Preparation method of flufenoxuron intermediate

Abstract

The invention relates to the field of organic synthesis, and discloses a preparation method of a flufenoxuron intermediate. According to the preparation method disclosed by the invention, 3-fluoro-4-acetaminophenol and 3-chloro-4-fluorobenzotrifluoride are taken as reaction raw materials, and an isomer impurity 4-(5-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline which is difficult to separate is not generated. When the Williamson reaction is carried out, the No.4 site of the 3-chloro-4-fluorobenzotrifluoride is a fluorine element, so that the 3-fluoro-4-acetaminophenol can be better positioned and then substituted, the reaction efficiency is higher, the reaction is more complete, and the yield is higher. The purity of the product 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy) acetanilide (an intermediate of the target product 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline) in the step is higher, and the purity of the target product 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline is finally improved.

Description

Technical Field

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

[0002] Flufenoxuron is a benzoylurea insect growth regulator that appeared in the 1980s. It is a chitin synthesis inhibitor with unique insecticidal activity, insecticidal spectrum and action speed. It has good leaf retention and is especially active against immature mites and pests. The chemical structure of flufenoxuron is as follows:

[0003] 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline is a key intermediate in the synthesis of flufenoxuron, and its chemical structure is as follows:

[0004] There are two main methods for synthesizing 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline. As reported in the literature (Journal of Labelled Compounds and Radiophannaceuticals, 1989, XXVII: 1409, DOI: 10.1002 / jlcr.2580271208), 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline is prepared using 3-fluoro-4-aminophenol and 3-chloro-4-fluorobenzotrifluoride as raw materials, potassium hydroxide as a base, and cyclopentane as a solvent. The reaction equation is as follows: However, the product yield of the method reported in the literature is only 40%, and the product purity is not high. Flufenoxuron prepared with it as a raw material needs to be separated and purified by preparative liquid chromatography. Therefore, this method is far from meeting the requirements of industrial production.

[0005] For example, in the patent application publication number CN103709048A, 3-fluoro-4-aminophenol is used as a raw material, and 3-fluoro-4-acetylaminophenol is prepared by acylation reaction with acid anhydride, and then condensed with 3-chloro-4-fluorobenzotrifluoride in a polar solvent in the presence of an alkaline compound to obtain 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide, and then deprotected and alkalized to obtain 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline. The reaction equation is as follows: The synthetic route of patent CN103709048A has a high yield for synthesizing 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline. The total molar yield of the products of the last three steps is 87.6% based on 3-fluoro-4-acetylaminophenol. However, the purity of the product is poor, and the qualitative content of gas chromatography is only 96%. The synthetic route of CN103709048A for preparing 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline has the following problems: (1) The product contains an isomeric impurity 4-(5-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline (isomer), the chemical structure of which is shown below: The impurity has similar physical and chemical properties to 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline, and the product is a high-boiling point liquid, which is difficult to purify by distillation, and is not conducive to the subsequent production of flubendiamide.

[0006] (2) In this route, after the condensation reaction to obtain 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide, 80% of the DMSO solvent is evaporated and water is directly added to precipitate the solid product, which will lead to a decrease in product yield and also generate a large amount of wastewater.

[0007] (3) During the deprotection and alkalization reactions, the target product is separated by extraction, but there is a serious problem of emulsification, and part of the product will dissolve in water, resulting in a reduced yield and difficult operation, which is not conducive to industrial production. Summary of the invention

[0008] The existing synthetic product of 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline contains an isomeric impurity 4-(5-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline, and has a low purity. In order to solve this problem, the present invention provides a method for preparing a flufenoxuron intermediate.

[0009] The specific technical scheme of the present invention is: A method for preparing a flufenoxuron intermediate comprises the following steps: Step S1: using 3-fluoro-4-acetaminophenol and 3-chloro-4-fluorobenzotrifluoride as reaction raw materials to prepare 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide; Step S2: performing a deacetylation reaction on 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide to prepare 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)aniline salt; Step S3: taking the product of the deacetylation protection reaction and adding it to a solvent, adding an alkaline solution, then heating to remove moisture, filtering while hot, and taking the filtrate to perform a solvent removal operation to obtain 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)aniline.

[0010] As a preferred embodiment of the above preparation method, in step S3, the solvent is one or more of toluene, chlorobenzene and dichlorobenzene.

[0011] As a preferred embodiment of the above preparation method, in step S3, the alkaline solution is a potassium hydroxide solution and / or a sodium hydroxide solution.

[0012] As a preferred embodiment of the above preparation method, an alkaline solution is added until the pH of the mixed solution is 7-8.

[0013] As a preferred embodiment of the above preparation method, in step S3, the method of heating to remove moisture is: removing moisture by thermal reflux.

[0014] As a preferred embodiment of the above preparation method, in step S3, the solvent removal operation is vacuum distillation or rotary evaporation.

[0015] As a preferred embodiment of the above preparation method, in step S1, the step of preparing 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide is: mixing 3-fluoro-4-acetaminophenol with a polar solvent and an alkaline solution, heating for reaction, removing water until the water content in the mixed solution does not exceed 1%, then adding 3-chloro-4-fluorotrifluorotoluene, heating for reaction, and removing the solvent by reduced pressure distillation to obtain 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide.

[0016] Further preferably, in step S1, the alkaline solution is a potassium hydroxide solution with a mass fraction of 30-50% or / and a sodium hydroxide solution with a mass fraction of 30-50%.

[0017] As a preferred embodiment of the above preparation method, in step S1, the molar ratio of 3-fluoro-4-acetaminophenol to the base is 1:1.00-1.60; the molar ratio of 3-fluoro-4-acetaminophenol to 3-chloro-4-fluoro-trifluorotoluene is 1:1.00-2.00.

[0018] As a preferred embodiment of the above preparation method, in step S2, the step of preparing 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)aniline salt is: adding 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide, acid and alcohol to a solvent, reflux reaction, and removing the solvent from the reaction solution to obtain 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)aniline salt.

[0019] Specifically, the synthetic route of the above-mentioned preparation method provided by the present invention is as follows: Compared with the prior art, the present invention has the following technical effects: (1) The preparation method of the present invention uses 3-fluoro-4-acetaminophenol and 3-chloro-4-fluorobenzotrifluoride as reaction raw materials, and does not produce the isomeric impurity 4-(5-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline which is difficult to separate. When the Williamson reaction is carried out, the 4th position of 3-chloro-4-fluorobenzotrifluoride is a fluorine element, which can make 3-fluoro-4-acetaminophenol better positioned, and then substituted, so that the reaction efficiency is higher and the reaction is more complete. The product of this step 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide (an intermediate of the target product 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline) has a higher purity, and finally the purity of the target product 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline is improved.

[0020] (2) Based on the fact that 3-fluoro-4-acetaminophenol and 3-chloro-4-fluorobenzotrifluoride are the starting materials for the reaction, in the process of adding a base to promote the reaction, the base is added in the form of an alkaline solution, so that the base can replace the phenolic hydroxyl group of 3-fluoro-4-acetaminophenol more completely and faster, and then the 3-fluoro-4-acetaminophenol can replace the fluorine element at the 4 position of 3-chloro-4-fluorobenzotrifluoride more completely and faster. More complete replacement can improve the yield of the product of this step, 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide, and faster replacement can improve the purity of the product of this step, 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide, and finally, the purity and yield of the target product 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline are improved.

[0021] (3) Based on the use of 3-fluoro-4-acetaminophenol and 3-chloro-4-fluorobenzotrifluoride as the reaction starting materials, the present invention also removes moisture and solvent by heating to remove moisture and then directly removing the solvent during the alkalization reaction to prepare the final product 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline, thereby reducing product loss and achieving a high yield of the target product 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline.

[0022] (4) The preparation method of the present invention has the advantages of less three wastes and simple operation, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is a liquid phase analysis diagram of the product 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)aniline of Example 1; Figure 2 This is the H NMR spectrum of the product 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)aniline of Example 1; Figure 3 The carbon NMR spectrum of the product 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)aniline of Example 1; Figure 4 LC-MS spectrum of the product of Comparative Example 1; Figure 5 It is the liquid chromatogram of the product of Comparative Example 2. DETAILED DESCRIPTION

[0024] The existing synthetic product of 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline contains an isomeric impurity 4-(5-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline, and the purity is low. Since the isomeric impurity 4-(5-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline is difficult to separate from 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide, in order to avoid the generation of the isomeric impurity, the present invention provides a preparation method of flufenoxuron intermediate (2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy) aniline), comprising the following steps: Step S1: using 3-fluoro-4-acetaminophenol and 3-chloro-4-fluorobenzotrifluoride as reaction raw materials to prepare 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide; Step S2: performing a deacetylation reaction on 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide to prepare 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)aniline salt; Step S3: taking the product of the deacetylation protection reaction and adding it to a solvent, adding an alkaline solution, then heating to remove moisture, filtering while hot, and taking the filtrate to perform a solvent removal operation to obtain 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)aniline.

[0025] One of the advantages of the preparation method of the present invention is that the preparation method of the present invention uses 3-fluoro-4-acetaminophenol and 3-chloro-4-fluorobenzotrifluoride as reaction raw materials, and does not produce the isomeric impurity 4-(5-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline which is difficult to separate. When the Williamson reaction is carried out, the 4th position of 3-chloro-4-fluorobenzotrifluoride is a fluorine element, which can make 3-fluoro-4-acetaminophenol better positioned, and then substituted, so that the reaction efficiency is higher and the reaction is more complete. The product 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide (an intermediate of the target product 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline) of this step has a higher purity, and finally the purity of the target product 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline is improved.

[0026] The second advantage of the preparation method of the present invention is that: based on using 3-fluoro-4-acetaminophenol and 3-chloro-4-fluorobenzotrifluoride as the reaction starting materials, when the present invention performs an alkalization reaction to prepare the final product 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline, water and solvent are removed by heating to remove water and then directly removing the solvent, so that product loss can be reduced, and the yield of the obtained target product 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline is high.

[0027] As a preferred embodiment of the above preparation method, in step S3, the solvent is one or more of toluene, chlorobenzene and dichlorobenzene.

[0028] As a preferred embodiment of the above preparation method, in step S3, the alkaline solution is a potassium hydroxide solution and / or a sodium hydroxide solution.

[0029] As a preferred embodiment of the above preparation method, in step S3, an alkaline solution is added until the pH of the mixed solution is 7-8.

[0030] As a preferred embodiment of the above preparation method, in step S3, the method of heating to remove moisture is: removing moisture by thermal reflux.

[0031] As a preferred embodiment of the above preparation method, in step S3, the solvent removal operation is vacuum distillation or rotary evaporation.

[0032] As a preferred embodiment of the above preparation method, in step S3, the solvent is one or more of toluene, chlorobenzene and dichlorobenzene, and the mass amount of the solvent is 2 to 10 times the mass of the product of the deacetylation protection reaction.

[0033] As a preferred embodiment of the above preparation method, in step S1, the step of preparing 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide is: mixing 3-fluoro-4-acetaminophenol with a polar solvent and an alkaline solution, heating for reaction, removing water until the water content in the mixed solution does not exceed 1% (mass fraction), then adding 3-chloro-4-fluorotrifluorotoluene, heating for reaction, and removing the solvent by reduced pressure distillation to obtain 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide.

[0034] Based on the fact that 3-fluoro-4-acetaminophenol and 3-chloro-4-fluorobenzotrifluoride are the reaction starting materials, in the process of adding a base to promote the reaction, the base is added in the form of an alkaline solution, so that the base can replace the phenolic hydroxyl group of 3-fluoro-4-acetaminophenol more completely and faster, and then the 3-fluoro-4-acetaminophenol can replace the fluorine element at the 4th position of 3-chloro-4-fluorobenzotrifluoride more completely and faster. More complete replacement can improve the yield of the product 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide of this step, and faster replacement can improve the product 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide of this step, and finally, the purity and yield of the target product 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline are improved.

[0035] More preferably, in step S1, the polar solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, and sulfolane. The mass amount of the solvent is 3 to 15 times the mass of 3-fluoro-4-acetaminophenol.

[0036] Further preferably, in step S1, the alkaline solution is a potassium hydroxide solution with a mass fraction of 30-50% or / and a sodium hydroxide solution with a mass fraction of 30-50%.

[0037] More preferably, in step S1, the molar ratio of 3-fluoro-4-acetaminophenol to the base is 1:1.00-1.60; the molar ratio of 3-fluoro-4-acetaminophenol to 3-chloro-4-fluoro-trifluorotoluene is 1:1.00-2.00.

[0038] More preferably, in step S1, the temperature of the heating reaction of 3-fluoro-4-acetaminophenol and the base is 60 to 100° C., and the reaction time is 1 to 3 hours.

[0039] More preferably, in step S1, the heating reaction (condensation reaction) after adding 3-chloro-4-fluorobenzotrifluoride is carried out at a temperature of 100 to 160° C. and a time of 3 to 12 hours.

[0040] The purpose of removing water until the water content in the mixed liquid does not exceed 1% is to ensure the smooth progress of the condensation reaction.

[0041] As a preferred embodiment of the above preparation method, in step S2, the step of preparing 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)aniline salt is: adding 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide, acid and alcohol to a solvent, reflux reaction, and removing the solvent from the reaction solution to obtain 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)aniline salt.

[0042] More preferably, in step S2, the acid is concentrated sulfuric acid or concentrated hydrochloric acid; and the molar ratio of 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide to the acid is 1:1.10-2.20.

[0043] More preferably, in step S2, the alcohol is methanol, ethanol or propanol; and the molar ratio of 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide to the alcohol is 1:1.10-2.00.

[0044] More preferably, in step S2, the solvent is ethyl acetate, toluene, dichloromethane or tetrahydrofuran; and the amount of the solvent is 3 to 10 times the mass of 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide.

[0045] More preferably, in step S2, the reflux reaction time is 3 to 8 hours.

[0046] Specifically, the synthesis process of the above-mentioned preparation method provided by the present invention is as follows: The present invention will be further described below in conjunction with embodiments. Those of ordinary skill in the art will be able to implement the present invention based on these descriptions. In addition, the embodiments of the present invention involved in the following description are generally only embodiments of a part of the present invention, rather than all embodiments. Therefore, based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work should belong to the scope of protection of the present invention.

[0047] Example 1 Step S1: 8.5 g of 3-fluoro-4-acetaminophenol (0.050 mol), 30 mL of DMSO, and 6.5 g of a 50% potassium hydroxide aqueous solution (containing 0.058 mol of potassium hydroxide) were added to a 100 mL three-necked flask equipped with a thermometer and a magnetic stirrer, heated to 70° C. with stirring, and kept warm for 1 h. Water was distilled off under reduced pressure until the water content in the reaction solution was less than 1%, and then 12.4 g of 3-chloro-4-fluorotrifluorotoluene (0.063 mol) was added, and heated to 140° C. with stirring, and kept warm for 5 h. Samples were taken for HPLC detection, which showed that the raw material content was less than 0.5%, and then the temperature was lowered to 80° C. and distilled under reduced pressure until the product in the flask was thick and no solvent was evaporated, and then the temperature was lowered to 40° C.

[0048] Step S2: Add 50mL of ethyl acetate and 5mL of ethanol to the flask where the operation of step S1 is finished to dissolve the distillation residue, and stir continuously, then slowly drop 6.3g of concentrated hydrochloric acid (0.063mol) with a mass fraction of 36%, and slowly drop for a total of 15min. After the dropwise addition, heat and reflux, react for 8h, take samples for HPLC detection, and show that the raw materials are completely reacted, and then evaporate the solvent. The reason for adding ethyl acetate and ethanol to dissolve the distillation residue first is that the distillation residue is relatively thick and will become solid at room temperature, and it is necessary to add a solvent to dissolve it in advance.

[0049] Step S3: Add 60 mL of toluene to the flask where step S2 is completed, adjust the pH of the reaction solution to 7.5 with a 30% NaOH aqueous solution, then heat and reflux to remove water from the system, then filter while hot, wash the filter cake with toluene, and combine the filtrate to obtain 15.2 g of brown liquid. The brown liquid was characterized by liquid chromatography normalization method, and the content of the target product 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline was 99.1%, and the 100 molar yield was 97.2%. The liquid chromatogram of the brown liquid is shown in Figure 1 .

[0050] The product was taken for NMR analysis. The NMR hydrogen spectrum and carbon spectrum are shown in Figure 2 and 3 , the data is as follows: 1 H NMR (400MHz, Chloroform-d: δ7.84(d,J=2.3Hz,1H),7.57(dd,J=8.9Hz,1H),6.94(d,J=2.6Hz,1H),6.91(t,J=2.8Hz,1H),6.87(m,J=8.6Hz,1H),5.17(s,2H); 13 C NMR (101MHz, Chloroform-d): δ157.5, 151.9, 149.5, 144.0 (d, J = 9.4Hz), 134.7 (d, J = 12.7Hz), 127.9 (q, J = 3.6Hz), 126 .1(q,J=3.7Hz), 123.9(d,J=270.0Hz), 124.2(q,J=32.7Hz), 123.2, 117.4, 117.0(dd,J=9.9Hz), 108.7(d,J=21.3Hz).

[0051] Example 2 Step S1: In a 100mL three-necked flask equipped with a thermometer and a magnetic stirrer, 8.5g of 3-fluoro-4-acetaminophenol (0.050mol), 30mL of DMSO, and 7.3g of a 50% potassium hydroxide aqueous solution (containing 0.065mol of potassium hydroxide) were added, and the mixture was heated to 70°C with stirring for 1h, and the water was evaporated by reduced pressure distillation until the water content in the reaction solution was less than 1%, and then 13.7g of 3-chloro-4-fluorotrifluorotoluene (0.065mol) was added, and the mixture was heated to 140°C with stirring for 5h, and the temperature was lowered to 80°C, and the mixture was distilled under reduced pressure until the product in the flask was thick and no solvent was evaporated, and the temperature was lowered to 40°C.

[0052] Step S2: Add 50 mL of ethyl acetate and 5 mL of ethanol to the flask where step S1 is completed to dissolve the distillation residue and stir continuously, then slowly drop 7.0 g of 36% concentrated hydrochloric acid (0.070 mol) for a total of 15 minutes. After the addition is complete, reflux for 7 hours and evaporate the solvent.

[0053] Step S3: Add 60 mL of toluene to the flask where the step S2 operation is completed, adjust the pH of the reaction solution to 7 with a 50% by mass sodium hydroxide aqueous solution, then heat and reflux to remove water from the system; filter while hot, wash the filter cake with toluene, and combine the filtrate to concentrate under reduced pressure to obtain 14.9 g of a brown liquid. The brown liquid is characterized by a liquid chromatography normalization method. The content of the target product 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline is 98.7%, and the 100 molar yield is 96.4%.

[0054] Example 3 Step S1: 8.5 g of 3-fluoro-4-acetaminophenol (0.050 mol), 30 mL of DMSO, and 4.6 g of a 50% sodium hydroxide aqueous solution (containing 0.058 mol of sodium hydroxide) were added to a 100 mL three-necked flask equipped with a thermometer and a magnetic stirrer, and the mixture was heated to 70° C. and kept warm for 1 h under stirring. Water was distilled off under reduced pressure until the water content in the reaction solution was less than 1%, and then 13.7 g of 3-chloro-4-fluorotrifluorotoluene (0.065 mol) was added, and the mixture was heated to 120° C. and kept warm for 5 h under stirring. HPLC detection showed that the raw materials were not completely reacted. The reaction was continued for 4 h until HPLC detection showed that the raw material content did not change. The mixture was cooled to 80° C. and distilled under reduced pressure until the product in the flask was thick and no solvent was evaporated, and the mixture was cooled to 40° C.

[0055] Step S2: Add 50 mL of toluene and 5 mL of ethanol to the flask where step S1 is completed to dissolve the distillation residue and stir continuously, then slowly drop 8.0 g of 36% concentrated hydrochloric acid (0.080 mol) for a total of 15 minutes. After the addition is complete, heat to reflux, react for 5 hours, and evaporate the solvent.

[0056] Step S3: Add 60 mL of chlorobenzene to the flask where the step S2 operation is completed, adjust the pH of the reaction solution to 8 with a 50% by mass potassium hydroxide aqueous solution, then heat and reflux to remove water from the system; filter while hot, wash the filter cake with chlorobenzene, and combine the filtrate to concentrate under reduced pressure to obtain 14.6 g of a brown liquid. The brown liquid is characterized by a liquid chromatography normalization method. The content of the target product 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline is 98.3%, and the 100 molar yield is 94.1%.

[0057] Comparative Example 1 The only difference from Example 1 is that the raw material 0.063 mol of 3-chloro-4-fluorobenzotrifluoride in step S1 is replaced by 0.063 mol of 3,4-dichlorobenzotrifluoride. The rest is the same as Example 1.

[0058] This comparative example was carried out according to the following steps: Step S1: 8.5g of 3-fluoro-4-acetaminophenol (0.050mol), 30mL DMSO, and 6.5g of a 50% potassium hydroxide aqueous solution (containing 0.058mol potassium hydroxide) were added to a 100mL three-necked flask equipped with a thermometer and a magnetic stirrer, heated to 70°C under stirring, kept warm for 1h, and distilled under reduced pressure to remove water until the water content in the reaction solution was less than 1%, then 0.063mol of 3.4-dichlorotrifluorotoluene was added, heated to 140°C under stirring, kept warm for 5h, then cooled to 80°C, distilled under reduced pressure until the product in the flask was thick and no more solvent was distilled, and then cooled to 40°C. Sampling and testing found that the product contained an isomeric impurity 4-(5-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline.

[0059] Step S2: Add 50 mL of ethyl acetate and 5 mL of ethanol to the flask where step S1 was completed, dissolve the residual liquid, distill and stir continuously, then slowly drop 6.3 g of 36% concentrated hydrochloric acid (0.063 mol), the slow drop time is 15 min, after the drop addition is complete, heat and reflux, react for 8 h, take a sample for HPLC detection, which shows that the raw material is completely reacted, and then evaporate the solvent.

[0060] Step S3: Add 60 mL of toluene to the flask where the step S2 operation is completed, adjust the pH of the reaction solution to 7.5 with a 30% NaOH aqueous solution by mass fraction, then heat and reflux to remove water in the system, then filter while hot, wash the filter cake with toluene, and combine the filtrate to obtain a brown liquid under reduced pressure. The brown liquid is characterized by a liquid chromatography normalization method, and the content of the target product 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline is 95.1%, and the 100 molar yield is 91.2%.

[0061] It can be seen from this comparative example that the preparation method of the present invention has better purity and higher yield for preparing 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline.

[0062] Further, the brown liquid obtained in step S3 is put into the subsequent reaction to prepare the flufenoxuron product. The product can be detected by LC-MS as the flufenoxuron isomer 1-[2-fluoro-4-(2-chloro-5-trifluoromethylphenoxy)phenyl]-3-(2,6-difluorobenzoyl)urea, and the structural formula is as follows:

[0063] The flufenoxuron isomer 1-[2-fluoro-4-(2-chloro-5-trifluoromethylphenoxy)phenyl]-3-(2,6-difluorobenzoyl)urea is difficult to remove by purification.

[0064] Comparative Example 2 Prepared according to Example 7 of patent publication number CN103709048A. Due to some phenomena during the experiment, it is impossible to completely follow the method of patent CN103709048A, so there are slight differences in the operation, as follows: Step S1: Under nitrogen protection, 265 g of DMSO, 18.8 g (0.333 mol) of potassium hydroxide, and 52.3 g (0.303 mol) of 3-fluoro-4-acetaminophenol were added in sequence to a 250 ml four-necked bottle equipped with a thermometer, a stirrer, a reflux condenser and a nitrogen protection device, and heated and stirred to (60-70)°C for 0.5 h of heat preservation reaction, and then 30 g of solvent was distilled off, and the water content of the reaction liquid in the kettle was less than 1%. At 75°C, 72.3 g (0.333 mol) of 3.4-dichlorotrifluorotoluene was added, and the mixture was heated to 115°C for 4 hours of heat preservation reaction. HPLC detection showed that the raw materials were not completely reacted, and the heat preservation reaction was continued for 6 h until HPLC detection showed that the raw material content did not change. Then the temperature was lowered to 55°C, and the solvent DMSO was distilled under reduced pressure to distill off 80% of the DMSO solvent.

[0065] After adding 3,4-dichlorotrifluorotoluene and reacting for 3 hours, samples were taken for LC-MS detection. The results are shown in Figure 4 , where M=169 is the peak of raw material 3-fluoro-4-acetaminophenol.

[0066] LC-MS detection shows that the product of step S1 contains an isomeric impurity 4-(5-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline. The impurity has similar physical and chemical properties to 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline, and the product is a high-boiling liquid, which is difficult to purify by distillation, and is not conducive to the subsequent production of flubendiamide.

[0067] Step S2: Under nitrogen protection, 188.2 grams of 95% ethanol, 0.18mol (in terms of 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide) of step S1 are added successively in a 250 ml four-necked bottle equipped with a thermometer, a stirrer, a reflux condenser and a nitrogen protection device, and 35.5 grams (0.36mol) of 36% hydrochloric acid are added dropwise to naturally heat up, and the reaction mixture is heated to 78°C and refluxed for 5 hours, and the HPLC raw material reaction is complete. Ethanol is distilled at normal pressure to 98°C of kettle temperature, and the reaction solution presents a viscous state, and solid is evaporated to dryness, and a beating operation (mixed solvent and solid mixed mass ratio 8:3) is performed with a mixed solvent obtained by mixing mass ratio of 1:3 with ethanol and 12% hydrochloric acid solution (mass fraction), filtered, filter cake is added with ethyl acetate and dissolved in water, and then 30% (mass fraction) sodium hydroxide solution is added dropwise to pH 7.5, 400mL of ethyl acetate is added and stirred for extraction, and the upper organic layer is separated, and high vacuum distillation is concentrated to obtain a light brown liquid. During the extraction process, it was found that the extraction system had serious emulsification phenomenon and some products were dissolved in water.

[0068] The product light brown liquid was characterized by liquid chromatography normalization method, and the content of the target product 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline was 98.5%, but the 100 molar yield was only 68.0%. The liquid chromatogram of the brown liquid is shown in Figure 5 .

[0069] The yield of the target product in this comparative example is relatively low, which may be caused by the emulsification phenomenon in the extraction process. At the same time, when repeating the operation of patent CN103709048A, this comparative example performed an anti-solvent pulping operation, and the purity / content reached 98.5%. It can be seen that if the operation of patent CN103709048A is directly followed, the content of 98.5% cannot be achieved.

[0070] Comparative Example 3 The only difference from Example 1 is that in step S1, 6.5 g of 50% potassium hydroxide aqueous solution is replaced by 0.058 mol of solid potassium hydroxide. The rest is the same as Example 1.

[0071] The brown liquid product of this comparative example was characterized by a liquid chromatography normalization method. The content of the target product 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline was 98.6%, and the 100 molar yield was 90.2%.

[0072] By this comparative example and embodiment 1 comparative analysis, alkali is added in the form of solid alkali, there will be the problem of incomplete reaction, alkali is added in the form of the aqueous solution of alkali, the homogeneous phase of reaction solution can be maintained, the reaction of step S1 can be promoted, and the yield of final product is increased. Further analysis of its reason is: alkali is added in the form of alkaline solution, the phenolic hydroxyl group of alkali replacement 3-fluoro-4-acetaminophenol can be made more complete and faster, and then 3-fluoro-4-acetaminophenol is made to replace the 4th position fluorine element of 3-chloro-4-fluorobenzotrifluoride more completely and faster, and the replacement can improve the yield of this step product 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy) acetanilide more completely, and the replacement can improve this step product 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy) acetanilide faster, and finally, the purity and yield of target product 4-(4-trifluoromethyl-2-chlorophenoxy)-2-fluoroaniline are improved.

[0073] The raw materials and equipment used in the present invention, unless otherwise specified, are all commonly used raw materials and equipment in the art; the methods used in the present invention, unless otherwise specified, are all conventional methods in the art.

[0074] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any way. Any simple modification, change and equivalent transformation made to the above embodiment based on the technical essence of the present invention still falls within the protection scope of the technical solution of the present invention.

Claims

1. A method for preparing a flufenoxuron intermediate, characterized in that: The following steps are involved: Step S1: using 3-fluoro-4-acetaminophenol and 3-chloro-4-fluorobenzotrifluoride as reaction raw materials to prepare 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide; Step S2: performing a deacetylation reaction on 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide to prepare 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)aniline salt; Step S3: taking the product of the deacetylation protection reaction and adding it to a solvent, adding an alkaline solution, then heating to remove moisture, filtering while hot, and taking the filtrate to perform a solvent removal operation to obtain 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)aniline.

2. The method for preparing a flufenoxuron intermediate according to claim 1, characterized in that: In step S3, the solvent is one or more of toluene, chlorobenzene, and dichlorobenzene.

3. The method for preparing a flufenoxuron intermediate according to claim 1, characterized in that: In step S3, the alkaline solution is a potassium hydroxide solution and / or a sodium hydroxide solution.

4. A method for preparing a flufenoxuron intermediate as claimed in claim 1 or 3, characterized in that: Add alkaline solution until the pH of the mixture is 7-8.

5. The method for preparing a flufenoxuron intermediate according to claim 1, characterized in that: In step S3, the method of heating to remove moisture is: removing moisture by thermal reflux.

6. The method for preparing a flufenoxuron intermediate according to claim 1, characterized in that: In step S3, the solvent removal operation is vacuum distillation or rotary evaporation.

7. The method for preparing a flufenoxuron intermediate according to claim 1, characterized in that: In step S1, the step of preparing 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide is: mixing 3-fluoro-4-acetaminophenol with a polar solvent and an alkaline solution, heating for reaction, removing water until the water content in the mixed solution does not exceed 1%, then adding 3-chloro-4-fluorotrifluorotoluene, heating for reaction, and removing the solvent by reduced pressure distillation to obtain 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide.

8. The method for preparing a flufenoxuron intermediate according to claim 7, characterized in that: The alkaline solution is a potassium hydroxide solution with a mass fraction of 30-50% or / and a sodium hydroxide solution with a mass fraction of 30-50%.

9. The method for preparing a flufenoxuron intermediate according to claim 7, characterized in that: The molar ratio of 3-fluoro-4-acetaminophenol to the base is 1:1.00-1.60; the molar ratio of 3-fluoro-4-acetaminophenol to 3-chloro-4-fluoro-trifluorotoluene is 1:1.00-2.

00.

10. The method for preparing a flufenoxuron intermediate according to claim 1 or 7, characterized in that: In step S2, the step of preparing 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)aniline salt is: adding 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)acetanilide, acid and alcohol to a solvent, reflux reaction, and removing the solvent from the reaction solution to obtain 2-fluoro-4-(2-chloro-4-trifluoromethylphenoxy)aniline salt.

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