A method for separating artemisinin / artemisene by using a stimuli-responsive polyionic liquid

Abstract

The application discloses a method for extracting and separating artemisinin / arteannuin by using a stimulus-responsive polyionic liquid, and the specific process is as follows: a mixed organic solution containing artemisinin and arteannuin is mixed with a polyionic liquid aqueous solution, after extraction, the water phase is induced to phase separation by adding salt and heating, the polyionic liquid is recycled, and the organic phase is crystallized to obtain artemisinin products; the polyionic liquid is prepared by free radical copolymerization of an ionic liquid monomer containing an aromatic ring and N-isopropyl acrylamide. The method is simple in operation, green and environment-friendly, has the advantages of stable and recyclable catalyst, small environmental hazards and the like compared with a column chromatography method. Efficient purification of artemisinin helps to reduce the cost of anti-malarial drugs and promote the development of the pharmaceutical industry.

Description

Technical Field

[0001] This invention belongs to the field of natural product separation and purification technology, specifically relating to a method for purifying artemisinin, and more particularly to a method for efficiently and selectively separating artemisinin / artemisinene using stimulus-responsive polyionic liquids. Background Technology

[0002] Artemisinin, extracted from Artemisia annua, is globally recognized as the most effective antimalarial drug and has shown potential value in the treatment of other diseases, resulting in significant global demand. Its structural analogue, artemisininene, differs from artemisinin only by a single C=C double bond. Artemisinin exhibits very similar polarity, solubility, and chromatographic behavior, and readily co-crystallizes with artemisinin during extraction. Because artemisininene and artemisinin (structural formula see...) are similar... Figure 1 Due to their high similarity in physicochemical properties, conventional separation methods are insufficient to achieve efficient and selective purification, which seriously affects the final yield and purity of artemisinin.

[0003] The existing methods for separating artemisinin mainly include column chromatography and crystallization. Although column chromatography can improve purity, it consumes a large amount of organic solvents, causes serious pollution, has low efficiency, and a long operation cycle. Crystallization, on the other hand, is prone to co-crystallization or mixed crystallization due to the similar crystallization characteristics of both methods, making it difficult to achieve deep purification. The purity of the product is usually below 85%, which cannot meet the requirements of pharmaceutical-grade raw materials.

[0004] Ionic liquids possess strong structural design capabilities, multi-site synergy, and strong molecular recognition abilities, making them widely used in catalysis, separation, and other fields. In the separation of natural products, the selective separation of target products can be achieved by introducing functional groups such as benzene rings into the ionic liquid structure, enabling π-π complexation and hydrogen bonding interactions with specific substances. A new process for the selective separation of trace artemisinin from artemisinin using an ammonium-functionalized ionic liquid (N-allyl-N,N,N-trimethylammonium chloride) was reported (AIChEJournal, 2022, 68(8), e17711), achieving a selectivity of 12.23 under optimal conditions. However, existing ionic liquid separation systems suffer from the problem of non-recyclability, making it difficult to meet the requirements of green and efficient industrial separation.

[0005] To address the aforementioned problems, this invention is proposed. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of existing technologies and provide a method for the efficient separation of artemisinin / artemisinene using a stimulus-responsive (heat / salt) polyionic liquid. This method utilizes the π-π interaction between the polyionic liquid and artemisinene to achieve green and highly selective separation of artemisinin / artemisinene, and the materials are recyclable.

[0007] To achieve the above objectives, the present invention adopts the following technical solution: A method for separating artemisinin / artemisinene by stimulation-responsive polyionic liquid extraction involves mixing a mixed organic solution containing artemisinin and artemisinene (e.g., a cyclohexane solution containing artemisinin and artemisinene) with an aqueous solution of polyionic liquid, extracting at a certain temperature for a period of time, and separately collecting the polyionic liquid phase rich in artemisinene and the cyclohexane phase rich in artemisinin. The polyionic liquid phase is recycled by adding inorganic salts and heating to above the cloud point to precipitate the polyionic liquid, and the cyclohexane phase is crystallized to obtain a high-purity artemisinin product.

[0008] A method for separating artemisinin / artemisinene using a stimulus-responsive polyionic liquid involves mixing a mixed organic solution containing artemisinin and artemisinene with an aqueous solution of the polyionic liquid for liquid-liquid extraction. After extraction, phase separation is induced by salt addition and heating to obtain artemisinin. The polyionic liquid is prepared by free radical copolymerization of an aromatic ring-containing ionic liquid monomer with N-isopropylacrylamide (NIPAM), with the general structural formula Poly(ILn-co-NIPAMm). The synthetic route is described below. Figure 2 IL is 1-vinyl-3-butylimidazole chloride, and the molar ratio of n to m is 1:9 to 3:7.

[0009] Specifically, the concentration of the polyionic liquid aqueous solution is 1-10 mg / mL; in the mixed organic solution of artemisinin and artemisinene, the concentrations of both artemisinin and artemisinene are 0.1-0.2 mg / mL. As a preferred embodiment of the present invention, the concentration of the polyionic liquid aqueous solution can be 1 mg / mL, 3 mg / mL, 5 mg / mL, and 7 mg / mL, etc. The concentration of each of artemisinin and artemisinene in the mixed organic solution is 0.1 mg / mL, and it is prepared by dissolving 5 mg of artemisinene, 5 mg of artemisinin, and 50 mL of cyclohexane.

[0010] Specifically, in the liquid-liquid extraction process, a mixed organic solution containing artemisinin and artemisinene is mixed with a polyionic liquid aqueous solution at a volume ratio of 1:1-2.

[0011] Furthermore, the extraction is performed by shaking at 30-50°C for 1-4 hours, followed by standing at the same temperature until the two phases are completely separated. As a preferred embodiment of the present invention, in the liquid-liquid extraction process, a mixed organic solution (such as the cyclohexane phase) containing artemisinin and artemisinene is mixed with a polyionic liquid aqueous solution at a volume ratio of 1:1, and extracted by shaking at 30-40°C and 200 r / min for 1 hour, followed by standing at the same temperature for 3 hours until the two phases are completely separated.

[0012] Furthermore, as a preferred embodiment of the present invention, 25-100 mg / mL of NaCl or CaCl2 is added to an aqueous solution of the polyionic liquid with a concentration of 1-10 mg / mL to induce phase separation; the temperature is raised to 40-70°C, and the mixture is allowed to stand for 1-3 hours. The cloud point temperature of the system can be controlled by adding inorganic salts to the aqueous solution of the polyionic liquid. When the concentration of the polyionic liquid is 10 mg / mL, adding 25-50 mg / mL of NaCl or CaCl2 can lower the cloud point temperature to 25-36°C.

[0013] As a preferred embodiment of the present invention, the cloud point temperature of the polyionic liquid aqueous solution decreases with increasing concentration, and the cloud point temperature changes differently for polyionic liquids with different compositions at the same concentration change factor. For example, the cloud point of 10 mg / mL Poly(CBVIM1-co-NIPAM9) is 45°C, which drops to 39°C at 20 mg / mL.

[0014] As a preferred technical solution of the present invention, the preferred process conditions are: polyionic liquid concentration of 5 mg / mL, extraction temperature of 35°C, and extraction time of 1 h.

[0015] Furthermore, the preparation method of the polyionic liquid includes the following steps: 1) Dissolve the ionic liquid monomers 1-vinyl-3-butylimidazolium chloride, N-isopropylacrylamide (in an amount of 1.42-5.47 times the mass of the ionic liquid monomers), and the initiator azobisisobutyronitrile (AIBN) in methanol or acetonitrile; 2) React at 70±10℃ for 24±2h under a nitrogen atmosphere; 3) After the reaction is complete, the mixture is washed with ether, filtered, and vacuum dried (at 40-60℃ for 10-14 hours) to obtain the polyionic liquid.

[0016] Furthermore, the amount of the initiator azobisisobutyronitrile is 2-18% of the mass of the ionic liquid monomer, and the concentration of 1-vinyl-3-butylimidazolium chloride in methanol or acetonitrile is 18.6-55.8 mg / mL.

[0017] A polyionic liquid is prepared by free radical copolymerization of an aromatic ring-containing ionic liquid monomer and N-isopropylacrylamide, with the general structural formula Poly(ILn-co-NIPAMm), wherein IL is 1-vinyl-3-butylimidazole chloride, and the molar ratio of n to m is 1:9 to 3:7.

[0018] The present invention also provides the application of the above-mentioned polyionic liquid in the separation of artemisinin / artemisinene.

[0019] As a preferred embodiment of the present invention, 1 mL of each of the upper organic phase and the lower polyionic liquid phase after extraction and separation is taken, diluted to 10 mL with chromatographic grade methanol, shaken well, and then analyzed by HPLC.

[0020] As a preferred embodiment of the present invention, the method for recycling the polyionic liquid is as follows: After completing the first extraction under optimal separation conditions, the extract phase and the raffinate phase are separated; NaCl is added to the obtained extract phase to make the salt concentration 0.1 g / mL, and the mixture is allowed to stand in an oven at 50°C for 2 hours, during which the polyionic liquid precipitates out in the lower layer; the upper liquid is removed with a pipette, and the remaining solid is dried further. After drying, deionized water is added to dissolve the solid, and the next extraction and separation can be performed, thus repeating the process.

[0021] This invention develops a stimulus-responsive polyionic liquid. Using an aromatic ring-containing ionic liquid monomer copolymerized with N-isopropylacrylamide as the separation medium, artemisinin is selectively enriched into the polyionic liquid phase through extraction at a specific temperature for a period of time. High-purity artemisinin is obtained by cooling and crystallizing the organic phase. The aqueous phase is separated by heating and salt addition to induce phase separation, yielding the polyionic liquid for recycling. Compared with column chromatography and ionic liquid methods, this invention offers simple operation, high separation selectivity, environmental friendliness, and recyclable materials.

[0022] This invention employs the partition coefficient D and the artemisinin / artemisinin separation selectivity S. ARE / ART As a quantitative evaluation index of separation performance: 1. Partition coefficient D: The ratio of the equilibrium concentration of the analyte in the polyionic liquid aqueous phase to the equilibrium concentration in the cyclohexane organic phase after extraction equilibrium; the higher the partition coefficient value, the easier it is for the analyte to be captured by the polyionic liquid extraction phase. 2. Separation selectivity S ARE / ART =D ARE / D ART : Characterizes the selective ability of polyionic liquids to distinguish between artemisinin and artemisinin, which have similar structures; a selectivity greater than 1 indicates that the polyionic liquid preferentially extracts artemisinin; the higher the selectivity value, the better the separation effect of a single extraction.

[0023] Compared with existing column chromatography and ionic liquid systems, the method of the present invention has the following advantages and beneficial effects: 1) Green, environmentally friendly, and recyclable: Using water as a solvent avoids the use of large amounts of organic solvents. Polyionic liquids can achieve phase separation and regeneration through simple temperature or salt concentration changes; 2) Simple operation and high efficiency: The separation process only requires temperature control or salt addition, without the need for complex equipment. The extraction time is short and the separation efficiency is significantly improved compared with column chromatography. Attached Figure Description

[0024] Figure 1 This is a chemical structure diagram of artemisinin (left) and artemisinene (right).

[0025] Figure 2 The synthetic route for Poly(CBVIMn-co-NIPAMm) is shown.

[0026] Figure 3 This is the synthesis route for PCCVIM. Detailed Implementation

[0027] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0028] In the following examples, all raw materials used were commercially available products that could be directly purchased, or could be prepared using conventional techniques in the art. The purity and partition coefficient of artemisinin and artemisinene were determined by high-performance liquid chromatography. Example 1

[0029] The extraction medium was polyisopropylacrylamide (PNIPAM, a commercially available product), and the concentration of the polyionic liquid aqueous solution was 5 mg / mL. In the mixed organic solution (cyclohexane solution) of artemisinin and artemisinene, the concentrations of both artemisinin and artemisinene were 0.1 mg / mL. During the liquid-liquid extraction process, the mixed organic solution containing artemisinin and artemisinene was mixed with the polyionic liquid aqueous solution at a volume ratio of 1:1. Extraction was performed with shaking at 30°C for 1 h, followed by standing at the same temperature until complete separation of the two phases. The separation selectivity of artemisinene / artemisinin was S. ARE / ART It is 1.05. Example 2

[0030] Synthesis of PCBVIM (see synthesis route) Figure 3 ): Dissolve 1 g of 1-vinyl-3-butylimidazole chloride in 10 mL of DMF, and dissolve 0.02 g of AIBN in 5 mL of DMF. Add both to a 50 mL three-necked flask and polymerize at 70 °C for 24 h under a nitrogen atmosphere. After the reaction is complete, transfer the reaction solution to a 50 mL centrifuge tube, add 25 mL of deionized water, and centrifuge at 8000 r / min for 5 min. Pour off the supernatant in the centrifuge tube, add water again, and repeat the centrifugation operation 3 times. Finally, dry the brown solid obtained by centrifugation in a vacuum drying oven at 30 °C overnight.

[0031] The extraction medium was poly(1-vinyl-3-butylimidazolium chloride) (PCBVIM), and the concentration of the polyionic liquid aqueous solution was 5 mg / mL. In the mixed organic solution (cyclohexane solution) of artemisinin and artemisinene, the concentrations of both artemisinin and artemisinene were 0.1 mg / mL. During the liquid-liquid extraction process, the mixed organic solution containing artemisinin and artemisinene was mixed with the polyionic liquid aqueous solution at a volume ratio of 1:1. Extraction was performed with shaking at 30°C for 1 h, followed by standing at the same temperature until complete separation of the two phases. The separation selectivity of artemisinene / artemisinin was S0. ARE / ART It is 2.21. Example 3

[0032] Synthesis of Poly(CBVIM1-co-NIPAM9): N-isopropylacrylamide (45 mmol, 5.09 g) and 1-vinyl-3-butylimidazole chloride (5 mmol, 0.93 g) were dissolved in 50 mL of acetonitrile. AIBN (1 mmol, 164.21 mg) was added to the solution, and the solution was transferred to a 50 mL three-necked flask. The reaction was carried out at 70°C for 24 h under a nitrogen atmosphere. After the reaction was completed and cooled to room temperature, the solution was slowly added dropwise to 100 mL of diethyl ether for washing. The mixture was filtered to obtain a light orange polyionic liquid precipitate. The precipitate was dried in a vacuum drying oven at 50°C for 12 h to obtain the final polyionic liquid product.

[0033] The extraction medium was Poly(CBVIM1-co-NIPAM9), with an aqueous solution concentration of 5 mg / mL. In the mixed organic solution (cyclohexane solution) of artemisinin and artemisinene, the concentrations of both artemisinin and artemisinene were 0.1 mg / mL. During the liquid-liquid extraction process, the mixed organic solution containing artemisinin and artemisinene was mixed with the aqueous solution of the polyionic liquid at a volume ratio of 1:1. Extraction was performed at 30°C with shaking for 1 h, followed by standing at the same temperature until complete separation of the two phases (separation of the extract phase and raffinate phase, with NaCl added to the extract phase at a concentration of 0.1 g / mL, and standing in a 50°C oven for 2 h). Under the synergistic stimulation of heating and salting out, the polyionic liquid precipitated in the upper layer, and artemisinin was collected from the organic phase. The precipitated polyionic liquid solid was dried and reconstituted with 5 mL of deionized water for use in the next extraction round. The separation selectivity of artemisinene / artemisinin was S0. ARE / ART It is 2.53. Example 4

[0034] Synthesis of Poly(CBVIM2-co-NIPAM8): N-isopropylacrylamide (40 mmol, 4.52 g) and 1-vinyl-3-butylimidazole chloride (10 mmol, 1.86 g) were dissolved in 50 mL of acetonitrile, and AIBN (1 mmol, 164.21 mg) was added to the solution. The reaction was carried out in N2 at 70 °C for 24 h. After the reaction was completed, the reaction solution was added dropwise to 100 mL of diethyl ether, and filtered to obtain a pale yellow polyionic liquid precipitate. The precipitate was dried in a vacuum drying oven at 50 °C for 12 h to obtain the final polyionic liquid product.

[0035] The extraction medium was Poly(CBVIM2-co-NIPAM8), with a polyionic liquid aqueous solution concentration of 5 mg / mL. In the mixed organic solution (cyclohexane solution) of artemisinin and artemisinene, the concentrations of both artemisinin and artemisinene were 0.1 mg / mL. During the liquid-liquid extraction process, the mixed organic solution containing artemisinin and artemisinene was mixed with the polyionic liquid aqueous solution at a volume ratio of 1:1. Extraction was performed at 30°C with shaking for 1 h, followed by standing at the same temperature until complete separation of the two phases (separation of the extract phase and raffinate phase, with NaCl added to the extract phase at a concentration of 0.1 g / mL, and standing in a 50°C oven for 2 h). Under the synergistic stimulation of heating and salting out, the polyionic liquid precipitated in the upper layer, and artemisinin was collected from the organic phase. The precipitated polyionic liquid solid was dried and reconstituted with 5 mL of deionized water for use in the next extraction round. The separation selectivity of artemisinene / artemisinin was S. ARE / ART It is 2.58.

[0036] Example 5

[0037] Synthesis of Poly(CBVIM3-co-NIPAM7): N-isopropylacrylamide (35 mmol, 3.96 g) and 1-vinyl-3-butylimidazole chloride (15 mmol, 2.79 g) were dissolved in 50 mL of acetonitrile, and AIBN (1 mmol, 164.21 mg) was added to the solution. The reaction was carried out in N2 at 70°C for 24 h. After the reaction was completed, the reaction solution was added dropwise to 100 mL of diethyl ether, and filtered to obtain a yellow polyionic liquid precipitate. The precipitate was dried in a vacuum drying oven at 50°C for 12 h to obtain the final polyionic liquid product.

[0038] The extraction medium was Poly(CBVIM3-co-NIPAM7), and the concentration of the polyionic liquid aqueous solution was 5 mg / mL. In the mixed organic solution (cyclohexane solution) of artemisinin and artemisinene, the concentrations of both artemisinin and artemisinene were 0.1 mg / mL. During the liquid-liquid extraction process, the mixed organic solution containing artemisinin and artemisinene was mixed with the polyionic liquid aqueous solution at a volume ratio of 1:1. Extraction was performed at 30°C with shaking for 1 h, followed by standing at the same temperature until complete separation of the two phases (separation of the extract phase and raffinate phase, and the addition of NaCl (0.1 g / mL) to the extract phase, followed by standing in a 50°C oven for 2 h). Under the synergistic stimulation of heating and salting out, the polyionic liquid precipitated in the upper layer, and artemisinin was collected from the organic phase. The precipitated polyionic liquid solid was dried and reconstituted with 5 mL of deionized water for use in the next extraction round. The separation selectivity of artemisinene / artemisinin was S. ARE / ART It is 2.69. Example 6

[0039] The extraction medium was Poly(CBVIM3-co-NIPAM7), and the concentration of the polyionic liquid aqueous solution was 3 mg / mL. In the mixed organic solution (cyclohexane solution) of artemisinin and artemisinene, the concentrations of both artemisinin and artemisinene were 0.1 mg / mL. During the liquid-liquid extraction process, the mixed organic solution containing artemisinin and artemisinene was mixed with the polyionic liquid aqueous solution at a volume ratio of 1:1. Extraction was performed at 30°C with shaking for 1 h, followed by standing at the same temperature until complete separation of the two phases (separation of the extract phase and raffinate phase, and the addition of NaCl (0.1 g / mL) to the extract phase, followed by standing in a 50°C oven for 2 h). Under the synergistic stimulation of heating and salting out, the polyionic liquid precipitated in the upper layer, and artemisinin was collected from the organic phase. The precipitated polyionic liquid solid was dried and reconstituted with 5 mL of deionized water for use in the next extraction round). The separation selectivity of artemisinene / artemisinin was S. ARE / ART It is 2.56. Example 7

[0040] The extraction medium was Poly(CBVIM3-co-NIPAM7), and the concentration of the polyionic liquid aqueous solution was 5 mg / mL. In the mixed organic solution (cyclohexane solution) of artemisinin and artemisinene, the concentrations of both artemisinin and artemisinene were 0.1 mg / mL. During the liquid-liquid extraction process, the mixed organic solution containing artemisinin and artemisinene was mixed with the polyionic liquid aqueous solution at a volume ratio of 1:1. Extraction was performed at 30°C with shaking for 2 h, followed by standing at the same temperature until complete separation of the two phases (separation of the extract phase and raffinate phase, and the addition of NaCl (0.1 g / mL) to the extract phase, followed by standing in a 50°C oven for 2 h). Under the synergistic stimulation of heating and salting out, the polyionic liquid precipitated in the upper layer, and artemisinin was collected from the organic phase. The precipitated polyionic liquid solid was dried and reconstituted with 5 mL of deionized water for use in the next extraction round. The separation selectivity of artemisinene / artemisinin was S. ARE / ART It is 2.38. Example 8

[0041] The extraction medium was Poly(CBVIM3-co-NIPAM7), and the concentration of the polyionic liquid aqueous solution was 3 mg / mL. In the mixed organic solution (cyclohexane solution) of artemisinin and artemisinene, the concentrations of both artemisinin and artemisinene were 0.1 mg / mL. During the liquid-liquid extraction process, the mixed organic solution containing artemisinin and artemisinene was mixed with the polyionic liquid aqueous solution at a volume ratio of 1:1. Extraction was performed at 35°C with shaking for 1 h, followed by standing at the same temperature until complete separation of the two phases (separation of the extract phase and raffinate phase, and the addition of NaCl (0.1 g / mL) to the extract phase, followed by standing in a 50°C oven for 2 h). Under the synergistic stimulation of heating and salting out, the polyionic liquid precipitated in the upper layer, and artemisinin was collected from the organic phase. The precipitated polyionic liquid solid was dried and reconstituted with 5 mL of deionized water for use in the next extraction round). The separation selectivity of artemisinene / artemisinin was S. ARE / ART It is 2.78. Example 9

[0042] The extraction medium was Poly(CBVIM3-co-NIPAM7), and the concentration of the polyionic liquid aqueous solution was 5 mg / mL. In the mixed organic solution (cyclohexane solution) of artemisinin and artemisinene, the concentrations of both artemisinin and artemisinene were 0.1 mg / mL. During the liquid-liquid extraction process, the mixed organic solution containing artemisinin and artemisinene was mixed with the polyionic liquid aqueous solution at a volume ratio of 1:1. Extraction was performed at 35°C with shaking for 1 h, followed by standing at the same temperature until complete separation of the two phases (separation of the extract phase and raffinate phase, and the addition of NaCl (0.1 g / mL) to the extract phase, followed by standing in a 50°C oven for 2 h). Under the synergistic stimulation of heating and salting out, the polyionic liquid precipitated in the upper layer, and artemisinin was collected from the organic phase. The precipitated polyionic liquid solid was dried and reconstituted with 5 mL of deionized water for use in the next extraction round. The separation selectivity of artemisinene / artemisinin was S0. ARE / ART It is 2.88.

[0043] Example 10

[0044] The extraction medium was Poly(CBVIM3-co-NIPAM7), and the concentration of the polyionic liquid aqueous solution was 7 mg / mL. In the mixed organic solution (cyclohexane solution) of artemisinin and artemisinene, the concentrations of both artemisinin and artemisinene were 0.1 mg / mL. During the liquid-liquid extraction process, the mixed organic solution containing artemisinin and artemisinene was mixed with the polyionic liquid aqueous solution at a volume ratio of 1:1. Extraction was performed at 35°C with shaking for 1 h, followed by standing at the same temperature until complete separation of the two phases (separation of the extract phase and raffinate phase, and the addition of NaCl at a concentration of 0.1 g / mL to the extract phase, followed by standing in a 50°C oven for 2 h). Under the synergistic stimulation of heating and salting out, the polyionic liquid precipitated in the upper layer, and artemisinin was collected from the organic phase. The precipitated polyionic liquid solid was dried and reconstituted with 5 mL of deionized water for use in the next extraction round. The separation selectivity of artemisinene / artemisinin was S. ARE / ART It is 2.63.

[0045] Example 11

[0046] The extraction medium was Poly(CBVIM3-co-NIPAM7), and the concentration of the polyionic liquid aqueous solution was 5 mg / mL. In the mixed organic solution (cyclohexane solution) of artemisinin and artemisinene, the concentrations of both artemisinin and artemisinene were 0.1 mg / mL. During the liquid-liquid extraction process, the mixed organic solution containing artemisinin and artemisinene was mixed with the polyionic liquid aqueous solution at a volume ratio of 1:1. Extraction was performed at 35°C with shaking for 2 h, followed by standing at the same temperature until complete separation of the two phases (separation of the extract phase and raffinate phase, and the addition of NaCl (0.1 g / mL) to the extract phase, followed by standing in a 50°C oven for 2 h). Under the synergistic stimulation of heating and salting out, the polyionic liquid precipitated in the upper layer, and artemisinin was collected from the organic phase. The precipitated polyionic liquid solid was dried and reconstituted with 5 mL of deionized water for use in the next extraction round. The separation selectivity of artemisinene / artemisinin was S0. ARE / ART It is 2.58.

[0047] Example 12

[0048] The extraction medium was Poly(CBVIM3-co-NIPAM7), and the concentration of the polyionic liquid aqueous solution was 5 mg / mL. In the mixed organic solution (cyclohexane solution) of artemisinin and artemisinene, the concentrations of both artemisinin and artemisinene were 0.1 mg / mL. During the liquid-liquid extraction process, the mixed organic solution containing artemisinin and artemisinene was mixed with the polyionic liquid aqueous solution at a volume ratio of 1:1. Extraction was performed at 40°C with shaking for 1 h, followed by standing at the same temperature until complete separation of the two phases (separation of the extract phase and raffinate phase, and the addition of NaCl (0.1 g / mL) to the extract phase, followed by standing in a 50°C oven for 2 h). Under the synergistic stimulation of heating and salting out, the polyionic liquid precipitated in the upper layer, and artemisinin was collected from the organic phase. The precipitated polyionic liquid solid was dried and reconstituted with 5 mL of deionized water for use in the next extraction round). The separation selectivity of artemisinene / artemisinin was S. ARE / ART It is 2.46.

[0049] Example 13

[0050] The extraction medium was Poly(CBVIM3-co-NIPAM7), and the concentration of the polyionic liquid aqueous solution was 3 mg / mL. In the mixed organic solution (cyclohexane solution) of artemisinin and artemisinene, the concentrations of both artemisinin and artemisinene were 0.1 mg / mL. During the liquid-liquid extraction process, the mixed organic solution containing artemisinin and artemisinene was mixed with the polyionic liquid aqueous solution at a volume ratio of 1:1. Extraction was performed at 40°C with shaking for 2 h, followed by standing at the same temperature until complete separation of the two phases (separation of the extract phase and raffinate phase, and the addition of NaCl (0.1 g / mL) to the extract phase, followed by standing in a 50°C oven for 2 h). Under the synergistic stimulation of heating and salting out, the polyionic liquid precipitated in the upper layer, and artemisinin was collected from the organic phase. The precipitated polyionic liquid solid was dried and reconstituted with 5 mL of deionized water for use in the next extraction round. The separation selectivity of artemisinene / artemisinin was S. ARE / ART It is 2.35.

[0051] Comparative Example 1

[0052] Under the conditions of water as the extraction medium (concentration 5 mg / mL), extraction temperature 40℃, and extraction time 1 h, the separation selectivity coefficient S was... ARE / ART It is 1.08.

[0053] In summary, the method of this invention is simple to operate, has a rapid reaction time, and can obtain high-purity artemisinin. Compared with column chromatography, it has advantages such as high selectivity, environmental friendliness, and recyclable materials. The highest selectivity coefficient for artemisinin reaches 2.88. This method provides a new approach for the efficient separation of structural analogs and helps to reduce the production cost of artemisinin.

[0054] The above description is merely a specific implementation step of this invention, but the scope of protection of this invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in this invention should be included within the scope of protection of this invention.

Claims

1. A method for separating artemisinin / artemisinin using a stimulus-responsive polyionic liquid, characterized in that, A mixed organic solution containing artemisinin and artemisinene was mixed with an aqueous solution of a polyionic liquid for liquid-liquid extraction. After extraction, the phase was separated by adding salt and heating to obtain artemisinin. The polyionic liquid was prepared by free radical copolymerization of an aromatic ring-containing ionic liquid monomer and N-isopropylacrylamide, with the general structural formula Poly(ILn-co-NIPAMm), where IL is 1-vinyl-3-butylimidazole chloride, and the molar ratio of n to m is 1:9 to 3:

7.

2. The method as described in claim 1, characterized in that, The concentration of the polyionic liquid aqueous solution is 1-10 mg / mL; in the mixed organic solution of artemisinin and artemisinene, the concentrations of artemisinin and artemisinene are both 0.1-0.2 mg / mL.

3. The method as described in claim 1, characterized in that, In the liquid-liquid extraction process, a mixed organic solution containing artemisinin and artemisinene is mixed with a polyionic liquid aqueous solution at a volume ratio of 1:1-2.

4. The method as described in claim 1, characterized in that, Extract by shaking at 30-50℃ for 1-4 hours, and then let stand at the same temperature until the two phases are completely separated.

5. The method as described in claim 1, characterized in that, Add 25-100 mg / mL NaCl or CaCl2 to an aqueous solution of a polyionic liquid with a concentration of 1-10 mg / mL to induce phase separation; raise the temperature to 40-70℃ and let stand for 1-3 hours.

6. The method as described in claim 1, characterized in that, The preparation method of the polyionic liquid includes the following steps: 1) Dissolve the ionic liquid monomers 1-vinyl-3-butylimidazolium chloride, N-isopropylacrylamide, and the initiator azobisisobutyronitrile in methanol or acetonitrile; 2) React at 70±10℃ for 24±2h under a nitrogen atmosphere; 3) After the reaction is complete, the product is washed with ether, filtered, and dried under vacuum to obtain the polyionic liquid.

7. The method as described in claim 6, characterized in that, The amount of the initiator azobisisobutyronitrile is 2-18% of the mass of the ionic liquid monomer, and the amount of N-isopropylacrylamide is 1.42-5.47 times the mass of the ionic liquid monomer.

8. A polyionic liquid, characterized in that, It is prepared by free radical copolymerization of an aromatic ring-containing ionic liquid monomer and N-isopropylacrylamide, with the general structural formula Poly(ILn-co-NIPAMm), where IL is 1-vinyl-3-butylimidazole chloride, and the molar ratio of n to m is 1:9 to 3:

7.

9. The application of the polyionic liquid of claim 8 in the separation of artemisinin / artemisinene.

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