A preparation method of entecavir intermediate

Abstract

The present invention provides a method for preparing an entecavir intermediate. This method utilizes a di-acidic ionic liquid as a catalyst for the synthesis of the entecavir intermediate 4-methoxyphenyldiphenylmethane, aligning with the development trend of green chemistry. The catalyst is readily available, and the post-processing process is simple, eliminating the need for complex post-processing operations and reducing operating costs. Furthermore, the entecavir intermediate produced by the preparation method has a high yield and purity, facilitating industrial production.

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 analog developed by Bristol-Myers Squibb and first marketed in the United States in 2005. It inhibits hepatitis B virus (HBV) replication and reduces serum viral DNA levels. It boasts rapid onset of action, strong antiviral activity, and low drug resistance, making it a first-line antiviral treatment for HBV. Among the currently reported synthetic processes for entecavir, Bristol-Myers Squibb's original process is the most commercially viable one. The raw materials and reagents used in this process are relatively simple and readily available. The starting material, cyclopentadiene, is converted to sodium monoxide, which is then alkylated, asymmetric hydroboration-oxidation, epoxidation, overprotection, substitution, and ring-opening to yield an alcohol intermediate. This alcohol intermediate then undergoes alkylation with 4-methoxyphenyldiphenylmethane, followed by Dess-Martin oxidation and methylenation, and finally deprotection to yield entecavir. Therefore, 4-methoxyphenyldiphenylmethane is a key intermediate in the synthesis of entecavir.

[0003] The prior art documents report that the synthesis of compound 4-methoxyphenyl diphenylmethane mainly includes the following methods:

[0004] The first method uses p-bromoanisole as a raw material to first prepare a magnesium bromide Grignard reagent, which is then subjected to a Grignard reaction with benzophenone to prepare a benzyl alcohol intermediate. The hydroxyl group is then chlorinated using acetyl chloride, thionyl chloride, or hydrogen chloride as a chlorination reagent to synthesize the compound of formula (I). The synthetic route is:

[0005]

[0006] Because the first and second steps of this process require the preparation of Grignard reagents and the Grignard reaction, they have very high water requirements. The use of chlorination reagents such as acetyl chloride in the third step produces large amounts of hydrochloric acid, which not only corrodes equipment but also pollutes the environment. Furthermore, using acetyl chloride as the chlorination reagent also produces hydroxyl acetylated impurities, which are difficult to handle. Therefore, this process is not easy to industrialize and operate conveniently.

[0007] The second method uses 4-hydroxytriphenylmethanol as the main raw material and synthesizes the compound of formula (I) through a two-step reaction of methylation and chlorination. The synthetic route is:

[0008]

[0009] This process is prone to the generation of impurities in the methylation reaction that simultaneously methylate phenolic hydroxyl groups and alcoholic hydroxyl groups. This impurity is structurally similar to the compound of formula (I) and is difficult to remove. Dimethyl sulfate is used as the methylation reagent in the methylation, but this reagent is highly toxic. In addition, the raw material 4-hydroxytriphenylmethanol is expensive and difficult to obtain, which is not conducive to industrial production.

[0010] 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:

[0011]

[0012] This technology is simpler, but this Friedel-Crafts reaction is owing to the very strong AlCl of using conventional catalytic activity Be catalyzer, and reaction is carried out in homogeneous phase, except easily at the methoxyl group para-position, Friedel-Crafts reaction generation formula (I) compound occurs, also can at the methoxyl group ortho-position, Friedel-Crafts reaction occurs and produces ortho-position Friedel-Crafts reaction product, and produces impurities such as product of the Friedel-Crafts reaction that diphenyldichloromethane self phenyl ring occurs. Multiple impurity polarity is close, is difficult to separate and remove with main product, in addition, wash with water and remove AlCl in the process of catalyzer, can cause the hydrolysis of chlorine atom in formula (I) compound molecule, therefore, also need to carry out chloro with chlorination reagents such as acetyl chloride or thionyl chloride after the water treatment drying; Also have, reaction starting raw material diphenyldichloromethane is also difficult to obtain.

[0013] CN112409141 A discloses an improved method for this process, wherein carbon tetrachloride and benzene undergo a Friedel-Crafts alkylation reaction in the presence of catalyst 1 to produce diphenyldichloromethane; diphenyldichloromethane and anisole undergo a Friedel-Crafts alkylation reaction in the presence of catalyst 2 to produce 4-methoxyphenyldiphenylchloromethane. Catalyst 2 is an iron heteropolyacid-supported SBA-15 mesoporous molecular sieve; Catalyst 1 is a Schiff base binuclear iron complex having the structure:

[0014] .

[0015] Liu Zhi et al. (Fine Chemical Intermediates, 2021, Vol. 51, No. 1, pp. 11-14) used benzene as the raw material and reacted with carbon tetrachloride in the presence of catalyst A to produce diphenyldichloromethane in a Friedel-Crafts alkylation reaction. The yield was 84.7% under optimized conditions. Diphenyldichloromethane and anisole were then subjected to a Friedel-Crafts alkylation reaction in the presence of catalyst A to obtain 4-methoxyphenyldiphenylchloromethane, a key intermediate of entecavir, in an 85.9% yield under optimized conditions. The product purity was 99.1%. The structures of catalysts A and B are as follows:

[0016]

[0017] Although the above two improved methods also successfully prepared 4-methoxyphenyldiphenylmethane, the catalysts used were metal complexes, and the preparation methods of the catalysts were complicated and costly, making them unsuitable for industrial production.

[0018] Traditional Friedel-Crafts alkylation reactions are typically carried out in the presence of homogeneous acid catalysts (such as AlCl₃, HF, and H₂SO₄). These catalysts not only require high chemical reaction stoichiometry and are difficult to separate and recover after the reaction, but also present environmental challenges such as corrosion, volatility, and toxicity. In recent years, with increasing awareness of environmental protection and green chemistry, the development of environmentally friendly catalysts to replace traditional acid catalysts has become a hot topic in the green Friedel-Crafts alkylation process. As a new type of green liquid catalyst, acidic ionic liquids not only exhibit unique physicochemical properties, such as excellent thermal and chemical stability, low vapor pressure, tunable solubility, and reusability, but also offer extensive designability. A variety of functional ionic liquids can be designed by combining different anions and cations or by introducing specialized functional groups. These ionic liquids hold great potential as an alternative to traditional acid catalysts in the industrial application of Friedel-Crafts alkylation reactions. Based on their acidity, acidic ionic liquids can be categorized into Lewis acidic ionic liquids, Bronsted acidic ionic liquids, and Bronsted-Lewis (BL) diacidic ionic liquids.

[0019] Currently, the metal halides in Lewis-acidic ionic liquids used in Friedel-Crafts alkylation reactions are primarily metal chlorides (such as AlCl₃, FeCl₃, and ZnCl₂), while the organic cations are primarily imidazolium, organic ammonium, and pyridinium ions. Lewis-acidic ionic liquids vary in their acidic properties, depending on factors such as the type of metal ion and the ratio between the metal ion and the organic onium ion, and thus have varying effects on their catalytic performance in Friedel-Crafts alkylation reactions. Furthermore, the catalytic performance of alkylation reactions is closely related to the reaction conditions. Furthermore, the introduction of a second metal ion into an ionic liquid forms a new composite high-metal ion. Fine-tuning the ratio of different metal ions in an ionic liquid can alter its physical and chemical properties, improving its catalytic activity. This offers a promising approach for designing and developing highly active and adaptable Lewis-acidic catalysts.

[0020] Bronsted acidic ionic liquids are those that can give H +Ionic liquids can be categorized by their functional groups as Bronsted-acid anions and sulfonic acid-functionalized cations. The acidic groups in the former are derived from anions containing active acidic protons, while the latter are derived from precursors chemically modified during synthesis to introduce Bronsted-acidic sulfonic acid groups (SO₃H). Bronsted-acidic ionic liquids offer the advantages of water stability and metal-free catalysis, making them ideal green catalysts. Researchers typically manipulate the properties of ionic liquids by adjusting the type of organic onium ions and anions, or by utilizing immobilized supports (porous molecular sieves, metal MOFs, etc.) to improve the physicochemical and catalytic properties of ionic liquids.

[0021] Bronsted-Lewis diacidic ionic liquids are formed by introducing Lewis acidic compounds into Bronsted acidic ionic liquids 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 diacidic acid sites enhances the catalytic activity of the ionic liquid, 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 aryl imidazole magnetic ionic liquid with BL diacidity based on the charge distribution of the para-substituent of the aryl imidazole group. The combination of a proton and sp2 aryl substituents on the two nitrogen atoms of the imidazole group synthesized an aryl imidazole magnetic ionic liquid with BL diacidity. The L acidity is determined by FeCl4 - Acidity is provided by the imidazolyl cation. It exhibits excellent catalytic activity in the alkylation of p-xylene with benzyl chloride. Liu et al. (Journal of Molecular Catalysis A: Chemical, 2015, 398: 133) proposed the use of a chloroaluminate ionic liquid modified with cuprous chloride ([Et3NH]Cl-AlCl3-CuCl) as a catalyst for the alkylation of isobutane with 2-butene, achieving a product selectivity of 87.5% and an octane number (RON) of 100.5.

[0022] The existing synthesis process for 4-methoxyphenyldiphenylmethane suffers from high product cost, the use of a large amount of toxic or corrosive raw materials, and low yield and purity. Therefore, the development of a production process with low cost, convenient processing, and high product yield and purity has important economic value and market prospects. Summary of the Invention

[0023] To address the above technical problems in the prior art, the present invention provides a method for preparing an entecavir intermediate. The method has mild reaction conditions, readily available catalysts, is energy-efficient and environmentally friendly, and has high product yield and purity, making it more suitable for industrial production.

[0024] The present invention provides a method for preparing an entecavir intermediate, which is characterized by comprising the following steps:

[0025] 3) In the presence of a di-acidic ionic liquid, carbon tetrachloride and benzene undergo an alkylation reaction to obtain the intermediate compound diphenyldichloromethane;

[0026] 4) In the presence of a diacidic ionic liquid and an additive, diphenyldichloromethane and anisole are subjected to an alkylation reaction to obtain the entecavir intermediate 4-methoxyphenyldiphenylchloromethane. The reaction scheme is as follows:

[0027]

[0028] Wherein: Steps 1) and 2) the di-acidic ionic liquid is [4(C3SO3H-CPL)Zn]Cl2, the structure is .

[0029] The additive in step 2) is selected from one or more of AlCl3, FeCl3, CuCl2, CuCl, and NiCl2.

[0030] Preferably, after the reaction in 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 in step 2) can be directly carried out.

[0031] Preferably, the reaction temperature in step 1) is 0°C to 80°C, more preferably 40°C to 60°C, and most preferably 50°C.

[0032] Preferably, the reaction time of step 1) is 1 to 8 hours, more preferably 2 to 6 hours, and most preferably 4 to 5 hours.

[0033] 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.

[0034] Preferably, in step 1), the mass ratio of carbon tetrachloride to diacidic ionic liquid is 1:3-50, more preferably 1:8-15.

[0035] 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.

[0036] Preferably, the reaction temperature in step 2) is 20°C to 120°C, more preferably 70°C to 90°C.

[0037] Preferably, the reaction time of step 2) is 1 to 6 hours, more preferably 2 to 4 hours.

[0038] Step 1) of the present invention is a Friedel-Crafts alkylation reaction. The carbon tetrachloride starting material in step 1) contains four chlorine atoms. Theoretically, it can undergo Friedel-Crafts alkylation with up to four molecules of benzene. However, as the reaction proceeds, the steric hindrance to subsequent Friedel-Crafts alkylation increases after the chlorine atoms are replaced by benzene, resulting in a decrease in the activity of the reactants and, in turn, hindering the continued Friedel-Crafts alkylation reaction. Generally, it is difficult for all four chlorine atoms on the carbon tetrachloride to be replaced by phenyl groups. Therefore, the catalyst used in the first step is crucial for the product. If the catalyst activity is low, a significant portion of the alkylation reaction will proceed only once, resulting in a large amount of monosubstituted product (i.e., trichloromethylbenzene) in the product. If the catalyst activity is too high, the carbon tetrachloride may undergo two alkylation reactions and then proceed to a third or even fourth alkylation reaction, resulting in a product containing a large amount of byproducts (such as monochlorotriphenylmethane and tetraphenylmethane). Therefore, selecting a suitable catalyst is a challenge in this step.

[0039] 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 used in step 1), otherwise the reaction will not proceed smoothly. Of course, the activity of the catalyst cannot be too high, otherwise the remaining chlorine atom may continue to undergo Friedel-Crafts alkylation, thereby producing unwanted by-products. In addition, there is a technical difficulty in this step. The anisole used as a raw material contains a methoxy substitution on its benzene ring. The methoxy group itself is an ortho- and para-positioning group. When it undergoes the Friedel-Crafts alkylation reaction, in addition to the Friedel-Crafts reaction that easily occurs at the para position of the methoxy group to produce the target compound, it also undergoes a Friedel-Crafts reaction at the ortho position of the methoxy group to produce an ortho- Friedel-Crafts reaction product, as well as impurities such as the Friedel-Crafts reaction product of the benzene ring of the diphenyldichloromethane itself, thereby greatly reducing the yield and purity of the product. Prior art reports use a complex metal complex (CN112409141 A; Fine Chemical Intermediates, 2021, Vol. 51, No. 1, pp. 11-14) as a catalyst for the second-step Friedel-Crafts alkylation reaction, achieving a product yield of up to 90% and a purity of 99%. This may be due to the use of a complex metal complex as a catalyst, which creates a larger space around the catalyst, further increasing the influence of steric effects. The presence of a methoxy group on the benzene ring of anisole, when both the raw material diphenyldichloromethane and the catalyst are sterically hindered, will preferentially attack the benzene ring away from the methoxy group, thereby achieving a favorable para-positional effect to the methoxy group, reducing the probability of byproducts and enabling the target product to be obtained in high yield and purity.

[0040] Through extensive experimentation, the inventors of the present invention unexpectedly identified a unique class of di-acidic ionic liquids that effectively achieve excellent selectivity in the Friedel-Crafts alkylation reaction in step 1), improving reaction yield and product purity. Furthermore, after completion of step 1), only excess raw benzene and unreacted carbon tetrachloride need to be evaporated and removed, eliminating the need for further purification, allowing direct use in step 2. This reduces post-processing, saves costs, and is environmentally friendly. Furthermore, in step 2, simply adding a co-catalyst to the reaction system in step 1 enhances the catalytic activity of the di-acidic ionic liquid, facilitating smooth progress in step 2. Furthermore, because the di-acidic ionic liquid's groups are relatively crowded and sterically hindered, it can better achieve para-substitution of the methoxy group during the Friedel-Crafts alkylation reaction with anisole, thereby improving reaction selectivity, yield, and product purity.

[0041] Compared with the prior art, the present invention has the following advantages:

[0042] 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.

[0043] 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.

[0044] 3. The catalyst of the present invention is simple and easy to obtain, and the preparation method is mature. Moreover, the ionic liquid of the present invention is easy to separate and can be reused after simple activation, thus saving production costs and facilitating industrial production.

[0045] 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

[0046] The present invention is described in detail below by way of examples. In the present invention, 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.

[0047] Synthesis Example 1 Preparation of diacidic ionic liquid catalyst

[0048] The diacidic ionic liquid used in the present invention is , called [4(C3SO3H-CPL)Zn]Cl2, was prepared according to the method of Example 2 of patent document CN 109796406 A. The specific steps are as follows:

[0049] Add 1 mol of zinc chloride and 4 mol of caprolactam to a reactor, start mechanical stirring, and slowly heat to 80°C to form a eutectic solution. The reaction is complete until all reactants have dissolved, resulting in a clear, transparent liquid. After the complex intermediate cools to room temperature, add 1200 mL of toluene and 488 g of 1,3-propane sultone. Continue heating to 80°C and reflux for 4 hours. After the reaction is complete, cool the reaction solution and separate the layers. Discard the upper layer of toluene and unreacted raw materials, and distill the lower layer under reduced pressure to remove the remaining toluene, yielding the di-acidic ionic liquid [4(C3SO3H-CPL)Zn]Cl2.

[0050] Example 1

[0051] 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 uniformly mixed, then heat to about 50°C and keep the reaction warm for 4 hours until the carbon tetrachloride in the reaction solution is basically reacted.

[0052] Step 2): The reaction mixture from 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 3 hours.

[0053] 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.

[0054] 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).

[0055] The filtrate after filtration is subjected to reduced pressure 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.

[0056] Example 2

[0057] 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 the reaction warm for 5 hours until the carbon tetrachloride in the reaction solution is basically reacted.

[0058] Step 2): The reaction mixture from 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 3 hours.

[0059] 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.

[0060] The filtrate after filtration is subjected to reduced pressure 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.

[0061] Example 3

[0062] 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 uniformly mixed, then heat to about 50°C and keep the reaction warm for 4 hours until the carbon tetrachloride in the reaction solution is basically reacted.

[0063] Step 2): The reaction mixture from 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 of FeCl3 were added to the remaining reaction solution, stirred evenly, and heated to 80°C for 3 hours.

[0064] 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.

[0065] The filtrate after filtration is subjected to reduced pressure 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.

[0066] Example 4

[0067] 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%.

[0068] Comparative Example 1

[0069] 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 uniformly mixed, then heat to about 50°C and keep the reaction warm for 4 hours until the carbon tetrachloride in the reaction solution is basically reacted.

[0070] Step 2): The reaction mixture from 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 3 hours.

[0071] HPLC analysis of the reaction solution revealed that the diphenyldichloromethane in the reaction solution had not reacted. The reason for this was probably 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.

[0072] Comparative Example 2

[0073] The same method as in Example 1 was used, except that 150 g of the 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. 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 the intermediate compound diphenyldichloromethane; 2) In the presence of a diacidic ionic liquid and an additive, diphenyldichloromethane and anisole undergo an alkylation reaction to obtain the entecavir intermediate 4-methoxyphenyldiphenylchloromethane. The reaction scheme is as follows: Wherein: Steps 1) and 2) the di-acidic ionic liquid is [4(C3SO3H-CPL)Zn]Cl2, 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, wherein: After the reaction in step 1) is completed, it is only necessary to remove the benzene and carbon tetrachloride in the reaction solution before directly proceeding to the reaction in step 2).

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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