CN111592612B

CN111592612B - Polyion liquid inhibitor and preparation method and application thereof

Info

Publication number: CN111592612B
Application number: CN202010429899.4A
Authority: CN
Inventors: 王慧; 张迎; 曹莹莹; 张永强; 张锁江
Original assignee: Institute of Process Engineering of CAS
Current assignee: Institute of Process Engineering of CAS
Priority date: 2020-05-20
Filing date: 2020-05-20
Publication date: 2021-07-20
Anticipated expiration: 2040-05-20
Also published as: CN111592612A

Abstract

The invention provides a polyion liquid inhibitor and a preparation method and application thereof, wherein the polyion liquid inhibitor is obtained by copolymerizing acrylate and 1-vinyl-3-alkyl imidazole bromide. The obtained polyion liquid inhibitor can improve the fluidity of wax oil in the artemisinin-containing extract, and can remarkably inhibit the co-precipitation of the wax oil and the artemisinin in the crystallization process by reducing the freezing point of the wax oil, so that the purity of the finally obtained artemisinin product is improved; moreover, the polyion liquid inhibitor can be recycled, and the problems of poor separation effect, complex process and the like in the artemisinin purification process are solved.

Description

Polyion liquid inhibitor and preparation method and application thereof

Technical Field

The invention belongs to the technical field of separation, relates to an inhibitor, and a preparation method and application thereof, and particularly relates to a polyion liquid inhibitor, and a preparation method and application thereof.

Background

Artemisinin is sesquiterpene lactone containing peroxy group, has colorless needle shape, is the most effective antimalarial specific drug after pyrimethamine, chloroquine and primaquine, and has the characteristics of quick acting, low toxicity and the like. The antimalarial mechanism is mainly that artemisinin is activated to generate free radicals, the free radicals are combined with plasmodium proteins and act on the membrane system structure of plasmodium, the vesicle membrane, the nuclear membrane and the plasma membrane of the plasmodium are damaged, mitochondria swell and the inner membrane and the outer membrane are separated, so that the cellular structure of the plasmodium is damaged. Besides the antimalarial effect, the artemisinin also has the pharmacological effects of resisting bacteria, tumors, lupus erythematosus, parasites and the like, and is a natural medicine with great development potential.

At present, the main process for industrially producing artemisinin is to extract artemisia annua leaves by using an organic solvent. The content of artemisinin in the artemisia annua leaves is low, the content difference of artemisinin in the artemisia annua leaves in different producing areas is obvious, and the maximum content of artemisinin in the artemisia annua leaves is only 1-1.6% of the weight of the artemisia annua leaves. During the extraction process, wax oil with complex components in the artemisia annua leaves is also extracted, and in order to obtain high-quality artemisinin, the extracted components need to be purified and separated.

CN 107827904 a discloses a purification method of artemisinin, which comprises the following steps: s1, separating and purifying an artemisinin extracting solution by using a column to obtain column eluent, wherein the content of an impurity B in the column eluent is more than or equal to 0.5%; s2, concentrating the column eluent at the temperature of 40-85 ℃, wherein the volume of the concentrated eluent is 1/10-1/20 before concentration, obtaining concentrated solution, standing for crystallization, taking out crystals, and drying to obtain a crude product; s3, adding alcohol into the crude product, dissolving, sequentially filtering by using kieselguhr and a microporous filter membrane, standing for crystallization, filtering, and taking crystals to obtain artemisinin. The purification method utilizes adsorption and crystallization methods to purify the artemisinin, and has the defects of high organic solvent consumption and easy cocrystallization of wax oil and the artemisinin, so that the separation efficiency is poor and the purity of the obtained artemisinin is low.

CN 103819485A discloses a method for rapidly separating artemisinin, which comprises the steps of adopting an acidic aqueous solvent to destroy plant epidermal cells and carbonize the fiber structure of artemisia annua, dissolving the obtained crude crystals with 95% ethanol, adding activated carbon and activated carbon powder, wherein the ratio of the activated carbon to the dissolved solution is 1:100(g/mL), stirring for 30 minutes, filtering, heating the filtrate, concentrating until crystals are separated out, stopping heating, standing for 6 hours for crystallization, filtering the crystals, and drying to obtain a refined artemisinin product. The method also utilizes a crystallization method to purify the artemisinin, and has the defects of large using amount of organic solvent and easy cocrystallization of wax oil and the artemisinin, so that the separation efficiency is poor and the purity of the obtained artemisinin is low.

CN 101597296A discloses a novel method for efficiently extracting and producing artemisinin by using ionic liquid, which comprises the following steps: (1) pulverizing Artemisia annua raw material, mixing the pulverized Artemisia annua raw material with imidazole ionic liquid halide salt and water, and extracting artemisinin under ultrasonic condition to obtain extract containing artemisinin; (2) mixing the extract containing artemisinin obtained in the step (1) with an organic extractant, performing organic extraction for 1-5 times, and recycling the raffinate phase; (3) evaporating the organic extraction phase obtained in the step (2) to recover the organic extractant to obtain crude artemisinin; (4) and (4) dissolving the crude artemisinin obtained in the step (3), and further refining by column chromatography and recrystallization to obtain high-purity artemisinin. Although the purity of the obtained artemisinin can be improved to 99%, the method is complex in process flow and low in efficiency, and is not beneficial to industrial application of artemisinin extraction.

CN 109320523A discloses a method for efficiently purifying artemisinin, which comprises extracting artemisinin from artemisia annua leaves with an extraction solvent to obtain an extract, concentrating the extract to obtain an extract, and dissolving the extract with an extractant to obtain an extract; adding the functionalized wax oil inhibitor into the extract, stirring, cooling for crystallization, carrying out solid-liquid separation, drying to obtain a crude artemisinin product, and recrystallizing the crude artemisinin product to obtain a high-purity artemisinin product. According to the method, through the functions of anticoagulation and wax oil precipitation prevention of the functionalized wax oil inhibitor, the artemisinin in the extraction liquid is precipitated, so that the purity of the obtained artemisinin is improved, but the purity of the artemisinin needs to be further improved.

The invention improves the purity of the obtained artemisinin product by reducing the freezing point of the wax oil and inhibiting the co-precipitation of the wax oil and the artemisinin, thereby solving the problems of poor separation effect, complex process and the like in the artemisinin purification process and realizing high-efficiency purification and separation of the artemisinin.

Disclosure of Invention

Aiming at the defects in the prior art, the invention aims to provide a polyion liquid inhibitor and a preparation method and application thereof. Moreover, the polyion liquid inhibitor is simple in preparation method and convenient to apply, and facilitates industrial application of separation and purification of artemisinin products.

In order to achieve the purpose, the invention adopts the following technical scheme:

in a first aspect, the present invention provides a method for preparing a polyion liquid inhibitor, comprising the following steps:

(1) mixing N-vinyl imidazole and 1-bromoalkane, and reacting to obtain 1-vinyl-3-alkyl imidazole bromine;

(2) mixing acrylate, an initiator and the 1-vinyl-3-alkyl imidazole bromide obtained in the step (1), and carrying out polymerization reaction in an inert atmosphere to obtain the polyion liquid inhibitor.

The polyion liquid inhibitor capable of obviously reducing the freezing point of artemisia annua wax oil is prepared by firstly preparing 1-vinyl-3-alkyl imidazole bromide and then utilizing the prepared 1-vinyl-3-alkyl imidazole bromide. When the polyion liquid inhibitor is applied to separation and purification of artemisinin, artemisinin products with purity more than or equal to 99% can be obtained.

Preferably, the 1-bromoalkane described in step (1) includes any one or a combination of at least two of 1-bromodecane, 1-bromododecane, 1-bromotetradecane, 1-bromohexadecane or 1-bromooctadecane, and typical but non-limiting combinations include a combination of 1-bromodecane and 1-bromododecane, a combination of 1-bromododecane and 1-bromotetradecane, a combination of 1-bromotetradecane and 1-bromohexadecane, a combination of 1-bromohexadecane and 1-bromooctadecane, a combination of 1-bromodecane, 1-bromododecane and 1-bromotetradecane, a combination of 1-bromododecane, 1-bromotetradecane and 1-bromohexadecane, a combination of 1-bromotetradecane and 1-bromotetradecane, A combination of 1-bromohexadecane and 1-bromooctadecane, a combination of 1-bromodecane, 1-bromododecane, 1-bromotetradecane and 1-bromohexadecane, a combination of 1-bromododecane, 1-bromotetradecane, 1-bromohexadecane and 1-bromooctadecane, or a combination of 1-bromodecane, 1-bromododecane, 1-bromotetradecane, 1-bromohexadecane and 1-bromooctadecane.

Preferably, the molar ratio of the N-vinylimidazole to the 1-bromoalkane is 1 (0.8-1.2), and may be, for example, 1:0.8, 1:0.9, 1:1, 1:1.1 or 1:1.2, but is not limited to the recited values, and other values not recited in the numerical range are also applicable, and preferably 1 (0.9-1.1).

Preferably, the reaction temperature in step (1) is 55 to 75 ℃, for example 55 ℃, 60 ℃, 65 ℃, 70 ℃ or 75 ℃, but not limited to the recited values, and other values not recited in the range of values are equally applicable, preferably 60 to 70 ℃.

Preferably, the reaction time in step (1) is 2-48h, for example, 2h, 6h, 12h, 15h, 18h, 20h, 24h, 28h, 32h, 36h, 40h, 42h, 45h or 48h, but not limited to the recited values, and other values not recited in the range of values are also applicable.

Preferably, the molar ratio of the acrylate, initiator and 1-vinyl-3-alkylimidazole bromine obtained in step (1) in step (2) is (1-12): 0.01-0.1):1, and may be, for example, 1:0.01:1, 3:0.03:1, 6:0.05:1, 9:0.08:1 or 12:0.1:1, but is not limited to the values listed, and other values not listed within the range of values are equally applicable.

Preferably, the acrylate in step (2) comprises any one of decyl acrylate, dodecyl acrylate, tetradecyl acrylate, hexadecyl acrylate or octadecyl acrylate or a combination of at least two of the above; typical but non-limiting combinations include decyl acrylate in combination with dodecyl acrylate, dodecyl acrylate in combination with tetradecyl acrylate, tetradecyl acrylate in combination with hexadecyl acrylate, hexadecyl acrylate or octadecyl acrylate, decyl acrylate, dodecyl acrylate in combination with tetradecyl acrylate, dodecyl acrylate, tetradecyl acrylate in combination with hexadecyl acrylate, dodecyl acrylate in combination with hexadecyl acrylate, tetradecyl acrylate in combination with hexadecyl acrylate, or decyl acrylate, dodecyl acrylate, tetradecyl acrylate, hexadecyl acrylate in combination with octadecyl acrylate.

Preferably, the initiator of step (2) comprises azobisisobutyronitrile.

Preferably, the inert gas atmosphere of step (2) comprises a nitrogen gas atmosphere and/or an inert gas atmosphere; the inert gas includes any one or a combination of at least two of helium, argon or neon, and typical but non-limiting combinations include helium with argon, argon with neon, helium with neon or helium, argon with neon.

Preferably, the polymerization temperature in step (2) is 50-100 ℃, for example 50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃ or 100 ℃, but not limited to the recited values, and other values not recited in the range of values are equally applicable; the time is 1-6h, for example 1h, 2h, 3h, 4h, 5h or 6h, but is not limited to the values listed, and other values not listed in the numerical range are equally applicable.

In a second aspect, the invention provides a polyion liquid inhibitor prepared by the preparation method of the first aspect.

The polyion liquid inhibitor can obviously reduce the freezing point of the wax oil in the artemisinin extraction liquid, and avoids the separation of the wax oil in the artemisinin crystallization process, thereby ensuring the purity of the obtained artemisinin product.

In a third aspect, the invention provides an application of the polyion liquid inhibitor as described in the second aspect in separation and purification of artemisinin, and the application comprises the following steps: mixing the polyion liquid inhibitor and the extraction liquid containing the artemisinin, and sequentially cooling, crystallizing, carrying out solid-liquid separation and drying to obtain the artemisinin product.

Preferably, the mass ratio of the polyionic liquid inhibitor to the extraction liquid is (0.01-0.2):1, and may be, for example, 0.01:1, 0.03:1, 0.05:1, 0.07:1, 0.09:1, 0.1:1, 0.12:1, 0.15:1, 0.18:1 or 0.2:1, but is not limited to the values recited, and other values within the range of values are equally applicable, preferably (0.03-0.07): 1.

Preferably, the mixing is mechanical stirring at 30-60 ℃ for 30-120 min.

The temperature of the mixing according to the invention is 30 to 60 ℃, for example 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃ or 60 ℃, but is not limited to the values listed, and other values not listed in the numerical range are equally applicable, preferably 45 to 55 ℃; the mechanical stirring time is 30-120min, such as 30min, 40min, 50min, 60min, 70min, 80min, 90min, 100min, 110min or 120min, but is not limited to the values listed, and other values not listed in the range of values are equally applicable, preferably 60-120 min.

Preferably, the temperature of the cooling crystallization is 5 to 30 ℃, for example, 5 ℃, 10 ℃, 15 ℃, 20 ℃, 25 ℃ or 30 ℃, but not limited to the recited values, and other values not recited in the numerical range are equally applicable, preferably 10 to 20 ℃.

Preferably, the cooling crystallization time is 1 to 5 hours, for example 1 hour, 2 hours, 3 hours, 4 hours or 5 hours, but not limited to the recited values, and other values not recited in the numerical range are equally applicable, preferably 2 to 4 hours.

Preferably, the solid-liquid separation method comprises suction filtration and/or centrifugal separation.

Preferably, the method of drying comprises vacuum drying.

Preferably, the extract containing artemisinin is an extract containing artemisinin prepared by the following method, which comprises the following steps:

(a) extracting Artemisia annua leaves with extractant under reflux to obtain extract containing artemisinin;

(b) concentrating the extract containing artemisinin obtained in step (a) to obtain extract;

(c) mixing an extracting agent with the extract obtained in the step (b), extracting the extract, and performing solid-liquid separation after extraction to obtain an extraction liquid containing artemisinin.

The extract containing artemisinin extracted by the method has artemisinin concentration of 0.005-0.2g/mL, such as 0.005g/mL, 0.01g/mL, 0.05g/mL, 0.1g/mL, 0.15g/mL or 0.2g/mL, but is not limited to the recited values, and other values in the range are also applicable.

Preferably, the leaching agent of step (a) comprises any one or a combination of at least two of petroleum ether, isohexane, ethyl acetate, diethyl ether or toluene; typical but non-limiting combinations include combinations of petroleum ether and isohexane, isohexane and ethyl acetate, ethyl acetate and diethyl ether, diethyl ether and toluene, petroleum ether, isohexane and ethyl acetate, isohexane, ethyl acetate and diethyl ether, ethyl acetate, diethyl ether and toluene, petroleum ether, isohexane, ethyl acetate and diethyl ether, isohexane, ethyl acetate, diethyl ether and toluene, or petroleum ether, isohexane, ethyl acetate, diethyl ether and toluene.

Preferably, the reflux extraction of step (a) is performed 1 to 3 times, for example, 1, 2 or 3 times.

Preferably, the liquid-to-solid ratio of the leaching agent to the artemisia annua leaves in the step (a) is (3-20):1, and for example, can be 3:1, 5:1, 7:1, 8:1, 10:1, 12:1, 15:1, 16:1, 18:1 or 20:1, but is not limited to the enumerated values, and other unrecited values in the range of values are equally applicable, in mL/g.

The liquid-solid ratio of the leaching agent to the artemisia annua leaves is the liquid-solid ratio of each reflux extraction.

Preferably, the reflux extraction temperature of step (a) is 30-60 ℃, for example 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃ or 60 ℃, but not limited to the recited values, and other values not recited in the range of values are equally applicable; the time of single reflux extraction is 30-120min, such as 30min, 40min, 50min, 60min, 70min, 80min, 90min, 100min, 110min or 120min, but not limited to the values listed, and other values not listed in the range of values are also applicable.

Preferably, the concentration in step (b) is carried out at a temperature of 40-60 ℃, for example 40 ℃, 45 ℃, 50 ℃, 55 ℃ or 60 ℃, but not limited to the values recited, and other values not recited within the range of values are equally applicable.

Preferably, the extractant in step (c) comprises 5-95% methanol aqueous solution by volume concentration and/or 5-95% ethanol aqueous solution by volume concentration.

The volume concentration of methanol in the aqueous methanol solution of the present invention is 40 to 95%, for example, 40%, 50%, 60%, 70%, 80%, 90% or 95%, but not limited to the recited values, and other values not recited in the numerical range are also applicable; the concentration of ethanol in the aqueous ethanol solution of the present invention is 40 to 95% by volume, and may be, for example, 40%, 50%, 60%, 70%, 80%, 90% or 95%, but is not limited to the recited values, and other values not recited in the numerical ranges are also applicable.

Preferably, the number of extractions of step (c) is 1-3, and may be, for example, 1, 2 or 3.

Preferably, the liquid-solid ratio of the extractant to the extract in step (c) is (1-20):1, and may be, for example, 1:1, 3:1, 5:1, 10:1, 13:1, 15:1, 18:1 or 20:1, but is not limited to the enumerated values, and other unrecited values within the numerical range are also applicable, and the unit of the liquid-solid ratio is mL/g.

The liquid-solid ratio of the extracting agent to the extract is the liquid-solid ratio of each extraction.

Preferably, the temperature of the extraction in step (c) is 40-60 ℃, for example 40 ℃, 45 ℃, 50 ℃, 55 ℃ or 60 ℃, but not limited to the recited values, and other values not recited in the numerical range are equally applicable; the time for a single extraction is 10-60min, for example 10min, 20min, 30min, 40min, 50min or 60min, but is not limited to the values listed, and other values not listed in the range of values are equally applicable.

As a preferable technical solution of the application of the third aspect of the present invention, the application includes the steps of:

mixing the polyion liquid inhibitor and the extract containing the artemisinin according to a mass ratio of (0.01-0.2) 1, wherein the mixing is mechanically stirring for 30-120min at the temperature of 30-60 ℃, then sequentially cooling and crystallizing for 1-5h at the temperature of 5-30 ℃, and performing suction filtration and vacuum drying to obtain an artemisinin product;

the extraction liquid containing artemisinin is prepared by the following method, and the method comprises the following steps:

(a) extracting Artemisia annua leaves with lixiviant under reflux for 1-3 times, wherein the liquid-solid ratio of single reflux extraction is (3-20):1, the temperature of single reflux extraction is 30-60 ℃, the time of single reflux extraction is 30-120min, and the unit of the liquid-solid ratio is mL/g, to obtain leaching liquor containing artemisinin; the lixiviant comprises any one or combination of at least two of petroleum ether, isohexane, ethyl acetate, diethyl ether or toluene;

(b) concentrating the extract containing artemisinin obtained in step (a) at 40-60 deg.C to obtain extract;

(c) mixing an extracting agent with the extract obtained in the step (b), extracting the extract for 1-3 times, wherein the liquid-solid ratio of the extracting agent to the extract used in single extraction is (1-20):1, the temperature of the single extraction is 40-60 ℃, the time of the single extraction is 10-60min, the unit of the liquid-solid ratio is mL/g, and after the extraction is finished, carrying out solid-liquid separation to obtain an extraction liquid containing artemisinin; the extractant comprises 40-95% methanol water solution and/or 40-95% ethanol water solution.

The recitation of numerical ranges herein includes not only the above-recited values, but also any values between any of the above-recited numerical ranges not recited, and for brevity and clarity, is not intended to be exhaustive of the specific values encompassed within the range.

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

(1) the preparation method of the polyion liquid inhibitor provided by the invention is simple, and the obtained polyion liquid inhibitor is an environment-friendly medium; when the obtained polyion liquid inhibitor is used for separating and purifying artemisinin, the polyion liquid inhibitor can be repeatedly utilized, so that the cost of separating and purifying artemisinin is reduced;

(2) the polyion liquid inhibitor provided by the invention can enable artemisinin to be separated out independently in the crystallization process by reducing the freezing point of wax oil in the artemisinin extraction liquid, thereby ensuring the purity of an artemisinin product and enabling the purity of the obtained artemisinin product to be more than or equal to 99%.

Detailed Description

The technical solution of the present invention is further explained by the following embodiments.

Example 1

The embodiment provides an application of separating and purifying artemisinin by utilizing a polyion liquid inhibitor, wherein the polyion liquid inhibitor is prepared by adopting the following method:

(1) mixing N-vinyl imidazole and 1-bromo-octadecane according to the molar ratio of 1:1, and reacting for 25 hours at 65 ℃ to obtain 1-vinyl-3-octadecyl imidazole bromide;

(2) and (2) mixing dodecyl acrylate, azobisisobutyronitrile and the 1-vinyl-3-octadecyl imidazole bromide obtained in the step (1) according to a molar ratio of 6:0.05:1, and carrying out polymerization reaction for 3 hours in a nitrogen atmosphere at the temperature of 75 ℃ to obtain the poly ionic liquid inhibitor, namely the dodecyl polyacrylate-1-vinyl-3-octadecyl imidazole bromide.

The application comprises the following steps:

mixing the polyion liquid inhibitor and the extract containing artemisinin according to the mass ratio of 0.05:1, wherein the mixing is mechanically stirring for 90min at 50 ℃, then sequentially cooling and crystallizing for 3h at 15 ℃, filtering and vacuum drying to obtain an artemisinin product;

(a) extracting Artemisia annua leaves by petroleum ether reflux for 3 times, wherein the liquid-solid ratio of single reflux extraction is 12:1, the temperature of single reflux extraction is 45 ℃, the time of single reflux extraction is 70min, and the unit of the liquid-solid ratio is mL/g, so as to obtain extract containing artemisinin;

(b) concentrating the extract containing artemisinin obtained in step (a) at 50 deg.C to obtain extract;

(c) and (c) mixing a methanol aqueous solution with the volume concentration of 50% with the extract obtained in the step (b), extracting the extract for 3 times, wherein the liquid-solid ratio of the methanol aqueous solution used in single extraction to the extract is 20:1, the temperature of the single extraction is 50 ℃, the time of the single extraction is 40min, the unit of the liquid-solid ratio is mL/g, and performing solid-liquid separation after the extraction is finished to obtain an extraction liquid containing artemisinin.

Example 2

(1) mixing N-vinyl imidazole and 1-bromotetradecane according to the molar ratio of 1:0.9, and reacting at 60 ℃ for 32 hours to obtain 1-vinyl-3-tetradecyl imidazole bromide;

(2) and (2) mixing tetradecyl acrylate, azobisisobutyronitrile and the 1-vinyl-3-tetradecyl imidazole bromide obtained in the step (1) according to a molar ratio of 3:0.03:1, and carrying out polymerization reaction for 5 hours in a helium atmosphere at the temperature of 60 ℃ to obtain the poly (tetradecyl acrylate) -1-vinyl-3-tetradecyl imidazole bromide serving as the polyion liquid inhibitor.

The application comprises the following steps:

mixing the polyion liquid inhibitor and the extract containing artemisinin according to the mass ratio of 0.03:1, wherein the mixing is mechanically stirring for 105min at the temperature of 45 ℃, then sequentially cooling and crystallizing for 2h at the temperature of 10 ℃, and carrying out centrifugal separation and vacuum drying to obtain an artemisinin product;

(a) extracting Artemisia annua leaves with ethyl acetate under reflux for 3 times, wherein the liquid-solid ratio of single reflux extraction is 6:1, the temperature of single reflux extraction is 40 ℃, the time of single reflux extraction is 90min, and the unit of the liquid-solid ratio is mL/g, so as to obtain extract containing artemisinin;

(b) concentrating the extract containing artemisinin obtained in step (a) at 55 deg.C to obtain extract;

(c) and (c) mixing a 70% methanol aqueous solution with the extract obtained in the step (b), extracting the extract for 3 times, wherein the liquid-solid ratio of the methanol aqueous solution used in single extraction to the extract is 10:1, the temperature of the single extraction is 45 ℃, the time of the single extraction is 50min, the unit of the liquid-solid ratio is mL/g, and performing solid-liquid separation after the extraction is finished to obtain an extraction liquid containing artemisinin.

Example 3

(1) mixing N-vinyl imidazole and 1-bromodecane according to the molar ratio of 1:1.1, and reacting at 70 ℃ for 12 hours to obtain 1-vinyl-3-decylimidazole bromide;

(2) mixing cetyl acrylate, azodiisobutyronitrile and the 1-vinyl-3-decylimidazole bromide obtained in the step (1) according to a molar ratio of 9:0.08:1, and carrying out polymerization reaction for 2h in an argon atmosphere at the temperature of 90 ℃ to obtain the poly-ionic liquid inhibitor poly-cetyl acrylate-1-vinyl-3-decylimidazole bromide.

The application comprises the following steps:

mixing polyion liquid inhibitor and extract containing artemisinin according to the mass ratio of 0.07: 1; the mixing is mechanically stirring for 75min at 55 ℃, then sequentially cooling and crystallizing for 4h at 20 ℃, filtering and vacuum drying to obtain an artemisinin product;

(a) extracting Artemisia annua leaves with diethyl ether under reflux for 3 times, wherein the liquid-solid ratio of single reflux extraction is 16:1, the temperature of single reflux extraction is 50 ℃, the time of single reflux extraction is 50min, and the unit of the liquid-solid ratio is mL/g, to obtain extract containing artemisinin;

(b) concentrating the extract containing artemisinin obtained in step (a) at 45 ℃ to obtain extract;

(c) mixing an ethanol aqueous solution with the volume concentration of 80% with the extract obtained in the step (b), extracting the extract for 3 times, wherein the liquid-solid ratio of the methanol aqueous solution used in single extraction to the extract is 5:1, the temperature of the single extraction is 55 ℃, the time of the single extraction is 30min, the unit of the liquid-solid ratio is mL/g, and carrying out solid-liquid separation after the extraction is finished to obtain an extraction liquid containing artemisinin.

Example 4

(1) mixing N-vinyl imidazole and 1-bromo-octadecane according to the molar ratio of 1:0.8, and reacting for 48 hours at 55 ℃ to obtain 1-vinyl-3-octadecyl imidazole bromide;

(2) mixing octadecyl acrylate, azobisisobutyronitrile and the 1-vinyl-3-octadecyl imidazole bromide obtained in the step (1) according to the molar ratio of 1:0.01:1, and carrying out polymerization reaction for 1h in a nitrogen atmosphere at the temperature of 100 ℃ to obtain the poly-ionic liquid inhibitor poly-octadecyl acrylate-1-vinyl-3-octadecyl imidazole bromide.

The application comprises the following steps:

mixing the polyion liquid inhibitor and the extract containing artemisinin according to the mass ratio of 0.01: 1; the mixing is mechanically stirring for 120min at 30 ℃, then sequentially cooling and crystallizing for 1h at 5 ℃, filtering and vacuum drying to obtain an artemisinin product;

(a) extracting Artemisia annua leaves with isohexane under reflux for 2 times, wherein the liquid-solid ratio of single reflux extraction is 20:1, the temperature of single reflux extraction is 30 deg.C, and the time of single reflux extraction is 120min, and the unit of the liquid-solid ratio is mL/g, to obtain extract containing artemisinin;

(b) concentrating the extract containing artemisinin obtained in step (a) at 60 deg.C to obtain extract;

(c) and (c) mixing a 40% methanol aqueous solution with the extract obtained in the step (b), extracting the extract for 3 times, wherein the liquid-solid ratio of the methanol aqueous solution used in single extraction to the extract is 15:1, the temperature of the single extraction is 60 ℃, the time of the single extraction is 10min, the unit of the liquid-solid ratio is mL/g, and performing solid-liquid separation after the extraction is finished to obtain an extraction liquid containing artemisinin.

Example 5

(1) mixing N-vinyl imidazole and 1-bromohexadecane according to the molar ratio of 1:1.2, and reacting for 2h at 75 ℃ to obtain 1-vinyl-3-hexadecyl imidazole bromide;

(2) mixing octadecyl acrylate, azobisisobutyronitrile and the 1-vinyl-3-hexadecyl imidazole bromide obtained in the step (1) according to a molar ratio of 12:0.1:1, and carrying out polymerization reaction for 6 hours in a neon atmosphere at the temperature of 50 ℃ to obtain the poly-ionic liquid inhibitor poly-octadecyl acrylate-1-vinyl-3-hexadecyl imidazole bromide.

The application comprises the following steps:

mixing the polyion liquid inhibitor and the extract containing artemisinin according to the mass ratio of 0.2:1, wherein the mixing is that mechanical stirring is carried out for 60min at the temperature of 60 ℃, then cooling crystallization is carried out for 5h at the temperature of 30 ℃, centrifugal separation and vacuum drying are carried out in sequence, and an artemisinin product is obtained;

(a) extracting Artemisia annua leaves by toluene reflux for 1 time, wherein the liquid-solid ratio of single reflux extraction is 3:1, the temperature of single reflux extraction is 60 ℃, the time of single reflux extraction is 30min, and the unit of the liquid-solid ratio is mL/g, so as to obtain extract containing artemisinin;

(b) concentrating the extract containing artemisinin obtained in step (a) at 40 deg.C to obtain extract;

(c) and (c) mixing a methanol aqueous solution with a volume concentration of 95% with the extract obtained in the step (b), extracting the extract for 1 time, wherein the liquid-solid ratio of the methanol aqueous solution used in single extraction to the extract is 1:1, the temperature of the single extraction is 40 ℃, the time of the single extraction is 60min, the unit of the liquid-solid ratio is mL/g, and performing solid-liquid separation after the extraction is finished to obtain an extraction liquid containing artemisinin.

Example 6

(1) mixing N-vinyl imidazole and 1-bromododecane according to the molar ratio of 1:1, and reacting at 65 ℃ for 25 hours to obtain 1-vinyl-3-dodecyl imidazole bromide;

(2) and (2) mixing decyl acrylate, azodiisobutyronitrile and the 1-vinyl-3-dodecyl imidazole bromide obtained in the step (1) according to a molar ratio of 6:0.06:1, and carrying out polymerization reaction for 3 hours in a nitrogen atmosphere at the temperature of 75 ℃ to obtain the polysebacate-1-vinyl-3-dodecyl imidazole bromide serving as the polyion liquid inhibitor.

The application comprises the following steps:

(a) extracting Artemisia annua leaves with diethyl ether under reflux for 3 times, wherein the liquid-solid ratio of the three times of reflux extraction is 8:1, 6:1 and 6:1 respectively, the temperature of the single reflux extraction is 45 ℃, the time of the single reflux extraction is 70min, and the unit of the liquid-solid ratio is mL/g, so as to obtain extract containing artemisinin;

(c) and (c) mixing a methanol aqueous solution with the volume concentration of 80% with the extract obtained in the step (b), extracting the extract for 3 times, wherein the liquid-solid ratio of the methanol aqueous solution used in single extraction to the extract is 7:1, the temperature of the single extraction is 50 ℃, the time of the single extraction is 40min, the unit of the liquid-solid ratio is mL/g, and performing solid-liquid separation after the extraction is finished to obtain an extraction liquid containing artemisinin.

Example 7

(1) mixing N-vinyl imidazole and 1-bromohexadecane according to the molar ratio of 1:1, and reacting for 25 hours at 65 ℃ to obtain 1-vinyl-3-hexadecyl imidazole bromide;

(2) and (2) mixing tetradecyl acrylate, azobisisobutyronitrile and the 1-vinyl-3-hexadecyl imidazole bromide obtained in the step (1) according to a molar ratio of 6:0.06:1, and carrying out polymerization reaction for 3 hours in a nitrogen atmosphere at 75 ℃ to obtain the poly-ionic liquid inhibitor namely the poly-tetradecyl acrylate-1-vinyl-3-hexadecyl imidazole bromide.

The application comprises the following steps:

(a) extracting Artemisia annua leaves by petroleum ether under reflux for 3 times, wherein the liquid-solid ratio of the three reflux extractions is 3:1, 12:1 and 20:1 respectively, the temperature of the single reflux extraction is 45 ℃, the time of the single reflux extraction is 70min, and the unit of the liquid-solid ratio is mL/g, so as to obtain a leaching solution containing artemisinin;

Example 8

(2) and (2) mixing dodecyl acrylate, azobisisobutyronitrile and the 1-vinyl-3-hexadecylimidazole bromide obtained in the step (1) according to a molar ratio of 6:0.06:1, and carrying out polymerization reaction for 3 hours in a nitrogen atmosphere at the temperature of 75 ℃ to obtain the poly ionic liquid inhibitor, namely the dodecyl polyacrylate-1-vinyl-3-hexadecylimidazole bromide.

The application comprises the following steps:

(a) extracting Artemisia annua leaves with ethyl acetate under reflux for 3 times, wherein the liquid-solid ratio of the three times of reflux extraction is 6:1, 6:1 and 12:1 respectively, the temperature of the single reflux extraction is 45 ℃, the time of the single reflux extraction is 70min, and the unit of the liquid-solid ratio is mL/g, so as to obtain extract containing artemisinin;

Example 9

(1) mixing N-vinyl imidazole and 1-bromotetradecane according to the molar ratio of 1:1, and reacting at 65 ℃ for 25 hours to obtain 1-vinyl-3-tetradecyl imidazole bromide;

(2) mixing octadecyl acrylate, azobisisobutyronitrile and the 1-vinyl-3-tetradecyl imidazole bromide obtained in the step (1) according to a molar ratio of 6:0.06:1, and carrying out polymerization reaction for 3 hours in a nitrogen atmosphere at 75 ℃ to obtain the poly-ionic liquid inhibitor poly-octadecyl acrylate-1-vinyl-3-tetradecyl imidazole bromide.

The application comprises the following steps:

(a) extracting Artemisia annua leaves with diethyl ether under reflux for 3 times, wherein the liquid-solid ratio of the three reflux extractions is 12:1, 16:1 and 12:1 respectively, the temperature of each reflux extraction is 45 ℃, the time of each reflux extraction is 70min, and the unit of the liquid-solid ratio is mL/g, so as to obtain extract containing artemisinin;

(c) mixing an ethanol aqueous solution with the volume concentration of 80% with the extract obtained in the step (b), extracting the extract for 3 times, wherein the liquid-solid ratio of the methanol aqueous solution used in single extraction to the extract is 10:1, the temperature of the single extraction is 50 ℃, the time of the single extraction is 40min, the unit of the liquid-solid ratio is mL/g, and carrying out solid-liquid separation after the extraction is finished to obtain an extraction liquid containing artemisinin.

Example 10

(2) and (2) mixing tetradecyl acrylate, azobisisobutyronitrile and the 1-vinyl-3-octadecyl imidazole bromide obtained in the step (1) according to a molar ratio of 6:0.06:1, and carrying out polymerization reaction for 3h in a nitrogen atmosphere at the temperature of 75 ℃ to obtain the poly-ionic liquid inhibitor, namely the poly-tetradecyl acrylate-1-vinyl-3-octadecyl imidazole bromide.

The application comprises the following steps:

(c) and (c) mixing a methanol aqueous solution with the volume concentration of 80% with the extract obtained in the step (b), extracting the extract for 3 times, wherein the liquid-solid ratio of the methanol aqueous solution used in single extraction to the extract is 4:1, the temperature of the single extraction is 50 ℃, the time of the single extraction is 40min, the unit of the liquid-solid ratio is mL/g, and performing solid-liquid separation after the extraction is finished to obtain an extraction liquid containing artemisinin.

Example 11

(2) mixing cetyl acrylate, azodiisobutyronitrile and the 1-vinyl-3-dodecyl imidazole bromide obtained in the step (1) according to the molar ratio of 6:0.06:1, and carrying out polymerization reaction for 3 hours in a nitrogen atmosphere at the temperature of 75 ℃ to obtain the poly ionic liquid inhibitor poly (cetyl acrylate) -1-vinyl-3-dodecyl imidazole bromide.

The application comprises the following steps:

(a) extracting Artemisia annua leaves by petroleum ether under reflux for 3 times, wherein the liquid-solid ratio of the three reflux extractions is 8:1, 6:1 and 6:1 respectively, the temperature of the single reflux extraction is 45 ℃, the time of the single reflux extraction is 70min, and the unit of the liquid-solid ratio is mL/g, so as to obtain extract containing artemisinin;

(c) mixing an ethanol aqueous solution with the volume concentration of 80% with the extract obtained in the step (b), extracting the extract for 3 times, wherein the liquid-solid ratio of the methanol aqueous solution used in single extraction to the extract is 7:1, the temperature of the single extraction is 50 ℃, the time of the single extraction is 40min, the unit of the liquid-solid ratio is mL/g, and carrying out solid-liquid separation after the extraction is finished to obtain an extraction liquid containing artemisinin.

Example 12

The application comprises the following steps:

(c) and (c) mixing a 50% methanol aqueous solution and the extract obtained in the step (b), extracting the extract for 3 times, wherein the liquid-solid ratio of the methanol aqueous solution and the extract used in single extraction is 10:1, the temperature of the single extraction is 50 ℃, the time of the single extraction is 40min, the unit of the liquid-solid ratio is mL/g, and performing solid-liquid separation after the extraction is finished to obtain an extraction liquid containing artemisinin.

Comparative example 1

This comparative example provides an application of separation and purification of artemisinin by using wax oil inhibitor, which is the same as example 1 except that the polyionic liquid in example 1 is replaced by ethylene-vinyl acetate copolymer of equal mass as compared with example 1. The ethylene-vinyl acetate copolymer is disclosed in CN 109320523 a in example 1.

Comparative example 2

This comparative example provides the use of a polyionic liquid inhibitor for the isolation and purification of artemisinin, which is the same as example 1 except that 1-bromooctadecane is replaced with an equimolar amount of 1-bromoeicosane as compared to example 1.

Comparative example 3

This comparative example provides the use of polyion liquid inhibitor for isolation and purification of artemisinin, which is the same as example 1 except that 1-bromooctadecane is replaced with an equimolar amount of 1-bromooctane as compared to example 1.

Comparative example 4

This comparative example provides the use of polyion liquid inhibitor for isolation and purification of artemisinin, which is the same as example 1 except that lauryl acrylate is replaced with an equimolar amount of behenyl acrylate as compared to example 1.

Comparative example 5

This comparative example provides the use of polyion liquid inhibitor to separate and purify artemisinin, which is the same as example 1 except that lauryl acrylate is replaced with an equimolar amount of octyl acrylate as compared to example 1.

The mass fraction of artemisinin in the artemisinin products obtained in examples 1-12 and comparative examples 1-5 was determined by high performance liquid chromatography, and the artemisinin product obtained by cooling and crystallizing the extract containing artemisinin obtained in example 1 at 15 deg.C for 3h, filtering and vacuum drying was used as a control group, and the results are shown in Table 1.

TABLE 1

In conclusion, the preparation method of the polyion liquid inhibitor provided by the invention is simple, and the obtained polyion liquid inhibitor is an environment-friendly medium; when the obtained polyion liquid inhibitor is used for separating and purifying artemisinin, the polyion liquid inhibitor can be repeatedly utilized, so that the cost of separating and purifying artemisinin is reduced; the polyion liquid inhibitor provided by the invention can enable artemisinin to be separated out independently in the crystallization process by reducing the freezing point of wax oil in the artemisinin extraction liquid, thereby ensuring the purity of an artemisinin product and enabling the purity of the obtained artemisinin product to be more than or equal to 99%.

The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are only exemplary embodiments of the present invention, and are not intended to limit the present invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A preparation method of a polyion liquid inhibitor is characterized by comprising the following steps:

(2) mixing acrylate, an initiator and the 1-vinyl-3-alkyl imidazole bromide obtained in the step (1), and carrying out polymerization reaction in an inert atmosphere to obtain a polyion liquid inhibitor;

the 1-bromoalkane in the step (1) comprises any one or the combination of at least two of 1-bromodecane, 1-bromododecane, 1-bromotetradecane, 1-bromohexadecane or 1-bromooctadecane;

the molar ratio of the N-vinyl imidazole to the 1-bromoalkane is 1 (0.8-1.2);

the molar ratio of the acrylate, the initiator and the 1-vinyl-3-alkyl imidazole bromide obtained in the step (1) is (1-12): 0.01-0.1): 1;

the acrylate in the step (2) comprises any one or the combination of at least two of decyl acrylate, dodecyl acrylate, tetradecyl acrylate, hexadecyl acrylate or octadecyl acrylate.

2. The method according to claim 1, wherein the molar ratio of N-vinylimidazole to 1-bromoalkane is 1 (0.9-1.1).

3. The method according to claim 1, wherein the temperature of the reaction in the step (1) is 55 to 75 ℃.

4. The method according to claim 3, wherein the temperature of the reaction in the step (1) is 60 to 70 ℃.

5. The method according to claim 1, wherein the reaction time in step (1) is 2 to 48 hours.

6. The method according to claim 1, wherein the initiator in step (2) comprises azobisisobutyronitrile.

7. The production method according to claim 1, wherein the inert gas atmosphere of step (2) includes a nitrogen gas atmosphere and/or an inert gas atmosphere.

8. The method according to claim 1, wherein the polymerization in step (2) is carried out at a temperature of 50 to 100 ℃ for 1 to 6 hours.

9. A polyion liquid inhibitor prepared by the preparation method of any one of claims 1 to 8.

10. The use of polyion liquid inhibitor for separating and purifying artemisinin, as claimed in claim 9, comprises the following steps: mixing the polyion liquid inhibitor and the extraction liquid containing the artemisinin, and sequentially cooling, crystallizing, carrying out solid-liquid separation and drying to obtain the artemisinin product.

11. The use according to claim 10, wherein the mass ratio of polyionic liquid inhibitor to extraction liquid is (0.01-0.2): 1.

12. The use according to claim 11, wherein the mass ratio of polyionic liquid inhibitor to extraction liquid is (0.03-0.07): 1.

13. Use according to claim 10, wherein the mixing is mechanical stirring at 30-60 ℃ for 30-120 min.

14. Use according to claim 13, wherein the mixing is by mechanical stirring at 45-55 ℃ for 60-120 min.

15. Use according to claim 10, wherein the temperature of the cooled crystallization is 5-30 ℃.

16. Use according to claim 15, wherein the temperature of the cooling crystallization is 10-20 ℃.

17. Use according to claim 10, wherein the cooling crystallization time is 1-5 h.

18. Use according to claim 17, wherein the cooling crystallization time is 2-4 h.

19. Use according to claim 10, wherein the solid-liquid separation method comprises suction filtration and/or centrifugation.

20. Use according to claim 10, wherein the method of drying comprises vacuum drying.

21. The use of claim 11, wherein the artemisinin-containing extract is an artemisinin-containing extract prepared by a method comprising the steps of:

22. The use of claim 21, wherein the leaching agent of step (a) comprises any one of petroleum ether, isohexane, ethyl acetate, diethyl ether or toluene, or a combination of at least two thereof.

23. The use of claim 21, wherein the reflux extraction of step (a) is performed 1-3 times.

24. The use of claim 21, wherein the liquid-to-solid ratio of the leaching agent to artemisia annua leaves in step (a) is (3-20):1, and the unit of the liquid-to-solid ratio is mL/g.

25. The use of claim 21, wherein the reflux extraction temperature of step (a) is 30-60 ℃ and the time of a single reflux extraction is 30-120 min.

26. The use of claim 21, wherein the temperature of the concentration in step (b) is 40-60 ℃.

27. The use of claim 21, wherein the extractant of step (c) comprises 40-95% by volume aqueous methanol and/or 40-95% by volume aqueous ethanol.

28. Use according to claim 21, wherein the number of extractions of step (c) is 1-3.

29. The use of claim 21, wherein the ratio of the extractant to the extract in step (c) is (1-20):1, and the unit of the ratio is mL/g.

30. The use of claim 21, wherein the temperature of the extraction in step (c) is 40-60 ℃ and the time of a single extraction is 10-60 min.

31. The application of claim 21, wherein the application comprises the steps of: