Preparation method of entecavir intermediate

Abstract

The invention provides a preparation method of an entecavir intermediate. According to the invention, the double acidic ionic liquid is used as the catalyst for synthesizing the entecavir intermediate 4-methoxyphenyl diphenyl chloromethane for the first time, which accords with the development trend of green chemistry. The catalyst is simple and easy to obtain, the post-treatment process is simple, complex post-treatment operation is not needed, and the operation cost is saved. In addition, the entecavir intermediate prepared by the preparation method is high in yield and purity, and industrial production is facilitated.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and in particular to a method for preparing an entecavir intermediate. Background Art

[0002] Entecavir is a guanine nucleoside analogue developed by Bristol-Myers Squibb and first launched in the United States in 2005. It can inhibit the replication of hepatitis B virus and reduce the DNA level of serum virus. It has the characteristics of rapid onset, strong ability to resist viruses and low drug resistance. It has been used as a first-line antiviral drug for the treatment of hepatitis B. Among the current reports on the synthesis process of entecavir, the original research process of Bristol-Myers Squibb is the process that has been industrialized well. The raw materials and reagents used in this process are relatively simple and easy to obtain. The starting raw material cyclopentadiene is made into sodium cyclopentadiene and then alkylated, asymmetric hydroboration-oxidation, epoxidation, protection, substitution, and ring opening to obtain an alcohol intermediate. Then, the alcohol intermediate is alkylated with 4-methoxyphenyl diphenylmethane, Dess-Martin oxidation and methylenation, and finally deprotected to obtain entecavir. Therefore, the compound 4-methoxyphenyl diphenylmethane is an important intermediate for the synthesis of entecavir.

[0003] The prior art literature reports that the synthesis of the compound 4-methoxyphenyl diphenyl methyl chloride mainly includes the following methods: The first method uses p-bromoanisole as a raw material, first prepares a magnesium bromide Grignard reagent, then reacts it with benzophenone to produce a benzyl alcohol intermediate, and then uses acetyl chloride, thionyl chloride or hydrogen chloride as a chlorination reagent to produce a chlorination reaction of the hydroxyl group to synthesize the compound of formula (I). The synthetic route is:

[0004] Because the first and second steps of the process require the preparation of Grignard reagents and the occurrence of Grignard reactions, the water requirements are very high; the use of chlorination reagents such as acetyl chloride in the third step of the chlorination reaction will produce a large amount of hydrochloric acid, which will not only corrode equipment but also pollute the environment; in addition, if acetyl chloride is used as a chlorination reagent, hydroxyl acetylated impurities that are difficult to handle will also be generated. Therefore, this process is not easy to industrialize and operate conveniently.

[0005] The second method uses 4-hydroxytriphenylmethanol as the main raw material, and synthesizes the compound of formula (I) through two steps of methylation and chlorination. The synthetic route is:

[0006] In this process, during the methylation reaction, impurities such as methylation of phenolic hydroxyl groups and alcoholic hydroxyl groups are likely to occur. This impurity is similar in structure to the compound of formula (I) and is difficult to remove. Dimethyl sulfate is selected as the methylation reagent in the methylation, which is highly toxic. In addition, the raw material 4-hydroxytriphenylmethanol is expensive and difficult to obtain, which is not conducive to industrial production.

[0007] The third method uses diphenyldichloromethane and anisole as raw materials and synthesizes the compound of formula (I) in one step through Friedel-Crafts reaction. The synthetic route is:

[0008] This process is relatively simple, but the Friedel-Crafts reaction uses AlCl3, which is a very strong catalytic activity, as a catalyst, and the reaction is carried out in a homogeneous phase. In addition to the Friedel-Crafts reaction at the para-position of the methoxy group to generate the compound of formula (I), the Friedel-Crafts reaction at the ortho-position of the methoxy group also generates the ortho-position Friedel-Crafts reaction product, as well as the impurities such as the Friedel-Crafts reaction product generated by the benzene ring of diphenyldichloromethane itself. The various impurities have similar polarity and are difficult to separate and remove from the main product. In addition, after the Friedel-Crafts reaction, the AlCl3 catalyst is washed with water to remove the hydrolysis of the chlorine atom in the molecule of the compound of formula (I). Therefore, after the water treatment is dried, it is necessary to carry out chlorination with a chlorination agent such as acetyl chloride or dichlorothionyl; and the reaction starting raw material diphenyldichloromethane is also not easy to obtain.

[0009] CN112409141 A discloses an improved method of the process, wherein carbon tetrachloride and benzene are subjected to Friedel-Crafts alkylation reaction under the action of catalyst 1 to obtain diphenyl dichloromethane; diphenyl dichloromethane and anisole are subjected to Friedel-Crafts alkylation reaction under the action of catalyst 2 to obtain 4-methoxyphenyl diphenyl dichloromethane. The catalyst 2 is an iron heteropoly acid-supported SBA-15 mesoporous molecular sieve; the catalyst 1 is a Schiff base binuclear iron complex having the structure: .

[0010] Liu Zhi et al. (Fine Chemical Intermediates, 2021, Vol. 51, No. 1, pp. 11-14) used benzene as raw material, and in the presence of catalyst A, reacted with carbon tetrachloride to produce diphenyl dichloromethane, with a yield of 84.7% under optimized conditions; diphenyl dichloromethane and anisole were further reacted with Friedel-Crafts alkylation in the presence of catalyst A to obtain the key intermediate of entecavir, 4-methoxyphenyl diphenyl dichloromethane, with a yield of 85.9% under optimized conditions and a product purity of 99.1%. The structures of catalysts A and B are as follows:

[0011] Although the above two improved methods also successfully prepared 4-methoxyphenyl diphenylmethane, the catalysts used were all metal complexes, and the preparation methods of the catalysts were complicated and costly, and were not suitable for industrial production.

[0012] Traditional Friedel-Crafts alkylation reactions are usually carried out under the action of homogeneous acid catalysts (such as AlCl3, HF, H2SO4, etc.). Such catalysts not only have large chemical reaction quantities and are difficult to separate and recycle after the reaction, but also have environmental problems such as corrosion, volatility, and toxicity. In recent years, with the improvement of people's understanding of environmental protection and green chemistry, the active research and development of environmentally friendly catalysts to replace traditional acid catalysts has become one of the research hotspots of green Friedel-Crafts alkylation reactions. As a new type of green liquid catalyst, acidic ionic liquids not only present unique physical and chemical properties, such as excellent thermal stability, chemical stability, low vapor pressure, good adjustable solubility, reusability, etc., but also have sufficient designability. A variety of functional ionic liquids can be designed by combining different anion and cation types or introducing special functional groups. They have great potential to replace traditional acid catalysts in the industrial application of Friedel-Crafts alkylation reactions. According to the different acidity types of acidic ionic liquids, they can be divided into Lewis acidic ionic liquids, Bronsted acidic ionic liquids and Bronsted-Lewis (abbreviated as BL) di-acidic ionic liquids.

[0013] At present, the metal halides of Lewis acidic ionic liquids used for Friedel-Crafts alkylation are mainly metal chlorides (such as AlCl3, FeCl3, ZnCl2, etc.), and the organic cations are mainly imidazolium ions, organic ammonium ions, pyridinium ions, etc. The Lewis acidic ionic liquids have different acid properties due to different factors such as the type of metal ions and the ratio between metal ions and organic onium ions, which have different effects on the catalytic performance of the Friedel-Crafts alkylation reaction; in addition, the catalytic performance of the alkylation reaction is also closely related to the conditions of the alkylation reaction. In addition, the introduction of a second metal ion into the ionic liquid will form a new composite high-metal ion, and fine-tuning the ratio of different metal ions in the ionic liquid can change the physical and chemical properties of the ionic liquid, which is conducive to the improvement of catalytic activity. It is a way to design and develop highly active and highly adaptable Lewis acidic catalysts.

[0014] Bronsted acidic ionic liquids are those that can give H + Ionic liquids can be divided into Bronsted acid anion-based ionic liquids and sulfonic acid functionalized cation-based ionic liquids according to their functional groups. The acidic groups of the former are derived from anions containing active acidic protons, while the latter are obtained by chemically modifying the precursors during synthesis to introduce Bronsted acidic sulfonic acid groups -SO3H. Bronsted acidic ionic liquids are water-stable and metal-free catalytic, making them an ideal green catalyst. Researchers usually regulate the properties of ionic liquids by adjusting the types of organic onium ions and anions, or by using immobilized carriers (porous molecular sieves, metal MOFs, etc.) to improve the physicochemical and catalytic properties of ionic liquids.

[0015] Bronsted-Lewis di-acidic ionic liquids are formed by introducing Lewis acidic compounds into Bronsted acidic ionic liquids by using the coordination principle. They are composed of Bronsted acidic organic onium ions and Lewis acidic metal halide anions. They have both Lewis acidity and Bronsted acidity. The synergistic effect between the di-acidic acid sites enhances the catalytic activity of the ionic liquids, improves the conversion rate and selectivity of the reaction, and are potential ionic liquids for catalyzing Friedel-Crafts alkylation reactions. Yang et al. (Applied Sciences-Basel, 2019, 9(22): 4743) synthesized an adjustable arylimidazole magnetic ionic liquid with BL di-acidity based on the charge distribution of the para-substituent of the arylimidazole group, and the combination of a proton and sp2 aryl substituents on the two nitrogen atoms of the imidazole group. The L acidity is determined by FeCl4 - Provided by, B acidity is provided by imidazolyl cation. It has excellent catalytic activity in the alkylation reaction of p-xylene with benzyl chloride. Liu et al. (Journal of Molecular Catalysis A: Chemical, 2015, 398: 133) proposed the use of chloroaluminate ionic liquid modified by cuprous chloride ([Et3NH]Cl-AlCl3-CuCl) as a catalyst for the alkylation of isobutane / 2-butene, with a product selectivity of 87.5% and an octane number (RON) of the corresponding alkylate of 100.5.

[0016] In the prior art, the synthesis process of 4-methoxyphenyl diphenyl methyl chloride has the problems of high product cost, large amount of toxic or corrosive raw materials, low yield and purity, etc. Therefore, researching and developing a production process with low cost, convenient handling, high product yield and purity has important economic value and market prospects. Summary of the invention

[0017] In order to solve the above technical problems existing in the prior art, the present invention provides a method for preparing an entecavir intermediate. The method of the present invention has mild reaction conditions, simple and easy-to-obtain reaction catalysts, energy saving and environmental protection, high product yield and purity, and is more suitable for industrial production.

[0018] The present invention provides a method for preparing an entecavir intermediate, which is characterized by comprising the following steps: 3) In the presence of a di-acidic ionic liquid, carbon tetrachloride and benzene undergo an alkylation reaction to obtain an intermediate compound, diphenyldichloromethane; 4) In the presence of a di-acidic ionic liquid and an additive, diphenyldichloromethane and anisole are subjected to an alkylation reaction to obtain entecavir intermediate 4-methoxyphenyldiphenylchloromethane, and the reaction route is as follows:

[0019] Wherein: Steps 1) and 2) the di-acidic ionic liquid is [4(C3SO3H-CPL)Zn]Cl2, and the structure is .

[0020] The additive in step 2) is selected from one or more of AlCl3, FeCl3, CuCl2, CuCl, and NiCl2.

[0021] Preferably, after the reaction of step 1) of the present invention is completed, it is only necessary to remove benzene and carbon tetrachloride in the reaction solution before the reaction of step 2) can be directly carried out.

[0022] Preferably, the reaction temperature of step 1) is 0°C to 80°C, more preferably 40°C to 60°C, most preferably 50°C.

[0023] Preferably, the reaction time of step 1) is 1 to 8 hours, more preferably 2 to 6 hours, most preferably 4 to 5 hours.

[0024] Preferably, in step 1), the molar ratio of carbon tetrachloride to benzene is 1:2.0-3.0, more preferably 1:2.1-3.0.

[0025] Preferably, in step 1), the mass ratio of carbon tetrachloride to diacidic ionic liquid is 1:3-50, more preferably 1:8-15.

[0026] Preferably, the molar ratio of anisole in step 2) to carbon tetrachloride in step 1) is 1-2:1, more preferably 1.1-1.3:1.

[0027] Preferably, the reaction temperature of step 2) is 20°C to 120°C, more preferably 70°C to 90°C.

[0028] Preferably, the reaction time of step 2) is 1 to 6 hours, more preferably 2 to 4 hours. Step 1) of the present invention is a Friedel-Crafts alkylation reaction. The raw material carbon tetrachloride in step 1) contains four chlorine atoms. Theoretically, it can react with four molecules of benzene at most to react with Friedel-Crafts alkylation. However, as the reaction proceeds, when the chlorine atoms are replaced by benzene, the steric hindrance of the subsequent Friedel-Crafts alkylation reaction increases, resulting in a decrease in the activity of the reactants, thereby hindering the continued Friedel-Crafts alkylation reaction. Generally, it is difficult for all four chlorine atoms on carbon tetrachloride to be replaced by phenyl. Therefore, the effect of the catalyst in the first step reaction on the product is crucial. If the catalyst activity is low, a large part of the alkylation reaction will only undergo one alkylation, and at this time, a large amount of monosubstituted products (i.e., trichloromethylbenzene) will be present in the product; if the catalyst activity is too high, carbon tetrachloride may continue to undergo a third or even fourth alkylation after undergoing two alkylation reactions, and the product obtained will contain a large amount of by-products (such as monochlorotriphenylmethane and tetraphenylmethane). Therefore, how to select a suitable catalyst is the difficulty of this step.

[0029] Step 2) of the present invention is also a Friedel-Crafts alkylation reaction. In this reaction, the diphenyldichloromethane used as a raw material itself has a large steric hindrance. Therefore, when performing the Friedel-Crafts alkylation reaction, the catalyst activity used needs to be higher than the catalyst in step 1), otherwise the reaction is difficult to proceed smoothly. Of course, the activity of the catalyst cannot be too high, otherwise the remaining chlorine atom may continue to undergo the Friedel-Crafts alkylation reaction, thereby obtaining an unwanted by-product. In addition, there is a technical difficulty in this step that anisole used as a raw material contains a methoxy substitution on its benzene ring, and the methoxy group itself is an ortho- and para-positioning group. When it undergoes the Friedel-Crafts alkylation reaction, in addition to the easy occurrence of the Friedel-Crafts reaction at the para position of the methoxy group to generate the target compound, the Friedel-Crafts reaction will also occur at the ortho position of the methoxy group to produce the ortho-position Friedel-Crafts reaction product, as well as the product of the Friedel-Crafts reaction of the benzene ring of diphenyldichloromethane itself, and other impurities, thereby greatly reducing the yield and purity of the product. The prior art reports the use of complex metal complexes (CN112409141 A; Fine Chemical Intermediates, 2021, Vol. 51, No. 1, pp. 11-14) as catalysts for the second-step Friedel-Crafts alkylation reaction, and the yield of the obtained product can reach up to 90% and the purity can reach 99%. The reason for this may be that the use of complex metal complexes as catalysts has a larger space around the catalyst, which further increases the influence of the steric effect. There is a methoxy group on the benzene ring of anisole. When the steric hindrance of the raw material diphenyldichloromethane and the catalyst is large, when attacking the benzene ring of anisole, it will preferentially choose to attack the position away from the methoxy group, thereby achieving a good positioning effect of the para position of the methoxy group, reducing the probability of by-products, and being able to obtain the target product with a higher yield and purity.

[0030] The inventor of the present invention has unexpectedly screened out a special class of di-acidic ionic liquids through a large number of experiments. The ionic liquid can well achieve the selectivity of the Friedel-Crafts alkylation reaction in step 1), and improve the reaction yield and product purity. At the same time, after the reaction of step 1) is completed, it is only necessary to evaporate and remove the excess raw material benzene and the unreacted carbon tetrachloride, without further purification, and can be directly used for the reaction of step 2), which reduces the post-processing process, saves costs, and is more environmentally friendly. In addition, in the reaction of step 2), it is only necessary to add a co-catalyst to the reaction system of step 1), so as to improve the catalytic activity of the di-acidic ionic liquid, which is convenient for the smooth progress of step 2). And because the groups of the di-acidic ionic liquid are relatively crowded, its steric hindrance is relatively large, and when it is subjected to the Friedel-Crafts alkylation reaction with anisole, it can better achieve the para-substitution of the methoxy group, thereby improving the reaction selectivity, yield and product purity.

[0031] Compared with the prior art, the present invention has the following advantages: 1. The present invention uses a di-acidic ionic liquid as a catalyst for the first time to synthesize the entecavir intermediate 4-methoxyphenyldiphenylmethane, which is in line with the development trend of green chemistry.

[0032] 2. The preparation method of the present invention has a simple post-processing process and does not require complicated post-processing operations, thus saving operating costs and being conducive to industrial production.

[0033] 3. The catalyst of the present invention is simple and easy to obtain, and the preparation method is mature. The ionic liquid of the present invention is easy to separate and can be reused after simple activation, which saves production costs and is conducive to industrial production.

[0034] 4. The entecavir intermediate 4-methoxyphenyldiphenylmethane prepared by the preparation method of the present invention has high purity, and the total reaction yield is also greatly improved compared with the prior art. DETAILED DESCRIPTION

[0035] The following examples are provided to illustrate the present invention in detail. The following examples are provided to better illustrate the present invention and are not intended to limit the scope of the present invention. The materials, reagents, etc. used in the following examples, unless otherwise specified, can be obtained from commercial sources.

[0036] Synthesis Example 1 Preparation of diacidic ionic liquid catalyst The diacidic ionic liquid used in the present invention is , called [4(C3SO3H-CPL)Zn]Cl2, is prepared by referring to the method of Example 2 of patent document CN 109796406 A. The specific steps are as follows: Add 1 mol zinc chloride and 4 mol caprolactam to the reactor, start mechanical stirring, slowly heat up to 80°C for eutectic melting, wait until all reactants are dissolved and become clear and transparent liquid, the reaction is finished, and the coordination intermediate is obtained. After the coordination intermediate is cooled to room temperature, add 1200 mL toluene and 488 g 1,3-propane sultone, continue to heat up to 80°C, and reflux for 4 hours. After the reaction is completed, cool the reaction solution and separate the layers, pour out the mixture of upper toluene and unreacted raw materials, and distill the lower layer under reduced pressure to remove the remaining toluene, and obtain the di-acidic ionic liquid [4(C3SO3H-CPL)Zn]Cl2.

[0037] Example 1 Step 1): Add carbon tetrachloride (15.4 g, 0.10 mol) to a three-necked flask, then add 150 g of di-acidic ionic liquid [4(C3SO3H-CPL)Zn]Cl2 and stir for 10 minutes. Then, add benzene (18.0 g, 0.23 mol). Stir at room temperature for 20 minutes until the reaction solution is evenly mixed, then heat to about 50°C and keep warm for 4 hours until the carbon tetrachloride in the reaction solution is basically reacted.

[0038] Step 2): The reaction mixture of step 1 was subjected to reduced pressure distillation using a rotary evaporator to remove unreacted benzene and residual carbon tetrachloride. Anisole (11.9 g, 0.11 mol) and 8.5 g NiCl2 were added to the remaining reaction solution, stirred evenly, and heated to 80°C for reaction for 3 hours.

[0039] After the reaction was completed, the reaction solution was poured into water and filtered. The filter cake was slurried with 100 mL of n-hexane, the solid was filtered, and vacuum dried to obtain 28.4 g of a light orange solid with a yield of 92.2%. The purity was 98.9% as determined by HPLC.

[0040] 1 H NMR (400 MHz, CDCl3): 7.38~7.25 (m, 10H), 7.16~7.20 (d, 2H), 6.82~6.86 (d, 2H), 3.80 (s, 3H).

[0041] The filtrate after filtration is subjected to vacuum distillation to remove most of the water, and the residue is dried in an oven to recover the di-acidic ionic liquid, which can be further recycled. The residue can also be filtered, adsorbed with activated carbon to remove impurities, and then recycled.

[0042] Example 2 Step 1): Add carbon tetrachloride (15.4 g, 0.10 mol) to a three-necked flask, then add 150 g of di-acidic ionic liquid [4(C3SO3H-CPL)Zn]Cl2 and stir for 10 minutes. Then, add benzene (18.0 g, 0.21 mol). Stir at room temperature for 20 minutes until the reaction solution is evenly mixed, then heat to about 50°C and keep warm for 5 hours until the carbon tetrachloride in the reaction solution is basically reacted.

[0043] Step 2): The reaction mixture of step 1 was subjected to reduced pressure distillation using a rotary evaporator to remove unreacted benzene and residual carbon tetrachloride. Anisole (11.9 g, 0.11 mol) and 7.5 g AlCl3 were added to the remaining reaction solution, stirred evenly, and heated to 80°C for reaction for 3 hours.

[0044] After the reaction was completed, the reaction solution was poured into water and filtered. The filter cake was slurried with 100 mL of n-hexane, the solid was filtered, and vacuum dried to obtain 28.4 g of a light orange solid with a yield of 87.4%. The purity was 98.0% as determined by HPLC.

[0045] The filtrate after filtration is subjected to vacuum distillation to remove most of the water, and the residue is dried in an oven to recover the di-acidic ionic liquid, which can be further recycled. The residue can also be filtered, adsorbed with activated carbon to remove impurities, and then recycled.

[0046] Example 3 Step 1): Add carbon tetrachloride (15.4 g, 0.10 mol) to a three-necked flask, then add 200 g of di-acidic ionic liquid [4(C3SO3H-CPL)Zn]Cl2 and stir for 10 minutes. Then, add benzene (18.0 g, 0.23 mol). Stir at room temperature for 20 minutes until the reaction solution is evenly mixed, then heat to about 50°C and keep warm for 4 hours until the carbon tetrachloride in the reaction solution is basically reacted.

[0047] Step 2): The reaction mixture of step 1 was subjected to reduced pressure distillation using a rotary evaporator to remove unreacted benzene and residual carbon tetrachloride. Anisole (11.9 g, 0.11 mol) and 9.2 g FeCl3 were added to the remaining reaction solution, stirred evenly, and heated to 80°C for reaction for 3 hours.

[0048] After the reaction was completed, the reaction solution was poured into water and filtered. The filter cake was slurried with 100 mL of n-hexane, the solid was filtered, and vacuum dried to obtain 28.4 g of a light orange solid with a yield of 88.2%. The purity was 98.5% as determined by HPLC.

[0049] The filtrate after filtration is subjected to vacuum distillation to remove most of the water, and the residue is dried in an oven to recover the di-acidic ionic liquid, which can be further recycled. The residue can also be filtered, adsorbed with activated carbon to remove impurities, and then recycled.

[0050] Example 4 The same method as in Example 1 was used, except that the amount of benzene added in step 1) was 0.3 mol. The results showed that the yield of the two-step reaction was 89.5% and the purity was 98.4%.

[0051] Comparative Example 1 Step 1): Add carbon tetrachloride (15.4 g, 0.10 mol) to a three-necked flask, then add 150 g of di-acidic ionic liquid [4(C3SO3H-CPL)Zn]Cl2 and stir for 10 minutes. Then, add benzene (18.0 g, 0.23 mol). Stir at room temperature for 20 minutes until the reaction solution is evenly mixed, then heat to about 50°C and keep warm for 4 hours until the carbon tetrachloride in the reaction solution is basically reacted.

[0052] Step 2): The reaction mixture of step 1 was subjected to reduced pressure distillation using a rotary evaporator to remove unreacted benzene and residual carbon tetrachloride. Anisole (11.9 g, 0.11 mol) was added to the remaining reaction solution, stirred evenly, and heated to 80°C for reaction for 3 hours.

[0053] HPLC analysis of the reaction solution revealed that the diphenyldichloromethane in the reaction solution was largely unreacted. The reason for this may be that the catalytic activity of the di-acidic ionic liquid was insufficient, resulting in the failure of the second step alkylation reaction to proceed smoothly.

[0054] Comparative Example 2 The same method as in Example 1 was adopted, except that 150 g of di-acidic ionic liquid [HSO3-bN-(C2H5)]Cl-0.5ZnCl2 (prepared according to the method of CN107954954A) was used instead of the di-acidic ionic liquid in Example 1, and it was found that the target product could not be obtained.

Claims

1. A method for preparing an entecavir intermediate, characterized in that The steps include: 1) In the presence of a di-acidic ionic liquid, carbon tetrachloride and benzene undergo an alkylation reaction to obtain an intermediate compound, diphenyldichloromethane; 2) In the presence of a di-acidic ionic liquid and an additive, diphenyldichloromethane and anisole are subjected to an alkylation reaction to obtain the entecavir intermediate 4-methoxyphenyldiphenylchloromethane. The reaction route is as follows: Wherein: Steps 1) and 2) the di-acidic ionic liquid is [4(C3SO3H-CPL)Zn]Cl2, and the structure is . The additive in step 2) is selected from one or more of AlCl3, FeCl3, CuCl2, CuCl, and NiCl2.

2. The preparation method according to claim 1, characterized in that: After the reaction of step 1) is completed, the reaction of step 2) can be directly carried out after only removing the benzene and carbon tetrachloride in the reaction solution.

3. The preparation method according to claim 1 or 2, characterized in that: The reaction temperature of step 1) is 40°C to 60°C.

4. The preparation method according to claim 1 or 2, characterized in that: The reaction time of step 1) is 1 to 8 hours.

5. The preparation method according to claim 1 or 2, characterized in that: In step 1), the molar ratio of carbon tetrachloride to benzene is 1:2.0-3.

0.

6. The preparation method according to claim 1 or 2, characterized in that: In step 1), the mass ratio of carbon tetrachloride to diacidic ionic liquid is 1:3-50.

7. The preparation method according to claim 1 or 2, characterized in that: The molar ratio of anisole in step 2) to carbon tetrachloride in step 1) is 1-2:

1.

8. The preparation method according to claim 1 or 2, characterized in that: The reaction temperature of step 2) is 70°C to 90°C.

9. The preparation method according to claim 1 or 2, characterized in that: The reaction time of step 2) is 1 to 6 hours.

10. The preparation method according to claim 9, characterized in that: The reaction time of step 2) is 2 to 4 hours.

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