A method for synthesizing quaternary ammonium lipids

Abstract

The present invention belongs to the field of organic synthesis and discloses a method for synthesizing quaternary ammonium lipids. The method comprises the following steps: mixing a primary alcohol, a tertiary amine, a base, and chloromethylsulfonyl fluoride, and reacting the mixture to produce the quaternary ammonium lipid. The method uses the primary alcohol and the tertiary amine as raw materials, and synthesizes the quaternary ammonium lipid by chloromethylsulfonyl fluoride-mediated dehydroxylation coupling of the primary alcohol and the tertiary amine in the presence of a base. The method avoids the use of environmentally unfriendly organic halides, meeting the requirements of green chemistry. The chloromethylsulfonyl fluoride catalyst used can be easily synthesized using dichloromethane. The raw materials used are inexpensive, readily available, and pollution-free. The reaction conditions are mild, the conversion rate is high, the separation and purification steps are simple, and the product has high purity and a high yield, which is not less than 75%.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing quaternary ammonium lipids. Background Art

[0002] Liposomes are ordered molecular assemblies of phospholipids that spontaneously form in water through hydrophobic association, forming multilamellar vesicles. They possess advantages such as good biocompatibility, low toxicity, and a low immune response. As one of the new drug delivery systems successfully used in clinical practice, liposomes offer promising application prospects and numerous advantages. Compared with traditional dosage forms, their advantages include increasing the solubility of poorly soluble drugs, extending their in vivo half-life, enabling tumor targeting, improving drug pharmacokinetic properties, enhancing drug efficacy, and mitigating adverse reactions. Currently, liposomes are widely used in the pharmaceutical and cosmetic fields.

[0003] Cationic lipids can bind to negatively charged nucleic acids (DNA) and transport them from outside the cell into the nucleus, allowing DNA to be expressed in the nucleus, thereby regulating cell growth. This plays a vital role in research related to life sciences, and also has broad application prospects as a form of "gene therapy." However, there are still difficulties in the clinical application of cationic lipids. Because cationic lipid gene complexes always carry a positive charge on their surface, they are prone to non-specific adsorption with serum proteins in the plasma during blood circulation, forming large aggregates. These aggregates are easily cleared by the reticuloendothelial system, resulting in a short blood circulation time, poor stability, and low operating efficiency. Therefore, high-efficiency and low-toxic cationic lipids are urgently needed to be developed for application in medicine, clinical fields, and other fields.

[0004] The head of cationic lipids mostly contains amine groups, ranging from simple amino groups to quaternary ammonium salts substituted with methyl or hydroxyethyl groups. Currently, the main method for synthesizing quaternary ammonium lipids is still through the Menschutkin reaction, in which tertiary amine compounds react with organic halides to form quaternary ammonium salts. However, most organic halides are toxic, lipophilic, and difficult to metabolize biologically. Therefore, once they enter the body, they easily accumulate and are distributed throughout the body's organs through the blood, causing long-term and complex damage, affecting the normal division of cells, interfering with the activity of biological enzymes, and causing multiple diseases or physiological dysfunctions. In addition, these substances are environmentally persistent and can continuously migrate, transform, accumulate, and enrich in the ecosystem, which can seriously endanger the ecological environment.

[0005] Existing technologies utilize sulfuryl fluoride gas to catalyze the dehydroxylation of primary alcohols and the coupling reaction with amines, achieving the synthesis of ammonium salts. This simple reaction operation and wide substrate range are suitable. However, due to the gas-liquid heterogeneous reaction, this technical solution suffers from drawbacks such as difficult reaction control, long reaction times, and incomplete reactions, making it unsuitable for industrial production.

[0006] In addition, the reaction temperature of the synthesis method of quaternary ammonium lipids in the prior art is relatively high, which is not conducive to the synthesis of long-chain lipids, and the product yield is generally low.

[0007] Therefore, there is an urgent need to provide a new synthesis method of quaternary ammonium lipids, which can not only be carried out at low temperatures, but also is economical and efficient and has a high product yield. Summary of the Invention

[0008] The present invention aims to solve at least one of the technical problems existing in the above-mentioned prior art. To this end, the present invention provides a method for synthesizing a quaternary ammonium lipid. The synthetic method of the present invention avoids the use of environmentally unfriendly organic halides and synthesizes the quaternary ammonium lipid through the dehydroxylation coupling of a primary alcohol and a tertiary amine compound mediated by chloromethylsulfonyl fluoride. The synthetic method of the present invention has mild reaction conditions, simple operation, safety and environmental protection, cheap and readily available raw materials, simple and environmentally friendly post-processing, and high product purity and high yield.

[0009] The inventive concept of the present invention is that the product produced by the present invention is a quaternary ammonium lipid, which is synthesized from primary alcohols and tertiary amines as raw materials through chloromethylsulfonyl fluoride-mediated dehydroxylation coupling of the primary alcohols and tertiary amines in the presence of a base. The synthesis method has mild reaction conditions, simple operation, safety and environmental protection, economic efficiency, easy purification, and high yield (yield of not less than 75%). It can be applied to the synthesis of a series of quaternary ammonium lipids and meets the requirements for large-scale laboratory preparation and industrial production scale-up.

[0010] The present invention provides a method for synthesizing quaternary ammonium lipids.

[0011] Specifically, a method for synthesizing a quaternary ammonium lipid comprises the following steps:

[0012] The primary alcohol, tertiary amine, base and chloromethylsulfonyl fluoride are mixed and reacted to prepare the quaternary ammonium lipid.

[0013] That is, the above synthesis method uses primary alcohol and tertiary amine as raw materials, and synthesizes quaternary ammonium lipids by dehydroxylation coupling of primary alcohol and tertiary amine mediated by chloromethylsulfonyl fluoride in the presence of a base catalyst.

[0014] Preferably, the structural formula of the primary alcohol is R1-OH, and the structural formula of the tertiary amine is wherein R1, R2, R3, and R4 are independently selected from substituted or unsubstituted C1-C 25 Alkyl, C2-C 25 Alkenyl, C2-C 25 Alkynyl, C1-C 25 Cycloalkyl, H, and R1 is not H.

[0015] Preferably, the substituted C1-C 25 Alkyl, C2-C25 Alkenyl, C2-C 25 Alkynyl, C1-C 25 The substituent of cycloalkyl is C1-C 10 Hydrocarbon, C1-C 10 Cycloalkyl, oxymethyl, fluorine, substituted or unsubstituted phosphate.

[0016] Preferably, the C1-C 25 Alkyl, C2-C 25 Alkenyl, C2-C 25 Alkynyl, C1-C 25 The cycloalkyl group may or may not contain other functional groups, and the other functional groups include at least one of an ester group, a carbonyl group, a hydroxyl group, a carboxyl group, and a phosphate group.

[0017] Preferably, R1, R2, R3, and R4 are each or in combination connected to form a 4-10 membered heterocyclic ring, wherein the heterocyclic ring contains 1-6 heteroatoms selected from nitrogen, sulfur, or oxygen. The heterocyclic ring is present as R1, R2, R3, or R4 in a primary alcohol or a tertiary amine.

[0018] Preferably, the structural formula of the quaternary ammonium lipid is Among them, R1, R2, R3, and R4 are consistent with R1 in primary alcohols and R2, R3, and R4 in tertiary amines. - It is a halogen anion or an acid anion.

[0019] Preferably, the quaternary ammonium lipids are selected from

[0020] At least one of .

[0021] Preferably, the base is selected from at least one of N,N-diisopropylethylamine, triethylamine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium acetate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, potassium phosphate, potassium dihydrogen phosphate, and cesium carbonate, and preferably the base is sodium carbonate.

[0022] The synthetic route of the above synthetic method is as follows:

[0023]

[0024] Preferably, the reaction temperature is 10-80°C; further preferably, the reaction temperature is 20-80°C; more preferably, the reaction temperature is 20-25°C.

[0025] Preferably, the reaction time is 4-24 hours, preferably 6-24 hours, more preferably 6-12 hours. The reaction time varies depending on the type of raw materials used.

[0026] Preferably, the molar ratio of the primary alcohol, the tertiary amine, the chloromethylsulfonyl fluoride, and the base is 1:(0.1-6):(0.1-12):(0.1-11); further preferably, the molar ratio of the primary alcohol, the tertiary amine, the chloromethylsulfonyl fluoride, and the base is 1:(0.2-5):(0.2-10):(0.1-10); more preferably, the molar ratio of the primary alcohol, the tertiary amine, the chloromethylsulfonyl fluoride, and the base is 1.5:1:1.5:2.

[0027] Preferably, the reaction is carried out under solvent conditions, that is, each raw material is added to a solvent for reaction.

[0028] Preferably, the solvent is selected from at least one of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, benzene, toluene, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, chlorobenzene, dichloromethane, chloroform, ethylene glycol, and water, and the preferred solvent is chlorobenzene.

[0029] Preferably, after the reaction is completed, an acidification process is further included to adjust the pH of the acidification reaction product to acidic, preferably to 5-6.

[0030] Preferably, after the reaction is completed, the reaction is filtered, the filtrate is collected, acidified, extracted, concentrated, and recrystallized to obtain a high-purity product (quaternary ammonium lipid).

[0031] Preferably, the solvent used for the extraction is at least one of dichloromethane, dichloroethane, chloroform, ethyl acetate, ethyl ether, toluene, n-hexane, and benzene, preferably ethyl acetate.

[0032] Preferably, the solvent used for the recrystallization is at least one of water, N,N-dimethylformamide, chlorobenzene, xylene, toluene, acetonitrile, ethanol, tetrahydrofuran, chloroform, ethyl acetate, glacial acetic acid, carbon tetrachloride, benzene, cyclohexane, butanone, acetone, petroleum ether, diethyl ether, hexamethylphosphoramide, N-methylpyrrolidone, 1,4-dioxane, and ethylene glycol monomethyl ether, preferably toluene.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] (1) The present invention provides a method for synthesizing quaternary ammonium lipids, wherein the quaternary ammonium lipids are synthesized by using primary alcohols and tertiary amines as raw materials in the presence of a base through chloromethylsulfonyl fluoride-mediated dehydroxylation coupling of the primary alcohols and tertiary amines. This synthesis method avoids the use of environmentally unfriendly organic halides and meets the requirements of green chemistry. The chloromethylsulfonyl fluoride catalyst used can be easily synthesized using dichloromethane. The raw materials used are cheap, readily available, and pollution-free. The reaction conditions are mild, the conversion rate is high, the separation and purification steps are simple, the product purity is high, and the yield is high (the yield is not less than 75%).

[0035] (2) The quaternary ammonium lipids prepared by the present invention belong to cationic liposomes. The synthesis method of the present invention can be used to prepare a series of cationic liposomes, which greatly expands the substrate range of cationic liposomes and is expected to discover more efficient, stable and safe cationic liposomes, providing new ideas and methods for the in-depth study of cationic liposomes. DETAILED DESCRIPTION

[0036] In order to make the technical solution of the present invention more clearly understood by those skilled in the art, the following examples are given for illustration. It should be noted that the following examples do not limit the scope of protection claimed by the present invention.

[0037] Unless otherwise specified, the raw materials, reagents, or devices used in the following examples can be obtained from conventional commercial sources or by existing known methods.

[0038] Example 1

[0039] The structural formula is The preparation of quaternary ammonium lipids involves the following reaction equation (only the target product is recorded in the equation):

[0040]

[0041] The synthesis method of the above-mentioned quaternary ammonium lipid comprises the following steps:

[0042] Sodium carbonate (20 mmol), the above-mentioned tertiary amine (10 mmol), chloromethylsulfonyl fluoride (15 mmol), methanol (15 mmol) and chlorobenzene (150 mL) were added to a 500 mL flask, and the reaction was stirred at room temperature of 25°C ("rt" in the above equation represents room temperature of 25°C) for 12 h. Then, hydrochloric acid was added to acidify to pH 5, and then extracted three times with ethyl acetate. The organic phases obtained by the extractions were combined and dried over anhydrous Na2SO4 and concentrated to obtain a crude product. The crude product was dissolved in toluene and recrystallized. The solid product was collected and dried in vacuo to constant weight to obtain 5.45 g of the target product (purity of 98% by mass), and the yield of the target product was 76%.

[0043] The results of H NMR characterization of the quaternary ammonium lipid product prepared in this example are as follows: 1 H NMR (500MHz, CDCl3) δ (ppm) 5.6 (m, 1H); 5.28 (m, 4H); 4.5 (t, 2H); 4.05 (dd, 1H); 3.7 (dd, 1H,); 3.47 (s, 9H); 2.26 (m, 4H); 1.9 (m, 8H); 1.5 (m, 4H); 1.4-1.2 (m, 36H); 0.82 (dt, 6H).

[0044] Example 2

[0045] The structural formula is The preparation of quaternary ammonium lipids involves the following reaction equation (only the target product is recorded in the equation):

[0046]

[0047] The synthesis method of the above-mentioned quaternary ammonium lipid comprises the following steps:

[0048] To a 1000 mL flask were added triethylamine (i.e., Et3N, 200 mmol), the above-mentioned tertiary amine derivative (100 mmol), chloromethylsulfonyl fluoride (150 mmol), methanol (150 mmol), and chlorobenzene (300 mL). The mixture was stirred at room temperature ("rt" in the above equation represents room temperature, 25°C) for 12 h, and then acidified to pH 5.5 by adding hydrochloric acid. The resulting organic phases were then extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous Na2SO4 and concentrated to obtain a crude product. The crude product was dissolved in toluene and recrystallized. The solid product was collected and dried in vacuo to constant weight to obtain 56.5 g of the target product (98% purity by mass). The yield of the target product was 82%.

[0049] The results of H NMR characterization of the quaternary ammonium lipid product prepared in this example are as follows: 1 H NMR (500MHz, CDCl3) δ (ppm) 6.57 (dd, 1H); 6.29 (dd, 1H); 5.73 (dd, 1H); 5.59 (m, 1H); 4.47 (dd, 1H); 4.29 (d, 1H); 4.04 (m, 4H); 3.88 (m 2H); 3.41 (s, 3H); 3.38 (s, 3H); 3.27 (s, 3H); 2.28 (m, 4H); 1.54 (m, 4H); 1.22 (m, 40H); 0.84 (t, 6H).

[0050] Example 3

[0051] The structural formula is The preparation of quaternary ammonium lipids involves the following reaction equation (only the target product is recorded in the equation):

[0052]

[0053] The synthesis method of the above-mentioned quaternary ammonium lipid comprises the following steps:

[0054] Sodium carbonate (20 mmol), the above-mentioned tertiary amine (10 mmol), chloromethylsulfonyl fluoride (15 mmol), methanol (15 mmol) and chlorobenzene (150 mL) were added to a 500 mL flask. The reaction was stirred at 40° C. for 12 h, and then hydrochloric acid was added to acidify to pH 6. The mixture was extracted three times with ethyl acetate. The resulting organic phases were combined and dried over anhydrous Na2SO4. The crude product was concentrated to obtain a crude product, which was dissolved in toluene and recrystallized. The solid product was collected and dried in vacuo to constant weight to obtain 6.0 g of the target product (purity 99% by mass). The yield of the target product was 89%.

[0055] The results of H NMR characterization of the quaternary ammonium lipid product prepared in this example are as follows: 1 H NMR (500MHz, CDCl3) δ (ppm) 5.34 (m, 4H); 4.06-3.52 (m, 7H); 3.50-3.33 (m, 10H) ;2.08-1.90(m,8H);1.75(m,2H);1.52(m,8H);1.45-1.16(m,50H);0.85(t,6H).

[0056] Example 4

[0057] The structural formula is The preparation of quaternary ammonium lipids involves the following reaction equation (only the target product is recorded in the equation):

[0058]

[0059] The synthesis method of the above-mentioned quaternary ammonium lipid comprises the following steps:

[0060] Sodium carbonate (20 mmol), the above-mentioned tertiary amine (10 mmol), chloromethylsulfonyl fluoride (15 mmol), 4-hydroxymethylbenzoic acid (15 mmol) and chlorobenzene (150 mL) were added to a 500 mL flask. The reaction was stirred at room temperature ("rt" in the above equation represents room temperature 25°C) for 36 h, and then extracted three times with dichloromethane. The resulting organic phases were combined and dried over anhydrous Na2SO4 and concentrated to obtain a crude product. The crude product was dissolved in toluene and recrystallized. The solid product was collected and dried in vacuo to constant weight to obtain 6.25 g of the target product (purity 99% by mass), and the yield of the target product was 80%.

[0061] The results of H NMR characterization of the quaternary ammonium lipid product prepared in this example are as follows: 1 H NMR (500MHz, CDCl3) δ (ppm) 8.10 (m, 2H); δ 7.70 (m, 2H); δ 5.60 (m, 1H); δ 5.30 (m, 4H); δ 4.80 (m, 2H); δ 4.30 (m, 2H); δ 3. 90(m,2H); δ3.3(s,3H); δ3.20(s,3H); δ2.30(m,4H); δ2.04(m,8H); δ1.62(m,4H); δ1.20-1.50(m,40H); δ0.90(t,6H).

[0062] Example 5

[0063] The structural formula is The preparation of quaternary ammonium lipids involves the following reaction equation (only the target product is recorded in the equation):

[0064]

[0065] The synthesis method of the above-mentioned quaternary ammonium lipid comprises the following steps:

[0066] Sodium carbonate (200 mmol), the above-mentioned tertiary amine (100 mmol), chloromethylsulfonyl fluoride (150 mmol), alcohol (150 mmol) and chlorobenzene (300 mL) were added to a 1000 mL flask. The reaction was stirred at room temperature ("rt" in the above equation represents room temperature, 25°C) for 12 h. The reaction solution was acidified with bromic acid to pH 6 and extracted three times with ethyl acetate. The resulting organic phases were combined and dried over anhydrous Na2SO4. The crude product was dissolved in toluene and recrystallized. The solid product was collected and dried in vacuo to constant weight to obtain 65.1 g of the target product (purity: 99% by mass). The yield of the target product was 80%.

[0067] The results of H NMR characterization of the quaternary ammonium lipid product prepared in this example are as follows: 1 H NMR (500MHz, CDCl3) δ (ppm) 9.76 (t, 1H); 5.35 (m, 4H); 4.06-3.52 (m, 7H); 3.50-3.32 (m, 10H); 2.44(dt,2H); 2.07-1.90(m,8H); 1.75(m,2H); 1.54(m,6H); 1.43-1.17(m,50H); 0.87(t,6H).

[0068] Comparative Example 1

[0069] The structural formula is The preparation of quaternary ammonium lipids involves the following reaction equation (only the target product is recorded in the equation):

[0070]

[0071] The synthesis method of the above-mentioned quaternary ammonium lipid comprises the following steps:

[0072] Sodium carbonate (20 mmol), the above-mentioned tertiary amine (10 mmol), bromomethylsulfonyl fluoride (5 mmol), methanol (15 mmol) and chlorobenzene (150 mL) were added to a 500 mL flask, and the reaction was stirred at room temperature of 25° C. (“rt” in the above equation represents room temperature of 25° C.) for 12 h. Then, hydrochloric acid was added to acidify to pH 5, and then extracted three times with ethyl acetate. The organic phases obtained by the combined extractions were dried over anhydrous Na2SO4 and concentrated to obtain a crude product. The crude product was dissolved in toluene and recrystallized. The solid product was collected and dried in vacuo to constant weight to obtain 1.68 g of the target product (purity of 98% by mass), and the yield of the target product was 23%.

[0073] The nuclear magnetic resonance hydrogen spectrum characterization results of the quaternary ammonium lipid product prepared in this comparative example are: 1 H NMR (500MHz, CDCl3) δ (ppm) 5.6 (m, 1H); 5.28 (m, 4H); 4.5 (t, 2H); 4.05 (dd, 1H); 3.7 (dd, 1H,); 3.47 (s, 9H); 2.26 (m, 4H); 1.9 (m, 8H); 1.5 (m, 4H); 1.4-1.2 (m, 36H); 0.82 (dt, 6H).

[0074] Comparative Example 2

[0075] The structural formula is The preparation of quaternary ammonium lipids involves the following reaction equation (only the target product is recorded in the equation):

[0076]

[0077] The synthesis method of the above-mentioned quaternary ammonium lipid comprises the following steps:

[0078] Sodium carbonate (20 mmol), the above-mentioned tertiary amine (10 mmol), methanol (15 mmol) and chlorobenzene (150 mL) were added to a 500 mL flask, and sulfuryl fluoride gas (15 mmol) was introduced. The reaction was stirred at room temperature of 25° C. (“rt” in the above equation represents room temperature of 25° C.) for 12 h, and then hydrochloric acid was added to acidify to pH 5. The organic phases were then extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous Na2SO4 and concentrated to obtain a crude product. The crude product was dissolved in toluene and recrystallized. The solid product was collected and dried in vacuo to constant weight to obtain 1.1 g of the target product (purity of 98% by mass), and the yield of the target product was 16%.

[0079] The nuclear magnetic resonance hydrogen spectrum characterization results of the quaternary ammonium lipid product prepared in this comparative example are: 1 H NMR (500MHz, CDCl3) δ (ppm) 5.6 (m, 1H); 5.28 (m, 4H); 4.5 (t, 2H); 4.05 (dd, 1H); 3.7 (dd, 1H,); 3.47 (s, 9H); 2.26 (m, 4H); 1.9 (m, 8H); 1.5 (m, 4H); 1.4-1.2 (m, 36H); 0.82 (dt, 6H).

[0080] It can be seen from the results of the above examples that the yield of quaternary ammonium lipids prepared under the synthesis conditions of the present invention is significantly higher than that under the conditions of the comparative example.

Claims

1. A method for synthesizing a quaternary ammonium lipid, characterized in that: The following steps are involved: Mixing a primary alcohol, a tertiary amine, a base, and chloromethylsulfonyl fluoride, and reacting the mixture to prepare the quaternary ammonium lipid; The structural formula of the primary alcohol is The structural formula of tertiary amine is ; wherein R2, R3, R4 are independently selected from substituted or unsubstituted C1-C 25 Alkyl, C2-C 25 Alkenyl, C2-C 25 Alkynyl, C1-C 25 Cycloalkyl, H; R1 is selected from substituted or unsubstituted C1-C 25 Alkyl, C2-C 25 Alkenyl, C2-C 25 Alkynyl, C1-C 25 Cycloalkyl; The substituted C1-C 25 Alkyl, C2-C 25 Alkenyl, C2-C 25 Alkynyl, C1-C 25 The substituent of cycloalkyl is C1-C 10 Hydrocarbon, C1-C 10 Cycloalkyl, oxymethyl, fluorine, substituted or unsubstituted phosphate; The base is at least one selected from N,N-diisopropylethylamine, triethylamine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium acetate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, potassium phosphate, potassium dihydrogen phosphate, and cesium carbonate; The structural formula of the quaternary ammonium lipid is , where R1, R2, R3, and R4 are consistent with R1 in primary alcohol and R2, R3, and R4 in tertiary amine, A - It is a halogen anion; The reaction is carried out under solvent conditions, and the solvent is selected from at least one of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, benzene, toluene, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, chlorobenzene, dichloromethane, chloroform, ethylene glycol, and water; After the reaction is completed, the process of adding acid for acidification is also included.

2. The synthesis method according to claim 1, wherein The reaction temperature is 10-80°C.

3. The synthesis method according to claim 2, characterized in that The molar ratio of the primary alcohol, the tertiary amine, the chloromethylsulfonyl fluoride and the base is 1:(0.1-6):(0.1-12):(0.1-11).

4. The synthesis method according to claim 3, characterized in that After the reaction is completed, the reaction is filtered, the filtrate is collected, acidified, extracted, concentrated, and recrystallized to obtain the quaternary ammonium lipid.

5. The synthesis method according to claim 4, characterized in that The solvent used for the extraction is at least one of dichloromethane, dichloroethane, chloroform, ethyl acetate, ether, toluene, n-hexane, and benzene; the solvent used for the recrystallization is at least one of water, N,N-dimethylformamide, chlorobenzene, xylene, toluene, acetonitrile, ethanol, tetrahydrofuran, chloroform, ethyl acetate, glacial acetic acid, carbon tetrachloride, benzene, cyclohexane, butanone, acetone, petroleum ether, ether, hexamethylphosphoramide, N-methylpyrrolidone, 1,4-dioxane, and ethylene glycol monomethyl ether.

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