CN100519511C - Aniline oligomer, its aliphatic polyester copolymer and their prepn - Google Patents

Abstract

The invention provides aniline oligomer, its copolymer with aliphatic polyester and a preparation method. The invention provides two kinds of aniline oligomers synthesized from N-phenyl-1,4-p-phenylenediamine, and then copolymerized with aliphatic polyester (polylactide or polyε-caprolactone) to obtain a series of An electroactive biodegradable polymer, that is, first protect the terminal amino group of N-phenyl-1,4-p-phenylenediamine with succinic anhydride, and then react with amino-terminated aniline dimer and phenylenediamine respectively to obtain Aniline tetramers with one carboxyl group and one amino group at the end, and aniline pentamers terminated with two carboxyl groups. The aniline oligomer and the dihydroxy-terminated aliphatic polyester react to obtain a series of copolymers containing electroactive aniline oligomer blocks through polycondensation reaction. The copolymer combines the advantages of aniline oligomer and aliphatic polyester, has both electrical activity and biological activity, is biodegradable, and the degradation products can be excreted from the body. It is mainly used as a biomedical material, especially as a tissue engineering scaffold material for nerves and hearts.

Description

Aniline oligomer and aliphatic polyester block copolymer and preparation method thereof

technical field

The invention belongs to the field of biomedical polymer materials, and relates to an aniline oligomer and aliphatic polyester block copolymer and a preparation method.

Background technique

In recent decades, with the rapid development of polymer science and the rapid development of modern pharmacy, biology and engineering, the research on biomedical polymer materials has developed rapidly. Among them, biodegradable polymer materials have been widely used in the fields of surgical sutures, artificial skin, artificial blood vessels, bone fixation and repair, and controlled release of drugs because they do not require secondary surgery to remove after implantation. Biodegradable synthetic polymers mainly include aliphatic polyesters, polyamino acids, polyphosphates, polyanhydrides, polyorthoesters, polycarbonates, and the like. Aliphatic polyesters, such as polylactide (PLA), polyglycolide (PGA), polyε-caprolactone (PCL), have low immunogenicity and good biodegradability and biocompatibility, and have been It is widely used in the fields of biomedicine and medicine, such as fracture fixation, surgical sutures, tissue engineering scaffolds, drug sustained-release carriers, etc.

Recently, the interdisciplinary research of biodegradable polymers and conductive polymers has become a hot spot again. As we all know, polyaniline, as a conductive polymer material, has been a research hotspot in recent decades. Because of its controllable electrical conductivity, good thermal stability and redox properties, it is widely used as anti-corrosion coating, Batteries, sensors, separation membranes as well as anti-static clothing and protective screens against EMI. However, the latest research shows that electroactive polymers such as polyaniline can be used as a new type of smart material as a heart or nerve scaffold material. The basic point is that electrical or electrochemical signals can directly or indirectly affect cell proliferation, assembly, and differentiation, so electroactive scaffold materials can control the growth and proliferation of tissue cells by applying appropriate electrical signals. Recently, Wei Yan et al. (Guterman E., Cheng S., Palouian K., Bidez P., Lelkes P., and Wei Y. "Electroactive Copolymers Modified by Polypeptides for Tissue Engineering". Polym.Prepr.2002 , 43, 766-767) have used H9c2 cardiac myoblasts and PC12 bladder chromaffin tumor cells to prove that polyaniline and its derivatives as biocompatible matrix materials can make cells adhere well thereon , growth and differentiation. Other electroactive polymers, such as polypyrrole, have also been shown to enhance the effect of nerve growth factor on the differentiation of PC12 cells when stimulated by electrical signals. Therefore, the application of electroactive polymer materials in biomedicine has attracted widespread attention. However, if electroactive polymers such as polyaniline are directly used in the body, there are still many problems, such as poor biocompatibility, non-degradability and poor solubility. Difficult to process etc. Focusing on solving the above-mentioned shortcomings of electroactive polymers, a series of research work has been carried out.

In order to improve the biocompatibility of electroactive polymers, many methods have been used. At present, the most used methods are: blending with bioactive substances or grafting biocompatible substances on polymer side chains and polymerizing The main chain is connected with biocompatible blocks. For example, Wei Yan et al. combined polyaniline and natural biopolymers such as gels (Li, M.; Guo, Y.; Wei, Y.; MaCDiarmid, A.G.; Lelkes, P.I. Polyaniline electrospun fiber "Biomaterials 2006, 27, 2705-2715.) and other blends, or life active substances such as short peptides on the polyaniline side chains, make the biocompatibility of polyaniline greatly improved.

Electroactive polymers such as polyaniline generally have poor solubility and can only be dissolved in strong polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide and N-methylpyrrolidone. This has brought many problems for its processing application. The method used to improve the solubility of electroactive polymers is basically to introduce polymers that can increase solubility on the side chain of the polymer, such as polyethylene glycol and polyacrylic acid.

Another very important factor limiting the application of electroactive polymers in vivo is their non-degradability. If polyaniline and other electroactive polymers are used in the body for a long time, they can induce adverse reactions of joint inflammation. Since they are not degradable, they must be taken out by a second operation after use, which brings another pain to the patient, which is a great disadvantage of its application. . To solve this problem, the material needs to be made biodegradable. Such as Rivers et al. (River, T.J.; Hudson, T.W.; Schmidt, C.E. "Synthesis of a novel biodegradable conductive polymer for the field of biomedicine". Adv. Funct. Mater. 2002, 12, 33-37) Linking pyrrole oligomers to each other using ester linkages solved this problem.

Contents of the invention

At present, there is no material that can completely solve the three disadvantages of poor compatibility, non-degradability and poor solubility and difficult processing mentioned above. In order to fundamentally solve the problems raised above, the inventors formed copolymers from biodegradable aliphatic polyesters and aniline oligomers via ester bonds. Aniline oligomer has similar electrical activity to polyaniline, and has better solubility, and the introduction of aliphatic polyester can not only improve biological activity, but also solve the problem of degradation, which is a more feasible method. Therefore, the copolymer provides a good prospect for the application of electroactive materials in the human body, and opens up a new path for neural tissue engineering materials.

One of the purposes of the present invention is to provide aniline oligomers with bifunctional groups, including aniline tetramers and dicarboxyl-terminated aniline pentamers with one carboxyl-terminated amino group, and their structural formulas are respectively:

Two of object of the present invention is to provide the synthetic method of the aniline oligomer with bifunctional group described in object one, and its synthetic method comprises the following steps and conditions:

1) Take N-phenyl-1,4-p-phenylenediamine as raw material, dissolve it in dichloromethane, and add succinic anhydride with an equimolar number of N-phenyl-1,4-p-phenylenediamine , stirred at room temperature under nitrogen protection, the resulting precipitate was washed with ether until colorless, and the amino-terminated aniline dimer was obtained; the amino-terminated aniline dimer and the double-amino-terminated aniline dimer were obtained in the same molar ratio , was dissolved in a mixed solvent of dimethylformamide (hereinafter referred to as DMF) and 1M hydrochloric acid, and the hydrochloric acid (1M) solution of ammonium persulfate was added dropwise under stirring conditions at 0°C, and after the addition was completed, it was washed with distilled water, After dissolving the precipitate with aqueous ammonia, reduce it with hydrazine hydrate, adjust the pH value to 2-3 with hydrochloric acid, and extract with 1,2-dichloroethane and tetrahydrofuran respectively to obtain aniline tetramer with one carboxyl group at one end and amino group at the other end ( Hereinafter referred to as AT).

Its reaction equation is as follows:

2) Same as the method for preparing the amino-terminated aniline dimer in the above-mentioned 1), first obtain the amino-terminated aniline dimer; mix the amino-terminated aniline dimer and phenylenediamine with a molar ratio of 2:1 Add the mixed solvent of dimethylformamide and 1M hydrochloric acid, add the hydrochloric acid (1M) solution of ammonium persulfate dropwise under stirring at room temperature, after the dropwise addition, wash with distilled water, dissolve the precipitate with ammonia water, and hydrate Hydrazine reduced it, then adjusted the pH value to 2-3 with hydrochloric acid, and extracted with 1,2-dichloroethane and tetrahydrofuran respectively to obtain dicarboxyl-terminated aniline pentamer (hereinafter referred to as AP). Its reaction equation is as follows:

The structures of synthesized aniline tetramers with one carboxyl group at one end and amino group at one end and aniline pentamers with two carboxyl groups terminated were confirmed by matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF-MS). (See Figure 1 and Figure 2)

The third object of the present invention is to use the above-mentioned synthesized aniline oligomers with bifunctional groups and aliphatic polyesters obtained by ring-opening polymerization with aliphatic cyclic ester monomers to form aniline oligomers through polycondensation reactions. Multi-block copolymers of polymers and aliphatic polyesters. Multi-block copolymers of aniline oligomers and aliphatic polyesters include: (AB) of aniline tetramers formed by aniline tetramers with one carboxyl group and one amino terminal group and aliphatic polyesters terminated with double hydroxyl groups and aliphatic polyesters n-type multi-block copolymers and (ABA) n-type multi-block copolymers of aniline tetramers and dihydroxy-terminated aliphatic polyesters, wherein n>2, A represents aniline tetramers with one carboxyl group at one end and amino group at the other end, B represents aliphatic polyester; and (AB) n-type multi-block copolymer of aniline pentamer and aliphatic polyester formed by dicarboxyl-terminated aniline pentamer and dihydroxy-terminated aliphatic polyester and aniline pentamers (ABA) n-type multi-block copolymer of polymer and dihydroxyl-terminated aliphatic polyester, where n>2, A represents dihydroxyl-terminated aliphatic polyester, B represents dicarboxyl-terminated aniline pentamer) .

The fourth object of the present invention is to provide a synthesis method of the multi-block copolymer of aniline oligomer and aliphatic polyester described in the third object. The steps and conditions are as follows:

(1) The synthetic method of the aliphatic polyester of dihydroxyl termination, its synthetic method comprises the following steps and condition:

Under anhydrous and oxygen-free conditions, using toluene as a solvent and butanediol as an initiator, add 1/100 to 1 /1000 stannous octoate as a catalyst, under the conditions of heating 100-120oC and stirring, the polymerization time is 12-72h, the product is settled with a precipitant, filtered, washed, and vacuum-dried to obtain a fat with both terminal groups being hydroxyl groups family of polyesters; including double-hydroxyl-terminated polylactide (hereinafter referred to as PLA) and double-hydroxyl-terminated polyε-caprolactone (hereinafter referred to as PCL).

(2) The synthetic method of the (AB) n-type multi-block copolymer of the aniline tetramer formed by the aniline tetramer and the aliphatic polyester terminated by two hydroxyl groups and the aliphatic polyester with one carboxyl group at one end and an amino group at the other end, wherein n> 2; A represents an aniline tetramer with one carboxyl group at one end and amino group at the other end, and B represents aliphatic polyester. The steps and conditions are:

Dissolve the aniline tetramer (AT) with one carboxyl group at one end and amino group at the other end and succinic anhydride in equal molarity in DMF, stir at room temperature for 5 hours under nitrogen protection, settle out with distilled water, and drain to obtain dicarboxyl-terminated aniline tetramer body. Then under the condition of anhydrous and oxygen-free, the aliphatic polyester of the bis-hydroxy-terminated aliphatic polyester obtained in the two carboxyl-terminated aniline tetramers and the step (1) of equimolar number is dissolved in N-methylpyrrolidone (following (referred to as NMP), add dicyclohexylcarbodiimide (hereinafter referred to as DCC) with 2 to 5 times the molar number of dicarboxyl-terminated aniline tetramer as a condensing agent, and react for 48 to 72 hours under the conditions of ice-water bath and stirring ; The product is precipitated with a precipitating agent, filtered, washed, and dried in vacuum to obtain the (AB) n-type multi-block copolymer of the aniline tetramer and aliphatic polyester of the present invention. Its reaction process is as follows:

(3) The synthetic method of the (ABA) n-type multi-block copolymer of the aniline tetramer formed by the aniline tetramer and the aliphatic polyester end-capped by two hydroxyl groups and the aliphatic polyester with one end carboxyl group and one amino end, wherein n> 2; A represents an aniline tetramer with one carboxyl group at one end and amino group at the other end, and B represents aliphatic polyester. The steps and conditions are:

After first using di-tert-butyl dicarbonate (hereinafter referred to as (Boc) 20) to protect the amino group of the aniline tetramer with one carboxyl group and one amino group at the end, obtain the aniline tetramer with one carboxyl group at one end and amino group at the end protected by the tert-butyl group (hereinafter referred to as Boc-AT). Then, under anhydrous and oxygen-free conditions, take the above-mentioned dihydroxyl-terminated aliphatic polyester and Boc-AT whose molar number is 2 times that of the dihydroxyl-terminated aliphatic polyester, and dissolve it in NMP. DCC, which is 1 to 5 times that of the dihydroxy-terminated aliphatic polyester, is used as a condensing agent. Under the conditions of ice-water bath and stirring, the reaction time is 48-72 hours. The product is settled with a precipitant, filtered, washed, and vacuum-dried. Then remove the Boc- to obtain a triblock prepolymer of aniline tetramer and aliphatic polyester. Then, under anhydrous and oxygen-free conditions, add equimolar 1,6 hexamethylene diisocyanate (hereinafter referred to as HDI) in the triblock prepolymer of the aniline tetramer and aliphatic polyester, add aniline The three-block prepolymer of tetramer and aliphatic polyester has 0.1-1% stannous octoate as a catalyst, under 55-65oC and stirring conditions, the reaction time is 6-12h, and the product is settled with a precipitant, filtered , washed, and vacuum-dried to obtain the (ABA) n-type multi-block copolymer of aniline tetramer and aliphatic polyester of the present invention. Its reaction process is as follows:

(4) Synthetic method of (AB) n-type multi-block copolymer of aniline pentamer and aliphatic polyester formed by dicarboxyl-terminated aniline pentamer and dihydroxy-terminated aliphatic polyester, wherein n>2 ; A represents two hydroxyl-terminated aliphatic polyesters, and B represents two carboxyl-terminated aniline pentamers.

The steps and conditions are:

Under anhydrous and oxygen-free conditions, and then under anhydrous and oxygen-free conditions, take equimolar dicarboxy-terminated aniline tetramers and the above-mentioned dihydroxy-terminated aliphatic polyesters and dissolve them in NMP, add Dicarboxy-terminated aniline pentamers with 1 to 5 times the molar number of DCC as a condensing agent, under the conditions of ice-water bath and stirring, the reaction time is 12 to 72 hours, the product is settled with a precipitant, filtered, washed, and vacuum-dried to obtain The (AB) n-type multi-block copolymer of aniline pentamer and aliphatic polyester of the present invention. Its reaction process is as follows:

(5) Synthetic method of (ABA) n-type multi-block copolymer of aniline pentamer and aliphatic polyester formed by dicarboxyl-terminated aniline pentamer and dihydroxy-terminated aliphatic polyester, wherein n>2 ; A represents two hydroxyl-terminated aliphatic polyesters, and B represents two carboxyl-terminated aniline pentamers. The steps and conditions are:

Under anhydrous and oxygen-free conditions, take dicarboxy-terminated aniline pentamer (AP) and dihydroxy-terminated aliphatic polyester whose molar number is 2 times that of the dicarboxy-terminated aniline pentamer, and dissolve them in NMP , adding DCC whose molar number is 1 to 5 times that of the dicarboxyl-terminated aniline pentamer as a condensation agent, under the conditions of ice-water bath and stirring, the reaction time is 12 to 72 hours, and the product is settled with a precipitant, filtered, and washed. Vacuum drying, and then remove Boc-, to obtain a three-block prepolymer of aniline pentamer and aliphatic polyester. Then, under anhydrous and oxygen-free conditions, equimolar HDI is added to the three-block prepolymer of aniline tetramer and aliphatic polyester, and three blocks of aniline pentamer and aliphatic polyester are added. The stannous octoate with 0.1-1% molar number of the block prepolymer is used as a catalyst, under 55-65oC and stirring conditions, the reaction time is 6-12h, the product is precipitated with a precipitating agent, filtered, washed, and vacuum-dried to obtain the present invention. (ABA)n-type multi-block copolymers of aniline pentamers and aliphatic polyesters. Its reaction process is as follows:

Beneficial effect of the present invention is as follows:

Compared with other oligomers of the same kind, the aniline oligomer synthesized or obtained from the parent aniline dimer in the present invention has the advantage of having bifunctional groups, which can be used in copolymerization reactions with other substances to generate large molecular weights. The polymer provides the prerequisites and is of high purity (>99%) and very stable. The copolymer of aniline oligomer and aliphatic polyester has good electrical activity similar to polyaniline and aniline oligomer, and at the same time has the characteristics of good biocompatibility, biodegradability, and good solubility. Copolymers of polymers and aliphatic polyesters possess similar biocompatibility to polylactide and support the growth and differentiation of rat glioma cells. The film of the copolymer of aniline oligomer and aliphatic polyester can be degraded in the air in phosphate buffer solution containing pepsin, and has good biodegradability. Moreover, the copolymer of aniline oligomer and aliphatic polyester can be dissolved in most organic solvents, such as chloroform, tetrahydrofuran, etc., which provides convenience for the processing and utilization of materials in the future.

The copolymer of aniline oligomer and aliphatic polyester prepared in the invention is mainly used as biomedical material, especially as tissue engineering support material of nerve and heart.

Description of drawings

Figure 1: Matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF-MS) spectrogram of aniline tetramers with one carboxyl group and amino group at one end (specifically the matrix of the aniline tetramer at one carboxyl group and amino group at one end obtained in Example 2 assisted laser desorption time-of-flight mass spectrometry);

Figure 2: Matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF-MS) spectrogram of dicarboxy-terminated aniline pentamer (specifically the matrix-assisted laser desorption of dicarboxy-terminated aniline pentamer obtained in Example 3) desorption time-of-flight mass spectrometry);

Fig. 3: The proton nuclear magnetic resonance 1H spectrum of the (AB) n-type multi-block copolymer of aniline pentamer and aliphatic polyester and attribution (specifically the aniline pentamer and aliphatic polyester obtained in Example 16 (AB) n-type multi-block copolymer proton nuclear magnetic resonance 1H spectrum and assignment of polylactide).

Figure 4: (AB)n-type multi-block copolymer of aniline tetramer and aliphatic polyester polylactide (n>2, where A represents aniline tetramer with one carboxyl group at one end and amino group at one end, and B represents aliphatic polyester ) of the degradation curve (specifically the degradation curve of the product of Example 8).

Figure 5: (AB)n-type multi-block copolymer of aniline tetramer and aliphatic polyester polylactide (n>2, where A represents aniline tetramer with one carboxyl group at one end and amino group at one end, and B represents aliphatic polyester ) biocompatibility result (specifically the biocompatibility result of the product of Example 8).

Figure 6: (AB) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polylactide (n>2, where A represents aniline tetramer with one carboxyl group at one end and amino group at one end, and B represents aliphatic polyester ) of the degradation curve (specifically the degradation curve of the product of Example 9).

Figure 7: (AB) n-type multi-block copolymer (n>2) of aniline tetramer and aliphatic polyester polylactide (n>2, where A represents aniline tetramer with one carboxyl group at one end and amino group at one end, and B represents aliphatic polyester ) biocompatibility result (specifically the biocompatibility result of the product of Example 9).

Figure 8: (AB) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polyε-caprolactone (n>2, where A represents aniline tetramer with one carboxyl group at one end and amino group at one end, and B represents fat family polyester) degradation curve (specifically the degradation curve of the product of Example 10).

Figure 9: (AB) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polyε-caprolactone (n>2, where A represents aniline tetramer with one carboxyl group at one end and amino group at one end, and B represents fat The biocompatibility result of family polyester) (specifically the biocompatibility result of the product of Example 10).

Figure 10: (ABA) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polylactide (n>2, where A represents aniline tetramer with one carboxyl group at one end and amino group at one end, and B represents aliphatic polyester ) of the degradation curve (specifically the degradation curve of the product of Example 14).

Figure 11: (ABA) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polylactide (n>2, where A represents aniline tetramer with one carboxyl group at one end and amino group at one end, and B represents aliphatic polyester ) biocompatibility result (specifically the biocompatibility result of the product of Example 14).

Figure 12: (ABA) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polyε-caprolactone (n>2, where A represents an aniline tetramer with one carboxyl group and one amino group at the end, and B represents fat family polyester) degradation curve (specifically the degradation curve of the product of Example 15).

Figure 13: (ABA) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polyε-caprolactone (n>2, where A represents the aniline tetramer with one carboxyl group at one end and amino group at the other end, and B represents fat The biocompatibility result (specifically, the biocompatibility result of the product of Example 15)).

Figure 14: (AB)n-type multi-block copolymer of aniline pentamer and aliphatic polyester polylactide (n>2, where A represents aliphatic polyester and B represents dicarboxyl-terminated aniline pentamer) The degradation curve (specifically the degradation curve of the product of Example 16).

Figure 15: (AB)n-type multi-block copolymer of aniline pentamer and aliphatic polyester polylactide (n>2, where A represents aliphatic polyester and B represents dicarboxyl-terminated aniline pentamer) The biocompatibility result (specifically the biocompatibility result of the product of Example 16).

Figure 16: (AB) n-type multi-block copolymer of aniline pentamer and aliphatic polyester polyε-caprolactone (n>2, where A represents aliphatic polyester and B represents dicarboxyl-terminated aniline penta Polymer) degradation curve (specifically the degradation curve of the product of Example 17).

Figure 17: (AB) n-type multi-block copolymer of aniline pentamer and aliphatic polyester polyε-caprolactone (n>2, where A represents aliphatic polyester and B represents dicarboxyl-terminated aniline penta Polymer) biocompatibility results (specifically the biocompatibility results of the product of Example 17).

Figure 18: (ABA) n-type multi-block copolymer of aniline pentamer and aliphatic polyester polylactide (n>2, where A represents aliphatic polyester and B represents dicarboxyl-terminated aniline pentamer) The degradation curve (specifically the degradation curve of the product of Example 20).

Figure 19: (ABA) n-type multi-block copolymer of aniline pentamer and aliphatic polyester polylactide (n>2, where A represents aliphatic polyester and B represents dicarboxyl-terminated aniline pentamer) The biocompatibility result (specifically the biocompatibility result of the product of Example 20).

Figure 20: (ABA) n-type multi-block copolymer of aniline pentamer and aliphatic polyester polyε-caprolactone (n>2, where A represents aliphatic polyester and B represents dicarboxyl-terminated aniline penta Polymer) degradation curve (specifically the degradation curve of the product of Example 21).

Figure 21: (ABA) n-type multi-block copolymer of aniline pentamer and aliphatic polyester polyε-caprolactone (n>2, where A represents aliphatic polyester and B represents dicarboxyl-terminated aniline penta Polymer) biocompatibility results (specifically the biocompatibility results of the product of Example 21).

Detailed ways

The technical solutions of the present invention will be further described below in conjunction with specific examples.

Embodiment 1: the synthesis of the aniline dimer of terminal amino protection

In a 500mL three-necked flask equipped with mechanical stirring, nitrogen inlet, and nitrogen outlet, add N-phenyl-1,4-p-phenylenediamine 9.21g (0.05mol), succinic anhydride 5.00g (0.05mol), Dichloromethane 300mL, while stirring. As the reaction proceeded, a gray precipitate was produced. After the reaction was completed, it was filtered, and the obtained precipitate was washed with ether until the filtrate was colorless. The sample was dried in a vacuum oven for 12 hours to obtain the amino-terminated aniline dimer with a yield of 84.5%.

Example 2: Synthesis of aniline tetramers with one carboxyl group and one amino group at the end

2.85g (0.01mol) of aniline dimer and 3.5g (0.01mol) of amino-terminated dimer are dissolved in the mixed solution (comprising 100mlDMF, 15ml distilled water, 15ml concentrated hydrochloric acid), cooled to below zero, and then The hydrochloric acid solution of ammonium persulfate (2.28g is dissolved in 50ml 1M hydrochloric acid) is slowly added in the above-mentioned solution through the dropping funnel, stirs rapidly at the same time, ice salt maintains reaction below zero, dropwise, continue to react for 2h, then put the The solution was poured into 700ml of distilled water and filtered. Dissolve the obtained precipitate in 300ml of 1M ammonia water, add a hydration trap to stir and reduce overnight, then add an appropriate amount of 1M hydrochloric acid to adjust the pH value to 2-3, filter, and vacuum dry the precipitate at 35 degrees for 48 hours. The obtained sample was firstly extracted with 1,2-dichloroethane and then tetrahydrofuran in a Soxhlet extractor to obtain aniline tetramers with one carboxyl group at one end and amino group at the other end. Its matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF-MS) spectrum is shown in Figure 1.

Embodiment 3: the synthesis of dicarboxy-terminated aniline pentamer

Dissolve 2.85 g (0.01 mol) of amino-terminated aniline dimer and 0.54 g (0.005 mol) of p-phenylenediamine in 15 mL of DMF. Add precooled mixed solution 60mL (comprising 30mL DMF, 25mL distilled water, 5mL concentrated hydrochloric acid), then the hydrochloric acid solution of ammonium persulfate (2.28g is dissolved in the hydrochloric acid of 50mL 1mol/L) is slowly added in the above-mentioned solution through dropping funnel, Stir rapidly at the same time, after the dropwise addition is completed, continue to react for 1 h, then pour the solution into 300 mL of distilled water and filter. Dissolve the obtained precipitate in 300mL of 1mol/L ammonia water, add hydrazine hydrate and stir for reduction overnight, then add an appropriate amount of 1mol/L hydrochloric acid to adjust the pH to 2-3, filter, and vacuum-dry the precipitate at 45°C for 48h . The obtained 3.0g sample was dissolved in 15mL DMF, then slowly added dropwise to 150mL of rapidly stirring ethanol, filtered, the precipitate was dried under vacuum, and then firstly used 1,2-dichloroethane in a Soxhlet extractor, Then extracted with tetrahydrofuran to obtain dicarboxyl-terminated aniline pentamer with a yield of 84.3%. Its matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF-MS) spectrum is shown in Figure 2. Example 4: Synthesis of aliphatic polyester polylactide with a molecular weight of 2000 and two hydroxyl groups

Under anhydrous and oxygen-free conditions, toluene is used as a solvent, butanediol is used as an initiator, and butanediol with a monomer mole number of 1/25 is added to monomer lactide as an initiator, and the total mass of monomers is 1/25. 100% stannous octoate as a catalyst, under the conditions of heating (100-120oC) and stirring, the polymerization time is 12h, the product is settled with a precipitant, filtered, washed, and vacuum-dried to obtain polylactide with both terminal groups being hydroxyl groups. Homopolymers of esters.

Example 5: Synthesis of aliphatic polyester polylactide with a molecular weight of 2800 dihydroxyl end caps

Under anhydrous and oxygen-free conditions, using toluene as a solvent and butanediol as an initiator, add butanediol with a monomer molarity of 1/12 to the monomer lactide as an initiator, and the total mass of monomers is 5/ 1000 stannous octoate as a catalyst, under the conditions of heating (100-120oC) and stirring, the polymerization time is 48h, the product is settled with a precipitant, filtered, washed, and vacuum-dried to obtain polylactide with both terminal groups being hydroxyl groups. Homopolymers of esters.

Example 6: Synthesis of aliphatic polyester polyε-caprolactone with a molecular weight of 1500 dihydroxyl end caps

Under anhydrous and oxygen-free conditions, using toluene as a solvent and butanediol as an initiator, add butanediol with a monomer mole number of 1/12 to the monomer ε-caprolactone as an initiator, and the total mass of the monomer 1/1000 stannous octoate as a catalyst, under the conditions of heating (100-120oC) and stirring, the polymerization time is 72h, the product is settled with a precipitant, filtered, washed, and vacuum-dried to obtain a compound with both terminal groups being hydroxyl groups. Homopolymer of polyε-caprolactone.

Example 7: Synthesis of dicarboxy-terminated aniline tetramers

Dissolve 5mmol and 5mmol of succinic anhydride obtained in Example 2 in 30ml of DMF, under nitrogen protection, stir at room temperature for 5h, precipitate the reaction product with 400ml of distilled water, filter it with suction, and dry it in vacuum at 45oC for 48h to obtain dicarboxy-terminated aniline tetra Polymer.

Example 8: (AB) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polylactide (n>2, wherein A represents aniline tetramer with one carboxyl group at one end and amino group at one end, and B represents aliphatic polylactide ester) synthesis

Take 2mmol of the dicarboxyl-terminated aniline tetramer obtained in Example 7 and the molecular weight of 2000 obtained in Example 4. Add 2mmol and 4mmol of DCC to the polymerization reaction bottle, and stir and react in an ice-water bath for 24 Hour. The insoluble matter was filtered off, settled with ether, dissolved in chloroform, settled with ether, filtered, and vacuum-dried at 35°C until constant weight. That is, the (AB) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polylactide is obtained. The (AB) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polylactide has good solubility and can be dissolved in organic solvents such as chloroform, acetone, tetrahydrofuran, dimethyl sulfoxide, DMF, and NMP middle.

The comparison result of the gel permeation chromatography (GPC) of the product of Example 8 and the product of Example 4 in Table 1 proves that the (AB) n-type multi-block copolymer of this aniline tetramer and aliphatic polyester polylactide generation.

Substance name mw mn PDI Example 4 product 2.67×103 2.43×103 1.09 Example 8 product 4.32×104 3.15×104 1.37

Table I

Get the product of Example 8 and dissolve it in chloroform to spread the film to obtain a thin slice of 10×10×0.4mm, which is placed in a jar with 5ml0.05MTris buffer (containing 60mgL-1 of proteinase K), and placed In a constant temperature shaking box at 37°C, no proteinase K was added every 24 hours. The samples were taken out at regular intervals, washed three times with distilled water, and dried in a vacuum oven at 35°C until constant weight. The weight loss before and after degradation was weighed to obtain the degradation curve in Figure 4. This degradation curve demonstrates that (AB)n-type multi-block copolymers of aniline tetramer and aliphatic polyester polylactide are biodegradable.

The product of Example 8 was used to lay a membrane on the siliconized glass slide, and then plant rat neurokeratinoma C6 cells on it. The microscopic observation photos after 48 hours of culture are shown in FIG. 5 . The good adhesion and growth of C6 cells indicated that the (AB) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polylactide had good biocompatibility.

Example 9: (AB) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polylactide (n>2, wherein A represents aniline tetramer with one carboxyl group at one end and amino group at one end, and B represents aliphatic polylactide ester) synthesis

Take 2 mmol of the dicarboxyl-terminated aniline tetramer obtained in Example 7 and 2 mmol of the dihydroxy-terminated aliphatic polyester polylactide and 10 mmol DCC with a molecular weight of 2800 obtained in Example 5 and add them to a polymerization reaction bottle, and stir in an ice-water bath for 72 Hour. The insoluble matter was filtered off, settled with ether, dissolved in chloroform, settled with ether, filtered, and vacuum-dried at 35°C until constant weight. That is, the (AB) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polylactide is obtained. The (AB) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polylactide has good solubility and can be dissolved in organic solvents such as chloroform, acetone, tetrahydrofuran, dimethyl sulfoxide, DMF, and NMP middle.

The comparison result of the gel permeation chromatography (GPC) of example 9 product and embodiment 5 product in table two has proved the (AB) n type multi-block copolymer of this aniline tetramer and aliphatic polyester polylactide generate.

Substance name mw mn PDI Example 5 product 3.15×103 2.86×103 1.10 Example 9 product 6.56×104 5.12×104 1.28

Table II

Get the product of Example 9 and dissolve it in chloroform to spread the film to obtain a thin slice of 10×10×0.4mm, which is placed in a jar with 5ml0.05MTris buffer (containing 60mgL-1 of proteinase K), and placed In a constant temperature shaking box at 37°C, no proteinase K was added every 24 hours. The samples were taken out at regular intervals, washed three times with distilled water, and dried in a vacuum oven at 35°C until constant weight. The weight loss before and after degradation was weighed to obtain the degradation curve in Figure 6. This degradation curve demonstrates that (AB)n-type multi-block copolymers of aniline tetramer and aliphatic polyester polylactide are biodegradable.

The product of Example 9 was used to lay a film on the siliconized glass slide, and then plant rat neurokeratinoma C6 cells on it. The microscopic observation photos after 48 hours of culture are shown in FIG. 7 . The good adhesion and growth of C6 cells indicated that the (AB) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polylactide had good biocompatibility.

Example 10: (AB) n-type multi-block copolymer (n>2) of aniline tetramer and aliphatic polyester polyε-caprolactone (n>2, wherein A represents an aniline tetramer with one carboxyl group at one end and amino group at one end, and B represents Synthesis of aliphatic polyester)

Get the bis-carboxyl-terminated aniline tetramer 2mmol and 2mol of the dihydroxy-terminated aliphatic polyester polyε-caprolactone and 8mmol DCC of 1500 molecular weight obtained in Example 6 to join in the polymerization reaction bottle, in an ice-water bath The reaction was stirred for 56 hours. The insoluble matter was filtered off, settled with ether, dissolved in chloroform, settled with ether, filtered, and vacuum-dried at 35°C until constant weight. That is, the (AB) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polylactide is obtained. The (AB) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polylactide has good solubility and can be dissolved in organic solvents such as chloroform, acetone, tetrahydrofuran, dimethyl sulfoxide, DMF, and NMP middle.

The comparison result of the gel permeation chromatography (GPC) of the example 10 product and the embodiment 6 product in table three proves the (AB) n-type multi-block of this aniline tetramer and aliphatic polyester polyε-caprolactone Copolymer formation.

Substance name mw mn PDl Example 6 product 1.80×103 1.71×103 1.05 Example 10 product 6.56×104 5.12×104 1.28

Table three

Get the product of Example 10 and dissolve it in chloroform and spread the film to obtain a thin slice of 10 × 10 × 0.4mm, which is placed in a jar with 5ml0.05MTris buffer (containing 60mgL-1 of proteinase K), and placed In a constant temperature shaking box at 37°C, no proteinase K was added every 24 hours. The samples were taken out at regular intervals, washed three times with distilled water, and dried in a vacuum oven at 35°C until constant weight. The weight loss before and after degradation was weighed to obtain the degradation curve in Figure 8. This degradation profile demonstrates that (AB)n-type multi-block copolymers of aniline tetramer and aliphatic polyester polyε-caprolactone are biodegradable.

The product of Example 9 was used to lay a film on the siliconized glass slide, and then plant rat neurokeratinoma C6 cells on it. The microscopic observation photos after 48 hours of culture are shown in FIG. 9 . The good adhesion and growth of C6 cells indicated that the (AB) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polyε-caprolactone had good biocompatibility.

Example 11: Synthesis of Boc-protected aniline tetramer (Boc-AT) with one carboxyl group at one end and amino group at the other end

Get the aniline tetramer (AT) 5mmol and 5.5mmol (Boc) 20 and 30mlDMF obtained in Example 2 and mix, under nitrogen protection, stir for 6h, then precipitate with 400ml distilled water, filter, and wash with dichloromethane for 3 Then, vacuum-dry to constant weight at room temperature to obtain Boc-protected aniline tetramer (Boc-AT).

Example 12: Synthesis of triblock prepolymer (AT-PLA-AT) of aniline tetramer and aliphatic polyester polylactide

Take 2.5mmol of the Boc-protected aniline tetramer (Boc-AT) obtained in Example 11 and 1mmol of the dihydroxy-terminated polylactide and 5mmol of DCC obtained in Example 4 and add them to a polymerization reaction bottle, and stir in an ice-water bath for 24 hours. . Filter out insoluble matter from the product, settle with ether, then dissolve with chloroform, settle with ether, filter, and vacuum-dry at 35°C to constant weight, then add 20mmol of trifluoroacetic acid and 30ml of DMF to the obtained product, and stir the reaction at room temperature 2h. The resulting product was concentrated, precipitated with ether, and dried in vacuo at 35°C to constant weight. That is, a triblock prepolymer (AT-PLA-AT) of aniline tetramer and aliphatic polyester polylactide is obtained.

The comparison of the results of the gel permeation chromatography (GPC) between the product of Example 12 and the product of Example 4 in Table 4 can prove the generation of a triblock prepolymer of aniline tetramer and aliphatic polyester polylactide.

Substance name mw mn PDI Example 4 product 2.67×103 2.43×103 1.09 Example 12 product 3.63×103 3.30×103 1.10

Table four

Example 13: Synthesis of triblock prepolymer (AT-PCL-AT) of aniline tetramer and aliphatic polyester polyε-caprolactone

Get 2.5mmol of the Boc-protected aniline tetramer (Boc-AT) obtained in Example 11 and 1mmol of the dihydroxy-terminated polyε-caprolactone and 10mmol of DCC obtained in Example 6 and add them to the polymerization reaction bottle, and put them in an ice-water bath The reaction was stirred for 48 hours. Filter out insoluble matter from the product, settle with ether, then dissolve with chloroform, settle with ether, filter, and vacuum-dry at 35°C to constant weight, then add 20mmol of trifluoroacetic acid and 30ml of DMF to the obtained product, and stir the reaction at room temperature 2h. The resulting product was concentrated, precipitated with ether, and dried in vacuo at 35°C to constant weight. That is, a triblock prepolymer (AT-PCL-AT) of aniline tetramer and aliphatic polyester polyε-caprolactone is obtained.

The comparison of the results of gel permeation chromatography (GPC) between the product of Example 13 and the product of Example 6 in Table 5 can prove the generation of the triblock prepolymer of aniline tetramer and aliphatic polyester polyε-caprolactone.

Substance name mw mn PDI Example 6 product 1.80×103 1.71×103 1.05 Example 13 product 2.73×103 2.55×103 1.07

Table five

Example 14: (ABA) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polylactide (n>2, wherein A represents aniline tetramer with one carboxyl group at one end and amino group at one end, and B represents aliphatic polylactide ester) synthesis

Under anhydrous and oxygen-free conditions, take the diphenylmethane diisocyanate (MDI) of 0.001mol and 0.001mol of the three-block prepolymer of the aniline tetramer obtained in Example 12 and aliphatic polyester polylactide Dissolve in 20ml toluene, add 0.01mmol stannous octoate, and react with vigorous stirring at 55°C for 6 hours. The reaction product was settled with ether, filtered, and vacuum-dried at 35° C. to constant weight to obtain (ABA) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polylactide. The (ABA) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polylactide has good solubility and can be dissolved in organic solvents such as chloroform, acetone, tetrahydrofuran, dimethyl sulfoxide, DMF, and NMP middle.

The result contrast of the gel permeation chromatography (GPC) of example 14 product and embodiment 12 product in table 6 can prove that the (ABA) n-type multi-block copolymer of this aniline tetramer and aliphatic polyester polylactide generate.

Substance name mw mn PDI Example 12 product 3.63×103 3.30×103 1.10 Example 14 product 5.72×104 4.73×104 1.21

Table six

Get the product of Example 14 and dissolve it in chloroform and spread the film to obtain a thin slice of 10 × 10 × 0.4mm, which is placed in a jar with 5ml0.05MTris buffer (containing 60mgL-1 of proteinase K), and placed In a constant temperature shaking box at 37°C, no proteinase K was added every 24 hours. The samples were taken out at regular intervals, washed three times with distilled water, and dried in a vacuum oven at 35°C until constant weight. Weigh the weight loss before and after degradation to obtain the degradation curve in Figure 10. This degradation curve demonstrates that (ABA) n-type multi-block copolymers of aniline tetramer and aliphatic polyester polylactide are biodegradable.

The product of Example 14 was used to lay a film on the siliconized glass slide, and then plant rat neurokeratinoma C6 cells on it. The microscopic observation photos after 48 hours of culture are shown in FIG. 11 . The good adhesion and growth of C6 cells indicated that the (ABA) n-type multi-block copolymer of aniline-aniline tetramer and aliphatic polyester polylactide had good biocompatibility.

Example 15: (ABA) n-type multi-block copolymer (n>2) of aniline tetramer and aliphatic polyester polyε-caprolactone (n>2, wherein A represents an aniline tetramer with one carboxyl group at one end and amino group at one end, and B represents Synthesis of aliphatic polyester)

Under anhydrous and oxygen-free conditions, take the three-block prepolymer of the aniline tetramer obtained in Example 13 and the aliphatic polyester polyε-caprolactone 0.001mol and 0.001mol of diphenylmethane diisocyanate (MDI) was dissolved in 20ml of toluene, then 0.001mmol of stannous octoate was added, and the mixture was stirred vigorously at 60°C for 12 hours. The reaction product was settled with ether, filtered, and vacuum-dried to constant weight at 35°C to obtain (ABA) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polyε-caprolactone. The (ABA) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polyε-caprolactone has good solubility and can be dissolved in chloroform, acetone, tetrahydrofuran, dimethyl sulfoxide, DMF, NMP and other organic solvents.

The (ABA) n-type multi-block copolymer of this aniline tetramer and the aliphatic polyester polyε-caprolactone in table seven and the result comparison of the gel permeation chromatography (GPC) of the product of Example 12 can prove that aniline Generation of (ABA)n-type multiblock copolymers of tetramers with aliphatic polyester polyε-caprolactone.

Substance name mw mn PDI Example 13 product 2.73×103 2.55×103 1.07 Example 15 product 4.32×104 36.3×104 1.19

Table Seven

Get the product of Example 15 and dissolve it in chloroform and spread the film to obtain a thin slice of 10×10×0.4mm, which is placed in a jar with 5ml0.05MTris buffer (containing 60mgL-1 of proteinase K), and placed In a constant temperature shaking box at 37°C, no proteinase K was added every 24 hours. The samples were taken out at regular intervals, washed three times with distilled water, and dried in a vacuum oven at 35°C until constant weight. Weigh the weight loss before and after degradation to obtain the degradation curve in Figure 12. This degradation profile demonstrates that (ABA) n-type multi-block copolymers of aniline tetramer and aliphatic polyester polyε-caprolactone are biodegradable.

The product of Example 15 was used to lay a film on the siliconized glass slide, and then plant rat neurokeratinoma C6 cells on it. The microscopic observation photos after 48 hours of culture are shown in FIG. 13 . The good adhesion and growth of C6 cells indicated that the (ABA) n-type multi-block copolymer of aniline tetramer and aliphatic polyester polyε-caprolactone had good biocompatibility. Example 16: (AB) n-type multi-block copolymer (n>2) of aniline pentamer and aliphatic polyester polylactide (n>2, wherein A represents aliphatic polyester, and B represents dicarboxyl-terminated aniline pentamer )Synthesis

Under anhydrous and oxygen-free conditions, 1mmol of dicarboxy-terminated aniline pentamer (AP) obtained in Example 3 and 1 mmol of dihydroxy-terminated polylactide and 5 mmol of DCC obtained in Example 5 were added to the polymerization reaction bottle , stirred in an ice-water bath for 36 hours. The insoluble matter was filtered off from the product, settled with ether, dissolved in chloroform, settled with ether, filtered, and vacuum-dried at 35°C to constant weight to obtain (AB)n of aniline pentamer and aliphatic polyester polylactide. multi-block copolymers. The (AB) n-type multi-block copolymer of aniline pentamer and aliphatic polyester polylactide has good solubility and can be dissolved in organic solvents such as chloroform, acetone, tetrahydrofuran, dimethyl sulfoxide, DMF, and NMP middle.

The comparison result of the gel permeation chromatography (GPC) of example 16 product and embodiment 5 product in table 8 proves the generation of (AB) n type multi-block copolymer of aniline pentamer and aliphatic polyester polylactide .

Substance name mw mn PDI Example 5 product 3.15×103 2.86×103 1.10 Example 16 product 8.43×104 7.04×104 1.20

table eight

Get the product of Example 16 dissolved in chloroform and spread the film to obtain a thin slice of 10 × 10 × 0.4mm, which is placed in a jar with 5ml0.05MTris buffer (containing 60mgL-1 of proteinase K), and placed In a constant temperature shaking box at 37°C, no proteinase K was added every 24 hours. The samples were taken out at regular intervals, washed three times with distilled water, and dried in a vacuum oven at 35°C until constant weight. Weigh the weight loss before and after degradation to obtain the degradation curve in Figure 14. This degradation curve demonstrates that (AB)n-type multi-block copolymers of aniline pentamers and aliphatic polyester polylactide are biodegradable.

The product of Example 16 was used to lay a film on the siliconized glass slide, and then plant rat neurokeratinoma C6 cells on it. The microscopic observation photos after 48 hours of culture are shown in FIG. 15 . The good adhesion and growth of C6 cells indicated that the (AB) n-type multi-block copolymer of aniline pentamer and aliphatic polyester polylactide had good biocompatibility.

Example 17: (AB) n-type multi-block copolymer of aniline pentamer and aliphatic polyester polyε-caprolactone (n>2, wherein A represents aliphatic polyester, and B represents dicarboxyl-terminated aniline Pentamer) synthesis

Under anhydrous and oxygen-free conditions, 1 mmol of dicarboxy-terminated aniline pentamer (AP) obtained in Example 3 and 1 mmol of dihydroxy-terminated polyε-caprolactone and 3 mmol of DCC obtained in Example 6 were added to the polymerization In the reaction bottle, stir and react in an ice-water bath for 48 hours. The insoluble matter was filtered off from the product, settled with ether, dissolved with chloroform, settled with ether, filtered, and vacuum-dried to constant weight at 35°C to obtain a mixture of aniline pentamer and aliphatic polyester polyε-caprolactone ( AB) n-type multi-block copolymers. The (AB) n-type multi-block copolymer of aniline pentamer and aliphatic polyester polyε-caprolactone has good solubility and can be dissolved in chloroform, acetone, tetrahydrofuran, dimethyl sulfoxide, DMF, NMP and other organic solvents.

The comparison result of the gel permeation chromatography (GPC) of example 17 product and embodiment 6 product in table nine proves the (AB) n type multi-block copolymerization of aniline pentamer and aliphatic polyester polyε-caprolactone The generation of things.

Substance name mw mn PDI Example 6 product 1.80×103 1.71×103 1.05 Example 17 product 4.83×104 4.43×104 1.09

Table nine

Get the product of Example 17 and dissolve it in chloroform and spread the film to obtain a thin slice of 10 × 10 × 0.4mm, which is placed in a jar with 5ml0.05MTris buffer (containing 60mgL-1 of proteinase K), and placed In a constant temperature shaking box at 37°C, no proteinase K was added every 24 hours. The samples were taken out at regular intervals, washed three times with distilled water, and dried in a vacuum oven at 35°C until constant weight. The weight loss before and after degradation was weighed to obtain the degradation curve in Figure 16. This degradation profile demonstrates that (AB)n-type multi-block copolymers of aniline pentamers and aliphatic polyester polyε-caprolactone are biodegradable.

The product of Example 17 was used to lay a membrane on the siliconized glass slide, and then plant rat neurokeratinoma C6 cells on it. The microscopic observation photos after 48 hours of culture are shown in FIG. 17 . The good adhesion and growth of C6 cells indicated that the (AB) n-type multi-block copolymer of aniline pentamer and aliphatic polyester polyε-caprolactone had good biocompatibility.

Example 18: Synthesis of triblock prepolymer of aniline pentamer and aliphatic polyester polylactide

Under anhydrous and oxygen-free conditions, 1 mmol of the dicarboxyl-terminated aniline pentamer (AP) obtained in Example 3 and 2 mmol of the dihydroxy-terminated polylactide and 5 mmol DCC obtained in Example 4 were added to the polymerization reaction bottle , stirred and reacted in an ice-water bath for 48 hours. The insoluble matter was filtered off from the product, settled with ether, dissolved in chloroform, settled with ether, filtered, and vacuum-dried at 35°C to constant weight to obtain a triblock prepolymer of aniline pentamer and aliphatic polyester polylactide. Polymer.

The comparison of the results of gel permeation chromatography (GPC) between the product of Example 18 and the product of Example 4 in Table 10 can prove the generation of a triblock prepolymer of aniline pentamer and aliphatic polyester polylactide.

Substance name mw mn PDI Example 4 product 2.67×103 2.43×103 1.09 Example 18 product 5.73×103 5.07×103 1.13

table ten

Example 19: Synthesis of triblock prepolymer of aniline pentamer and aliphatic polyester polyε-caprolactone

Under anhydrous and oxygen-free conditions, the poly-ε-caprolactone and 2.5mmol DCC obtained by the 1mmol dicarboxy-terminated aniline pentamer (AP) obtained in Example 3 and the dihydroxy-terminated polyε-caprolactone and 2.5 mmol DCC obtained in 2mmol embodiment 6, were added Put it into a polymerization reaction bottle, stir and react in an ice-water bath for 24 hours. The insoluble matter was filtered off from the product, settled with ether, dissolved in chloroform, settled with ether, filtered, and vacuum-dried at 35°C to constant weight to obtain a three-dimensional compound of aniline pentamer and aliphatic polyester polyε-caprolactone. block prepolymer.

The result contrast of the gel permeation chromatography (GPC) of example 19 product and embodiment 4 product in table eleven can prove the generation of the triblock prepolymer of aniline pentamer and aliphatic polyester polyε-caprolactone .

Substance name mw mn PDI Example 5 product 1.80×103 1.71×103 1.05 Example 19 product 4.54×103 3.69×103 1.23

Table Eleven

Example 20: (ABA) n-type multi-block copolymer of aniline pentamer and aliphatic polyester polylactide (n>2, wherein A represents aliphatic polyester, and B represents aniline pentamer terminated by 28 carboxyl groups )Synthesis

Under anhydrous and oxygen-free conditions, 1 mmol and 1 mmol of diphenylmethane diisocyanate (MDI) of the three-block prepolymer of aniline pentamer and aliphatic polyester polylactide obtained in Example 18 were dissolved in 20ml of toluene was added, and then 0.05mmol of stannous octoate was added, and the reaction was stirred vigorously at 55°C for 12 hours. The reaction product was settled with ether, filtered, and vacuum-dried at 35° C. to constant weight to obtain (ABA) n-type multi-block copolymer of aniline pentamer and aliphatic polyester polylactide. The (ABA) n-type multi-block copolymer of aniline pentamer and aliphatic polyester polylactide has good solubility and can be dissolved in organic solvents such as chloroform, acetone, tetrahydrofuran, dimethyl sulfoxide, DMF, and NMP middle.

The result contrast of the gel permeation chromatography (GPC) of example 20 product and embodiment 18 product in table 12 can prove that the (ABA) n-type multi-block copolymer of aniline pentamer and aliphatic polyester polylactide generate.

Substance name mw mn PDI Example 18 product 5.73×103 5.07×103 1.13 Example 20 product 5.45×104 4.36×104 1.25

Table 12

Get the product of Example 20 and dissolve it in chloroform and spread the film to obtain a thin slice of 10 × 10 × 0.4mm, which is placed in a jar with 5ml0.05MTris buffer (containing 60mgL-1 of proteinase K), and placed In a constant temperature shaking box at 37°C, no proteinase K was added every 24 hours. The samples were taken out at regular intervals, washed three times with distilled water, and dried in a vacuum oven at 35°C until constant weight. The weight loss before and after degradation was weighed to obtain the degradation curve in Figure 18. This degradation curve demonstrates that (ABA) n-type multi-block copolymers of aniline pentamers and aliphatic polyester polylactide are biodegradable.

The product of Example 20 was used to lay a membrane on the siliconized glass slide, and then plant rat neurokeratinoma C6 cells on it. The microscopic observation photos after 48 hours of culture are shown in FIG. 19 . The good adhesion and growth of C6 cells indicated that the (ABA) n-type multi-block copolymer of aniline pentamer and aliphatic polyester polylactide had good biocompatibility.

Example 21: (ABA) n-type multi-block copolymer of aniline pentamer and aliphatic polyester ε-caprolactone (n>2,

Wherein A represents aliphatic polyester, and B represents the synthesis of aniline pentamer terminated by two carboxyl groups)

Under the condition of anhydrous and oxygen-free, take the diphenylmethane diisocyanate (MDI ) was dissolved in 20ml of toluene, then 0.01mmol of stannous octoate was added, and reacted with vigorous stirring at 60°C for 10 hours. The reaction product was settled with ether, filtered, and vacuum-dried to constant weight at 35°C to obtain (ABA) n-type multi-block copolymer of aniline pentamer and aliphatic polyester polyε-caprolactone. The (ABA) n-type multi-block copolymer of aniline pentamer and aliphatic polyester polyε-caprolactone has good solubility and can be dissolved in chloroform, acetone, tetrahydrofuran, dimethyl sulfoxide, DMF, NMP and other organic solvents.

The comparison of the results of the gel permeation chromatography (GPC) of the product of Example 21 and the product of Example 18 in Table 13 proves that (ABA) n-type multi-block copolymerization of aniline pentamer and aliphatic polyester ε-caprolactone The generation of things.

Substance name mw mn PDI Example 19 product 4.54×103 3.69×103 1.23 Example 21 product 5.17×104 4.04×104 1.28

Table 13

Take the product of Example 21 and dissolve it in chloroform to spread the film to obtain a thin slice of 10×10×0.4mm, which is placed in a jar with 5ml0.05MTris buffer (containing 60mgL-1 of proteinase K), and placed In a constant temperature shaking box at 37°C, no proteinase K was added every 24 hours. The samples were taken out at regular intervals, washed three times with distilled water, and dried in a vacuum oven at 35°C until constant weight. Weigh the weight loss before and after degradation to obtain the following degradation curve. This degradation curve demonstrates that (ABA) n-type multi-block copolymers of aniline pentamers and aliphatic polyester ε-caprolactone are biodegradable.

The product of Example 21 was used to lay a film on the siliconized glass slide, and then plant rat neurokeratinoma C6 cells on it. After 48 hours of culture, the microscopic observation photos are as follows. The good adhesion and growth of C6 cells indicated that the (ABA) n-type multi-block copolymer of aniline pentamer and aliphatic polyester ε-caprolactone had good biocompatibility.

Claims (2)

1. the segmented copolymer of aniline oligomer and aliphatic polyester, it is characterized in that this segmented copolymer is: (AB) n type that the aniline pentamer of the aniline tetramer of an end carboxyl one end amino or the aniline of an end carboxyl one end amino and two hydroxy-end capped aliphatic polyesters form or (ABA) n type segmented copolymer; N wherein〉2, A represents the aniline pentamer of the aniline of the aniline tetramer of an end carboxyl one end amino or an end carboxyl one end amino, and it is to obtain the homopolymer that two end groups are hydroxyl by aliphatics cyclic ester monomer rac-Lactide or 6-caprolactone by ring-opening polymerization that B represents aliphatic polyester; Described aniline oligomer is the aniline tetramer of an end carboxyl one end amino or the aniline pentamer of two carboxy blockings, and following two formulas are respectively its structural formula:

2. the preparation method of the segmented copolymer of aniline oligomer and aliphatic polyester is characterized in that step and condition are:

1) with N-phenyl-1, the 4-Ursol D is a raw material, and it is dissolved in the methylene dichloride, add and N-phenyl-1 Succinic anhydried of mole numbers such as 4-Ursol D, stirring at room reaction under the nitrogen protection, the gained precipitation to colourless, has obtained the aniline dimer of end amido protecting with the ether washing; Get aniline dimer and two amino-terminated aniline dimer of the end amido protecting of identical mol ratio, be dissolved in the mixed solvent of dimethyl formamide and 1M hydrochloric acid, 1M hydrochloric acid soln with ammonium persulphate under 0 ℃ of agitation condition dropwise adds, and after dropwising, uses distilled water wash, to precipitate with behind the ammonia solvent, hydrazine hydrate reduces to it, is 2～3 with the salt acid for adjusting pH value again, with 1,2-ethylene dichloride and tetrahydrofuran (THF) are distinguished extracting, obtain the aniline tetramer of an end carboxyl one end amino;

2) with above-mentioned 1) hold the dimeric method of aniline of amido protecting the same middle the preparation, obtain holding the aniline dimer of amido protecting earlier; The end aniline dimer of amido protecting and the phenylenediamine mol ratio with 2:1 is added in the mixed solvent of dimethyl formamide and 1M hydrochloric acid, 1M hydrochloric acid soln with ammonium persulphate under the stirring at room condition dropwise adds, after dropwising, behind distilled water wash, will precipitate and use ammonia solvent, hydrazine hydrate reduces to it, be 2～3 with the salt acid for adjusting pH value again, with 1,2-ethylene dichloride and tetrahydrofuran (THF) are distinguished extracting, obtain the aniline pentamer of two carboxy blockings;

The preparation method of (AB) n type segmented copolymer of the described aniline tetramer and aliphatic polyester, step and condition are:

(1) step and the condition of the synthetic method of two hydroxy-end capped aliphatic polyesters:

Under the condition of anhydrous and oxygen-free, with toluene is solvent, butyleneglycol is an initiator, and to the aliphatics cyclic ester monomer: the stannous octoate that adds monomer total mass 1/100～1/1000 in rac-Lactide or the 6-caprolactone is made catalyzer, under 100～120 ℃ of heating and stirring condition, polymerization time is 12～72h, product precipitation agent sedimentation is filtered, washing, vacuum-drying obtains the aliphatic polyester that two end groups are hydroxyl and is two hydroxy-end capped polylactides and two hydroxy-end capped poly-epsilon-caprolactones;

(2) earlier with the aniline tetramer of an end carboxyl one end amino and with its etc. the Succinic anhydried of mole number be dissolved in the dimethyl formamide, stirring at room 5h under the nitrogen protection settles out with distilled water, drains the aniline tetramer that obtains two carboxy blockings; Then under the condition of anhydrous and oxygen-free, the two hydroxy-end capped aliphatic polyester that makes in the aniline tetramer of two carboxy blockings of mole number and the step (1) such as getting is dissolved in the N-Methyl pyrrolidone, the dicyclohexylcarbodiimide that the aniline tetramer mole number of the two carboxy blockings of adding is 2～5 times is made condensing agent, under ice-water bath and stirring condition, reaction 48～72h; Product precipitation agent sedimentation is filtered, washing, and vacuum-drying obtains (AB) n type segmented copolymer of the aniline tetramer and aliphatic polyester;

The preparation method of (ABA) n type segmented copolymer of the described aniline tetramer and aliphatic polyester, step and condition are:

(1) step and the condition of the synthetic method of two hydroxy-end capped aliphatic polyesters:

Under the condition of anhydrous and oxygen-free, with toluene is solvent, butyleneglycol is an initiator, and to the aliphatics cyclic ester monomer: the stannous octoate that adds monomer total mass 1/100～1/1000 in rac-Lactide or the 6-caprolactone is made catalyzer, under 100～120 ℃ of heating and stirring condition, polymerization time is 12～72h, product precipitation agent sedimentation is filtered, washing, vacuum-drying obtains the aliphatic polyester that two end groups are hydroxyl and is two hydroxy-end capped polylactides and two hydroxy-end capped poly-epsilon-caprolactones;

(2), obtain the aniline tetramer of an end carboxyl one end amino of tertiary butyl protection earlier with after the tetrameric amido protecting of aniline of di-tert-butyl dicarbonic acid ester with an end carboxyl one end amino; Then under the condition of anhydrous and oxygen-free, the aniline tetramer of an end carboxyl one end amino of getting above-mentioned two hydroxy-end capped aliphatic polyester and mole number and be the tertiary butyl protection of 2 times of the hydroxy-end capped aliphatic polyester of this pair is dissolved in the N-Methyl pyrrolidone, the adding mole number is that the dicyclohexylcarbodiimide of 1～5 times of the hydroxy-end capped aliphatic polyester of this pair is made condensing agent, under ice-water bath and stirring condition, reaction times is 48～72h, product precipitation agent sedimentation, filter, washing, vacuum-drying, again the tertiary butyl is taken off, obtained three block prepolymers of the aniline tetramer and aliphatic polyester; Then under the condition of anhydrous and oxygen-free, in three block prepolymers of the described aniline tetramer and aliphatic polyester 1 of mole number such as adding, 6 hexamethylene diisocyanates add the aniline tetramer and make catalyzer with the stannous octoate of three block prepolymer mole numbers 0.1～1% of aliphatic polyester, 55～65 ℃ with agitation condition under, reaction times is 6～12h, product precipitation agent sedimentation is filtered, washing, vacuum-drying obtains (ABA) n type segmented copolymer of the aniline tetramer and aliphatic polyester;

The preparation method of (AB) n type segmented copolymer of described aniline pentamer and aliphatic polyester, step and condition are:

(1) step and the condition of the synthetic method of two hydroxy-end capped aliphatic polyesters:

Under the condition of anhydrous and oxygen-free, with toluene is solvent, butyleneglycol is an initiator, and to the aliphatics cyclic ester monomer: the stannous octoate that adds monomer total mass 1/100～1/1000 in rac-Lactide or the 6-caprolactone is made catalyzer, under 100～120 ℃ of heating and stirring condition, polymerization time is 12～72h, product precipitation agent sedimentation is filtered, washing, vacuum-drying obtains the aliphatic polyester that two end groups are hydroxyl and is two hydroxy-end capped polylactides and two hydroxy-end capped poly-epsilon-caprolactones;

(2) under the condition of anhydrous and oxygen-free, then under the condition of anhydrous and oxygen-free, the aniline pentamer of two carboxy blockings of mole number and above-mentioned two hydroxy-end capped aliphatic polyester such as getting is dissolved in the N-Methyl pyrrolidone, the dicyclohexylcarbodiimide that the aniline pentamer mole number of the two carboxy blockings of adding is 1～5 times is made condensing agent, under ice-water bath and stirring condition, reaction times is 12～72h, product precipitation agent sedimentation, filter, washing, vacuum-drying obtains (AB) n type segmented copolymer of aniline pentamer and aliphatic polyester;

The preparation method of (ABA) n type segmented copolymer of described aniline pentamer and aliphatic polyester, step and condition are:

(1) step and the condition of the synthetic method of two hydroxy-end capped aliphatic polyesters:

Under the condition of anhydrous and oxygen-free, with toluene is solvent, butyleneglycol is an initiator, and to the aliphatics cyclic ester monomer: the stannous octoate that adds monomer total mass 1/100～1/1000 in rac-Lactide or the 6-caprolactone is made catalyzer, under 100～120 ℃ of heating and stirring condition, polymerization time is 12～72h, product precipitation agent sedimentation is filtered, washing, vacuum-drying obtains the aliphatic polyester that two end groups are hydroxyl and is two hydroxy-end capped polylactides and two hydroxy-end capped poly-epsilon-caprolactones;

(2) under the condition of anhydrous and oxygen-free, the two hydroxy-end capped aliphatic polyester of getting 2 times of the aniline pentamer of two carboxy blockings and aniline pentamers that mole number is this pair carboxy blocking is dissolved in the N-Methyl pyrrolidone, the dicyclohexylcarbodiimide that adds mole number and be 1～5 times of the aniline pentamer of this pair carboxy blocking is made condensing agent, under ice-water bath and stirring condition, reaction times is 12～72h, product precipitation agent sedimentation, filter, washing, vacuum-drying, again the tertiary butyl is taken off, obtained three block prepolymers of aniline pentamer and aliphatic polyester; Then under the condition of anhydrous and oxygen-free, in three block prepolymers of the described aniline tetramer and aliphatic polyester 1 of mole number such as adding, 6 hexamethylene diisocyanates add the aniline pentamer and make catalyzer with the stannous octoate of three block prepolymer mole numbers 0.1～1% of aliphatic polyester, 55～65 ℃ with agitation condition under, reaction times is 6～12h, product precipitation agent sedimentation is filtered, washing, vacuum-drying obtains (ABA) n type segmented copolymer of aniline pentamer and aliphatic polyester.

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