirring for 10min under an ice bath condition, adding 5mL of triethylamine into the three-neck flask, then controlling the reaction temperature to be 40 ℃, stirring and reacting for 5min at the rotating speed of 100r/min, adding 0.1mol of oxalyl chloride, continuing stirring and reacting for 4h, after the reaction is finished, dropwise adding a sodium hydroxide solution with the mass fraction of 1% into the three-neck flask until precipitation is separated out, stopping dropwise adding, and then filtering, washing and drying to obtain an intermediate 2;

step A3, adding 4g of potassium carbonate and 20mL of dimethylformamide into a round-bottom flask, stirring for 40min at room temperature, adding 1.68g of 4-methyl-2-nitroaniline and 2.04g of 2-chloropropane, stirring at the rotating speed of 100r/min for reaction for 24h, after the reaction is finished, adding 50mL of deionized water into the round-bottom flask, extracting for 3 times by using ethyl acetate under the condition of ice-water bath, combining organic phases, drying by using anhydrous sodium sulfate, and purifying by using silica gel column chromatography to obtain an intermediate 3;

step A4, sequentially adding 8mmol of intermediate 3, 10mL of ethanol and 30mL of deionized water into a three-neck flask, heating to reflux, dropwise adding 20mL of sodium hydrosulfite aqueous solution with the mass fraction of 20% into the three-neck flask by using a constant-pressure dropping funnel, controlling the dropwise adding speed to be 3 drops/second, after the dropwise adding is finished, stopping heating after refluxing and stirring for 30min, cooling the solution to room temperature, extracting for 3 times by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, and performing evaporation concentration to obtain an intermediate 4, adding 1g of intermediate 4, 20mL of tetrahydrofuran and 0.5g of carbonyldiimidazole into a reaction kettle, stirring for 4h at the rotation speed of 150r/min under the room temperature condition, and obtaining an intermediate 5;

step A5, adding 1mmol of intermediate 5 and 20mL of dichloromethane into a reaction kettle, stirring for dissolving, adding 300 mu L of triethylamine, dropwise adding 5mL of dichloromethane solution of intermediate 2 into the reaction kettle through a constant-pressure dropping funnel at the temperature of 5 ℃, after dropwise adding, heating to room temperature, reacting for 2 hours at the rotation speed of 200r/min, washing 3 times with saturated sodium bicarbonate, water and saturated saline water respectively, finally drying through anhydrous sodium sulfate, and carrying out silica gel column chromatography to obtain an intermediate 6;

step A6, adding 1g of intermediate 6 and 30mL of dimethyl sulfoxide into a three-neck flask, heating to 100 ℃, adding 0.1g of potassium permanganate and 3mL of hydrochloric acid solution with the mass fraction of 17% into the three-neck flask, stirring and reacting for 40min at the rotation speed of 200r/min, filtering, transferring filtrate into a reaction kettle to obtain an intermediate 7 solution, then adding the intermediate 1 with the same molar weight as the intermediate 6 into the reaction kettle, dropwise adding concentrated sulfuric acid into the reaction kettle through a constant-pressure dropping funnel, finishing dropwise adding within 5min, heating to 50 ℃, keeping warm and stirring for reaction for 4h, adding deionized water after the reaction is finished, extracting for 3 times with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, and purifying with silica gel column chromatography to obtain the antibacterial agent.

Example 4

The composite polyacrylamide hydrogel comprises the following raw materials in parts by weight: 100 parts of acrylamide, 0.2 part of antibacterial agent in example 1, 0.05 part of cross-linking agent, 220 parts of deionized water, 0.1 part of initiator and 0.1 part of catalyst;

the composite polyacrylamide hydrogel is prepared by the following steps:

adding acrylamide and deionized water into a round-bottom flask, stirring and dissolving at the rotating speed of 60r/min, then adding a cross-linking agent into a reaction kettle, increasing the rotating speed to 300r/min, placing the round-bottom flask into an ice-water bath, introducing nitrogen for 5min, adding an initiator, a catalyst and an antibacterial agent, stirring for 5min, sucking into an injector, sealing in an environment at 4 ℃ for 48h to form hydrogel, then placing the product into distilled water for dialysis for 48h, and changing water once every 12h to obtain the composite polyacrylamide hydrogel.

The preparation method of the cross-linking agent comprises the following steps:

adding 11.5g of cystamine dihydrochloride and 60mL of deionized water into a four-neck flask, cooling to 0 ℃ in an ice-water bath, simultaneously dropwise adding 10mL of 0.01mol/mL acryloyl chloride dichloromethane solution and 20mL of 0.01mol/mL sodium hydroxide aqueous solution into the four-neck flask, stirring for 1h at the rotation speed of 100r/min, keeping the temperature at 0 ℃, stirring for 2h, filtering, extracting the filtrate with dichloromethane, drying for 24h with anhydrous sodium sulfate, removing dichloromethane solvent by rotary evaporation, and finally adding ethyl acetate and heptane in a volume ratio of 1: 2, recrystallizing in a solvent to obtain the cross-linking agent.

Example 5

The composite polyacrylamide hydrogel comprises the following raw materials in parts by weight: 100 parts of acrylamide, 0.8 part of antibacterial agent in example 2, 0.08 part of cross-linking agent, 250 parts of deionized water, 0.2 part of initiator and 0.2 part of catalyst;

the composite polyacrylamide hydrogel is prepared by the following steps:

adding acrylamide and deionized water into a round-bottom flask, stirring and dissolving at the rotating speed of 60r/min, then adding a cross-linking agent into a reaction kettle, increasing the rotating speed to 400r/min, placing the round-bottom flask into an ice-water bath, introducing nitrogen for 5min, adding an initiator, a catalyst and an antibacterial agent, stirring for 5min, sucking into an injector, sealing in an environment at 4 ℃ for 48h to form hydrogel, then placing the product into distilled water for dialysis for 48h, and changing water once every 12h to obtain the composite polyacrylamide hydrogel.

The preparation method of the cross-linking agent comprises the following steps:

adding 11.5g of cystamine dihydrochloride and 50mL of deionized water into a four-neck flask, cooling to 3 ℃ in an ice-water bath, simultaneously dropwise adding 10mL of a dichloromethane solution of acryloyl chloride with the concentration of 0.01mol/mL and 20mL of a sodium hydroxide aqueous solution with the concentration of 0.01mol/mL into the four-neck flask, stirring for 1h at the rotating speed of 150r/min, keeping the temperature at 3 ℃, stirring for 2h, filtering, extracting the filtrate with dichloromethane, drying for 24h with anhydrous sodium sulfate, removing the dichloromethane solvent by rotary evaporation, and finally performing vacuum distillation on ethyl acetate and heptane to obtain the mixture, wherein the volume ratio of the ethyl acetate to the heptane is 1: 2, recrystallizing in a solvent to obtain the cross-linking agent.

Example 6

The composite polyacrylamide hydrogel comprises the following raw materials in parts by weight: 100 parts of acrylamide, 1 part of an antibacterial agent in example 3, 1 part of a cross-linking agent, 290 parts of deionized water, 0.5 part of an initiator and 0.5 part of a catalyst;

the composite polyacrylamide hydrogel is prepared by the following steps:

adding acrylamide and deionized water into a round-bottom flask, stirring and dissolving at the rotating speed of 60r/min, then adding a cross-linking agent into a reaction kettle, increasing the rotating speed to 500r/min, placing the round-bottom flask into an ice-water bath, introducing nitrogen for 5min, adding an initiator, a catalyst and an antibacterial agent, stirring for 5min, sucking into an injector, sealing in an environment at 4 ℃ for 48h to form hydrogel, then placing the product into distilled water for dialysis for 48h, and changing water once every 12h to obtain the composite polyacrylamide hydrogel.

The preparation method of the cross-linking agent comprises the following steps:

adding 11.5g of cystamine dihydrochloride and 50mL of deionized water into a four-neck flask, cooling to 5 ℃ in an ice-water bath, simultaneously dropwise adding 10mL of a dichloromethane solution of acryloyl chloride with the concentration of 0.01mol/mL and 20mL of a sodium hydroxide aqueous solution with the concentration of 0.01mol/mL into the four-neck flask, stirring for 1h at the rotating speed of 200r/min, keeping the temperature at 5 ℃, stirring for 2h, filtering, extracting filtrate with dichloromethane, drying for 24h with anhydrous sodium sulfate, removing a dichloromethane solvent by rotary evaporation, and finally performing reaction on ethyl acetate and heptane in a volume ratio of 1: 2, recrystallizing in a solvent to obtain the cross-linking agent.

Example 7

The composite polyacrylamide hydrogel comprises the following raw materials in parts by weight: 100 parts of acrylamide, 1 part of cross-linking agent, 290 parts of deionized water, 0.5 part of initiator and 0.5 part of catalyst;

the composite polyacrylamide hydrogel is prepared by the following steps:

adding acrylamide and deionized water into a round-bottom flask, stirring and dissolving at the rotating speed of 60r/min, then adding a cross-linking agent into a reaction kettle, increasing the rotating speed to 500r/min, placing the round-bottom flask into an ice-water bath, introducing nitrogen for 5min, adding an initiator and a catalyst, stirring for 5min, sucking into an injector, sealing in an environment at 4 ℃ for 48h to form hydrogel, then placing the product into distilled water for dialysis for 48h, and changing water once every 12h to obtain the composite polyacrylamide hydrogel.

The preparation method of the cross-linking agent comprises the following steps:

adding 11.5g of cystamine dihydrochloride and 50mL of deionized water into a four-neck flask, cooling to 5 ℃ in an ice-water bath, simultaneously dropwise adding 10mL of a dichloromethane solution of acryloyl chloride with the concentration of 0.01mol/mL and 20mL of a sodium hydroxide aqueous solution with the concentration of 0.01mol/mL into the four-neck flask, stirring for 1h at the rotating speed of 200r/min, keeping the temperature at 5 ℃, stirring for 2h, filtering, extracting filtrate with dichloromethane, drying for 24h with anhydrous sodium sulfate, removing a dichloromethane solvent by rotary evaporation, and finally performing reaction on ethyl acetate and heptane in a volume ratio of 1: 2, recrystallizing in a solvent to obtain the cross-linking agent.

Comparative example

The comparative example is a composite polyacrylamide hydrogel commonly found in the market.

The hydrogels of examples 4-7 and comparative examples were subjected to performance testing, with the following test criteria:

and (3) testing tensile property: the tensile property of a universal tester is adopted for testing, a sample is cut into a cylinder with the diameter of about 4mm and the height of 45mm, the length of the initial length gauge length is 15mm, the loading speed is 100mm/min, and a clamp of a testing instrument is stuck with a layer of rough paper to prevent hydrogel from sliding during testing.

Swelling property test: naturally drying the composite gel sample until the composite gel sample loses all water, weighing the dry weight of the composite gel sample, then placing the composite gel sample in a buffer solution with the pH value of 7.4 prepared by sodium monohydrogen phosphate and sodium dihydrogen phosphate, soaking for 20 hours, and testing the swelling ratio, wherein the formula of the swelling ratio is SR (W)_s-W_d)/W_d×100％，W_sIs mass/g after water absorption, W_dIs dry weight mass;

testing hemolytic performance: centrifuging 5mL of fresh anticoagulated rabbit erythrocyte in a centrifuge tube under the condition of 2000r/min for 5min, taking out 0.2mL of centrifuged anticoagulated erythrocyte, adding the anticoagulated erythrocyte into a test tube, slowly adding 10mL of physiological saline, taking 5g of compound gel sample, slightly oscillating, mixing uniformly, placing the gel sample in a water bath at 37 ℃, keeping the temperature and oscillating for 60min, taking 10mL of physiological saline and rabbit erythrocyte as negative control, centrifuging the solution in the test tube in a centrifuge at the rotating speed of 2000rpm for 3min, taking supernatant, measuring the absorbance of the supernatant at 454nm by using a UV-vis spectrometer, recording test results, and calculating the Hemolysis Rate (HR), wherein (OD) is equal to (HR)_t-OD_n)/(OD_P-OD_n) X 100% where OD_t、OD_P、OD_nRespectively testing absorbance values of a test group, a positive control group and a negative control group, and performing parallel test for three times to obtain an average value;

and (3) antibacterial property test: the antibacterial performance of examples 4-7 and comparative examples was quantitatively characterized by the use of the decal method GB/T21866-. The test results are shown in the following table:

item	Tensile strength/MPa	Swelling ratio/%	Percent of hemolysis%	Inhibition of E.coli/%)
					Example 4	0.117	830	1.80	99.8
Example 5	0.120	850	1.72	99.5
					Example 6	0.119	870	1.77	99.7
Example 7	0.115	860	3.12	58.7
					Comparative example	0.080	1100	6	82.1

As can be seen from the above table, the composite gels of examples 4-6 are superior to comparative examples in tensile strength, swelling ratio, hemolytic rate and Escherichia coli bacteriostatic rate test processes, and the composite gels prepared by the invention have high mechanical property and antibacterial property and have great application value in the medical field.

The foregoing is merely exemplary and illustrative of the principles of the present invention and various modifications, additions and substitutions of the specific embodiments described herein may be made by those skilled in the art without departing from the principles of the present invention or exceeding the scope of the claims set forth herein.

Claims (3)

1. The composite polyacrylamide hydrogel is characterized by comprising the following raw materials in parts by weight: 100 portions of acrylamide, 0.2 to 1 portion of antibacterial agent, 0.05 to 1 portion of cross-linking agent, 290 portions of deionized water, 0.1 to 0.5 portion of initiator and 0.1 to 0.5 portion of catalyst;

wherein the antibacterial agent is prepared by the following steps:

step A1, adding dodecyl dimethyl tertiary amine and isopropanol into a beaker, stirring and reacting for 10min at room temperature, heating to 30-50 ℃, adding epoxy chloropropane into the beaker, controlling the reaction temperature to be 70-90 ℃, stirring and reacting for 7-9h, after the reaction is finished, carrying out reduced pressure rotary evaporation at 0.09MPa and 85 ℃ to remove the isopropanol, cooling to room temperature, dissolving with acetone, putting into a refrigerator at 5 ℃ for 3-5h, taking out, carrying out suction filtration, and drying a filter cake for 12h at 30-40 ℃ to obtain an intermediate 1;

step A2, adding sulfadiazine and absolute ethyl alcohol into a three-neck flask, stirring for 10min under an ice bath condition, adding triethylamine into the three-neck flask, controlling the reaction temperature to be 40 ℃, stirring for reacting for 5min, adding oxalyl chloride, continuing to stir for reacting for 2-4h, after the reaction is finished, dropwise adding a sodium hydroxide solution with the mass fraction of 1% into the three-neck flask until precipitation is separated out, and then filtering, washing and drying to obtain an intermediate 2;

step A3, adding potassium carbonate and dimethylformamide into a round-bottom flask, stirring for 40min at room temperature, adding 4-methyl-2-nitroaniline and 2-chloropropane, stirring for reacting for 24h, adding deionized water into the round-bottom flask after the reaction is finished, extracting for 3 times by using ethyl acetate under the condition of ice-water bath, combining organic phases, drying by using anhydrous sodium sulfate, and purifying by using silica gel column chromatography to obtain an intermediate 3;

step A4, sequentially adding the intermediate 3, ethanol and deionized water into a three-neck flask, heating to reflux, dropwise adding a sodium hydrosulfite aqueous solution, after dropwise adding, refluxing and stirring for 30min, stopping heating, cooling the solution to room temperature, extracting for 3 times by using ethyl acetate, combining organic phases, drying, evaporating and concentrating to obtain an intermediate 4, adding the intermediate 4, tetrahydrofuran and carbonyldiimidazole into a reaction kettle, and stirring for 2-4h at room temperature to obtain an intermediate 5;

step A5, adding the intermediate 5 and dichloromethane into a reaction kettle, stirring for dissolving, adding triethylamine, dropwise adding a dichloromethane solution of the intermediate 2 into the reaction kettle at the temperature of 0-5 ℃, heating to room temperature after dropwise adding, reacting for 2 hours, washing, drying, and performing silica gel column chromatography to obtain an intermediate 6;

step A6, adding the intermediate 6 and dimethyl sulfoxide into a three-neck flask, heating to 80-100 ℃, adding potassium permanganate and 17% by mass of hydrochloric acid solution into the three-neck flask, stirring for reaction for 20-40min, filtering, transferring filtrate into a reaction kettle to obtain an intermediate 7 solution, then adding the intermediate 1 into the reaction kettle, dropwise adding concentrated sulfuric acid into the reaction kettle, finishing dropwise adding within 5min, heating to 40-50 ℃ after finishing dropwise adding, keeping the temperature, stirring for reaction for 2-4h, adding deionized water after finishing the reaction, extracting for 3 times by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, and purifying by using a silica gel column chromatography to obtain the antibacterial agent.

2. The composite polyacrylamide hydrogel according to claim 1, wherein the cross-linking agent is prepared by the following method:

adding cystamine dihydrochloride and deionized water into a four-neck flask, cooling to 0-5 ℃ in an ice-water bath, simultaneously dropwise adding a dichloromethane solution of acryloyl chloride with the concentration of 0.01mol/mL and a sodium hydroxide aqueous solution with the concentration of 0.01mol/mL into the four-neck flask, stirring for 1h, keeping the temperature at 0-5 ℃, stirring for reaction for 2h, filtering, extracting filtrate with dichloromethane, drying for 24h with anhydrous sodium sulfate, removing a dichloromethane solvent by rotary evaporation, and finally adding ethyl acetate and heptane in a volume ratio of 1: 2, recrystallizing in a solvent to obtain the cross-linking agent.

3. The preparation method of the composite polyacrylamide hydrogel according to claim 1, characterized by comprising the following steps:

adding acrylamide and deionized water into a round-bottom flask, stirring and dissolving at the rotating speed of 60r/min, then adding a cross-linking agent into a reaction kettle, increasing the rotating speed to 300-500r/min, placing the round-bottom flask into an ice-water bath, introducing nitrogen for 5min, adding an initiator, a catalyst and an antibacterial agent, stirring for 5min, sucking into an injector, sealing in an environment at 4 ℃ for 48h to form hydrogel, then placing the product into distilled water for dialysis for 48h, and changing water once every 12h to obtain the composite polyacrylamide hydrogel.