阅读说明：本技术 一种葡聚糖基两亲嵌段共聚物及其制备方法 (Glucan-based amphiphilic block copolymer and preparation method thereof ) 是由 张书录 曹然信 马青岭 王素芹 张福新 于 2021-08-24 设计创作，主要内容包括：本发明公开了一种葡聚糖基两亲嵌段共聚物及其制备方法,所述制备方法包括将葡聚糖氧化成聚醛葡聚糖；将聚丁二酸丁二醇酯的端基进行氨基化得到氨基化聚丁二酸丁二醇酯；将氨基化聚丁二酸丁二醇酯与聚醛葡聚糖进行加热反应,制得所述葡聚糖基两亲嵌段共聚物；本发明制备方法高效简单,制备得到的葡聚糖基两亲嵌段共聚物具有良好的生物降解性和生物相容性；此外,该葡聚糖基两亲嵌段共聚物具有可修饰端基,能够作进一步的功能化,达到扩展应用和使用的效果。(The invention discloses a dextran-based amphiphilic block copolymer and a preparation method thereof, wherein the preparation method comprises the steps of oxidizing dextran into polyaldehyde dextran; carrying out amination on the end group of the poly (butylene succinate) to obtain aminated poly (butylene succinate); carrying out heating reaction on aminated polybutylene succinate and polyaldehyde glucan to prepare the glucan-based amphiphilic block copolymer; the preparation method is efficient and simple, and the prepared glucan-based amphiphilic block copolymer has good biodegradability and biocompatibility; in addition, the glucan-based amphiphilic block copolymer has a modifiable end group, can be further functionalized, and achieves the effects of expanding application and use.)

1. A preparation method of a glucan-based amphiphilic block copolymer is characterized by comprising the following steps:

(a) oxidizing dextran to polyaldehyde dextran;

(b) carrying out amination on the end group of the poly (butylene succinate) to obtain aminated poly (butylene succinate);

(c) carrying out heating reaction on aminated polybutylene succinate and polyaldehyde glucan to prepare the glucan-based amphiphilic block copolymer.

2. The process according to claim 1, wherein the oxidation of dextran to polyaldehyde dextran in step (a) comprises in particular:

under the protection of nitrogen, adding EDTA, 1, 4-benzenediol, sodium borohydride, NaOH and toluene into a glucan water solution, and stirring and refluxing for 2-4 hours to obtain a first mixed solution;

dropwise adding a 2-bromo-I, 1-diethoxyethane solution into the first mixed solution for 0.5-2 h, and then stirring and refluxing for 10-15 h to obtain a second mixed solution;

taking the organic phase in the second mixed solution, washing with water to obtain an aqueous solution, and adding the aqueous solution into methanol to obtain a hydroformylation sugar precursor precipitate;

dissolving the hydroformylation sugar precursor precipitate in water, adding toluenesulfonic acid to adjust the pH value to 1-2, heating for hydrolysis, adjusting to be neutral, and collecting the precipitate to obtain aldehyde group glucan.

3. The method according to claim 1, wherein the amination in the step (b) specifically comprises the steps of:

(1) reacting the poly (butylene succinate) with methylsulfonyl chloride to obtain methylsulfonyl poly (butylene succinate);

(2) reacting methylsulfonyl poly (butylene succinate) with sodium azide to obtain poly (butylene succinate azide); nitrine poly (butylene succinate) reacts with ammonium formate under the catalytic action of Pd/C to obtain aminated poly (butylene succinate).

4. The preparation method according to claim 3, wherein in the step (1), the molar ratio of the polybutylene succinate to the methylsulfonyl chloride is 1: 8-10;

the reaction process of the poly (butylene succinate) and the methylsulfonyl chloride is characterized in that the reaction is carried out for 15-24 hours under ice bath and stirring.

5. The preparation method according to claim 3, wherein in the step (2), the reaction temperature of the methylsulfonyl poly (butylene succinate) and the sodium azide is 90-95 ℃ and the reaction time is 20-30 h; the molar ratio of the methylsulfonyl poly (butylene succinate) to the sodium azide is 1: 1.5-3.

6. The preparation method according to claim 3, characterized in that in the step (2), the mass of Pd/C is 4-6% of that of poly (butylene azide succinate); the mass of the ammonium formate is 55-65% of that of the poly (butylene succinate) azide.

7. The preparation method of claim 3, wherein in the step (2), the temperature of the reaction between the poly (butylene succinate azide) and the ammonium formate under the catalytic action of Pd/C is 22-27 ℃, and the reaction time is 1.5-3 h.

8. The method according to claim 1, wherein in the step (c), the molar ratio of the aminated polybutylene succinate to the polyaldehyde glucan is (1.5-2.5) to 1.

9. The preparation method according to claim 1, wherein in the step (c), the heating reaction is carried out at 50-70 ℃ for 1-3 h; the catalyst adopted in the heating reaction process is acetic acid, and the addition amount of the catalyst is 1-1.5% of the total weight of the reactants.

10. The dextran-based amphiphilic block copolymer prepared by the preparation method of any one of claims 1 to 9.

Technical Field

The invention relates to the technical field of glucan, in particular to a glucan-based amphiphilic block copolymer and a preparation method thereof.

Background

Dextran (dextran), a water-soluble natural polysaccharide, is a non-toxic, harmless polysaccharide that can be degraded into dextran monomers in vivo. The glucan has good biocompatibility similar to PEG, has no immunogenicity, has protein adsorption resistance and other functions, and is beneficial to long-term circulation of the carrier in vivo. When being used as a drug carrier, the glucan has the characteristics of long circulation and invisibility similar to PEG, can reduce protein absorption in blood, and protects the drug from being damaged. The dextran has 5% of branched structure, the molecular structure contains a large number of hydroxyl groups which can be functionalized, and other targeting groups or fluorescent molecules can be easily bonded on the dextran through the reactivity of the hydroxyl groups.

At present, researches on synthesis of an amphiphilic graft copolymer by utilizing hydroxyl groups of glucan are very extensive, for example, Biomaterials (Vol.30, p 1363-1371, 2009) discloses a polycaprolactone-g-glucan amphiphilic graft copolymer which can form micelles in an aqueous solution and can be effectively used as a drug carrier. However, the existing glucan-based block copolymer generally has the problems of poor biodegradability and biocompatibility, complex preparation process steps, complex operation and the like.

Disclosure of Invention

The invention aims to provide a glucan-based amphiphilic block copolymer and a preparation method thereof.

In order to achieve the above purpose of the present invention, the following technical solutions are adopted:

the invention provides a preparation method of a glucan-based amphiphilic block copolymer, which comprises the following steps:

(a) oxidizing dextran to polyaldehyde dextran;

(b) carrying out amination on the end group of the poly (butylene succinate) to obtain aminated poly (butylene succinate);

(c) carrying out heating reaction on aminated polybutylene succinate and polyaldehyde glucan to prepare the glucan-based amphiphilic block copolymer.

Preferably, the oxidation of dextran to polyaldehyde dextran in step (a) specifically comprises:

under the protection of nitrogen, adding EDTA, 1, 4-benzenediol, sodium borohydride, NaOH and toluene into a glucan water solution, and stirring and refluxing for 2-4 hours to obtain a first mixed solution;

dropwise adding a 2-bromo-I, 1-diethoxyethane solution into the first mixed solution for 0.5-2 h, and then stirring and refluxing for 10-15 h to obtain a second mixed solution;

taking the organic phase in the second mixed solution, washing with water to obtain an aqueous solution, and adding the aqueous solution into methanol to obtain a hydroformylation sugar precursor precipitate;

dissolving the hydroformylation sugar precursor precipitate in water, adding toluenesulfonic acid to adjust the pH value to 1-2, heating for hydrolysis, adjusting to be neutral, and collecting the precipitate to obtain aldehyde group glucan.

Preferably, in the step (b), the amination specifically comprises the following steps:

(1) reacting the poly (butylene succinate) with methylsulfonyl chloride to obtain methylsulfonyl poly (butylene succinate);

(2) reacting methylsulfonyl poly (butylene succinate) with sodium azide to obtain poly (butylene succinate azide); nitrine poly (butylene succinate) reacts with ammonium formate under the catalytic action of Pd/C to obtain aminated poly (butylene succinate).

Preferably, in the step (1), the molar ratio of the polybutylene succinate to the methylsulfonyl chloride is 1: 8-10;

the reaction process of the poly (butylene succinate) and the methylsulfonyl chloride is characterized in that the reaction is carried out for 15-24 hours under ice bath and stirring.

Preferably, in the step (2), the reaction temperature of the methylsulfonyl poly (butylene succinate) and the sodium azide is 90-95 ℃ and the reaction time is 20-30 hours;

the molar ratio of the methylsulfonyl poly (butylene succinate) to the sodium azide is 1: 1.5-3.

Preferably, in the step (2), the mass of Pd/C is 4-6% of that of poly (butylene succinate) azide; the mass of the ammonium formate is 55-65% of that of the poly (butylene succinate) azide.

Preferably, in the step (2), the temperature of the reaction between the poly (butylene succinate azide) and the ammonium formate under the catalytic action of Pd/C is 22-27 ℃, and the time is 1.5-3 h.

Preferably, in the step (c), the molar ratio of the aminated polybutylene succinate to the polyaldehyde glucan is (1.5-2.5): 1.

Preferably, in the step (c), the heating reaction is carried out at the temperature of 50-70 ℃ for 1-3 h; the catalyst adopted in the heating reaction process is acetic acid, and the addition amount of the catalyst is 1-1.5% of the total weight of the reactants.

The second aspect of the invention provides a dextran-based amphiphilic block copolymer prepared by the preparation method.

Compared with the prior art, the invention has the beneficial effects that at least:

the preparation method is efficient and simple, and the prepared glucan-based amphiphilic block copolymer has good biodegradability and biocompatibility; in addition, the glucan-based amphiphilic block copolymer has a modifiable end group, can be further functionalized, and achieves the effects of expanding application and use.

Drawings

In order to more clearly illustrate the detailed description of the invention or the technical solutions in the prior art, the drawings that are needed in the detailed description of the invention or the prior art will be briefly described below. Throughout the drawings, like elements or portions are generally identified by like reference numerals. In the drawings, elements or portions are not necessarily drawn to scale.

FIG. 1 is a graph showing biodegradation curves of dextran-based amphiphilic block copolymers prepared in example 1 of the experimental examples of the present invention.

Detailed Description

The following describes embodiments of the present invention in detail with reference to the following embodiments. The following examples are only for illustrating the technical solutions of the present invention more clearly, and therefore are only examples, and the protection scope of the present invention is not limited thereby.

It is to be noted that, unless otherwise specified, technical or scientific terms used herein shall have the ordinary meaning as understood by those skilled in the art to which the invention pertains.

Example 1

This embodiment is a method for preparing a dextran-based amphiphilic block copolymer, including the steps of:

(a) oxidizing dextran to polyaldehyde dextran, the oxidation method specifically comprising:

under the protection of nitrogen, adding EDTA, 1, 4-benzenediol, sodium borohydride, NaOH and toluene into a glucan water solution, and stirring and refluxing for 3 hours to obtain a first mixed solution;

dropwise adding a 2-bromo-I, 1-diethoxyethane solution into the first mixed solution for 1h, and then stirring and refluxing for 12h to obtain a second mixed solution;

taking the organic phase in the second mixed solution, washing with water to obtain an aqueous solution, and adding the aqueous solution into methanol to obtain a hydroformylation sugar precursor precipitate;

dissolving the hydroformylation sugar precursor precipitate in water, adding toluenesulfonic acid to adjust the pH to 1.5, heating for hydrolysis, adjusting to be neutral, and collecting the precipitate to obtain aldehyde dextran;

(b) dissolving polybutylene succinate in pyridine, slowly dropwise adding methylsulfonyl chloride under the conditions of ice bath and stirring to react for 20 hours, settling and washing after the reaction is finished, and performing vacuum drying at 25 ℃ for 24 hours to obtain methylsulfonyl polybutylene succinate, wherein the molar ratio of the polybutylene succinate to the methylsulfonyl chloride is 1: 9;

dissolving methylsulfonyl poly (butylene succinate) in dimethyl sulfone, adding a catalyst, uniformly mixing, heating to 93 ℃ under the protection of nitrogen, adding sodium azide in batches for reacting for 24 hours, adding purified water which is 5 times of the reaction mixed solution, washing, settling, filtering and washing to obtain azido poly (butylene succinate), wherein the molar ratio of methylsulfonyl poly (butylene succinate) to sodium azide is 1: 1.5;

adding Pd/C and ammonium formate into poly (butylene succinate) azide, carrying out reflux reaction for 2 hours at 25 ℃ under the stirring condition, carrying out suction filtration to remove Pd/C, washing filter residues with a large amount of water, concentrating, carrying out suction filtration, and drying to obtain poly (butylene succinate) amide, wherein the mass of Pd/C is 5% of that of poly (butylene succinate) azide; the mass of the ammonium formate is 60 percent of that of the poly (butylene succinate) azide;

(c) dissolving polyaldehyde glucan in dimethyl sulfoxide, then sequentially adding aminated polybutylene succinate and acetic acid, heating to 50 ℃ under the stirring condition, and reacting for 1h to prepare the glucan-based amphiphilic block copolymer, wherein the molar ratio of the aminated polybutylene succinate to the polyaldehyde glucan is 2: 1; the amount of catalyst added was 1% of the total weight of the reactants.

Example 2

This embodiment is a method for preparing a dextran-based amphiphilic block copolymer, including the steps of:

(a) oxidizing dextran to polyaldehyde dextran, the oxidation method specifically comprising:

under the protection of nitrogen, adding EDTA, 1, 4-benzenediol, sodium borohydride, NaOH and toluene into a glucan water solution, and stirring and refluxing for 3 hours to obtain a first mixed solution;

dropwise adding a 2-bromo-I, 1-diethoxyethane solution into the first mixed solution for 1h, and then stirring and refluxing for 12h to obtain a second mixed solution;

taking the organic phase in the second mixed solution, washing with water to obtain an aqueous solution, and adding the aqueous solution into methanol to obtain a hydroformylation sugar precursor precipitate;

dissolving the hydroformylation sugar precursor precipitate in water, adding toluenesulfonic acid to adjust the pH to 1.5, heating for hydrolysis, adjusting to be neutral, and collecting the precipitate to obtain aldehyde dextran;

(b) dissolving polybutylene succinate in pyridine, slowly dropwise adding methylsulfonyl chloride under the conditions of ice bath and stirring to react for 18 hours, settling and washing after the reaction is finished, and performing vacuum drying at 25 ℃ for 24 hours to obtain methylsulfonyl polybutylene succinate, wherein the molar ratio of the polybutylene succinate to the methylsulfonyl chloride is 1: 8;

dissolving methylsulfonyl poly (butylene succinate) in dimethyl sulfone, adding a catalyst, uniformly mixing, heating to 90 ℃ under the protection of nitrogen, adding sodium azide in batches for reacting for 24 hours, adding purified water which is 5 times of the reaction mixed solution, washing, settling, filtering and washing to obtain azido poly (butylene succinate), wherein the molar ratio of methylsulfonyl poly (butylene succinate) to sodium azide is 1: 3;

adding Pd/C and ammonium formate into poly (butylene succinate) azide, carrying out reflux reaction for 3 hours at 25 ℃ under the stirring condition, carrying out suction filtration to remove Pd/C, washing filter residues with a large amount of water, concentrating, carrying out suction filtration, and drying to obtain poly (butylene succinate) amide, wherein the mass of Pd/C is 4% of that of poly (butylene succinate) azide; the mass of the ammonium formate is 65% of that of the poly (butylene succinate) azide;

(c) dissolving polyaldehyde glucan in dimethyl sulfoxide, sequentially adding aminated polybutylene succinate and acetic acid, heating to 70 ℃ under a stirring condition, and reacting for 3 hours to obtain the glucan-based amphiphilic block copolymer, wherein the molar ratio of the aminated polybutylene succinate to the polyaldehyde glucan is 2:1, and the addition amount of a catalyst is 1.5% of the total weight of reactants.

Example 3

This embodiment is a method for preparing a dextran-based amphiphilic block copolymer, including the steps of:

(a) oxidizing dextran to polyaldehyde dextran, the oxidation method specifically comprising:

under the protection of nitrogen, adding EDTA, 1, 4-benzenediol, sodium borohydride, NaOH and toluene into a glucan water solution, and stirring and refluxing for 3 hours to obtain a first mixed solution;

dropwise adding a 2-bromo-I, 1-diethoxyethane solution into the first mixed solution for 1h, and then stirring and refluxing for 12h to obtain a second mixed solution;

taking the organic phase in the second mixed solution, washing with water to obtain an aqueous solution, and adding the aqueous solution into methanol to obtain a hydroformylation sugar precursor precipitate;

dissolving the hydroformylation sugar precursor precipitate in water, adding toluenesulfonic acid to adjust the pH to 1.5, heating for hydrolysis, adjusting to be neutral, and collecting the precipitate to obtain aldehyde dextran;

(b) dissolving polybutylene succinate in pyridine, slowly dropwise adding methylsulfonyl chloride under the conditions of ice bath and stirring to react for 24 hours, settling and washing after the reaction is finished, and performing vacuum drying at 25 ℃ for 24 hours to obtain methylsulfonyl polybutylene succinate, wherein the molar ratio of the polybutylene succinate to the methylsulfonyl chloride is 1: 10;

dissolving methylsulfonyl poly (butylene succinate) in dimethyl sulfone, adding a catalyst, uniformly mixing, heating to 95 ℃ under the protection of nitrogen, adding sodium azide in batches, reacting for 20 hours, adding purified water which is 5 times of the reaction mixed solution, washing, settling, filtering, and washing again to obtain azido poly (butylene succinate), wherein the molar ratio of methylsulfonyl poly (butylene succinate) to sodium azide is 1: 2;

adding Pd/C and ammonium formate into poly (butylene succinate) azide, carrying out reflux reaction for 2.5h at 25 ℃ under the stirring condition, carrying out suction filtration to remove Pd/C, washing filter residues with a large amount of water, concentrating, carrying out suction filtration, and drying to obtain poly (butylene succinate) amide, wherein the mass of Pd/C is 6% of that of poly (butylene succinate) azide; the mass of the ammonium formate is 55% of that of the poly (butylene succinate) azide;

(c) dissolving polyaldehyde glucan in dimethyl sulfoxide, then sequentially adding aminated polybutylene succinate and acetic acid, heating to 60 ℃ under the stirring condition, and reacting for 2 hours to obtain the glucan-based amphiphilic block copolymer, wherein the molar ratio of the aminated polybutylene succinate to the polyaldehyde glucan is 2:1, and the addition amount of a catalyst is 1.2% of the total weight of reactants.

Comparative example 1

This comparative example is a preparation method of a dextran-based amphiphilic block copolymer, which is substantially the same as the preparation method of example 1 except that the reaction temperature in step (c) is 90 ℃.

Comparative example 2

This comparative example is a preparation method of a dextran-based amphiphilic block copolymer, which is substantially the same as the preparation method of example 1 except that the reaction time in step (c) is 4 hours.

Examples of the experiments

The glucan-based amphiphilic block copolymers prepared according to examples 1 to 3 and comparative examples 1 to 2 were respectively used to calculate the yield, which is 100% of the reaction product yield (mass of actually obtained product/mass of theoretically obtained product);

according to the GB/T19277 detection method, sample materials and compost inoculum are mixed and then put into a composting container, sufficient composting is carried out under the conditions of certain oxygen, temperature (58 +/-2 ℃) and humidity (50-55 percent), and CO is measured after 45 days of material degradation₂With actual CO₂The ratio of the release amount to the theoretical maximum release amount represents the biodegradation rate of the material. The detection reference substance is cellulose with the grain diameter smaller than 20 mu m, and the test is effective only when the degradation rate of the reference substance is larger than 70% after 45 days; each glucan-based amphiphilic block copolymer was repeated 3 times, wherein the biodegradation profile of the glucan-based amphiphilic block copolymer prepared in example 1 is shown in fig. 1; the results of the calculation of the biodegradation rates of the different dextran-based amphiphilic block copolymers are shown in table 1:

TABLE 1

Group of	Degradation rate of 45 days	Yield (%)
			Example 1	60％	91.2
Example 2	60.5％	91.6
			Example 3	64％	95.6
Comparative example 1	61％	82.5
			Comparative example 2	60.7％	83.1
Reference substance cellulose	76％

As can be seen from Table 1:

compared with the comparative examples 1 and 2, the glucan-based amphiphilic block copolymer prepared by the embodiment of the invention has more excellent biodegradability, and the yield of the glucan-based amphiphilic block copolymer prepared by the embodiment of the invention is reduced and the degradability is reduced by changing the temperature and time of the polycondensation reaction, namely increasing the reaction temperature and prolonging the reaction time.

Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; such modifications and substitutions do not depart from the spirit and scope of the present invention, and they should be construed as being included in the following claims and description.