Preparation method of 4-[(2-chloro-4-fluorophenyl)methoxy]aniline

Abstract

The invention belongs to the field of organic synthesis, and in particular to a method for preparing 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline. The invention uses 2-chloro-4-fluorotoluene as a starting material, and 2-chloro-4-fluorobenzyl chloride is obtained by chlorination with N-chlorosuccinimide, and etherification reaction is carried out between 2-chloro-4-fluorobenzyl chloride and p-aminophenol in a reaction solvent under the action of alkali metal alkoxide and catalyst zinc acetate and argon protection, and the reaction solution is purified to obtain 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline. The preparation method provided by the invention is simple and efficient, the product purification process is simple, the reaction conditions are mild, the final yield is high, and the catalyst zinc acetate is cheap, safe and environmentally friendly, and suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a preparation method of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline. Background Art

[0002] Compounds containing phenylsulfonylamino groups can be used as peroxisome proliferator-activated receptor (PPAR) agonists. PPARα activators, physicochemical compositions containing such compounds, and the use of these compounds to increase certain plasma lipid levels, including high-density lipoprotein-cholesterol, and to reduce certain other plasma lipid levels such as LDL-cholesterol and triglycerides, and accordingly to treat diseases exacerbated by low levels of LDL-cholesterol or high levels of LDL-cholesterol and triglycerides such as atherosclerosis and cardiovascular diseases in mammals (including humans). In addition, compounds containing phenylsulfonylamino groups can also treat negative energy balance (neb) and related diseases in ruminants. 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline, as a key intermediate for the synthesis of phenylsulfonylamino compounds, is a very important part in commercialization.

[0003] Patent WO2019141980A1 reported a synthesis method of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline. As shown in the following formula, using 4-[[(2-chloro-4-fluorophenyl)methoxy]-nitrobenzene as a raw material, it is catalytically hydrogenated and reduced in a palladium-carbon catalyst / ethanol system under a hydrogen atmosphere to obtain 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline. However, the use cost of the palladium-carbon catalyst is very high, it is easy to adhere and lose during reaction purification, and special filtration equipment and recovery treatment processes are required. In addition, it is difficult to regenerate the palladium-carbon after deactivation, and the re-calcination process after deactivation is complex.

[0004]

[0005] Currently, there are few preparation routes for the 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline intermediate, and the cost is relatively high. Therefore, developing a simple, efficient and high-yield synthesis route has important practical significance for the study of phenylsulfonylamino compounds. Summary of the Invention

[0006] Aiming at the problems existing in the prior art, the present invention provides a simple, efficient and low-cost preparation method of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline.

[0007] The technical solution adopted by the present invention is:

[0008] A preparation method of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline. Under an argon atmosphere, using 2-chloro-4-fluorotoluene as the starting material, 2-chloro-4-fluorobenzyl chloride is prepared by chlorination with N-chlorosuccinimide. Then, 2-chloro-4-fluorobenzyl chloride undergoes an etherification reaction with p-aminophenol. After the reaction solution is purified, 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline is obtained, specifically as shown in Formula I:

[0009]

[0010] It includes the following steps:

[0011] (1) Preparation of 2-chloro-4-fluorobenzyl chloride: 2-chloro-4-fluorotoluene is dissolved in acetonitrile. First, benzoyl peroxide is added, and then N-chlorosuccinimide is added in batches. After addition, heating and refluxing are carried out at 75 °C for 3 h. After the reaction ends, the reaction solution is washed and concentrated to obtain 2-chloro-4-fluorobenzyl chloride;

[0012] (2) Preparation of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline: p-aminophenol is dissolved in N,N-dimethylformamide. Alkali metal alkoxide is added in batches and stirred. Then, zinc acetate and 2-chloro-4-fluorobenzyl chloride are added in sequence. After addition, the reaction is carried out at 5 - 15 °C for 2 h. After the reaction ends, the reaction solution is purified to obtain 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline.

[0013] Preferably, in step (1), in terms of molar ratio, 2-chloro-4-fluorotoluene:N-chlorosuccinimide:benzoyl peroxide = 10:(10 - 11):1; 2-chloro-4-fluorotoluene:acetonitrile = 0.125 g:1 mL.

[0014] Preferably, in step (2), in terms of molar ratio, 2-chloro-4-fluorobenzyl chloride:p-aminophenol:zinc acetate = 10:(10 - 14):1; 2-chloro-4-fluorobenzyl chloride:N,N-dimethylformamide = 1 g:10 mL.

[0015] Preferably, in step (2), the alkali metal alkoxide is selected from one of lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide. In terms of molar ratio, 2-chloro-4-fluorobenzyl chloride:alkali metal alkoxide = 10:14.

[0016] Preferably, in step (1), the washing and concentration means cooling the reaction solution to 5 - 30 °C, filtering, washing the filter cake with acetonitrile, and concentrating the filtrate under reduced pressure to constant weight to obtain 2-chloro-4-fluorobenzyl chloride.

[0017] Preferably, during the whole reaction process, the reaction pressure is controlled at 0.02 - 0.05 MPa.

[0018] Preferably, in step (2), the purification process is specifically as follows:

[0019] (1) Pour the reaction solution into water for quenching, control the temperature at 5 - 30°C, add dichloromethane for extraction, combine the organic phases and wash with saturated brine, and reserve the organic phase;

[0020] (2) Place the organic phase in a reaction kettle, cool down to 10 - 20°C, introduce hydrogen chloride gas under stirring, and a large amount of solid will precipitate; continue stirring, perform suction filtration, wash the filter cake with dichloromethane, take out the filter cake and dry it to obtain a dark brown solid powder;

[0021] (3) Add water to the dark brown solid powder, cool down to 10 - 20°C, dropwise add an aqueous sodium hydroxide solution with a mass fraction of 30%, a large amount of solid will precipitate, continue stirring and then perform suction filtration, wash the filter cake with water, take out the filter cake and dry it to obtain 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline.

[0022] Among them, in step (2) of the purification process, the drying is carried out in a forced-air drying oven at 50°C until constant weight; in step (3) of the purification process, since the melting point of the final product is relatively low and it is not suitable for drying by heating, natural air drying until constant weight is selected.

[0023] Preferably, in step (1) of the purification process, by volume ratio, water:N,N-dimethylformamide = 2:1.

[0024] Advantages of the present invention:

[0025] (1) The preparation method of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline provided by the present invention is simple and efficient, the product purification process is simple, the equipment requirements are low, the synthesis cost is low, the reaction conditions are mild, the final yield and purity are high, it is safe and environmentally friendly, and it is suitable for large-scale industrial production.

[0026] (2) In the synthesis route of the present invention, the catalyst used in the etherification reaction is zinc acetate, which is cheap, non-toxic and harmless, and can reduce the reaction temperature and improve the product yield during the reaction process.

[0027] (3) In the synthesis route of the present invention, the etherification reaction temperature is controlled at 5 - 15°C, which reduces the reaction time, avoids the generation of by-products, and improves the product yield. Description of the Drawings

[0028] Figure 1 It is the NMR spectrum of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline in the present invention. Detailed Embodiments

[0029] To better illustrate the purpose, technical solution and advantages of the present invention, the present invention will be further described below in conjunction with the drawings and specific embodiments.

[0030] The raw materials and reagents involved in the examples were all purchased and used. The specific detailed information is shown in Table 1.

[0031] Table 1 Information Table of Raw Materials and Reagents

[0032]

[0033] Synthesis of 2-Chloro-4-fluorobenzyl Chloride in Example 1

[0034] Under an argon atmosphere, 8 L of acetonitrile was added to a 20 L reaction kettle, and 6.91 mol of 2-chloro-4-fluorotoluene was charged, resulting in a colorless and clear system. Then, 0.691 mol of benzoyl peroxide was continuously added to the reaction kettle, and it was basically dissolved. Subsequently, 7.26 mol of N-chlorosuccinimide was added in batches. After addition, it was a white turbid system. The reaction was started by heating at 75 °C for 3 h. The pressure during the reaction was controlled at 0.02 - 0.05 MPa. After the reaction ended, the reaction solution was cooled to 20 °C, filtered, and the filter cake was rinsed with acetonitrile (500 mL × 2 times). The filtrate was concentrated under reduced pressure (50 °C, -0.085 MPa) to a constant weight to obtain 2-chloro-4-fluorobenzyl chloride (the product content by TLC > 90%), and the yield was 92.4%.

[0035] Synthesis of 2-Chloro-4-fluorobenzyl Chloride in Example 2

[0036] Under an argon atmosphere, 8 L of acetonitrile was added to a 20 L reaction kettle, and 6.91 mol of 2-chloro-4-fluorotoluene was charged, resulting in a colorless and clear system. Then, 0.691 mol of benzoyl peroxide was continuously added to the reaction kettle, and it was basically dissolved. Subsequently, 6.91 mol of N-chlorosuccinimide was added in batches. After addition, it was a white turbid system. The reaction was started by heating at 75 °C for 3 h. The pressure during the reaction was controlled at 0.02 - 0.05 MPa. After the reaction ended, the reaction solution was cooled to 15 °C, filtered, and the filter cake was rinsed with acetonitrile (500 mL × 2 times). The filtrate was concentrated under reduced pressure (50 °C, -0.085 MPa) to a constant weight to obtain 2-chloro-4-fluorobenzyl chloride (the product content by TLC > 80%), and the yield was 83.1%.

[0037] Synthesis of 2-Chloro-4-fluorobenzyl Chloride in Example 3

[0038] Under an argon atmosphere, 8 L of acetonitrile was added to a 20 L reaction kettle, and 6.91 mol of 2-chloro-4-fluorotoluene was charged, resulting in a colorless and clear system. Then, 0.691 mol of benzoyl peroxide was further added to the reaction kettle, and it was basically dissolved clear. Subsequently, 7.6 mol of N-chlorosuccinimide was added in batches. After addition, it was a white turbid system. Heating was started and the reaction was carried out at 75 °C for 3 h. The pressure during the reaction was controlled at 0.02 - 0.05 MPa. After the reaction ended, the reaction solution was cooled to 10 °C, filtered, the filter cake was rinsed with acetonitrile (500 mL × 2 times), and the filtrate was concentrated under reduced pressure (50 °C, -0.085 MPa) to constant weight to obtain 2-chloro-4-fluorobenzyl chloride (product content by TLC > 80%), with a yield of 81.2%.

[0039] Example 4 Synthesis of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline

[0040] (1) Synthesis of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline

[0041] Under an argon atmosphere, 13.75 L of N,N-dimethylformamide was added to a 20 L dry and clean reaction kettle, and then 8.29 mol of p-aminophenol was added, resulting in a yellowish-brown clear system. Potassium tert-butoxide (9.67 mol) was added in batches, and the system turned black. After addition, it was stirred for 0.5 h. First, 0.691 mol of zinc acetate was added, and then 6.91 mol of 2-chloro-4-fluorobenzyl chloride prepared in Example 1 was added. The temperature was controlled at 10 °C and the pressure was controlled at 0.02 - 0.05 MPa throughout the process. The reaction was carried out for 2 h, and the reaction solution was obtained after the reaction was completed.

[0042] (2) Purification of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline

[0043] The reaction solution obtained in the above step (1) was poured into 27.5 L of water for quenching, and the temperature was controlled at 15 °C; it was extracted with dichloromethane (4 L × 2 times), the organic phases were combined, and the organic phase was washed with saturated brine (2 L × 2 times), and the separated organic phase was reserved;

[0044] The separated organic phase was placed in a 20 L reaction kettle, cooled to 15 °C, and hydrogen chloride gas was introduced under stirring. A large amount of solid was precipitated. After continuing to stir for 0.5 h, suction filtration was carried out to obtain a dark brown solid. The filter cake was rinsed with dichloromethane (500 mL × 1 time), and suction filtration was continued until there were basically no liquid drops flowing down. The filter cake was taken out and dried in a blast drying oven at 50 °C to constant weight to obtain a dark brown solid powder;

[0045] Add 6 L of water to a 20 L reaction kettle, then add the obtained dark brown solid powder. A dark brown clear system is obtained. Cool the temperature to 15 °C, and slowly add an aqueous sodium hydroxide solution with a mass fraction of 30%. A large amount of solid is precipitated. Continue stirring for 0.5 h and then perform suction filtration. Wash the filter cake with water (2 L × 2 times), and perform suction filtration until there are basically no liquid drops flowing down to obtain a light brown solid. Air-dry it naturally until it reaches a constant weight to obtain 1,618 g of light brown solid powder, namely 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline; the product yield: 93.1%; the purity > 98%.

[0046] 5-[(2-chloro-4-fluorophenyl)methoxy]-aniline: 1 1H-NMR δH (600 MHz, DMSO-d6) 7.62 (dd, J = 6.2, 6.3 Hz, 1H), 7.51 (dd, J = 2.4, 2.6 Hz, 1H), 7.27 (td, J = 8.5, 2.6 Hz, 1H), 6.75 - 6.73 (m, 2H), 6.54 - 6.51 (m, 2H), 4.97 (s, 2H), 4.66 (s, 2H). The NMR spectrum of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline is shown in Figure 1 .

[0047] Example 5 Synthesis of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline

[0048] (1) Synthesis of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline

[0049] Under an argon atmosphere, add 13.75 L of N,N-dimethylformamide to a 20 L dry and clean reaction kettle. Then add 9.67 mol of p-aminophenol to form a yellowish-brown clear system. Add 9.67 mol of potassium tert-butoxide in batches. The system turns black. After addition, stir for 0.5 h. First, add 0.691 mol of zinc acetate, and then add 6.91 mol of 2-chloro-4-fluorobenzyl chloride prepared in Example 1. Control the temperature at 15 °C and the pressure at 0.02 - 0.05 MPa throughout the process. React for 2 h to obtain a reaction solution after the reaction is completed.

[0050] (2) Purification of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline

[0051] Pour the reaction solution obtained in the above step (1) into 27.5 L of water for quenching, and control the temperature at 20 °C; extract with dichloromethane (4 L × 2 times), combine the organic phases, wash the organic phases with saturated brine (2 L × 2 times), and set aside the separated organic phases;

[0052] The separated organic phase was placed in a 20 L reaction kettle, cooled to 20 °C, and hydrogen chloride gas was introduced with stirring. A large amount of solid was precipitated. After continuous stirring for 0.5 h, suction filtration was carried out to obtain a dark brown solid. The filter cake was rinsed with dichloromethane (500 mL × 1 time), and suction filtration was continued until there was basically no liquid dripping. The filter cake was taken out and dried in a blast drying oven at 50 °C to constant weight to obtain a dark brown solid powder;

[0053] 6 L of water was added to a 20 L reaction kettle, and then the above-obtained dark brown solid powder was added to form a dark brown clear system. The temperature was cooled to 20 °C, and an aqueous sodium hydroxide solution with a mass fraction of 30% was added dropwise. A large amount of solid was precipitated. After continuous stirring for 0.5 h, suction filtration was carried out. The filter cake was rinsed with water (2 L × 2 times), and suction filtration was continued until there was basically no liquid dripping to obtain a light brown solid, which was naturally air-dried to constant weight to obtain 1594 g of light brown solid powder, namely 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline; The product yield: 91.6%; Purity > 98%.

[0054] Example 6 Synthesis of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline

[0055] (1) Synthesis of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline

[0056] Under an argon atmosphere, 13.75 L of N,N-dimethylformamide was added to a 20 L dry and clean reaction kettle, and then 6.91 mol of p-aminophenol was added to form a yellow-brown clear system. 9.67 mol of potassium tert-butoxide was added in batches, and the system turned black. After addition, stirring was carried out for 0.5 h. First, 0.691 mol of zinc acetate was added, and then 6.91 mol of 2-chloro-4-fluorobenzyl chloride prepared in Example 1 was added. The temperature was controlled at 5 °C and the pressure was controlled at 0.02 - 0.05 MPa during the whole process. The reaction was carried out for 2 h, and after the reaction was completed, a reaction solution was obtained.

[0057] (2) Purification of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline

[0058] The reaction solution obtained in the above step (1) was poured into 27.5 L of water for quenching, and the temperature was controlled at 10 °C; Extraction was carried out with dichloromethane (4 L × 2 times), the organic phases were combined, and the organic phase was washed with saturated brine (2 L × 2 times), and the separated organic phase was reserved;

[0059] The separated organic phase was placed in a 20 L reaction kettle, cooled to 10 °C, and hydrogen chloride gas was introduced with stirring. A large amount of solid was precipitated. After continuous stirring for 0.5 h, suction filtration was carried out to obtain a dark brown solid. The filter cake was rinsed with dichloromethane (500 mL × 1 time), and suction filtration was continued until there was basically no liquid dripping. The filter cake was taken out and dried in a blast drying oven at 50 °C to constant weight to obtain a dark brown solid powder;

[0060] Add 6 L of water into a 20 L reaction kettle, and then add the obtained dark brown solid powder. A dark brown clear system is formed. Cool down to 10 °C, and dropwise add an aqueous sodium hydroxide solution with a mass fraction of 30%. A large amount of solid is precipitated. Continue stirring for 0.5 h and then perform suction filtration. Wash the filter cake with water (2 L × 2 times), and perform suction filtration until there are basically no liquid drops flowing down to obtain a light brown solid. Air-dry it naturally until it reaches a constant weight to obtain 1578 g of light brown solid powder, namely 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline; the product yield: 90.7%; the purity > 98%.

[0061] Example 7 Synthesis of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline

[0062] (1) Synthesis of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline

[0063] Under an argon atmosphere, add 13.75 L of N,N-dimethylformamide into a 20 L dry and clean reaction kettle. Then add 9.67 mol of p-aminophenol. A yellow-brown clear system is formed. Start adding 9.67 mol of potassium tert-butoxide in batches. The system turns black. After addition, stir for 0.5 h. First add 0.691 mol of zinc acetate, and then add 6.91 mol of 2-chloro-4-fluorobenzyl chloride prepared in Example 1. Control the temperature at 10 °C and the pressure at 0.02 - 0.05 MPa throughout the process. React for 2 h to obtain a reaction solution after the reaction is completed.

[0064] (2) Purification of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline

[0065] Pour the reaction solution obtained in the above step (1) into 27.5 L of water for quenching, and control the temperature at 15 °C; extract with dichloromethane (4 L × 2 times), combine the organic phases, wash the organic phases with saturated brine (2 L × 2 times), and set aside the separated organic phases;

[0066] Place the separated organic phases in a 20 L reaction kettle, cool down to 15 °C, and introduce hydrogen chloride gas under stirring. A large amount of solid is precipitated. Continue stirring for 0.5 h, and then perform suction filtration to obtain a dark brown solid. Wash the filter cake with dichloromethane (500 mL × 1 time), and perform suction filtration until there are basically no liquid drops flowing down. Take out the filter cake and dry it in a blast drying oven at 50 °C until it reaches a constant weight to obtain a dark brown solid powder;

[0067] Add 6 L of water into a 20 L reaction kettle, and then add the obtained dark brown solid powder. A dark brown clear system is obtained. Cool down the temperature to 15 °C, and dropwise add an aqueous sodium hydroxide solution with a mass fraction of 30%. A large amount of solid is precipitated. Continue to stir for 0.5 h and then perform suction filtration. Wash the filter cake with water (2 L × 2 times), and perform suction filtration until there are basically no liquid drops flowing down to obtain a light brown solid. Air-dry it naturally until it reaches a constant weight to obtain 1603 g of light brown solid powder, namely 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline; product yield: 92.1%; purity > 98%.

[0068] Comparative Example 1

[0069] This comparative example provides a preparation method of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline. The preparation process is the same as that of Example 4. The difference from Example 4 is that: when synthesizing 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline in step (2) of Example 4, only change the etherification reaction temperature, and the others are the same as those in Example 4. The product yield results are shown in Table 2.

[0070] Table 2 Product Yield Table of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline

[0071]

[0072] During the whole experiment process, when the temperature is lower than 5 °C, the reaction time will be prolonged and the yield will be reduced at the same time; when the temperature is higher than 15 °C, the by-products will increase and the yield will be reduced; therefore, the optimal temperature for the etherification reaction during the synthesis of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline is 5 - 15 °C.

[0073] Comparative Example 2

[0074] This comparative example provides a preparation method of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline. The preparation process is the same as that of Example 4. The difference from Example 4 is that: when synthesizing 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline in step (2) of Example 4, zinc acetate as a catalyst is not added, and the others are the same as those in Example 4; under the same process parameters such as reaction temperature and time, the product yield without adding a catalyst is 71.2%; it is proved that zinc acetate as a catalyst can accelerate the reaction rate and improve the product yield.

[0075] The results show that the optimal process conditions for the etherification reaction during the synthesis of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline in the present invention are to control the temperature at 5 - 15 °C for the reaction under the condition of adding zinc acetate as a catalyst.

[0076] The above are only individual embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made according to the technical solutions of the present invention should be included within the protection scope of the present invention.

Claims

1. A preparation method of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline, characterized in that, under an argon atmosphere, using 2-chloro-4-fluorotoluene as the starting material, 2-chloro-4-fluorobenzyl chloride is prepared by chlorination with N-chlorosuccinimide, and then 2-chloro-4-fluorobenzyl chloride reacts with p-aminophenol by etherification reaction. After the reaction solution is purified, 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline is obtained, as specifically shown in Formula I: The method comprises the following steps: (1) Preparation of 2-chloro-4-fluorobenzyl chloride: 2-chloro-4-fluorotoluene is dissolved in acetonitrile. First, benzoyl peroxide is added, and then N-chlorosuccinimide is added in batches. After adding, heating is started and the reaction is carried out at 75 °C for 3 h. After the reaction is completed, the reaction solution is washed and concentrated to obtain 2-chloro-4-fluorobenzyl chloride; (2) Preparation of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline: p-aminophenol is dissolved in N,N-dimethylformamide. Alkali metal alkoxide is added in batches and stirred. Then zinc acetate and 2-chloro-4-fluorobenzyl chloride are added in sequence. After adding, the reaction is carried out at 5-15 °C for 2 h. After the reaction is completed, the reaction solution is purified to obtain 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline; In the step (1), in terms of molar ratio, 2-chloro-4-fluorotoluene:N-chlorosuccinimide:benzoyl peroxide = 10:(10-11):1; 2-chloro-4-fluorotoluene:acetonitrile = 1.25 g:10 mL; In the step (2), the reaction pressure is maintained at 0.02-0.05 MPa; in terms of molar ratio, 2-chloro-4-fluorobenzyl chloride:p-aminophenol:zinc acetate = 10:(10-14):1; 2-chloro-4-fluorobenzyl chloride:N,N-dimethylformamide = 1 g:10 mL; the alkali metal alkoxide is selected from one of lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide; wherein in terms of molar ratio, 2-chloro-4-fluorobenzyl chloride:alkali metal alkoxide = 10:14; In the step (2), the purification process is specifically as follows: (1) The reaction solution is poured into water for quenching, the temperature is controlled at 5-30 °C, dichloromethane is added for extraction, the organic phases are combined and washed with saturated brine, and the organic phase is reserved; (2) The organic phase is placed in a reaction kettle, cooled to 10-20 °C, and hydrogen chloride gas is introduced under stirring, and a large amount of solid is precipitated; continue stirring, filter by suction, wash the filter cake with dichloromethane, and take out the filter cake and dry it to obtain a dark brown solid powder; (3) Water is added to the dark brown solid powder, cooled to 10-20 °C, and an aqueous solution of sodium hydroxide with a mass fraction of 30% is added dropwise, and a large amount of solid is precipitated. Continue stirring, filter by suction, wash the filter cake with water, and take out the filter cake and dry it to obtain 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline.

2. The preparation method of 4-[(2-chloro-4-fluorophenyl)methoxy]-aniline according to claim 1, characterized in that, in the step (1), the washing and concentration means that the reaction solution is cooled to 5-30 °C, filtered, the filter cake is washed with acetonitrile, and the filtrate is concentrated under reduced pressure to a constant weight to obtain 2-chloro-4-fluorobenzyl chloride.

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