CN102964582B - Segmented copolymer, preparation method thereof and hydrogel - Google Patents

Abstract

The present invention provides a block copolymer, comprising an A block with a structure of formula (I) or formula (II) and a B block with a structure of formula (III) or formula (IV). Mixing the block copolymer of left-handed configuration and the block copolymer of right-handed configuration in aqueous medium can gradually transform from solution to form a three-dimensional composite hydrogel material. Since the B block with the structure of formula (III) or formula (IV) contains aniline oligomer fragments, it has intermolecular π-π force, and the conjugated π electrons are conductive. Therefore, the prepared block Copolymers and hydrogels have good electrochemical response characteristics; at the same time, because the A block is very soluble in water, the assembled micelles formed by the A block and the B block are also soluble under a certain number of links. in water. Therefore, the block copolymer and hydrogel provided by the invention have good water solubility.

Description

A kind of block copolymer, its preparation method and hydrogel

technical field

The invention relates to the field of biomedical polymer materials, in particular to a block copolymer, its preparation method and hydrogel.

Background technique

Injectable hydrogel is a type of polymer with a cross-linked network structure that can absorb and retain a large amount of water. This type of material can be cross-linked based on physical forces, such as hydrophobic interaction, electrostatic composite, three-dimensional composite, hydrogen bond interaction, etc. , can also be cross-linked based on chemical reactions, such as Michael addition, photocross-linking, cycloaddition, oxidative coupling, enzyme cross-linking, etc., and then solution-gel transition occurs, so in regenerative medicine and drug controlled release, etc. It has a wide range of uses and is a new research direction in the field of biomedical materials in recent years. Because of its good fluidity, convenient use, long residence time, small wound, performance similar to human tissue, etc., and it has good permeability to low molecular solutes, excellent biocompatibility and good weight Due to its current nature and easy synthesis, it has received extensive attention.

Injectable hydrogel can make the embedded drug reach the body fluid in a stable and controllable manner. By mixing the drug with the polymer solution, it is then injected into the body in situ to form a gel to achieve the controlled release of the drug. Electroactive materials, such as conductive polymers, are also better used in the field of drug controlled release due to their advantages such as easy synthesis and low price. Among them, the electroactive aniline oligomers can undergo reversible doping with the change of pH, and can undergo electrochemical doping with the change of redox potential, causing changes in the assembly structure of polymer materials, which in turn have embedding, drug release and biological activities. Molecular capabilities, which allow it to be applied in the field of controlled drug release. At the same time, based on the fact that the reactions in vivo are related to electron transfer and the sensitivity of cells to electrical signals, cell adhesion, growth, differentiation, and apoptosis can be regulated by introducing electroactive materials. The fields of controlled release and tissue engineering have great advantages.

The prior art discloses a variety of injectable hydrogels, such as block copolymer hydrogels of polyethylene glycol and poly(L-lactic acid), which can achieve reversible changes in sol and gel when the temperature changes; polyethylene oxide -The block copolymer formed by polyoxypropylene polymer and polyalanine can also form injectable gel under certain concentration. However, none of the injectable hydrogels prepared by the prior art is electroactive.

Contents of the invention

In view of this, the technical problem to be solved in the present invention is to provide a block copolymer, its preparation method and hydrogel, the prepared block copolymer and hydrogel not only have good water solubility, but also have good Electrochemical response characteristics.

The present invention provides a block copolymer, comprising an A block with a structure of formula (I) or formula (II) and a B block with a structure of formula (III) or formula (IV):

in,

n is the degree of polymerization, 23≤n≤500;

m is the degree of polymerization, 3≤m≤90;

x is the degree of polymerization, 2≤x≤5.

Preferably, in the formula (III) or formula (IV), x is selected from 3 or 4.

Preferably, the B block accounts for 10%-50% by mass of the block copolymer.

The present invention also provides a kind of preparation method of block copolymer, comprising:

A) Polyethylene glycol or polyethylene glycol monomethyl ether is mixed with lactide and a catalyst for ring-opening polymerization to obtain a block copolymer intermediate, and the lactide is L-lactide or D-lactide - lactide;

B) mixing the block copolymer intermediate obtained in step A) with a coupling reagent and a compound having the structure of formula (V), and undergoing a condensation reaction to obtain a block copolymer;

in,

x is the degree of polymerization, 2≤x≤5.

Preferably, the molar ratio of polyethylene glycol or polyethylene glycol monomethyl ether to lactide is 1:1-45.

Preferably, the mass ratio of the block copolymer intermediate obtained in step A) to the compound having the structure of formula (V) is 1:0.01~1.

Preferably, the catalyst is stannous octoate, and the coupling reagent is selected from N,N-cyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt Any one or more of salts and 4-dimethylaminopyridine.

Preferably, in the step A), the temperature of the ring-opening polymerization reaction is 100°C-150°C, and the time of the ring-opening polymerization reaction is 12h-48h.

Preferably, in the step B), the temperature of the condensation reaction is 0°C~60°C, and the time of the condensation reaction is 24h~72h.

The present invention also provides a hydrogel, comprising an aqueous medium and a stereocomposite block copolymer, wherein the aqueous medium is selected from any one or several of water, physiological saline, buffer solution, tissue culture fluid or body fluid; The stereocomposite block copolymer is formed by the first block copolymer formed by formula (I) and formula (III) and the second block copolymer formed by formula (I) and formula (IV); or by the formula ( II) formation of a first block copolymer formed with formula (III) and a second block copolymer formed with formula (II) and formula (IV);

in,

n is the degree of polymerization, 23≤n≤500;

m is the degree of polymerization, 3≤m≤90;

x is the degree of polymerization, 2≤x≤5.

Preferably, the ratio of the number average molecular weight of the first block copolymer formed by formula (I) and formula (III) to the second block copolymer formed by formula (I) and formula (IV) is 0.5 ~1.5:1; the ratio of the number average molecular weight of the first block copolymer formed by the formula (II) and formula (III) to the second block copolymer formed by the formula (II) and formula (IV) 0.5~1.5:1.

Preferably, said x is selected from 3 or 4.

The block copolymer provided by the present invention comprises an A block with a structure of formula (I) or formula (II) and a B block with a structure of formula (III) or formula (IV). Since the B block with the structure of formula (III) or formula (IV) contains aniline oligomer fragments, it has intermolecular π-π force, and the conjugated π electrons are conductive. Therefore, the prepared block The copolymer has good electrochemical response characteristics; at the same time, because the micelle formed by the A and B blocks with a certain chain number ratio is soluble in water, the block copolymer provided by the invention also has good water solubility. Mixing the left-handed configuration block copolymer prepared in the present invention and the right-handed configuration block copolymer in an aqueous medium can gradually transform from a solution to form a three-dimensional composite hydrogel material, and the obtained hydrogel has electrical activity , water-soluble, degradable, injectable and other properties, can be used as drug carriers or scaffold materials in the field of biomedical materials.

Description of drawings

Fig. 1 is the proton nuclear magnetic resonance spectrogram of the block copolymer obtained in the embodiment of the present invention 8;

Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of the block copolymer prepared in embodiment 70 of the present invention;

Fig. 3 is the dynamic mechanical test figure of the hydrogel that the block copolymer that the embodiment of the present invention 58 and 82 prepares forms;

Fig. 4 is the ultraviolet absorption figure of the block copolymer prepared by the embodiment of the present invention 114;

Fig. 5 is an ultraviolet absorption diagram of the block copolymer prepared in Example 144 of the present invention.

Detailed ways

The present invention provides a block copolymer, comprising an A block with a structure of formula (I) or formula (II) and a B block with a structure of formula (III) or formula (IV):

in,

n is the degree of polymerization, 23≤n≤500;

m is the degree of polymerization, 3≤m≤90;

x is the degree of polymerization, 2≤x≤5.

Since the B block with the structure of formula (III) or formula (IV) contains aniline oligomer fragments, it has intermolecular π-π force, and the conjugated π electrons are conductive. Therefore, the prepared block Copolymer and hydrogel have good electrochemical response characteristics; Simultaneously, the micelle that the A block of certain chain number ratio and B block forms is soluble in water, therefore, the block copolymer provided by the present invention and water The gel also has good water solubility.

The block copolymer provided by the present invention comprises an A block with a structure of formula (I) or formula (II) and a B block with a structure of formula (III) or formula (IV), preferably, formula (I) and Formula (III) forms a poly(L) lactide-polyethylene glycol-poly(L) lactide block copolymer with a BAB block configuration, and formula (I) and formula (IV) form a BAB block structure Type poly(D) lactide-polyethylene glycol-poly(D) lactide block copolymer, formula (II) and formula (III) form polyethylene glycol monomethyl ether with AB block configuration - Poly(L) lactide block copolymer, a polyethylene glycol monomethyl ether-poly(D) lactide block copolymer of formula (II) and formula (IV) forming an AB block configuration.

Wherein, the n is the degree of polymerization, preferably, 23≤n≤500, more preferably, 30≤n≤450; the m is the degree of polymerization, preferably, 3≤m≤90, more preferably, 10≤ m≤80; the x is the degree of polymerization, preferably, 2≤x≤5, more preferably, x is 3 or 4.

The mass percentage of the B block in the block copolymer is preferably 10%-50%.

The number average molecular weight of the A block is preferably 1000~22000, more preferably 1500~20000; the number average molecular weight of the B block is preferably 200~8000, more preferably 200~6500.

The electroactive stereocomposite hydrogel material can be prepared by mixing the left-handed configuration block copolymer and the right-handed configuration block copolymer in aqueous medium.

The present invention also provides a kind of preparation method of block copolymer, comprises the following steps:

A) Polyethylene glycol or polyethylene glycol monomethyl ether is mixed with lactide and a catalyst for ring-opening polymerization to obtain a block copolymer intermediate, and the lactide is L-lactide or D-lactide - lactide;

B) mixing the block copolymer intermediate obtained in step A) with a coupling reagent and a compound having the structure of formula (V), and undergoing a condensation reaction to obtain a block copolymer;

in,

x is the degree of polymerization, 2≤x≤5.

Preferably, x is 3 or 4.

First, polyethylene glycol or polyethylene glycol monomethyl ether is mixed with lactide and a catalyst to carry out ring-opening polymerization.

In the present invention, the polyethylene glycol or polyethylene glycol monomethyl ether is used as the initiator of lactide ring-opening polymerization, and its number average molecular weight is preferably 1000~22000. There is no special requirement on the source and purity of glycol monomethyl ether, and it can be commercially available. The present invention has no special requirements on the source of the L-lactide or D-lactide (hereinafter referred to as (L/D) lactide), which can be generally commercially available. The catalyst is preferably stannous octoate, and the present invention has no special requirements on the source of the stannous octoate, which can be generally commercially available. In the present invention, the molar ratio of polyethylene glycol or polyethylene glycol monomethyl ether to (L/D) lactide is preferably 1:1~45, more preferably 1:2~30; the catalyst The mass ratio to (L/D) lactide is preferably 0.001-0.05:1, more preferably 0.005-0.03:1. In the present invention, the ring-opening polymerization reaction is preferably carried out in an organic solvent. The present invention has no special restrictions on the organic solvent, which can dissolve the polyethylene glycol or polyethylene glycol monomethyl ether and (L/D) lactide , catalyst, preferably any one or both of toluene and benzene. The present invention is preferably carried out under anhydrous and oxygen-free conditions, and the anhydrous and oxygen-free conditions are preferably nitrogen or argon protection.

Specifically, first use toluene or benzene to azeotropically remove water from polyethylene glycol or polyethylene glycol monomethyl ether, and then remove toluene or benzene in a vacuum. Stir; at the same time, use ethyl acetate to recrystallize and purify (L/D) lactide, and then vacuum remove ethyl acetate; then add a certain amount of dehydrated polyethylene glycol or polyethylene glycol monomethyl ether Mix with the recrystallized (L/D) lactide, and add a certain amount of stannous octoate in toluene or benzene solution under anhydrous and oxygen-free conditions, the concentration of the stannous octoate in toluene or benzene solution is preferably 0.02 mmol/mL ~ 0.08mmol/mL, then add a certain amount of toluene or benzene as a solvent to carry out ring-opening polymerization, the conditions of the reaction are preferably stirring reaction, the temperature of the ring-opening polymerization is preferably 100 ° C ~ 150°C, more preferably 110°C~140°C; the time for the ring-opening polymerization reaction is preferably 12h~48h, more preferably 24h~48h. The solvent for the reaction may be benzene or toluene, or a mixed solvent of benzene and toluene, which is not particularly limited in the present invention.

After the reaction, the product is purified. Preferably, the reaction solution is settled with ethanol/ether mixed solution, and the solid is obtained by suction filtration, and then the solid is dissolved in chloroform, then settled with ethanol/ether mixed solution, repeated several times, and vacuum-dried Finally, the block copolymer intermediate is obtained, that is, poly(L/D) lactide-polyethylene glycol-poly(L/D) lactide block copolymer or polyethylene glycol monomethyl ether-poly(L /D) Lactide block copolymer, its specific structure is as follows:

in,

n is the degree of polymerization, 23≤n≤500;

m is the degree of polymerization, 3≤m≤90.

After the block copolymer intermediate is obtained, it is mixed with a coupling reagent and a compound having the structure of formula (V) to undergo a condensation reaction, wherein the coupling reagent is preferably N,N-cyclohexylcarbodiimide ( Any one or more of DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 4-dimethylaminopyridine (DMAP), more It is preferably any one or both of EDC and DMAP. The present invention has no special requirements on the source of the coupling reagent, which can be generally commercially available.

The present invention has no special requirements on the source of the compound of formula (V), and it can be prepared according to the well-known synthetic method of those skilled in the art. The present invention is preferably prepared according to the following method:

a, reacting N-substituted 1,4-p-phenylenediamine derivatives under the action of an oxidizing agent to obtain aniline oligomers whose end groups are amino groups;

b. Reacting the obtained aniline oligomer whose terminal group is amino group with succinic anhydride to obtain a compound having the structure of formula (V).

First, the N-substituted 1,4-p-phenylenediamine derivative undergoes condensation reaction under the action of an oxidizing agent to obtain aniline oligomers whose terminal groups are amino groups. The N-substituted 1,4-p-phenylenediamine derivatives are preferably N-phenyl-1,4-p-phenylenediamine, N-(4-anilino)-1,4-p-phenylenediamine and N , any one or more of N-diphenyl-1,4-p-phenylenediamine, the present invention has no special requirement on the source of said N-substituted 1,4-p-phenylenediamine, it can be general commercially available. The oxidizing agent is preferably ammonium persulfate, which can be generally commercially available.

Specifically, the N-substituted 1,4-p-phenylenediamine derivative is preferably first dissolved in a mixed solution of concentrated hydrochloric acid, an organic solvent and water, and the organic solvent is an organic solvent miscible with water. The present invention It is preferably acetone or N,N-dimethylformamide; the mass ratio of the N-substituted 1,4-p-phenylenediamine derivative to concentrated hydrochloric acid, organic solvent and water is preferably 2g~4g:10mL~ 30mL: 80mL~120mL: 10mL~120mL. Then add an oxidant, the mass ratio of the oxidant to the N-substituted 1,4-p-phenylenediamine derivative is preferably 1:0.5~2; the oxidant is preferably first dissolved in a concentration of 0.8mol/L~1.5mol/L hydrochloric acid aqueous solution, and then added dropwise to the mixed solution of the N-substituted 1,4-p-phenylenediamine derivative to carry out the oxidation reaction, the dropping is preferably carried out in an ice-water bath, and the reaction time is preferably 1h~ 5h, the present invention has no special requirements on the temperature of the reaction, and the reaction is preferably carried out in an ice bath. After the reaction is finished, the solid can be obtained by filtration, and the solid is preferably washed with aqueous hydrochloric acid solution and acetone with a concentration of 0.1mol/L~0.8mol/L in sequence, and after filtration, it is back-doped with 0.1mol/L~0.6mol/L ammonia water Miscellaneous treatment, and finally washed to neutral and dried to obtain aniline oligomers whose terminal groups are amino groups.

After obtaining the aniline oligomer whose end group is an amino group, it is mixed with succinic anhydride and reacted. Preferably, the aniline oligomer whose end group is an amino group is dissolved in an organic solvent; then, under nitrogen protection, the Succinic anhydride is dissolved in an organic solvent; then the two are mixed and the reaction is stirred. The present invention has no special requirements on the organic solvent, it only needs to be able to dissolve the aniline oligomer and succinic anhydride whose terminal group is amino, and is preferably dichloromethane in the present invention; the aniline oligomer whose terminal group is amino The mol ratio of compound and succinic anhydride is preferably 1:5～15, more preferably 1:8～12; The time of described reaction is preferably 2h～10h, more preferably 3h～8h; The present invention is to described reaction There is no special requirement on the temperature, and it can be reacted at room temperature; in the present invention, the reaction is preferably carried out under the protection of nitrogen. After the reaction, preferably, the obtained solid is extracted with dichloromethane in a Soxhlet extractor, and then washed with water and dried to obtain a compound having the structure of formula (V).

In the present invention, the compound having the structure of formula (V) is preferably the following structure:

The compound shown in formula (V-a) is preferably prepared according to the following method:

reacting N-phenyl-1,4-p-phenylenediamine under the action of an oxidizing agent to obtain aniline tetramers whose end groups are amino groups;

The obtained aniline tetramer whose terminal group is amino is reacted with succinic anhydride to obtain a compound having the structure of formula (V-a).

First, N-phenyl-1,4-p-phenylenediamine is reacted under the action of an oxidizing agent. The oxidizing agent is preferably ammonium persulfate, which is generally commercially available. The N-phenyl-1,4-p-phenylenediamine is generally commercially available. Specifically, the N-phenyl-1,4-p-phenylenediamine is preferably first dissolved in a mixed solution of concentrated hydrochloric acid, an organic solvent and water, and the organic solvent is an organic solvent miscible with water. The present invention Preferably acetone or N,N-dimethylformamide; the volume ratio of the mass of N-phenyl-1,4-p-phenylenediamine to concentrated hydrochloric acid, organic solvent and water is preferably 2g~4g:10mL~ 30mL: 80mL~120mL: 10mL~120mL. Then add an oxidant, the mass ratio of the oxidant to N-phenyl-1,4-p-phenylenediamine is preferably 1:0.5~2; the oxidant is preferably first dissolved in a concentration of 0.8mol/L~1.5mol/L hydrochloric acid aqueous solution, and then added dropwise into the mixed solution of N-phenyl-1,4-p-phenylenediamine for oxidation reaction, the dropwise addition is preferably carried out in an ice-water bath, and the reaction time is preferably 1h~ 5h, the present invention has no special requirements on the temperature of the reaction, and the reaction is preferably carried out in an ice bath. After the reaction is finished, the solid can be obtained by filtration, and the solid is preferably washed with aqueous hydrochloric acid solution and acetone with a concentration of 0.1mol/L~0.8mol/L in sequence, and after filtration, it is back-doped with 0.1mol/L~0.6mol/L ammonia water Miscellaneous treatment, and finally washed to neutral and dried to obtain aniline tetramers whose terminal groups are amino groups.

After obtaining the aniline tetramer whose terminal group is an amino group, it is mixed with succinic anhydride and reacted. Preferably, the aniline tetramer whose terminal group is an amino group is dissolved in an organic solvent; then, under the protection of nitrogen, the Succinic anhydride is dissolved in an organic solvent; then the two are mixed and the reaction is stirred. The present invention has no special requirements on the organic solvent, it only needs to be able to dissolve the aniline tetramer and succinic anhydride whose terminal group is amino, and is preferably dichloromethane in the present invention; the aniline tetramer whose terminal group is amino The mol ratio of body and succinic anhydride is preferably 1:5～15, more preferably 1:8～12; The time of described reaction is preferably 2h～10h, more preferably 3h～8h; The present invention is to described reaction There is no special requirement on the temperature, and it can be reacted at room temperature; in the present invention, the reaction is preferably carried out under the protection of nitrogen. After the reaction, preferably, the obtained solid is extracted with dichloromethane in a Soxhlet extractor, and then washed with water and dried to obtain a compound having the structure of formula (V-a).

The compound shown in formula (Ⅴ-b) is preferably prepared according to the following method:

React N-(4-anilino)-1,4-p-phenylenediamine and N,N-diphenyl-1,4-p-phenylenediamine under the action of a catalyst to obtain aniline five Polymer;

The obtained aniline pentamer whose terminal group is amino is reacted with succinic anhydride to obtain a compound having the structure of formula (V-b).

First react N-(4-anilino)-1,4-p-phenylenediamine and N,N-diphenyl-1,4-p-phenylenediamine under the action of an oxidizing agent, preferably persulfuric acid Ammonium can be generally commercially available. The N-(4-anilino)-1,4-p-phenylenediamine and N,N-diphenyl-1,4-p-phenylenediamine are commercially available. Specifically, the N-(4-anilino)-1,4-p-phenylenediamine and N,N-diphenyl-1,4-p-phenylenediamine are preferably first dissolved in concentrated hydrochloric acid, an organic solvent and water In the mixed solution, the organic solvent is an organic solvent that can be miscible with water, and the present invention is preferably acetone or N,N-dimethylformamide; the N-(4-anilino)-1,4- The volume ratio of the mass of p-phenylenediamine and the mass of N,N-diphenyl-1,4-p-phenylenediamine to concentrated hydrochloric acid, organic solvent and water is preferably 2g~4g: 2g~4g: 10mL~30mL: 80mL~120mL: 10mL~120mL. Then add an oxidizing agent, the mass ratio of the oxidizing agent to the N-(4-anilino)-1,4-p-phenylenediamine and N,N-diphenyl-1,4-p-phenylenediamine is preferably 1 : 0.5~2: 0.5~2; the catalyst is preferably dissolved in an aqueous hydrochloric acid solution with a concentration of 0.8mol/L~1.5mol/L, and then added dropwise to the N-(4-anilino)-1,4-p Oxidation reaction is carried out in the mixed solution of phenylenediamine and N, N-diphenyl-1,4-p-phenylenediamine, and described dropping is preferably carried out in ice-water bath, and the time of described reaction is preferably 1h～5h, The present invention has no special requirements on the temperature of the reaction, and the reaction is preferably carried out in an ice bath. After the reaction is completed, the solid can be obtained by filtration, and the solid is preferably washed with hydrochloric acid and water with a concentration of 0.1mol/L~0.8mol/L in sequence, and after filtration, it is counter-doped with 0.1mol/L~0.6mol/L ammonia water treatment, and finally washed to neutral and dried to obtain aniline pentamers with amino groups as terminal groups.

After obtaining the aniline pentamer whose end group is amino, it is mixed with succinic anhydride and reacted. Preferably, the aniline pentamer whose end group is amino is dissolved in an organic solvent; then, under nitrogen protection, the Succinic anhydride is dissolved in an organic solvent; then the two are mixed and the reaction is stirred. The present invention has no special requirements on the organic solvent, it only needs to be able to dissolve the aniline pentamer and succinic anhydride whose end group is amino, and is preferably dichloromethane in the present invention; the aniline pentamer whose end group is amino The mol ratio of body and succinic anhydride is preferably 1:5～15, more preferably 1:8～12; The time of described reaction is preferably 2h～10h, more preferably 3h～8h; The present invention is to described reaction There is no special requirement on the temperature, and it can be reacted at room temperature; in the present invention, the reaction is preferably carried out under the protection of nitrogen. After the reaction, preferably, the obtained solid is extracted with dichloromethane in a Soxhlet extractor, and then washed with water and dried to obtain a compound having the structure of formula (V-b).

The block copolymer intermediate is mixed with the coupling reagent and the compound having the structure of formula (V) to undergo a condensation reaction, and the mass ratio of the block copolymer intermediate to the compound having the structure of formula (V) is preferably 1:0.01~1, more preferably 1:0.02~0.6; the mass ratio of the coupling reagent to the block copolymer intermediate is preferably 0.001~1:1, more preferably 0.003~0.8:1. In the present invention, the condensation reaction is preferably carried out in an organic solvent. The present invention has no special restrictions on the organic solvent, as long as it can dissolve the block copolymer intermediate, coupling reagent and compound with the structure of formula (V). The invention is preferably any one or more of N,N-dimethylformamide, dimethyl sulfoxide and N-methylpyrrolidone. The present invention is preferably carried out under nitrogen protection.

Specifically, the block copolymer intermediate, the coupling reagent and the compound having the structure of formula (V) are treated with organic reagents respectively, and then mixed and reacted. The organic reagent is preferably any one or more of N,N-dimethylformamide, dimethyl sulfoxide and N-methylpyrrolidone. In the present invention, the raw materials are preferably treated and mixed under the protection of nitrogen. reaction. The reaction temperature is preferably 0°C-60°C, more preferably 20°C-50°C; the condensation reaction time is preferably 24h-72h, more preferably 24h-48h.

After the reaction is finished, preferably, the reaction solution is settled with ether, and the crude product is obtained by suction filtration, then the crude product is dissolved with chloroform, the insoluble matter is removed by filtration, and the chloroform solution is settled with ethanol, and the solid is obtained by suction filtration, and repeated several times. The steps of dissolving hypochloroform and ethanol precipitation further purify the product, and dry to obtain the block copolymer.

The block copolymer is subjected to nuclear magnetic resonance analysis, and the result shows that the obtained block copolymer comprises A block having the structure of formula (I) or formula (II) and B block having the structure of formula (III) and formula (IV). block:

in,

n is the degree of polymerization, 23≤n≤500;

m is the degree of polymerization, 3≤m≤90;

x is the degree of polymerization, 2≤x≤5.

The ultraviolet absorption detection of the prepared block copolymer shows that the block copolymer provided by the invention has good electrical activity.

In the present invention, polyethylene glycol monomethyl ether or polyethylene glycol with different molecular weights are used as initiators to react with (L/D) lactide with different feeding amounts to obtain polyethylene glycol monomethyl ethers with different chain lengths. Alcohol monomethyl ether-poly(L/D) lactide or poly(L/D) lactide-polyethylene glycol-poly(L/D) lactide copolymer, then reacted with aniline oligomer By controlling the ratio of (L/D) lactide and the type of aniline oligomers, polymer materials with different concentrations and recombination rates, electroactive response properties, and optical properties can be prepared.

The invention also discloses a hydrogel, which comprises an aqueous medium and a three-dimensional composite block copolymer, and the aqueous medium is selected from any one or several of water, physiological saline, buffer solution, tissue culture fluid or body fluid; The stereocomposite block copolymer is formed by the first block copolymer formed by formula (I) and formula (III) and the second block copolymer formed by formula (I) and formula (IV); or by the formula ( II) formation of a first block copolymer formed with formula (III) and a second block copolymer formed with formula (II) and formula (IV);

in,

n is the degree of polymerization, 23≤n≤500;

m is the degree of polymerization, 3≤m≤90;

x is the degree of polymerization, 2≤x≤5.

Preferably, x is 3 or 4.

The block copolymer provided by the present invention is formed by condensation of polyethylene glycol monomethyl ether or polyethylene glycol and lactide. Since lactide has a left-handed or right-handed stereo configuration, the prepared block copolymer Segment copolymers also have a left-handed or a right-handed stereoconfiguration. Mix the left-handed configuration block copolymer with the right-handed configuration block copolymer with similar structure and similar number average molecular weight, such as polyethylene glycol monomethyl ether-poly(L) lactide coupled aniline tetramer The body is mixed with polyethylene glycol monomethyl ether-poly(D) lactide-coupled aniline tetramer, or poly(L)-lactide-polyethylene glycol-poly(L)-lactide-coupled aniline penta The polymer is mixed with poly(D) lactide-polyethylene glycol-poly(D) lactide coupled aniline pentamer to obtain a three-dimensional composite block copolymer. Mixing the stereocomplex block copolymer with an aqueous medium can gradually transform from a solution to form a stereocomplex hydrogel with electrical activity.

The ratio of the number average molecular weight of the first block copolymer formed by the formula (I) and the formula (III) to the second block copolymer formed by the formula (I) and the formula (IV) is preferably 0.5~1.5 : 1, more preferably 0.8~1.2: 1; the first block copolymer formed by the formula (II) and the formula (III) and the second block copolymer formed by the formula (II) and the formula (IV) The ratio of the number average molecular weight of the compound is preferably 0.5~1.5:1, more preferably 0.8~1.2:1.

Most preferably, in the first block copolymer formed by formula (I) and formula (III) and the second block copolymer formed by formula (I) and formula (IV), x has the same value ; In the first block copolymer formed by the formula (II) and the formula (III) and the second block copolymer formed by the formula (II) and the formula (IV), x has the same value.

The mass fraction of the stereocomposite block copolymer in the aqueous medium is preferably 5% to 30%, more preferably 10% to 25%.

By mixing the block copolymer of left-handed configuration and the block copolymer of right-handed configuration in a solvent, a stereocomposite hydrogel material with electroactivity can be prepared, and the segment length of the block copolymer can be adjusted and the concentration of the polymer solution to adjust the gelling time, strength and solubility of the stereocomposite hydrogel. Due to the introduction of aniline oligomers, the prepared hydrogel has good electrical activity. Since the prepared block copolymers all have good water solubility, the prepared hydrogel also has good water solubility. The degradation cycle was tested, and the results showed that the degradation cycle of the hydrogel was 4 to 8 weeks. Therefore, the hydrogel provided by the present invention has the characteristics of injectability, degradability, good biocompatibility, and good electrical activity, and can be used in the field of biomedical materials, especially in drug controlled release and tissue engineering. .

The block copolymer provided by the present invention comprises an A block with a structure of formula (I) or formula (II) and a B block with a structure of formula (III) or formula (IV). Since the B block with the structure of formula (III) or formula (IV) contains aniline oligomer fragments, it has intermolecular π-π force, and the conjugated π electrons are conductive. Therefore, the prepared block The copolymer has good electrochemical response characteristics; at the same time, because the micelles formed by the A block and the B block of a certain chain number ratio are soluble in water, the block copolymer provided by the present invention also has good water solubility. sex. Mix the block copolymer of left-handed configuration and the block copolymer of right-handed configuration prepared in the present invention in an aqueous medium, after a period of time, a three-dimensional composite hydrogel material can be formed, and the obtained hydrogel has electrical activity , water-soluble, degradable, injectable and other properties, can be used as drug carriers or scaffold materials in the field of biomedical materials.

In order to further illustrate the present invention, the block copolymer provided by the present invention, its preparation method and hydrogel are described in detail below in conjunction with examples.

Example 1

Dissolve 3.68g (0.02mol) of N-phenyl-1,4-p-phenylenediamine in a mixture of 100mL acetone, 100mL water and 25mL concentrated hydrochloric acid to obtain N-phenyl-1,4-p-phenylenediamine mixed solution, and frozen to 0°C; then weighed 4.56g (0.02mol) of ammonium persulfate (APS) and dissolved it in 50mL of 1mol/L HCl aqueous solution to obtain an APS solution, and slowly dropped the APS solution into N-phenyl-1 , in the 4-p-phenylenediamine mixture (dropped in about half an hour), reacted for 3 hours after dropping, then filtered to obtain a solid, and then washed the solid with 0.6mol/L HCl aqueous solution and acetone, and filtered with 0.5mol/L The solid was back-doped with L ammonia water, and finally the solid was washed three times with water to neutrality, freeze-dried and then vacuum-dried to obtain aniline tetramers whose terminal groups were amino groups. The yield was 80%.

Example 2

Dissolve 3.5g of N-(4-anilino)-1,4-p-phenylenediamine and 2.6g of N,N-diphenyl-1,4-p-phenylenediamine in 100mL N,N-dimethylformaldehyde A mixture of N-(4-anilino)-1,4-p-phenylenediamine and N,N-diphenyl-1,4-p-phenylenediamine was obtained from a mixture of amide, 15mL water and 15mL concentrated hydrochloric acid, and freeze to 0°C; then weigh 2.28 g (0.01 mol) of ammonium persulfate APS and dissolve it in 50 mL of 1 mol/L HCl aqueous solution to obtain an APS solution, and slowly drop the APS solution into N-(4-anilino)-1 , in the mixture of 4-p-phenylenediamine and N,N-diphenyl-1,4-p-phenylenediamine (dropped in about half an hour), react for 1 hour after dropping, and then pour the product into 700mL of water for Precipitate, filter to obtain solids, wash the solids with 0.1mol/L HCl aqueous solution and water three times in turn, then counter-dope the solids with 0.1mol/L ammonia water, and finally wash the solids three times with water once to neutrality, freeze-dry and vacuum Dry to obtain aniline pentamer whose end group is amino group. The yield is 80%.

Example 3

Dissolve 3 g of the aniline tetramer whose terminal group is an amino group obtained in Example 1 in dichloromethane to obtain an aniline tetramer solution; then take 4.1 g of succinic anhydride and dissolve it in 400 mL of dichloromethane to obtain For succinic anhydride solution, mix the aniline tetramer solution with the succinic anhydride solution, stir the reaction quickly, and a black precipitate gradually precipitates out. After 5 hours of reaction, the reaction product is filtered to obtain a black precipitate, which is used in a Soxhlet extractor. Extract with dichloromethane, wash with water three times at the end, freeze-dry and then vacuum-dry to obtain aniline tetramer whose terminal group is carboxyl. The yield was 80%.

Example 4

Dissolve 3 g of the aniline pentamer whose terminal group is an amino group obtained in Example 2 in dichloromethane to obtain an aniline pentamer solution; then take 5.6 g of succinic anhydride, and under nitrogen protection, dissolve it in 400 mL of dichloromethane to obtain For succinic anhydride solution, mix the aniline pentamer solution with the succinic anhydride solution, stir the reaction quickly, and a black precipitate gradually precipitates out. After reacting for 5 hours, filter the reaction product to obtain a black precipitate, which is used in a Soxhlet extractor. Extract with dichloromethane, wash with water for three times at the end, freeze-dry and then vacuum-dry to obtain aniline pentamer whose terminal group is carboxyl. The yield was 70%.

Embodiment 5~16

Polyethylene glycol monomethyl ether was placed in a dry reaction bottle, water was azeotropically removed with toluene in an oil bath at 140°C, and vacuum-dried to obtain polyethylene glycol monomethyl ether after water removal. Put L-lactide in a dry reaction bottle, recrystallize it three times with ethyl acetate, and vacuum-dry it to obtain recrystallized L-lactide. According to the ratio in Table 1, respectively add 5 g of polyethylene glycol monomethyl ether after water removal and L-lactide after recrystallization into the dry reaction bottle, under anhydrous and oxygen-free conditions, the addition concentration is 0.05 Mmol/mL stannous octoate catalyst toluene solution, then added toluene, placed in an oil bath at 120°C, and stirred for 24 hours. After the reaction, the reaction liquid was settled with 500mL ethanol/ether mixture, and the solid was obtained by suction filtration. The solid was dissolved with 50mL chloroform, and then settled with 500mL ethanol/ether mixture. This was repeated three times, and finally the obtained solid was vacuum-dried for 48 hour, the product was obtained. The yields were all above 80%.

The obtained block copolymer is carried out nuclear magnetic resonance analysis respectively, and the result is referring to Fig. 1, and Fig. 1 is the proton nuclear magnetic resonance spectrum figure of the block copolymer obtained in the embodiment of the present invention 8, can know by Fig. 1 chemical shift, 3.5ppm is The characteristic peak of polyethylene glycol monomethyl ether, lactide is 5.1ppm, indicating that polyethylene glycol monomethyl ether reacted with L-lactide to form a block copolymer. The number average molecular weight of the obtained block copolymer was tested by gel permeation chromatography (GPC), and the results are shown in Table 1. Table 1 is a summary of the amount of each raw material and the number average molecular weight of the product in Examples 5-16 of the present invention.

In table 1 embodiment of the present invention 5～16, each raw material consumption and product number average molecular weight are summarized

Example 17~28

Polyethylene glycol monomethyl ether was placed in a dry reaction bottle, water was azeotropically removed with toluene in an oil bath at 140°C, and vacuum-dried to obtain polyethylene glycol monomethyl ether after water removal. D-(D)-lactide was placed in a dry reaction flask, recrystallized three times with ethyl acetate, and vacuum-dried to obtain recrystallized D-lactide. According to the ratio in Table 2, 5 g of polyethylene glycol monomethyl ether after water removal and D-lactide after recrystallization were added into the dry reaction bottle together, under anhydrous and oxygen-free conditions, the addition concentration was 0.05 Mmol/mL stannous octoate catalyst toluene solution, then added toluene, placed in an oil bath at 120°C, and stirred for 24 hours. After the reaction, the reaction liquid was settled with 500mL ethanol/ether mixture, and the solid was obtained by suction filtration. The solid was dissolved with 50mL chloroform, and then settled with 500mL ethanol/ether mixture. This was repeated three times, and finally the obtained solid was vacuum-dried for 48 hour, the product was obtained. The yields were all above 80%.

The obtained block copolymers were subjected to nuclear magnetic resonance analysis, and the results showed that polyethylene glycol monomethyl ether reacted with D-lactide to generate block copolymers. The number-average molecular weight of the obtained block copolymer was tested by GPC, and the results are shown in Table 2. Table 2 is a summary of the amount of each raw material and the number-average molecular weight of the product in Examples 17-28 of the present invention.

Table 2 In the embodiment of the present invention 17～28, each raw material consumption and product number average molecular weight are summarized

Example 29~40

Put the polyethylene glycol in a dry reaction bottle, use toluene to azeotropically remove water in an oil bath at 140°C, and vacuum dry to obtain polyethylene glycol after water removal. The L-lactide was placed in a dry reaction bottle, recrystallized three times with ethyl acetate, and vacuum-dried to obtain the recrystallized L-lactide. According to the ratio in Table 3, respectively add 5 g of polyethylene glycol after water removal and L-lactide after recrystallization into the dry reaction bottle, under anhydrous and oxygen-free conditions, the concentration is 0.05mmol/mL The stannous octoate catalyst toluene solution was added, and toluene was added, placed in an oil bath at 120°C, and stirred for 24 hours. After the reaction, the reaction liquid was settled with 500mL ethanol/ether mixture, and the solid was obtained by suction filtration. The solid was dissolved with 50mL chloroform, and then settled with 500mL ethanol/ether mixture. This was repeated three times, and finally the obtained solid was vacuum-dried for 48 hour, the product was obtained. The yields were all above 80%.

NMR analyzes were carried out on the obtained block copolymers, and the results showed that polyethylene glycol reacted with L-lactide to generate block copolymers. The number-average molecular weight of the obtained block copolymer was tested by GPC, and the results are shown in Table 3. Table 3 is a summary of the amount of each raw material and the number-average molecular weight of the product in Examples 29-40 of the present invention.

In Table 3 Examples 29 to 40 of the present invention, the amount of each raw material and the number average molecular weight of the product are summarized

Example 41~52

Put the polyethylene glycol in a dry reaction bottle, use toluene to azeotropically remove water in an oil bath at 140°C, and vacuum dry to obtain polyethylene glycol after water removal. D-lactide was placed in a dry reaction flask, recrystallized three times with ethyl acetate, and vacuum-dried to obtain recrystallized D-lactide. According to the ratio in Table 4, respectively add 5 g of polyethylene glycol after dehydration and D-lactide after recrystallization into the dry reaction bottle, under anhydrous and oxygen-free conditions, the concentration is 0.05mmol/mL The stannous octoate catalyst toluene solution was added, and toluene was added, placed in an oil bath at 120°C, and stirred for 24 hours. After the reaction, the reaction liquid was settled with 500mL ethanol/ether mixture, and the solid was obtained by suction filtration. The solid was dissolved with 50mL chloroform, and then settled with 500mL ethanol/ether mixture. This was repeated three times, and finally the obtained solid was vacuum-dried for 48 hour, the product was obtained. The yields were all above 80%.

NMR analyzes were carried out on the obtained block copolymers, and the results showed that polyethylene glycol reacted with D-lactide to generate block copolymers. The number-average molecular weight of the obtained block copolymer was tested by GPC, and the results are shown in Table 4. Table 4 is a summary of the amount of each raw material and the number-average molecular weight of the product in Examples 41-52 of the present invention.

In Table 4 Examples 41 to 52 of the present invention, the amount of each raw material and the number average molecular weight of the product are summarized

Example 53~64

According to the ratio in Table 5, 1 g of the polyethylene glycol monomethyl ether-poly(L) lactide block copolymer intermediate prepared in Example 5 was mixed with 1-(3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride (EDC) and 4-dimethylaminopyridine (DMAP) were loaded into three reaction flasks with stirring bars, and after each reaction flask was replaced with nitrogen three times, 20mL was injected into each N,N-dimethylformamide was used as a solvent and reacted at room temperature for 2 days to obtain block copolymer solution, EDC solution and DMAP solution respectively. Put the carboxy-terminated aniline tetramer prepared in Example 3 into a reaction bottle, and after changing nitrogen three times, inject 10 mL of N,N-dimethylformamide to completely dissolve it to obtain aniline tetramer solution; The segment copolymer solution, the EDC solution, the DMAP solution and the aniline tetramer solution were mixed, and the temperature was raised to 50° C. for 24 hours to react. After the reaction, the reaction solution was settled with ether, and the crude product was obtained by suction filtration. To purify the crude product, first dissolve the solid with chloroform, remove the insoluble matter by filtration, settle the chloroform solution with ethanol, filter with suction to obtain the solid, continue to dissolve it with chloroform, repeat this three times, and dry the solid in vacuum at room temperature for 24 hours Finally, polyethylene glycol monomethyl ether-poly(L) lactide coupled aniline tetramer block copolymers were obtained, and the yields were all higher than 80%.

Carry out nuclear magnetic resonance analysis to the obtained block copolymer, the result shows, the characteristic peak of aniline tetramer appears at 6.5-7.5ppm place, shows that aniline tetramer and polyethylene glycol monomethyl ether-poly (L) lactate The esters react to form block copolymers. GPC was used to detect the molecular weight of the obtained block copolymer, and the results are shown in Table 5. Table 5 is a summary of the amount of each raw material and the number average molecular weight of the product in Examples 53-64 of the present invention.

In Table 5 Examples 53 to 64 of the present invention, the amount of each raw material and the number average molecular weight of the product are summarized

Example 65~76

According to the ratio in Table 6, 1 g of the poly(L) lactide-polyethylene glycol-poly(L) lactide block copolymer intermediate prepared in Example 29 and 1-(3-dimethyl Aminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 4-dimethylaminopyridine (DMAP) were loaded into three reaction flasks with stirring bars, and nitrogen gas was changed three times in each reaction flask Afterwards, 20 mL of N,N-dimethylformamide was injected as a solvent, and reacted at room temperature for 2 days to obtain a block copolymer solution, an EDC solution, and a DMAP solution, respectively. Put the carboxy-terminated aniline tetramer prepared in Example 3 into a reaction bottle, and after changing nitrogen three times, inject 10 mL of N,N-dimethylformamide to completely dissolve it to obtain aniline tetramer solution; The segment copolymer solution, the EDC solution, the DMAP solution and the aniline tetramer solution were mixed, and the temperature was raised to 50° C. for 24 hours to react. After the reaction, the reaction solution was settled with ether, and the crude product was obtained by suction filtration. To purify the crude product, first dissolve the solid with chloroform, remove the insoluble matter by filtration, settle the chloroform solution with ethanol, filter with suction to obtain the solid, continue to dissolve it with chloroform, repeat this three times, and dry the solid in vacuum at room temperature for 24 hours Finally, poly(L) lactide-polyethylene glycol-poly(L) lactide coupled aniline tetramer block copolymers are obtained, and the yields are all higher than 80%.

The obtained block copolymer is carried out nuclear magnetic resonance analysis, and the results are shown in Fig. 2, and Fig. 2 is the proton nuclear magnetic resonance spectrogram of the block copolymer prepared in the embodiment of the present invention 70, as can be seen from Fig. 2, 6.5-7.5ppm place appeared The characteristic peaks of the aniline tetramer indicate that the aniline tetramer reacted with poly(L) lactide-polyethylene glycol-poly(L) lactide to form a block copolymer. GPC was used to detect the molecular weight of the obtained block copolymer, and the results are shown in Table 6. Table 6 is a summary of the amount of each raw material and the number average molecular weight of the product in Examples 65-76 of the present invention.

Table 6 In Examples 65 to 76 of the present invention, the amount of each raw material and the number average molecular weight of the product are summarized

Example 77~88

According to the ratio in Table 7, 1 g of the polyethylene glycol monomethyl ether-poly(D) lactide block copolymer intermediate prepared in Example 17 and 1-(3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride (EDC) and 4-dimethylaminopyridine (DMAP) were loaded into three reaction flasks with stirring bars, and after each reaction flask was replaced with nitrogen three times, 20mL was injected into each N,N-dimethylformamide was used as a solvent and reacted at room temperature for 2 days to obtain block copolymer solution, EDC solution and DMAP solution respectively. The carboxyl-terminated aniline tetramer prepared in Example 3 was put into a reaction bottle, and after changing nitrogen three times, 10 mL of N,N-dimethylformamide was injected to completely dissolve it to obtain an aniline tetramer solution. Under the protection of nitrogen, the block copolymer solution, the EDC solution, the DMAP solution and the aniline tetramer solution were mixed, and the temperature was raised to 50° C. to react for 24 hours. After the reaction, the reaction solution was settled with ether, and the crude product was obtained by suction filtration. To purify the crude product, first dissolve the solid with chloroform, remove the insoluble matter by filtration, settle the chloroform solution with ethanol, filter with suction to obtain the solid, continue to dissolve it with chloroform, repeat this three times, and dry the solid in vacuum at room temperature for 24 hours Finally, polyethylene glycol monomethyl ether-poly(D) lactide coupled aniline tetramer block copolymers were obtained, with yields higher than 80%.

Carry out nuclear magnetic resonance analysis to the obtained block copolymer, the result shows, the characteristic peak of aniline tetramer appears at 6.5-7.5ppm place, shows that aniline tetramer and polyethylene glycol monomethyl ether-poly (D) lactate The esters react to form block copolymers. GPC was used to detect the molecular weight of the obtained block copolymer, and the results are shown in Table 7. Table 7 is a summary of the amount of each raw material and the number average molecular weight of the product in Examples 77-88 of the present invention.

In Table 7, in Examples 77 to 88 of the present invention, the amount of each raw material and the number average molecular weight of the product are summarized

Example 89~100

According to the ratio in Table 8, 1 g of the poly(D) lactide-polyethylene glycol-poly(D) lactide block copolymer intermediate prepared in Example 41 and 1-(3-dimethyl Aminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 4-dimethylaminopyridine (DMAP) were loaded into three reaction flasks with stirring bars, and nitrogen gas was changed three times in each reaction flask Afterwards, 20 mL of N,N-dimethylformamide was injected as a solvent, and reacted at room temperature for 2 days to obtain a block copolymer solution, an EDC solution, and a DMAP solution, respectively. The carboxyl-terminated aniline tetramer prepared in Example 3 was put into a reaction bottle, and after changing nitrogen three times, 10 mL of N,N-dimethylformamide was injected to completely dissolve it to obtain an aniline tetramer solution. Under the protection of nitrogen, the block copolymer solution, the EDC solution, the DMAP solution and the aniline tetramer solution were mixed, and the temperature was raised to 50° C. to react for 24 hours. After the reaction, the reaction solution was settled with ether, and the crude product was obtained by suction filtration. To purify the crude product, first dissolve the solid with chloroform, remove the insoluble matter by filtration, settle the chloroform solution with ethanol, filter with suction to obtain the solid, continue to dissolve it with chloroform, repeat this three times, and dry the solid in vacuum at room temperature for 24 hours Finally, poly(D) lactide-polyethylene glycol-poly(D) lactide-coupled aniline tetramer block copolymers are obtained, and the yields are all higher than 80%.

Carry out nuclear magnetic resonance analysis to the obtained block copolymer, the result shows, the characteristic peak of aniline tetramer appears at 6.5-7.5ppm place, shows that aniline tetramer and poly(D) lactide-polyethylene glycol-polyethylene (D) Lactide reacts to form block copolymers. GPC was used to detect the molecular weight of the obtained block copolymer, and the results are shown in Table 8. Table 8 is a summary of the amount of each raw material and the number average molecular weight of the product in Examples 89-100 of the present invention.

In Table 8 Examples 89 to 100 of the present invention, the amount of each raw material and the number average molecular weight of the product are summarized

Example 101~112

According to the ratio in Table 9, 1 g of the polyethylene glycol monomethyl ether-poly(L) lactide block copolymer intermediate prepared in Example 5 and 1-(3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride (EDC) and 4-dimethylaminopyridine (DMAP) were loaded into three reaction flasks with stirring bars, and after each reaction flask was replaced with nitrogen three times, 20mL was injected into each N,N-dimethylformamide was used as a solvent and reacted at room temperature for 2 days to obtain a block copolymer solution, an EDC solution, and a DMAP solution. The carboxyl-terminated aniline pentamer prepared in Example 4 was put into a reaction bottle, and after changing nitrogen three times, 10 mL of N,N-dimethylformamide was injected to completely dissolve it to obtain aniline pentamer solution. Under the protection of nitrogen, the block copolymer solution, the EDC solution, the DMAP solution and the aniline pentamer solution were mixed, and the temperature was raised to 50° C. to react for 24 hours. After the reaction, the reaction solution was settled with ether, and the crude product was obtained by suction filtration. To purify the crude product, first dissolve the solid with chloroform, remove the insoluble matter by filtration, settle the chloroform solution with ethanol, filter with suction to obtain the solid, continue to dissolve it with chloroform, repeat this three times, and dry the solid in vacuum at room temperature for 24 hours Finally, polyethylene glycol monomethyl ether-poly(L) lactide coupled aniline pentamer block copolymers were obtained, with yields higher than 80%.

The NMR analysis of the obtained block copolymer showed that the aniline pentamer reacted with polyethylene glycol monomethyl ether-poly(L) lactide to form a block copolymer. GPC was used to detect the molecular weight of the obtained block copolymer, and the results are shown in Table 9. Table 9 is a summary of the amount of each raw material and the number average molecular weight of the product in Examples 101-112 of the present invention.

In Table 9 Examples 101 to 112 of the present invention, the amount of each raw material and the number average molecular weight of the product are summarized

Example 113~124

According to the ratio in Table 10, 1 g of the poly(L) lactide-polyethylene glycol-poly(L) lactide block copolymer intermediate prepared in Example 29 and 1-(3-dimethyl Aminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 4-dimethylaminopyridine (DMAP) were loaded into three reaction flasks with stirring bars, and nitrogen gas was changed three times in each reaction flask Afterwards, 20 mL of N,N-dimethylformamide was injected as a solvent, and reacted at room temperature for 2 days to obtain a block copolymer solution, an EDC solution, and a DMAP solution, respectively. The carboxyl-terminated aniline pentamer prepared in Example 4 was put into a reaction bottle, and after changing nitrogen three times, 10 mL of N,N-dimethylformamide was injected to completely dissolve it to obtain aniline pentamer solution. Under the protection of nitrogen, the block copolymer solution, the EDC solution, the DMAP solution and the aniline pentamer solution were mixed, and the temperature was raised to 50° C. to react for 24 hours. After the reaction, the reaction solution was settled with ether, and the crude product was obtained by suction filtration. To purify the crude product, first dissolve the solid with chloroform, remove the insoluble matter by filtration, settle the chloroform solution with ethanol, filter with suction to obtain the solid, continue to dissolve it with chloroform, repeat this three times, and dry the solid in vacuum at room temperature for 24 hours Finally, poly(L) lactide-polyethylene glycol-poly(L) lactide-coupled aniline pentamer block copolymers are obtained, and the yields are all higher than 80%.

NMR analysis of the resulting block copolymer showed that the aniline pentamer reacted with poly(L)lactide-polyethylene glycol-poly(L)lactide to form a block copolymer . GPC was used to detect the molecular weight of the obtained block copolymer, and the results are shown in Table 10. Table 10 is a summary of the amount of each raw material and the number average molecular weight of the product in Examples 113-124 of the present invention.

In Table 10 Examples 113 to 124 of the present invention, the amount of each raw material and the number average molecular weight of the product are summarized

Example 125~136

According to the ratio in Table 11, 1 g of the polyethylene glycol monomethyl ether-poly(D) lactide block copolymer intermediate prepared in Example 17 and 1-(3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride (EDC) and 4-dimethylaminopyridine (DMAP) were loaded into three reaction flasks with stirring bars, and after each reaction flask was replaced with nitrogen three times, 20mL was injected into each N,N-dimethylformamide was used as a solvent and reacted at room temperature for 2 days to obtain block copolymer solution, EDC solution and DMAP solution respectively. The carboxyl-terminated aniline pentamer prepared in Example 4 was put into a reaction bottle, and after changing nitrogen three times, 10 mL of N,N-dimethylformamide was injected to completely dissolve it to obtain aniline pentamer solution. Under the protection of nitrogen, the block copolymer solution, the EDC solution, the DMAP solution and the aniline pentamer solution were mixed, and the temperature was raised to 50° C. to react for 24 hours. After the reaction, the reaction solution was settled with ether, and the crude product was obtained by suction filtration. To purify the crude product, first dissolve the solid with chloroform, remove the insoluble matter by filtration, settle the chloroform solution with ethanol, filter with suction to obtain the solid, continue to dissolve it with chloroform, repeat this three times, and dry the solid in vacuum at room temperature for 24 hours Finally, polyethylene glycol monomethyl ether-poly(D) lactide coupled aniline pentamer block copolymers were obtained, and the yields were all higher than 80%.

The NMR analysis of the obtained block copolymers showed that the aniline pentamer reacted with polyethylene glycol monomethyl ether-poly(D) lactide to form a block copolymer. GPC was used to detect the molecular weight of the obtained block copolymer, and the results are shown in Table 11. Table 11 is a summary of the amount of each raw material and the number average molecular weight of the product in Examples 125-136 of the present invention.

In Table 11, in Examples 125 to 136 of the present invention, the amount of each raw material and the number average molecular weight of the product are summarized

Example 137~148

According to the ratio in Table 12, 1 g of the poly(D) lactide-polyethylene glycol-poly(D) lactide block copolymer intermediate prepared in Example 41 and 1-(3-dimethyl Aminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 4-dimethylaminopyridine (DMAP) were loaded into three reaction flasks with stirring bars, and nitrogen gas was changed three times in each reaction flask Afterwards, 20 mL of N,N-dimethylformamide was injected as a solvent, and reacted at room temperature for 2 days to obtain a block copolymer solution, an EDC solution, and a DMAP solution, respectively. The carboxyl-terminated aniline pentamer prepared in Example 4 was put into a reaction bottle, and after changing nitrogen three times, 10 mL of N,N-dimethylformamide was injected to completely dissolve it to obtain aniline pentamer solution. Under the protection of nitrogen, the block copolymer solution, the EDC solution, the DMAP solution and the aniline pentamer solution were mixed, and the temperature was raised to 50° C. to react for 24 hours. After the reaction, the reaction solution was settled with ether, and the crude product was obtained by suction filtration. To purify the crude product, first dissolve the solid with chloroform, remove the insoluble matter by filtration, settle the chloroform solution with ethanol, filter with suction to obtain the solid, continue to dissolve it with chloroform, repeat this three times, and dry the solid in vacuum at room temperature for 24 hours Finally, poly(D) lactide-polyethylene glycol-poly(D) lactide-coupled aniline pentamer block copolymers are obtained, and the yields are all higher than 80%.

NMR analysis of the resulting block copolymer revealed that the aniline pentamer reacted with poly(D)lactide-polyethylene glycol-poly(D)lactide to form a block copolymer . GPC was used to detect the molecular weight of the obtained block copolymer, and the results are shown in Table 12. Table 12 is a summary of the amount of each raw material and the number average molecular weight of the product in Examples 137-148 of the present invention.

In Table 12, in Examples 137 to 148 of the present invention, the amount of each raw material and the number average molecular weight of the product are summarized

Example 149

The block copolymers prepared in Examples 53 to 148 were formulated into aqueous solutions with a mass concentration of 20%, and the aniline tetramer and polyethylene glycol monomethyl ether-poly(L) lactide were coupled to Monomethyl ether-poly(D)lactide-coupled aniline tetramer pairing, poly(L)lactide-polyethylene glycol-poly(L)lactide-coupled aniline tetramer and poly(D) Lactide-polyethylene glycol-poly(D) lactide-coupled aniline tetramer pairing, polyethylene glycol monomethyl ether-poly(L)-lactide-coupled aniline pentamer and polyethylene glycol Monomethyl ether-poly(D)lactide-coupled aniline pentamer pairing, poly(L)lactide-polyethylene glycol-poly(L)lactide-coupled aniline pentamer and poly(D) The pairing method of lactide-polyethylene glycol-poly(D) lactide coupled aniline pentamer, block copolymers with correspondingly close molecular weight and different chirality, such as Example 58 and Example 82 , or prepare Example 67 and Example 91 respectively into solutions with a concentration of 10wt%, take 0.5mL each and mix evenly, let it stand for a period of time, observe the viscosity change by using the small tube inversion method, and the small tube will not flow into a gel within 30s melt point.

Experimental results show that mixing the block copolymer of the left-handed configuration and the block copolymer of the right-handed configuration provided by the present invention in an aqueous medium can gradually transform from solution to form a three-dimensional composite hydrogel material.

Example 150

The block copolymers prepared in Examples 53 to 148 of the present invention were prepared into three-dimensional composite hydrogels according to the method of Example 149, and then 3 mL of phosphate buffer solution was added to the above hydrogels, and the solution was taken out every other day , analyze the sample by weighing method, and then add 3 mL of new buffer solution. The results show that the degradation period of the block copolymer prepared by the present invention is 4 to 8 weeks.

Example 151

The block copolymers prepared in Examples 53-148 of the present invention were made into three-dimensional composite hydrogels according to the method of Example 149, and the change of the three-dimensional composite modulus of the polymer aqueous solution over time was measured by a rheometer. The experimental results are shown in Fig. 3. Fig. 3 is a dynamic mechanical test diagram of the hydrogel formed by the block copolymers prepared in Examples 58 and 82. As can be seen from Fig. 3, the three-dimensional composite hydrogel prepared by the present invention has an elastic modulus higher than its loss modulus.

Example 152

The block copolymers prepared in Examples 53 to 148 of the present invention were formulated into 0.05 mg/mL aqueous solution, and 0.1 mol/L hydrochloric acid aqueous solution was gradually added thereto, and the ultraviolet absorption change process of gradual doping of aniline oligomers in the material was observed . The experimental results are shown in Figure 4, and Figure 4 is the UV absorption diagram of the poly(L) lactide-polyethylene glycol-poly(L) lactide coupled aniline pentamer block copolymer prepared in Example 114 of the present invention , as can be seen from Figure 4, the block copolymer provided by the present invention has good electrical activity.

Example 153

The block copolymers prepared in Examples 53 to 148 of the present invention were formulated into 0.05 mg/mL aqueous solution, and 0.01 mmol/L ammonium persulfate solution was gradually added thereto, and the ultraviolet absorption of aniline oligomers gradually oxidized in the material was observed. transformation. The experimental results are shown in Figure 5, and Figure 5 is the ultraviolet absorption diagram of the poly(D) lactide-polyethylene glycol-poly(D) lactide coupled aniline pentamer block copolymer prepared in Example 144 of the present invention , as can be seen from Figure 5, the block copolymer provided by the present invention has good electrical activity.

Comparative example 1

The block copolymers prepared in Examples 5-52 of the present invention were prepared into a 0.05 mg/mL aqueous solution, and the ultraviolet absorption test was carried out according to the method of Example 152. Experimental results show that the block copolymers prepared in Examples 5-52 do not have electrical activity.

As can be seen from the above examples and comparative examples, the block copolymer provided by the present invention has good water solubility and electrical activity, and the block copolymer of the left-handed configuration and the block copolymer of the right-handed configuration are mixed in an aqueous medium After a period of time, a three-dimensional composite hydrogel material can be formed, which has properties such as electroactivity, water solubility, degradability, and injectability, and can be used as a drug carrier or scaffold material in the field of biomedical materials.

The descriptions of the above embodiments are only used to help understand the method and core idea of the present invention. It should be pointed out that for those skilled in the art, without departing from the principle of the present invention, some improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims (12)

1. A block copolymer for preparing a hydrogel, comprising an A block having a structure of formula (I) or formula (II) and a B block having a structure of formula (III) or formula (IV):

wherein,

n is polymerization degree, n is more than or equal to 23 and less than or equal to 500;

m is polymerization degree, and m is more than or equal to 3 and less than or equal to 90;

x is polymerization degree, and x is more than or equal to 2 and less than or equal to 5.

2. The block copolymer of claim 1, wherein in formula (III) or formula (IV), x is selected from 3 or 4.

3. The block copolymer according to claim 1 or 2, wherein the B block accounts for 10 to 50% by mass of the block copolymer.

4. A method for preparing a block copolymer, comprising:

A) mixing polyethylene glycol or polyethylene glycol monomethyl ether with lactide and a catalyst, and carrying out ring-opening polymerization reaction to obtain a block copolymer intermediate, wherein the lactide is levorotatory-lactide or dextrorotatory-lactide;

B) mixing the block copolymer intermediate obtained in the step A) with a coupling reagent and a compound with a structure of a formula (V) to perform condensation reaction to obtain a block copolymer;

wherein,

x is polymerization degree, and x is more than or equal to 2 and less than or equal to 5.

5. The method according to claim 4, wherein the molar ratio of polyethylene glycol or polyethylene glycol monomethyl ether to lactide is 1: 1 to 45.

6. The method according to claim 4, wherein the mass ratio of the block copolymer intermediate obtained in step A) to the compound having the structure of formula (V) is 1: 0.01 to 1.

7. The method of claim 4, wherein the catalyst is stannous octoate, and the coupling reagent is selected from any one or more of N, N-cyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine.

8. The method according to claim 4, wherein the temperature of the ring-opening polymerization reaction in the step A) is 100 ℃ to 150 ℃, and the time of the ring-opening polymerization reaction is 12h to 48 h.

9. The method according to claim 4, wherein in the step B), the temperature of the condensation reaction is 0-60 ℃, and the time of the condensation reaction is 24-72 h.

10. A hydrogel comprises an aqueous medium and a stereo composite block copolymer, wherein the aqueous medium is selected from any one or more of water, normal saline, buffer solution, tissue culture solution or body fluid; the stereo composite block copolymer is formed by a first block copolymer formed by a formula (I) and a formula (III) and a second block copolymer formed by a formula (I) and a formula (IV); or a first block copolymer formed from formula (II) and formula (III) and a second block copolymer formed from formula (II) and formula (IV);

wherein,

n is polymerization degree, n is more than or equal to 23 and less than or equal to 500;

m is polymerization degree, and m is more than or equal to 3 and less than or equal to 90;

x is polymerization degree, and x is more than or equal to 2 and less than or equal to 5.

11. The hydrogel according to claim 10, wherein the ratio of the number average molecular weight of the first block copolymer of formula (I) and formula (III) to the number average molecular weight of the second block copolymer of formula (I) and formula (IV) is 0.5 to 1.5: 1; the ratio of the number average molecular weight of the first block copolymer formed by the formula (II) and the formula (III) and the number average molecular weight of the second block copolymer formed by the formula (II) and the formula (IV) is 0.5-1.5: 1.

12. the hydrogel of claim 10, wherein x is selected from 3 or 4.