Efficient preparation method of hydrophobic chitosan

Abstract

The invention provides an efficient preparation method of hydrophobic chitosan. Chitosan can be directly alkylated to realize efficient synthesis of the hydrophobic chitosan only through one-step reaction. Compared with an existing indirect synthesis mode, the method has the advantages that firstly, extra consumption generated by any intermediate step is not needed, namely, the hydrophobic chitosan is efficiently synthesized by a one-pot one-step method; secondly, not only is amino in the chitosan directly alkylated, but also hydroxyl which cannot be indirectly alkylated can be alkylated to generate hydrophobic chitosan with both N-alkylated and O-alkylated, and the hydrophobic chitosan obtained by the method has more efficient hemostatic performance. Therefore, the method for producing hydrophobic chitosan through direct alkylation is more efficient, higher in yield, low in cost and more excellent in performance.

Description

Technical Field

[0001] The present invention belongs to the technical field of medical materials, and particularly relates to a method for efficiently preparing hydrophobic chitosan. Background Art

[0002] Chitosan is a material widely used in hemostatic agents. Its coagulation ability depends on the electrostatic interaction between the amino groups on its molecular backbone and the negatively charged erythrocyte membrane on the one hand; on the other hand, the coagulation efficiency of chitosan is affected by the hydrophilicity and hydrophobicity in its molecular structure. Therefore, for unmodified chitosan, it only has limited coagulation ability and is not sufficient for efficient application in practice, especially for rapid hemostasis of wounded soldiers on the battlefield.

[0003] Compared with chitosan that promotes coagulation through electrostatic interaction, hydrophobic chitosan can insert into blood cell membranes and immediately form clots with blood, thus achieving a rapid and efficient hemostatic effect. For hydrophobic chitosan with the characteristics of high molecular materials, it can not only use the hydrophobic surface to limit the liquid exchange between the external environment and the wound tissue, but also form a dense and porous protective film on the wound surface, so as to have a certain air permeability while preventing the entry of aerosol bacteria in the air. In this way, chitosan with a hydrophobic surface can achieve efficient hemostasis while protecting the wound from the risk of infection.

[0004] In response to the above practical needs, in order to improve the coagulation ability of chitosan, chemical modification of chitosan is the main means to enhance its coagulation ability. At present, alkylation of chitosan is the main method for hydrophobic modification of chitosan. However, at present, the preparation of hydrophobic chitosan needs to be completed through two-step reactions: the first step is to react sodium hydroxide with the hydrogen on the amino group of chitosan to complete the acylation of chitosan and obtain the acylated intermediate of chitosan. Since the intermediate has an acyl group, the second step needs to be carried out. The second step is to use sodium borohydride to carry out a reduction reaction on the acylated intermediate of the first step to eliminate the acyl group and obtain the final product, and the final product is N-alkylated chitosan. It can be seen that the existing technology mainly carries out alkylation reaction through the amino group of chitosan, and can only generate N-alkylated chitosan, and the above method needs two-step reactions to complete the production of hydrophobic chitosan, which belongs to the indirect alkylation of chitosan, with low synthesis efficiency and additional consumption. Summary of the Invention

[0005] In order to solve the above problems existing in the prior art, the present invention provides a method for efficiently preparing hydrophobic chitosan. The technical problems to be solved by the present invention are realized through the following technical solutions:

[0006] The present invention provides a method for efficiently preparing hydrophobic chitosan, including:

[0007] adding chitosan into the flask to form a reaction system in the flask;

[0008] Adding N,N-dimethylformamide as a solvent of the reaction system into the flask, and inserting a mechanical stirrer into the reaction system for stirring, so that the chitosan is fully dissolved to obtain a solution;

[0009] Adding sodium hydride to the reaction system and stirring with the mechanical stirrer to allow the negative hydrogen radicals of the sodium hydride to react with the hydrogen radicals in the amino groups and hydroxyl groups in the chitosan;

[0010] An alkylating agent is added to the reaction system and stirred sufficiently. After the reaction system is cooled to room temperature, water is added to the reaction system to precipitate N- and O-alkylated hydrophobic chitosan.

[0011] Optionally, the content of chitosan is 1.0eq.

[0012] Optionally, the step of adding N,N-dimethylformamide as a solvent of the reaction system into the flask, and inserting a mechanical stirrer into the reaction system for stirring to fully dissolve the chitosan to obtain a solution comprises:

[0013] Adding N,N-dimethylformamide as a solvent of the reaction system into the flask;

[0014] The reaction system was heated to 60° C., and a mechanical stirrer was inserted into the reaction system for stirring for 10 hours.

[0015] Optionally, adding sodium hydride to the reaction system and stirring with the mechanical stirrer so that the negative hydrogen radicals of the sodium hydride react with the hydrogen in the amino group and the hydroxyl group in the solution comprises:

[0016] 4.0 eq of sodium hydride was added to the reaction system, and the system was stirred for 5 hours using the mechanical stirrer to allow the negative hydrogen radicals of the sodium hydride to react with the hydrogen radicals of the amino groups and hydroxyl groups in the solution.

[0017] Optionally, the step of adding an alkylating agent to the reaction system and stirring the mixture sufficiently, and then adding water to the reaction system after the reaction system is cooled to room temperature to precipitate N- and O-alkylated hydrophobic chitosan comprises:

[0018] Add 8.0 eq of an alkylating agent to the reaction system and stir for 10 hours;

[0019] Waiting for the reaction system to cool to room temperature, and then adding water to the reaction system to precipitate a hydrophobic chitosan product;

[0020] Filter the precipitated product and put it into a drying oven. Set the drying temperature to 80 °C to obtain N- and O-alkylated hydrophobic chitosan by drying.

[0021] Optionally, the alkylating agent is a haloalkane, which enters the stirred reaction system by dropwise addition.

[0022] Beneficial effects:

[0023] The present invention provides a method for efficiently preparing hydrophobic chitosan. Only one-step reaction is required to directly alkylate chitosan to achieve the efficient synthesis of hydrophobic chitosan. Compared with the existing indirect synthesis methods, first, the present invention does not require any additional consumption generated by intermediate steps, that is, one-pot one-step method for efficiently synthesizing hydrophobic chitosan. Second, the present invention not only directly alkylates the amino group in chitosan, but also can alkylate the hydroxyl group that cannot be completed by indirect alkylation to produce hydrophobic chitosan with both N-alkylation and O-alkylation. The hydrophobic chitosan obtained by using this method has more efficient hemostatic performance. Therefore, the method for directly alkylating to produce hydrophobic chitosan in the present invention is more efficient, has higher yield, lower cost and more excellent performance.

[0024] The following will further describe the present invention in detail with reference to the drawings and embodiments. Brief description of the drawings

[0025] Figure 1 is a schematic flow chart of a method for efficiently preparing hydrophobic chitosan provided by the present invention;

[0026] Figure 2 is a reaction schematic diagram of the reaction system provided by the present invention. Detailed embodiments

[0027] The following further describes the present invention in detail with specific embodiments, but the embodiments of the present invention are not limited thereto.

[0028] As Figure 1 shown, the present invention provides a method for efficiently preparing hydrophobic chitosan, including:

[0029] S100, adding chitosan into a flask to form a reaction system in the flask; the content of the chitosan is 1.0 eq.

[0030] S200, adding N,N-dimethylformamide as the solvent of the reaction system into the flask, and inserting a mechanical stirrer into the reaction system to stir, so that the chitosan is fully dissolved to obtain a solution;

[0031] In this step, N,N-dimethylformamide is added as the solvent of the reaction system into the flask; the reaction system is heated to 60 °C, and a mechanical stirrer is inserted into the reaction system and stirred for 10 hours. In the reaction process of the present invention, N,N-dimethylformamide (DMF) is used as the solvent of the reaction system, and the reaction system can obtain the property of uniform mechanical stirring at 60 °C.

[0032] S300, sodium hydride is added to the reaction system and stirred using the mechanical stirrer so that the hydride anion of sodium hydride reacts with the hydrogen in the amino group and hydroxyl group of chitosan in the solution;

[0033] Reference Figure 2 , in this step, 4.0 eq of sodium hydride is added to the reaction system and stirred using the mechanical stirrer for 5 hours so that the hydride anion of sodium hydride reacts with the hydrogen in the amino group and hydroxyl group of chitosan in the solution.

[0034] S400, an alkylating agent is added to the reaction system and stirred thoroughly. After waiting for the reaction system to cool to room temperature, water is added to the reaction system to precipitate the N- and O-alkylated hydrophobic chitosan.

[0035] The alkylating agent of the present invention is a haloalkane, which enters the stirred reaction system by dropwise addition. In this step, an alkylating agent (such as n-hexyl bromide) is added to the reaction system, and the mechanical stirrer is used to stir for 10 hours so that the amino group and hydroxyl group in the chitosan react fully with the alkylating agent, and a hydrophobic chitosan product with both nitrogen alkylation and oxygen alkylation is obtained.

[0036] It should be noted that: the reaction activity of haloalkanes is very active. Through electrophilic substitution reactions, they can directly alkylate bioactive macromolecules (such as DNAs, RNAs, and proteins), or haloalkanes can generate free radicals under the action of light or other excitation energies. In the substitution reaction of haloalkanes, usually the halogen becomes an ion and leaves, and a halide is formed. The hydrocarbon part of the haloalkane forms a carbocation (R + ), and reacts with the attacking reagent.

[0037] In this step, 8.0 eq of the alkylating agent is added to the reaction system and stirred for 10 hours; after waiting for the reaction system to cool to room temperature, water is added to the reaction system to precipitate the product of hydrophobic chitosan; the precipitated product is filtered and then placed in a drying oven to be dried to obtain the N- and O-alkylated hydrophobic chitosan. The alkylating agent of the present invention is a haloalkane, which enters the stirred reaction system by dropwise addition.

[0038] From the perspective of chemical synthesis methodology, the efficiency of indirect alkylation is not only lower than that of direct alkylation, but its cost is also higher than that of direct alkylation. The present invention directly conducts a direct alkylation reaction on chitosan, which increases the degree of alkylation of chitosan. The present invention can achieve the efficient synthesis of hydrophobic chitosan in only one step without any additional consumption generated by intermediate steps, that is, the one-pot synthesis of hydrophobic chitosan. At the same time, the present invention also alkylates the hydroxyl groups of chitosan to produce N- and O-alkylated hydrophobic chitosan, which has more efficient hemostatic performance. Therefore, the method for directly alkylating to produce hydrophobic chitosan in the present invention is more efficient, has a higher yield, lower cost, and more excellent performance.

[0039] The following experimental examples are used to illustrate the yield of the method of the present invention.

[0040] Example:

[0041] Reference Figure 2 , Figure 2 Figure is a schematic diagram of the reaction of N,N-dimethylformamide (DMF), sodium hydride with atoms on chitosan. Chitosan (6.0 g, 1.0 eq) was added to a 250 mL flask, 90 mL of N,N-dimethylformamide was added to the flask, a stirrer was inserted into the reaction flask, the reaction was heated to 60 °C and stirred for 10 hours. After the chitosan was dissolved, sodium hydride (3.0 g, 4.0 eq) was added to the reaction system and stirred for 5 hours. Then, 1-bromohexane (12.0 mL, 8.0 eq) was added to the reaction system as an alkylating agent, and it was stirred at 60 °C for another 10 h. Then, deionized water (50 mL) was slowly added to the reaction system. After the reaction product precipitated, it was filtered out and dried in an oven to obtain hydrophobic chitosan with a yield of 93.8%.

[0042] In addition, the terms "first" and "second" are only used for descriptive purposes and cannot be construed as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. Thus, features defined with "first" and "second" may explicitly or implicitly include one or more of such features. In the description of the present invention, "a plurality of" means two or more unless otherwise specifically defined.

[0043] Although the present application has been described in conjunction with various embodiments herein, however, in the process of implementing the claimed present application, those skilled in the art can understand and achieve other variations of the disclosed embodiments by viewing the accompanying drawings, the disclosed content, and the appended claims. In the claims, the word "comprising" does not exclude other components or steps, and "a" or "an" does not exclude a plurality of cases.

[0044] The above content is a further detailed description of the present invention in combination with specific preferred embodiments. It cannot be determined that the specific implementation of the present invention is only limited to these descriptions. For those of ordinary skill in the technical field to which the present invention pertains, without departing from the concept of the present invention, several simple deductions or substitutions can still be made, and all should be regarded as belonging to the protection scope of the present invention.

Claims

1. An efficient preparation method of hydrophobic chitosan, It is characterized in that include: adding chitosan into the flask to form a reaction system in the flask; Adding N,N-dimethylformamide as a solvent of the reaction system into the flask, and inserting a mechanical stirrer into the reaction system for stirring, so that the chitosan is fully dissolved to obtain a solution; Adding sodium hydride to the reaction system and stirring with the mechanical stirrer to allow the negative hydrogen radicals of the sodium hydride to react with the hydrogen radicals in the amino groups and hydroxyl groups in the chitosan; An alkylating agent is added to the reaction system and stirred sufficiently. After the reaction system is cooled to room temperature, water is added to the reaction system to precipitate N- and O-alkylated hydrophobic chitosan.

2. The efficient preparation method of hydrophobic chitosan according to claim 1, It is characterized in that The content of the chitosan is 1.0 eq.

3. The efficient preparation method of hydrophobic chitosan according to claim 1, It is characterized in that The step of adding N,N-dimethylformamide as a solvent of the reaction system into the flask, and inserting a mechanical stirrer into the reaction system for stirring so that the chitosan is fully dissolved to obtain a solution comprises: Adding N,N-dimethylformamide as a solvent of the reaction system into the flask; The reaction system was heated to 60°C, and a mechanical stirrer was inserted into the reaction system for stirring for 10 hours.

4. The efficient preparation method of hydrophobic chitosan according to claim 1, It is characterized in that The step of adding sodium hydride to the reaction system and stirring the system with the mechanical stirrer so that the negative hydrogen radicals of the sodium hydride react with the hydrogen radicals in the amino groups and hydroxyl groups in the solution comprises: 4.0 eq of sodium hydride was added to the reaction system, and the system was stirred for 5 hours using the mechanical stirrer to allow the negative hydrogen radicals of the sodium hydride to react with the hydrogen radicals of the amino groups and hydroxyl groups in the solution.

5. The efficient preparation method of hydrophobic chitosan according to claim 1, It is characterized in that The step of adding an alkylating agent to the reaction system and stirring the reaction system sufficiently, and then adding water to the reaction system after the reaction system is cooled to room temperature to precipitate N- and O-alkylated hydrophobic chitosan comprises: Add 8.0 eq of an alkylating agent to the reaction system and stir for 10 hours; Waiting for the reaction system to cool to room temperature, and then adding water to the reaction system to precipitate a hydrophobic chitosan product; The precipitated product was filtered and placed in a drying oven. The drying temperature was set to 80°C and dried to obtain N- and O-alkylated hydrophobic chitosan.

6. The efficient preparation method of hydrophobic chitosan according to claim 5, It is characterized in that The alkylating agent is a halogenated alkane, which is added dropwise into the stirred reaction system.

Images