Functional polyion liquid composite material as well as preparation method and application thereof

Abstract

The invention provides a functional polyion liquid composite material as well as a preparation method and application thereof, polyion liquid in the functional polyion liquid composite material is formed by an ionic liquid monomer 1-vinylbenzyl-4-dodecyl imidazole chloride and octadecyl acrylate through a free radical polymerization reaction, and heating and melting the polyion liquid and a gelatin solution, ultrasonically defoaming, forming and drying to obtain the functional polyion liquid composite material. The obtained functional polyion liquid composite material can selectively recognize artemisinene and artemisia apiacea wax oil impurities in an artemisinin extract through pi-pi, hydrogen bonds and hydrophobic interaction, synchronous removal of multi-component impurities is achieved, the purity of an artemisinin product is improved, and the problems that in the artemisinin purification process, separation selectivity is poor, the organic solvent dosage is large, and steps are tedious are solved.

Description

Technical Field

[0001] The present invention relates to the field of natural product separation, and particularly to a functional polyionic liquid composite material, a preparation method thereof and an application thereof. Background Art

[0002] Artemisinin is the most effective antimalarial drug recommended by the World Health Organization. Since its advent, it has saved millions of lives. The main method for industrial production of artemisinin is to extract Artemisia annua with organic solvents, and then separate and purify to obtain artemisinin raw materials. However, the extract of Artemisia annua has a large number of components. When extracted with organic solvents, artemisinin is extracted together with structurally similar substances such as artemene and artemisia wax oil components, resulting in a cumbersome subsequent separation process and high energy consumption. Column chromatography is the main process for separating and purifying artemisinin. The purity of the obtained artemisinin product can meet the requirements for producing downstream derivatives. However, this method has problems such as a complex process, difficulty in regenerating silica gel fillers, high energy consumption, large consumption of organic solvents, and inability to identify artemisinin / artemene. The crystallization technology mainly separates artemisinin by utilizing the solubility differences of artemisinin and various impurity components in the extract at different temperatures. The crystallization method is simple to operate and can be used for large-scale industrial purification and separation of artemisinin. However, during the crystallization process, artemisia wax oil is easily adsorbed on artemisinin crystals, and qualified artemisinin products can only be obtained after multiple crystallizations.

[0003] Developing new media is the key to achieving efficient separation of artemisinin. Ionic liquids are a special type of media with designable structures and properties, having unique characteristics such as low vapor pressure, excellent chemical stability, and strong ability to identify structurally similar substances. They are considered media that can replace traditional solvents and show good development prospects in the field of natural product separation. Patent CN113583017 A reports a method for efficiently separating artemene from crude artemisinin using hydrophilic ionic liquids, achieving selective separation through the π-π complexation between the ionic liquid and artemene. Polyionic liquids retain the characteristics of ionic liquids and have excellent mechanical properties of polymers, and their toxicity is lower than that of traditional ionic liquids. In recent years, polyionic liquids have developed rapidly in the field of natural product separation. Patent CN 111592612 B has developed a polyionic liquid that can efficiently separate artemisinin and artemisia wax oil. This polyionic liquid is prepared by copolymerizing 1-vinyl-3-alkylimidazolium bromide (1-vinyl-3-octadecylimidazolium bromide, 1-vinyl-3-tetradecylimidazolium bromide, or 1-vinyl-3-decylimidazolium bromide) and acrylate substances (decyl acrylate, dodecyl acrylate, or octadecyl acrylate). By adsorbing part of the wax oil components, changing the wax oil composition in the solution, and lowering its freezing point, the co-precipitation of wax oil and artemisinin during crystallization is significantly inhibited, and the purity of the artemisinin product obtained from a single crystallization is increased to 99 wt%. The above two inventions have respectively achieved the effective separation of artemisinin / artemene and artemisinin / artemisia wax oil, but still need to remove artemisia wax oil and artemene impurities step by step. Summary of the Invention

[0004] Artemisia annua has complex components. During the extraction of Artemisia annua with organic solvents, components such as ketones and aromatic alcohols in Artemisia annua wax oil and analogues of the artemene structure will be extracted together with artemisinin, resulting in a cumbersome subsequent separation and purification process. Aiming at the above problems, the purpose of the present invention is to provide a functional polyionic liquid composite material, its preparation method and application. The functional polyionic liquid composite material can selectively recognize artemene and Artemisia annua wax oil impurities in the artemisinin extract through π-π, hydrogen bond and hydrophobic interactions, realize the synchronous removal of multi-component impurities, improve the purity of artemisinin products, and solve the problems of poor separation selectivity, cumbersome steps, high energy consumption and high cost in the artemisinin purification process.

[0005] To achieve this purpose, the present invention adopts the following technical solutions:

[0006] In the first aspect, the present invention provides a preparation method of a functional polyionic liquid composite material, and the preparation method includes the following steps:

[0007] S1. 4-Vinylbenzyl chloride and N-dodecylimidazole with a molar ratio of 1:1 are respectively dropped into a round-bottom flask, and the two undergo a quaternization reaction in a nitrogen atmosphere. The reaction temperature is 40-60 °C, and the time is 24-72 h. Subsequently, the solution is washed with ethyl acetate to obtain a pale yellow ionic liquid monomer.

[0008] S2. The ionic liquid monomer and octadecyl acrylate are dissolved in a quantitative methanol solution according to a molar ratio of 9:1-6:4 and then transferred to a three-necked flask. A small amount of azobisisobutyronitrile (accounting for 0.5% of the monomer mass) is added dropwise thereto, and reflux condensation is carried out. A free radical polymerization reaction occurs in a nitrogen atmosphere. The reaction temperature is 60-80 °C, and the time is 24-72 h. Subsequently, it is washed with a methanol solution to obtain a polyionic liquid.

[0009] S3. An 8-15 wt% aqueous gelatin solution and a polyionic liquid (accounting for 2% of the gelatin solution mass) are added to the flask, heated and stirred, and defoamed by ultrasonic treatment to obtain a polyionic liquid / gelatin solution, and the functional polyionic liquid composite material is obtained by drying. The heating temperature is 50-60 °C, and the ultrasonic time is 0.5-2 h.

[0010] Preferably, in the step S1, the reaction temperature is 40 °C and the time is 48 h.

[0011] Preferably, in the step S2, the reaction temperature is 80 °C and the time is 40 h.

[0012] Preferably, in the step S3, the heating temperature of the solution is 55 °C, the time is 1 h, and the ultrasonic time is 1 h.

[0013] Second aspect, the present invention provides a functional polyionic liquid composite material obtained by the preparation method described in the first aspect.

[0014] The functional polyionic liquid composite material can form π-π, hydrogen bonds and hydrophobic interactions with artemisylene and artemisia wax oil in the artemisinin extract, thereby selectively recognizing artemisylene and artemisia wax oil impurities, realizing the synchronous removal of multi-component impurities, and thus improving the purity of artemisinin products.

[0015] Third aspect, the present invention provides an application of the functional polyionic liquid composite material described in the second aspect in separating and purifying artemisinin, and the application includes the following steps:

[0016] (1) Weigh 150 g of dry Artemisia annua leaves into a round-bottom flask, add 1200 mL of petroleum ether (boiling range 60 - 90 °C), heat and stir at 55 °C for 2 h, filter and collect the filtrate, and rotary evaporate to remove petroleum ether to obtain artemisinin extract. Weigh 1 g of artemisinin extract into a centrifuge tube, then add 7 mL of methanol aqueous solution (methanol volume fraction is 70%) thereto, stir at 55 °C for 30 min, filter while it is hot to obtain a methanol extract. During the filtration, due to the low temperature, some wax oil and artemisinin precipitate in the suction flask. Add a small amount of methanol aqueous solution with a volume fraction of 70% and dissolve it by ultrasound to finally obtain 10 g of artemisinin extract.

[0017] (2) Add a certain amount of the functional polyionic liquid composite material to 10 g of the methanol extract of artemisinin, stir at 30 °C and 300 rpm for a period of time, then crystallize at low temperature, filter by suction, take out the functional polyionic liquid composite material, and dry it in vacuo at 50 °C for 12 h to obtain artemisinin crystals, and determine the product purity by high performance liquid chromatography.

[0018] The stirring treatment time of the artemisinin extract / methanol aqueous solution in step (1) is 0.5 - 2 h.

[0019] The addition amount of the functional polyionic liquid composite material in step (2) accounts for 1 - 10 wt% of the mass of the artemisinin extract.

[0020] The crystallization temperature in step (2) is 5 - 20 °C, and the crystallization time is 1 - 10 h.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows: the preparation method of the provided functional polyionic liquid composite material is simple and is an environmentally friendly medium; the provided functional polyionic liquid composite material selectively recognizes artemisylene and artemisia wax oil impurities in the artemisinin extract through π-π, hydrogen bonds and hydrophobic interactions, realizes the synchronous removal of different kinds of impurities and the highly selective separation of artemisinin. Under optimized conditions, the purity of the artemisinin product obtained by one crystallization is 99.9%. Detailed implementation manners

[0022] To describe the technical content and implementation objectives of the present invention in detail, the following is an explanation in combination with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention. The reagents, materials, instruments, etc. used in the following examples can all be obtained through commercial means.

[0023] Comparative Example 1

[0024] This comparative example is the process of separating and purifying artemisinin without adding any functional polyionic liquid composite materials.

[0025] Take 10 g of artemisinin extract, stir at 30 °C and 300 rpm for 1 h, crystallize in a low-temperature constant-temperature bath at 15 °C for 1 h, filter by suction, and dry in a vacuum at 50 °C for 12 h to obtain artemisinin crystals. The purity of the artemisinin product is measured by high-performance liquid chromatography to be 89.8%, and the artemisinene content is 0.30%.

[0026] Comparative Example 2

[0027] Add 1.00 g of pure gelatin film to 10 g of artemisinin extract, stir at 30 °C and 300 rpm for 1 h, crystallize in a low-temperature constant-temperature bath at 15 °C for 1 h, filter by suction, and dry in a vacuum at 50 °C for 12 h to obtain artemisinin crystals. The purity of the artemisinin product is measured by high-performance liquid chromatography to be 90.2%, and the artemisinene content is 0.29%.

[0028] Comparative Example 3

[0029] Dissolve 1.62 g (5 mmol) of octadecyl acrylate in 15 mL of methanol. Weigh a certain amount of initiator 2,2-azobisisobutyronitrile (AIBN, 0.5% of the monomer mass), dissolve it in 5 mL of methanol and transfer it to a constant-pressure dropping funnel. Evacuate the three-necked flask containing the octadecyl acrylate methanol solution and then fill it with nitrogen. Completely add the initiator solution to the flask within 30 min, and react under reflux condensation at 80 °C for 40 h. After the reaction is completed, remove the methanol solvent by rotary evaporation at 50 °C to obtain a white precipitate, then pour it into 20 mL of methanol and repeat the washing three times. Subsequently, remove the solvent by rotary evaporation and place it in a vacuum drying oven at 50 °C for 48 h to obtain a white flaky solid of polyoctadecyl acrylate. Weigh 4 g of gelatin solution (10 wt%) and 0.08 g of polyoctadecyl acrylate and add them to the flask. Heat and stir at 50 °C for 1 h and defoam by ultrasonic wave at 50 °C for 1 h to obtain a milky white polymer / gelatin solution. Pour the solution into a polytetrafluoroethylene mold and dry it in an oven at 50 °C for 12 h to obtain a light yellow polyoctadecyl acrylate / gelatin composite material.

[0030] Add 1 g of octadecyl acrylate / gelatin composite material to 10 g of artemisinin extraction solution, treat it at 30 °C and 300 rpm for 1 h, then crystallize at 15 °C for 1 h, filter and dry to obtain artemisinin product. Analyze the purity of the artemisinin product by high performance liquid chromatography, which is 93.6%, and the content of artemene is 0.30%.

[0031] Example 1

[0032] Weigh 1.95 g (6 mmol) of octadecyl acrylate and 7.76 g (4 mmol) of ionic liquid monomer respectively, dissolve them in 100 mL of methanol and transfer them to a three-necked flask. Dissolve azobisisobutyronitrile (0.5% of the monomer mass) in a small amount of methanol, and then transfer it to a constant pressure dropping funnel. After evacuating the three-necked flask and filling it with nitrogen, completely add the initiator solution dropwise to the flask within 30 min, and react under reflux condensation at 80 °C for 40 h. After the reaction, remove the methanol solvent by rotary evaporation at 50 °C, add 20 mL of methanol and repeat the washing three times, and then dry it under vacuum at 50 °C for 48 h to obtain white flaky polyionic liquid. Add the polyionic liquid (2 wt% of the gelatin solution) to 4 g of gelatin solution (10 wt%), heat and stir at 50 °C for 1 h, and defoam by ultrasonic wave for 1 h to obtain a milky white polyionic liquid / gelatin solution. Pour the solution into a polytetrafluoroethylene mold and dry it in an oven at 50 °C for 12 h to obtain a light yellow functional polyionic liquid composite material (PIL-1).

[0033] Add 0.20 g of functional polyionic liquid composite material (PIL-1) to 10 g of artemisinin extraction solution, treat it at 30 °C and 300 rpm for 1 h, then crystallize at 15 °C for 1 h, filter, and dry it under vacuum at 50 °C to obtain artemisinin product. Analyze the purity of the artemisinin product by high performance liquid chromatography, which is 96.5%, and the content of the impurity artemene is 0.08%.

[0034] Example 2

[0035] Weigh 2.92 g (9 mmol) of octadecyl acrylate and 1.94 g (1 mmol) of ionic liquid monomer separately. After dissolving them in 100 mL of methanol, transfer the solution to a three-necked flask. Dissolve azobisisobutyronitrile (0.5% of the monomer mass) in a small amount of methanol, and then transfer it to a constant-pressure dropping funnel. After evacuating the three-necked flask and filling it with nitrogen, add the initiator solution dropwise to the flask completely within 30 min, and carry out a condensation reflux reaction at 80 °C for 40 h. After the reaction is completed, remove the methanol solvent by rotary evaporation at 50 °C, add 20 mL of methanol and repeat the washing three times, and then dry it under vacuum at 50 °C for 48 h to obtain white flaky polyionic liquid. Add the polyionic liquid (2 wt% of the gelatin solution) to 4 g of gelatin solution (10 wt%), heat and stir at 50 °C for 1 h, and carry out ultrasonic defoaming for 1 h to obtain a milky white polyionic liquid / gelatin solution. Pour the solution into a polytetrafluoroethylene mold and dry it in an oven at 50 °C for 12 h to obtain a light yellow functional polyionic liquid composite material (PIL-2).

[0036] Add 0.20 g of the functional polyionic liquid composite material (PIL-2) to 10 g of artemisinin extraction solution, treat it at 30 °C and 300 rpm for 1 h, then crystallize at 15 °C for 1 h, filter, and dry it under vacuum at 50 °C to obtain artemisinin product. Analyze the purity of the artemisinin product by high-performance liquid chromatography, and the purity is 98.1%, and the content of impurity artemene is 0.07%.

[0037] Example 3

[0038] Add 0.40 g of the functional polyionic liquid composite material PIL-2 to 10 g of artemisinin extraction solution, stir and treat it at 30 °C and 300 rpm for 1 h, crystallize at 15 °C for 1 h, filter, and dry it under vacuum at 50 °C to obtain artemisinin product. Analyze the purity of the artemisinin product by high-performance liquid chromatography, and the purity is 98.6%, and the content of impurity artemene is 0.07%.

[0039] Example 4

[0040] Add 1.0 g of the functional polyionic liquid composite material PIL-2 to 10 g of artemisinin extraction solution, stir and treat it at 30 °C and 300 rpm for 1 h, then crystallize at 15 °C for 4 h, filter, and dry it under vacuum at 50 °C to obtain artemisinin product. Analyze the purity of artemisinin by high-performance liquid chromatography, and the purity is 99.9%, and the content of artemene is 0.04%.

[0041] Example 5

[0042] Mix 10 g of artemisinin extraction solution with the functional polyionic liquid composite material (0.10 g PIL-2) and stir and treat it at 30 °C and 300 rpm for 1 h, then crystallize at 5 °C for 1 h, filter, and dry it under vacuum at 50 °C to obtain artemisinin product. Analyze the purity of artemisinin by high-performance liquid chromatography, and the purity is 98.0%, and the content of artemene is 0.10%.

[0043] Example 6

[0044] 10 g of artemisinin extract and the functional polyionic liquid composite material (0.20 g of PIL-2) were stirred at 30 °C and 300 rpm for 0.5 h, then crystallized at 20 °C for 2 h, filtered, and dried in vacuo at 50 °C to obtain the artemisinin product. The purity of artemisinin analyzed by high performance liquid chromatography was 98.9%, and the artemisinene content was 0.06%.

[0045] Example 7

[0046] The functional polyionic liquid composite material (0.50 g of PIL-2) and 10 g of artemisinin extract were stirred at 30 °C and 300 rpm for 1 h, then crystallized at 15 °C for 10 h, filtered, and dried in vacuo at 50 °C to obtain the artemisinin product. The purity of artemisinin analyzed by high performance liquid chromatography was 99.6%, and the artemisinene content was 0.05%.

[0047] Example 8

[0048] The functional polyionic liquid composite material (0.70 g of PIL-2) and 10 g of artemisinin extract were stirred at 30 °C and 300 rpm for 2 h, then crystallized at 15 °C for 5 h, filtered, and dried in vacuo at 50 °C to obtain the artemisinin product. The purity of artemisinin analyzed by high performance liquid chromatography was 99.8%, and the artemisinene content was 0.05%.

[0049] When the functional polyionic liquid composite material was used as an additive to enhance the separation process, the purity of artemisinin could be increased from 89.8% in Comparative Example 1 to 99.9%. This was mainly because the non-polar long alkyl chains and polar ester groups in the functional polyionic liquid composite material interacted with artemisinin wax oil (mostly long alkyl chain acids), adsorbed the wax oil components, inhibited the co-crystallization of wax oil and artemisinin, and enhanced the separation of artemisinin. At the same time, the artemisinene content was also lower than that in the product obtained in Comparative Example 1, which was attributed to the π-π interaction between the functional polyionic liquid composite material and artemisinene and the selective adsorption of artemisinene. Therefore, the synthesized functional polyionic liquid composite material had excellent performance in enhancing the purification and separation of artemisinin.

[0050] The present invention overcomes the problems of poor selectivity, large amount of organic solvents used, and cumbersome process in the separation process of artemisinin. Functional polyionic liquids were obtained through quaternization reaction and free radical polymerization reaction, effectively enhancing the recognition ability for artemisinene structure analogs and wax oil components, realizing the synchronous removal of impurity components, and improving the purity of artemisinin products.

[0051] The above examples are only used to illustrate the technical solutions of the present invention, rather than to limit it; any improvement or transformation using the content of this specification, directly or indirectly applied in the relevant technical fields, is within the scope of the patent protection of the present invention.

Claims

1. A method for preparing a functional polyionic liquid composite material, characterized in that: The preparation method comprises the following steps: S1. Equimolar amounts of 4-vinylbenzyl chloride and N-dodecyl imidazole were added dropwise into a round-bottom flask respectively, and the two reacted in a nitrogen atmosphere to undergo a quaternization reaction at a temperature of 40 to 60° C. for 24 to 72 hours. After the reaction, the obtained solution was washed with ethyl acetate to purify the ionic liquid to obtain a light yellow ionic liquid monomer; S2, dissolving octadecyl acrylate and ionic liquid monomer in a methanol solution according to a certain molar ratio and transferring the solution to a three-necked flask, then dropping 0.5% of azobisisobutyronitrile by weight of the monomer into the solution, condensing and refluxing, and allowing free radical polymerization to occur in a nitrogen atmosphere at a reaction temperature of 60 to 80° C. for 24 to 72 hours, and then washing with a methanol solution to obtain a polyionic liquid; S3. Add 8-15 wt % gelatin aqueous solution and polyionic liquid (accounting for 2 wt % of the gelatin solution mass) into a flask, stir at 50-60° C. for 0.5-2 h, perform ultrasonic defoaming for 0.5-2 h to obtain a polyionic liquid / gelatin solution, and dry to obtain a functional polyionic liquid composite material.

2. The preparation method according to claim 1, characterized in that: In the step S2, the molar ratio of octadecyl acrylate to the ionic liquid monomer is 9:1 to 6:

4.

3. The preparation method according to claim 1, characterized in that: The drying method in step S3 is to place the polyionic liquid / gelatin solution in a polytetrafluoroethylene mold and dry it in an oven at 50° C. for 12 hours.

4. A functional polyionic liquid composite material prepared by the preparation method according to any one of claims 1 to 3.

5. An application of the functional polyionic liquid composite material as claimed in claim 4 for separating artemisinin, characterized in that: The application comprises the following steps: adding a certain amount of functional polyionic liquid composite material to artemisinin extract, stirring at 30°C and 300 rpm for a period of time, then low-temperature crystallizing the solution, filtering, and vacuum drying the product at 50°C for 12 hours to obtain artemisinin crystals.

6. The use according to claim 5, characterized in that: The artemisinin extract is obtained by stirring 1 g of Artemisia annua extract with 7 mL of methanol aqueous solution (volume fraction 70%) at 55° C. for 30 minutes and filtering while hot.

7. The use according to claim 5, characterized in that: Artemisia annua extract is obtained by extracting dry leaves of Artemisia annua with an organic solvent petroleum ether (boiling range 60-90°C) at 55°C for 2 hours, filtering and collecting the filtrate, and then rotary evaporating to remove the solvent.

8. The use according to claim 5, characterized in that: The added amount of the functional polyionic liquid composite material accounts for 1-10wt% of the mass of the artemisinin extract.

9. The use according to claim 5, characterized in that: The stirring treatment time is 0.5 to 2 hours.

10. The use according to claim 5, characterized in that: The crystallization temperature is 5 to 20°C, and the crystallization time is 1 to 10 hours.