Preparation method of 2, 4, 5-trifluorophenylacetic acid

Abstract

The invention provides a preparation method of 2, 4, 5-trifluorophenylacetic acid, which comprises the following steps: by taking tetrachloro-terephthalonitrile as a raw material, carrying out substitution reaction on tetrachloro-terephthalonitrile and a substitution reagent in the presence of first alkali to obtain a substitution product; then carrying out a fluorination reaction on the substitution product and fluoride salt to obtain a fluorinated product; and finally, sequentially carrying out hydrolysis and decarboxylation reaction on the fluorinated product to prepare the 2, 4, 5-trifluorophenylacetic acid. According to the preparation method, tetrachloro-terephthalonitrile is taken as a raw material, substitution reaction is carried out firstly, then fluorination reaction is carried out, and compared with a traditional method that fluorination is carried out firstly and then substitution is carried out, the specific synthesis sequence not only can effectively improve the selectivity of the reaction, but also can reduce the usage amount of fluoride salt and reduce the preparation cost. The preparation cost can be further reduced by using tetrachloro-terephthalonitrile which is low in price and wide in source as a raw material. The optimization of the synthesis method especially has obvious progressive significance in large-scale production of the 2, 4, 5-trifluorophenylacetic acid.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical intermediate preparation, and more particularly to a method for preparing 2,4,5-trifluorophenylacetic acid. Background Art

[0002] Since sitagliptin (with the structure shown in formula (Ⅱ)) was discovered, due to its significant hypoglycemic effect, excellent safety and tolerance, and low toxicity and side effects, it has quickly become one of the preferred drugs for the treatment of type 2 diabetes. As an inhibitor of dipeptidyl peptidase-4 (DPP-4), it can effectively increase the level of glucagon-like peptide-1 (GLP-1) in the body, thereby promoting insulin secretion by pancreatic islet β cells and reducing blood sugar. In the synthesis route of sitagliptin, 2,4,5-trifluorophenylacetic acid (with the structure shown in formula (Ⅲ)) is a crucial intermediate. There have been many studies on the sitagliptin intermediate - 2,4,5-trifluorophenylacetic acid, which are listed as follows.

[0003]

[0004] US20040068141 proposed a method for preparing 2,4,5-trifluorophenylacetic acid by using 2,4,5-trifluorobromobenzene and diethyl malonate as raw materials, and carrying out a substitution reaction of bromine atoms on the benzene ring under the condition of using sodium tert-butoxide as a strong base, and then through hydrolysis. However, this route not only has a low yield due to harsh reaction conditions, but also has difficulties in obtaining the starting material trifluorobromobenzene, which limits its application in industrial production. Its reaction route is as follows:

[0005]

[0006] US6870067 improved the synthesis process of the 2,4,5-trifluorobromobenzene raw material, introduced an allyl group through a Grignard reagent reaction, and then oxidized it with a catalyst RuCl 3 and an oxidant NaIO 4 to obtain the target product. This route is extremely sensitive to environmental factors. The potential explosion risk during the preparation of the Grignard reagent, as well as the use of expensive catalysts and oxidants, make it not advantageous in terms of cost and safety and is not conducive to large-scale production. Its reaction route is as follows:

[0007]

[0008] CN106866406A proposed a new process for synthesizing 2,4,5-trifluorophenylacetic acid. The starting materials of this process are difficult to obtain, and the selectivity of the substitution reaction is not high, with many by-products, and the decarboxylation reaction does not perform well under acidic conditions. This leads to a reduction in the overall yield and the complexity of the treatment of the three wastes. Its reaction route is as follows:

[0009]

[0010] CN1749232 provides a synthetic route including chloromethylation, cyanidation and hydrolysis. However, the low yield of the chloromethylation reaction and the large amount of three wastes generated, together with the high toxicity of sodium cyanide, significantly increase the risks of this process in industrial production. The reaction route is as follows:

[0011]

[0012] CN101244994 provides a synthetic route based on 1,2,4-trifluorobenzene, involving F-C acylation, Willegerodt-Kindler reaction and hydrolysis. Although attempts have been made to reduce wastewater discharge, this route is complex in operation, has harsh reaction conditions and is uneconomical.

[0013] CN1749232 uses 1,2,4-trifluorobenzene as the raw material, chlorosulfonic acid and zinc chloride as the chlorinating agents, and reacts with paraformaldehyde through the Blanc reaction to prepare 2,4,5-trifluorobenzyl chloride. In this method, the yield of the chloromethylation reaction of this process is very low and the three wastes are excessive. Chlorosulfonic acid has a very strong pungent smell, poor safety, and the phase transfer catalyst is difficult to recycle, with poor atom economy, a substantial increase in production costs and poor environmental friendliness. Therefore, it is not suitable for industrial production.

[0014] CN107522609 discloses a process starting from aniline. Sodium nitrite is added to glacial acetic acid, and then an aqueous solution of sodium fluoroborate is added dropwise to react to obtain 2,3,5-trifluoroaniline; then 2,3,5-trifluoroaniline and tin(IV) chloride-polystyrene complex are added to glacial acetic acid, and then liquid bromine is added. After post-treatment, 2,3,5-trifluoro-6-bromoaniline is obtained. Then NaH and ethyl acetate are added, and the reaction is carried out under the action of copper bromide at high temperature, acidified, and then sodium nitrite is added for diazotization to obtain the corresponding product 2,3,5-trifluorophenylacetic acid. The product yield of the first fluorination reaction in this process is still uncertain, and there are no similar commercial application examples. According to the reported literature, the yield of the third reaction is generally too low and it has no production potential. The intermediate for the fourth step of de-NH2 is prone to runaway explosion, and the raw materials liquid bromine and NaH used in the reaction process are also dangerous substances, with poor safety.

[0015] CN107522609A discloses a process for preparing 2,3,5-trifluorophenylacetic acid. In this process, aniline is used as the raw material, and 2,3,5-trifluoroaniline is obtained through the reaction of glacial acetic acid, sodium nitrite and an aqueous solution of sodium tetrafluoroborate, followed by subsequent conversion. However, the yield of the fluorination reaction in this process is uncertain, and liquid bromine and NaH are used in the subsequent diazotization reaction. The hazards of these raw materials increase the safety risks during the production process, and no further commercial application of this route has been reported. The reaction route is as follows:

[0016]

[0017] CN117776910A proposes a scheme for synthesizing 2,3,5-trifluorophenylacetic acid using 2,4,5-trifluoronitrobenzene as the raw material through nitro reduction, diazotization and hydrolysis reactions. However, the raw materials and catalysts used in this route are inconvenient to obtain, the operating conditions include high temperature and the hazards of the diazotization reaction, and the large amount of industrial wastewater generated makes it difficult to meet the requirements of industrial production as a whole. The reaction route is as follows:

[0018]

[0019] In summary, in the existing preparation methods of 2,3,5-trifluorophenylacetic acid, there are certain limitations due to dangerous reaction conditions, pollution problems, cost problems, or high risk coefficients of reaction conditions. These defects limit the production of the drug sitagliptin to a certain extent. Therefore, there is an urgent need to develop a synthesis method of 2,4,5-trifluorophenylacetic acid that can reduce the production cost of 2,4,5-trifluorophenylacetic acid while improving the yield and reducing pollution. For this reason, the present invention is specifically proposed. SUMMARY OF THE INVENTION

[0020] The main object of the present invention is to provide a preparation method of 2,4,5-trifluorophenylacetic acid to solve the problems of low reaction efficiency, high preparation cost and serious pollution existing in the synthesis of 2,4,5-trifluorophenylacetic acid, which is an intermediate of sitagliptin, in the prior art.

[0021] The present invention provides a method for preparing 2,4,5-trifluorophenylacetic acid. The preparation method includes: substitution: dissolving tetrachloroterephthalonitrile, a first base, and a substitution reagent in a first organic solvent to carry out a substitution reaction, and subjecting the obtained substitution reaction solution to a first separation to obtain a substitution product; fluorination: mixing the substitution product with a fluoride salt and a second organic solvent to carry out a fluorination reaction, and subjecting the obtained fluorination reaction solution to a second separation to obtain a fluorination product; hydrolysis: carrying out a hydrolysis reaction on the fluorination product in an aqueous acid solution, and subjecting the obtained hydrolysis reaction solution to a third separation to obtain a hydrolysis product; decarboxylation: mixing the hydrolysis product with a decarboxylating agent and a third organic solvent to carry out a decarboxylation reaction, and subjecting the obtained decarboxylation reaction solution to a fourth separation to obtain a 2,4,5-trifluorophenylacetic acid product; the substitution reagent has a structure shown in the following formula (I): Wherein, R 1 is an alkyl group of C 1 ~C 10 ; R 2 is -CN or -COOR 3 , and R 3 is H or an alkyl group of C 1 ~C 10 .

[0022] Further, in formula (I), R 1 is at least one of methyl, ethyl or isopropyl; preferably, R 3 is at least one of methyl, ethyl or isopropyl; preferably, the molar ratio of the fluoride salt to the substitution product is (3-7):1; more preferably, the molar ratio of the fluoride salt to the substitution product is (3.5-5):1.

[0023] Further, the decarboxylating agent is a carbonate; preferably, the decarboxylating agent is one or more of potassium carbonate, sodium bicarbonate, potassium bicarbonate or sodium carbonate; preferably, the molar ratio of the decarboxylating agent to the hydrolysis product is (0.03-0.1):1; preferably, the fluoride salt is potassium fluoride.

[0024] Further, the temperature of the substitution reaction is 40-120 °C, and the time of the substitution reaction is 8-12 h; preferably, the temperature of the substitution reaction is 45-80 °C; preferably, the first base is one or more of potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide; preferably, the molar ratio of the first base, the substitution reagent and tetrachloroterephthalonitrile is (1.1-3.2):(1.2-3.5):1; more preferably, the molar ratio of the first base, the substitution reagent and tetrachloroterephthalonitrile is (1.2-2.2):(1.5-3):1.

[0025] Further, the temperature of the fluorination reaction is 100-180 °C, and the time of the fluorination reaction is 3-5 h; more preferably, the temperature of the fluorination reaction is 140-160 °C.

[0026] Furthermore, the temperature of the hydrolysis reaction is 50 to 150 °C, and the time of the hydrolysis product is 4 to 6 h; preferably, the temperature of the hydrolysis reaction is 100 to 120 °C; preferably, the aqueous solution of the acid is an aqueous sulfuric acid solution; preferably, the mass concentration of the aqueous solution of the acid is 10 to 60%; more preferably, the mass concentration of the acid solution is 25 to 40%.

[0027] Furthermore, the temperature of the decarboxylation reaction is 90 to 120 °C, and the time of the decarboxylation reaction is 4 to 6 h.

[0028] Furthermore, the first organic solvent is one or more of acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, ethyl acetate, and dimethyl sulfoxide; preferably, the second organic solvent is an aprotic organic solvent; more preferably, the second organic solvent is one or more of N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and N,N-dimethylacetamide; preferably, the third organic solvent is N,N-dimethylformamide.

[0029] Furthermore, the first separation includes: removing the first organic solvent from the substitution reaction solution, adding water thereto, and sequentially performing first pulping and first filtration to obtain a substitution product; and / or, the second separation includes: removing the second organic solvent from the fluorination reaction solution, adding water thereto, and sequentially performing second pulping and second filtration to obtain a fluorinated product; and / or, the third separation includes: cooling the hydrolysis reaction solution to 25 to 35 °C, precipitating the hydrolysis product from the hydrolysis reaction solution, and then sequentially performing centrifugation and water washing to obtain the hydrolysis product; and / or, the fourth separation includes: removing the third organic solvent from the decarboxylation reaction solution, adding water thereto, sequentially performing third pulping and third filtration, and acidifying the obtained second solid substance to obtain a decarboxylation product; preferably, the acid used in the acidification process is sulfuric acid.

[0030] Furthermore, the weight ratio of the first organic solvent to tetrachloroterephthalonitrile is (3 to 6):1; preferably, the weight ratio of the second organic solvent to the substitution product is (4 to 9):1; more preferably, the weight ratio of the second organic solvent to the substitution product is (5 to 8):1; preferably, the weight ratio of the third solvent to the hydrolysis product is (3 to 5):1; preferably, the weight ratio of the aqueous solution of the acid to the fluorinated product is (4 to 7):1.

[0031] The present invention provides a method for preparing 2,4,5-trifluorophenylacetic acid. In this preparation method, tetrachloroterephthalonitrile is used as the raw material. First, a substitution reaction is carried out with a substitution reagent in the presence of a first base to obtain a substitution product; then the substitution product is subjected to a fluorination reaction with a fluoride salt to obtain a fluorination product; finally, the obtained fluorination product is successively subjected to hydrolysis and decarboxylation reactions to prepare 2,4,5-trifluorophenylacetic acid. In the above preparation method, using tetrachloroterephthalonitrile, which is inexpensive and widely available, as the raw material can effectively reduce the production cost of 2,4,5-trifluorophenylacetic acid. In addition, in the present invention, using tetrachloroterephthalonitrile as the raw material, first carrying out the substitution reaction and then the fluorination reaction, compared with the traditional method of first fluorination and then substitution, the above specific synthesis sequence proposed by the present invention can not only effectively improve the selectivity of the reaction, but also further reduce the preparation cost. First, the chlorine in tetrachloroterephthalonitrile has lower reactivity than fluorine. Using tetrachloroterephthalonitrile as the raw material for the substitution reaction can avoid the situation where multiple halogen atoms in the raw material are substituted due to overreaction, thereby reducing the occurrence of side reactions, further improving the selectivity of the substitution reaction, and increasing the purity and yield of the substitution product; second, the above specific reaction sequence can reduce the usage amount of the fluoride salt in the fluorination process. The reduction in the usage amount of the fluoride salt can not only reduce the cost of the synthesis reaction, but also reduce the amount of fluorine-containing by-products metabolized from fluorine in the synthesis process, which is beneficial to further reducing the cost of treating wastewater and waste liquid, and can further alleviate the pollution problem caused thereby. In short, using the method for preparing 2,4,5-trifluorophenylacetic acid provided by the present invention can effectively reduce the preparation cost of 2,4,5-trifluorophenylacetic acid, improve the selectivity of the reaction, and increase the production efficiency. The optimization of the above synthesis method, especially for the large-scale production of 2,4,5-trifluorophenylacetic acid, has important significance. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] The accompanying drawings forming a part of this application are used to provide a further understanding of the present invention. The schematic embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the drawings:

[0033] Figure 1 shows the hydrogen spectrum of 2,4,5-trifluorophenylacetic acid prepared according to Example 1 of the present invention;

[0034] Figure 2 shows the carbon spectrum of 2,4,5-trifluorophenylacetic acid prepared according to Example 1 of the present invention;

[0035] Figure 3 shows the fluorine spectrum of 2,4,5-trifluorophenylacetic acid prepared according to Example 1 of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0036] It should be noted that, without conflict, the embodiments in the present application and the features in the embodiments can be combined with each other. The present invention will be described in detail below with reference to the accompanying drawings and in combination with the embodiments.

[0037] As described in the background art section, sitagliptin has significant hypoglycemic effects, excellent safety and tolerance, and low toxic side effects, and has quickly become one of the preferred drugs for the treatment of type 2 diabetes. 2,4,5-Trifluorophenylacetic acid is an important intermediate in the preparation of sitagliptin. However, in the prior art, when preparing 2,4,5-trifluorophenylacetic acid, there are certain limitations either due to dangerous reaction conditions, pollution problems, or cost problems. Therefore, there is an urgent need to develop a method for synthesizing 2,4,5-trifluorophenylacetic acid, which can reduce the production cost of 2,4,5-trifluorophenylacetic acid while also increasing the yield and reducing pollution.

[0038] To solve the above problems, the present invention provides a method for preparing 2,4,5-trifluorophenylacetic acid, which comprises: Substitution: dissolving tetrachloroterephthalonitrile, a first base, and a substitution reagent in a first organic solvent to carry out a substitution reaction, and subjecting the obtained substitution reaction solution to a first separation to obtain a substitution product; Fluorination: mixing the substitution product with a fluoride salt and a second organic solvent to carry out a fluorination reaction, and subjecting the obtained fluorination reaction solution to a second separation to obtain a fluorination product; Hydrolysis: carrying out a hydrolysis reaction on the fluorination product in an aqueous solution of an acid, and subjecting the obtained hydrolysis reaction solution to a third separation to obtain a hydrolysis product; Decarboxylation: mixing the hydrolysis product with a decarboxylating agent and a third organic solvent to carry out a decarboxylation reaction, and subjecting the obtained decarboxylation reaction solution to a fourth separation to obtain a 2,4,5-trifluorophenylacetic acid product; The substitution reagent has the structure shown in the following formula (I):

[0039] Wherein, R 1 is an alkyl group of C 1 ~C 10 ; R 2 is -CN or -COOR 3 , and R 3 is H or an alkyl group of C 1 ~C 10 .

[0040] The above method for preparing 2,4,5-trifluorophenylacetic acid uses tetrachloroterephthalonitrile as the starting material. First, a substitution reaction is carried out with a substitution reagent in the presence of a first base to obtain a substitution product; then, the obtained substitution product is subjected to a fluorination reaction with a fluoride salt to obtain a fluorination product; finally, the obtained fluorination product is successively subjected to a hydrolysis reaction and a decarboxylation reaction to prepare 2,4,5-trifluorophenylacetic acid.

[0041] On the one hand, the above-mentioned preparation method uses low-priced and widely available tetrachloroterephthalonitrile as the starting material, which can effectively reduce the production cost of 2,4,5-trifluorophenylacetic acid. On the other hand, compared with the traditional method of first fluorination and then substitution, the present invention uses tetrachloroterephthalonitrile as the raw material, first performs a substitution reaction and then performs a fluorination reaction. This synthesis sequence can not only effectively improve the selectivity of the synthesis reaction, but also further reduce the preparation cost. First, the chlorine in tetrachloroterephthalonitrile has a lower reaction activity than fluorine. Using tetrachloroterephthalonitrile as the raw material for the substitution reaction can avoid the situation where multiple halogen atoms in the raw material are replaced due to overreaction, thereby reducing the occurrence of side reactions and improving the choice of reaction; and the activity of the product after the substitution reaction of a chlorine atom in tetrachloroterephthalonitrile is relatively stable, which ensures the reaction efficiency. Two reasons ensure the purity, yield and reaction efficiency of the substituted product, and then ensure the purity, yield and reaction efficiency of the final target product. Secondly, the above-mentioned specific reaction sequence can reduce the amount of fluoride salt used in the fluorination process. The reduction in the amount of fluoride salt used can not only reduce the cost of the synthesis reaction, but also reduce the amount of fluorine-containing substances metabolized by fluorine in the synthesis process, further reduce the cost of treating wastewater and waste liquid, and further alleviate the pollution problems caused thereby.

[0042] In summary, the method for preparing 2,4,5-trifluorophenylacetic acid provided by the present invention can not only make the yield of each reaction process within a good range, but also reduce the cost of raw materials and the cost in the preparation process. The optimization of the above-mentioned synthesis method is of great significance, especially for the large-scale production of 2,4,5-trifluorophenylacetic acid. The specific reaction route of the above-mentioned preparation method is as follows:

[0043]

[0044] In a preferred embodiment, in formula (I), R 1 is at least one of methyl, ethyl or isopropyl; preferably, R 3is at least one of methyl, ethyl or isopropyl. Selecting a substitution reagent having the above groups can further increase the rate of the substitution reaction. Preferably, the substitution reagent is at least one of methyl cyanoacetate, ethyl cyanoacetate, isopropyl cyanoacetate, dimethyl malonate, diethyl malonate and diisopropyl malonate, and the substitution effect of the above substitution reagents is better. Preferably, the molar ratio of the fluoride salt to the substitution product is (3-7):1, specifically such as 3:1, 3.2:1, 3.5:1, 3.8:1, 4.0:1, 4.3:1, 4.5:1, 4.8:1, 5:1, 5.3:1, 5.5:1, 5.8:1, 6:1, 6.5:1, 6.8:1, 7:1, or any ratio between any two of the above ratios. In the process of preparing 2,4,5-trifluorophenylacetic acid, the present invention adopts a specific order of substitution first and then fluorination. After the substitution reaction, there are only three chlorination sites to be fluorinated during the fluorination reaction of the substitution product, which can effectively reduce the usage amount of the fluoride salt during the fluorination reaction. Controlling the molar ratio of the fluoride salt to the substitution product within the above range can make the fluorination reaction more complete. More preferably, the molar ratio of the fluoride salt to the substitution product is (3.5-5):1, specifically such as 3:1, 3.2:1, 3.5:1, 3.8:1, 4.0:1, 4.3:1, 4.5:1, 4.8:1, 5:1, or any ratio between any two of the above ratios. Controlling the molar ratio of the fluoride salt to the substitution product within the above more preferred range can not only make the fluorination reaction proceed better, but also further reduce the usage amount of the fluoride salt and further reduce the preparation cost. More preferably, the molar ratio of the fluoride salt to the substitution product is (3.5-4):1. Controlling the molar ratio of the fluoride salt to the substitution product within the above range can further reduce the preparation cost.

[0045] In a preferred embodiment, the decarboxylating agent is a carbonate; preferably, the decarboxylating agent is one or more of potassium carbonate, sodium bicarbonate, potassium bicarbonate, or sodium carbonate. Selecting a weak base of carbonate as the decarboxylating agent, compared with the traditional decarboxylation method using strong acid at high temperature, the reaction conditions are milder; in addition, precisely because the decarboxylation conditions are milder, it avoids the acetic acid group in 2,4,5-trifluorophenylacetic acid from being removed to generate impurities of non-target products, enabling a higher yield of the decarboxylation reaction and fewer impurities in the decarboxylated product. Preferably, the molar ratio of the decarboxylating agent to the hydrolysis product is (0.03 - 0.1):1, specifically, for example, 0.03:1, 0.04:1, 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1, 0.1:1, or any ratio between any two of the above. Controlling the molar ratio of the decarboxylating agent to the hydrolysis product within the above range can better decarboxylate to produce 2,4,5-trifluorophenylacetic acid product. Preferably, the fluoride salt is potassium fluoride. As a relatively common chemical, potassium fluoride has the advantage of lower production cost compared to other fluoride salts and also has good fluorination effect.

[0046] In a preferred embodiment, the temperature of the substitution reaction is 40 - 120 °C, and the time of the substitution reaction is 8 - 12 h; preferably, the temperature of the substitution reaction is 45 - 80 °C. Preferably, the first base is one or more of potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide; preferably, the molar ratio of the first base, the substitution reagent, and tetrachloroterephthalonitrile is (1.1 - 3.2):(1.2 - 3.5):1; more preferably, the molar ratio of the first base, the substitution reagent, and tetrachloroterephthalonitrile is (1.2 - 2.2):(1.5 - 3):1. Controlling the parameters of the substitution reaction process within the above range can make the reaction proceed more fully, better obtain the substitution product, and further improve the yield of 2,4,5-trifluorophenylacetic acid. In addition, the above substitution reaction conditions also have the characteristic of mildness. Especially for large-scale chemical reactions, mild reactions can further improve production safety.

[0047] In a preferred embodiment, the temperature of the fluorination reaction is 100 - 180 °C, and the time of the fluorination reaction is 3 - 5 h; more preferably, the temperature of the fluorination reaction is 140 - 160 °C. Controlling the parameters in the fluorination reaction process within the above range can completely fluorinate the chlorine in the substitution product, which is beneficial to further improving the yield of 2,4,5-trifluorophenylacetic acid.

[0048] In a preferred embodiment, the temperature of the hydrolysis reaction is 50 to 150 °C, and the time of the hydrolysis product is 4 to 6 h; preferably, the aqueous acid solution is an aqueous sulfuric acid solution; preferably, the mass concentration of the aqueous acid solution is 10 to 60%; controlling the parameters in the hydrolysis reaction within the above ranges can make the hydrolysis reaction proceed more fully. Preferably, the temperature of the hydrolysis reaction is 100 to 120 °C; more preferably, the mass concentration of the acid solution is 25 to 40%. Controlling the parameters in the hydrolysis reaction within the above preferred ranges can make the hydrolysis reaction proceed better.

[0049] In a preferred embodiment, the temperature of the decarboxylation reaction is 90 to 120 °C, and the time of the decarboxylation reaction is 4 to 6 h. Controlling the temperature and time of the decarboxylation reaction within the above ranges can make the decarboxylation reaction proceed more fully.

[0050] By way of example and not limitation, the first organic solvent is one or more of acetonitrile (ACN), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), tetrahydrofuran (THF), ethyl acetate (EA), and dimethyl sulfoxide (DMSO); preferably, the second organic solvent is an aprotic organic solvent; more preferably, the second organic solvent is one or more of N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), and N,N-dimethylacetamide (DMAC); preferably, the third organic solvent is N,N-dimethylformamide (DMF).

[0051] In a preferred embodiment, the first separation includes: removing the first organic solvent from the substitution reaction solution, adding water thereto, and successively performing first pulping and first filtration to obtain a substitution product; and / or, the second separation includes: removing the second organic solvent from the fluorination reaction solution, adding water thereto, and successively performing second pulping and second filtration to obtain a fluorination product; and / or, the third separation includes: cooling the hydrolysis reaction solution to 25 to 35 °C, precipitating the hydrolysis product from the hydrolysis reaction solution, and then successively performing centrifugation and water washing to obtain the hydrolysis product; and / or, the fourth separation includes: removing the third organic solvent from the decarboxylation reaction solution, adding water thereto, successively performing third pulping and third filtration, and acidifying the obtained second solid substance to obtain a decarboxylation product; preferably, the acid used in the acidification process is sulfuric acid. Selecting the above separation and purification methods is not only simple and convenient to operate, but also can obtain products with higher purity, thereby further improving the yield of each step.

[0052] In a preferred embodiment, the weight ratio of the first organic solvent to tetrachloroterephthalonitrile is (3 - 6):1; preferably, the weight ratio of the second organic solvent to the substitution product is (4 - 9):1; more preferably, the weight ratio of the second organic solvent to the substitution product is (5 - 8):1; preferably, the weight ratio of the third solvent to the hydrolysis product is (3 - 5):1; preferably, the weight ratio of the aqueous acid solution to the fluorinated product is (4 - 7):1. Controlling the concentrations of the substitution reaction, fluorination reaction, hydrolysis reaction, and decarboxylation reaction within the above ranges can enable the reactions in each reaction step to proceed more stably and fully.

[0053] The following further describes the present application in detail with specific examples, and these examples should not be construed as limiting the scope claimed by the present application.

[0054] Example 1

[0055] Substitution: Add 100 g of tetrachloroterephthalonitrile, 62.3 g of potassium carbonate, and 300 g of the first organic solvent acetonitrile to a 500 mL single-necked flask. While stirring, add 44.7 g of methyl cyanoacetate dropwise. After the addition is complete, react at 50 °C for 8 h. Monitored by HPLC, the raw materials have reacted completely. Remove the organic solvent under reduced pressure, then add water for pulping, centrifugal filtration, and drying to obtain the substitution product (red solid, 119.9 g, yield 95.6%, purity 98.5%). The hydrogen spectrum and carbon spectrum information of the obtained substitution product are as follows:

[0056] 1 H NMR(500MHz,DMSO-d6):δ3.48(s,1H),3.37(s,3H).

[0057] 13 C NMR(126MHz,DMSO)δ167.7,144.4,135.8,133.9,127.6,123.7,118.2,118.1,115.5,114.1,55.4,49.9.

[0058] Fluorination: Take 100 g of the above-obtained substitution product, add it to a 1000 mL single-necked flask, add 61.7 g of potassium fluoride and 500 g of the second organic solvent DMF, stir and heat up to 140 °C for heat preservation reaction for 3 h. Monitored by HPLC, the raw materials have reacted completely. After the reaction mixture is cooled to room temperature (25 °C), remove the organic solvent under reduced pressure, then add water for pulping, centrifugal filtration, and drying to obtain the fluorinated product (red solid, 81.5 g, yield 95.8%, purity 98.3%). The hydrogen spectrum, carbon spectrum, and fluorine spectrum information of the obtained fluorinated product are as follows:

[0059] 11H NMR (500 MHz, DMSO-d6) δ 3.50 (s, 4H), 3.36 (s, 1H).

[0060] 13 13C NMR (126 MHz, DMSO-d6) δ 167.4, 154.8 (d, J = 255.2 Hz), 147.7 (ddd, J = 252.2, 15.6, 3.9 Hz), 143.3 (ddd, J = 252.2, 15.6, 5.1 Hz), 131.8 (dd, J = 15.6, 3.9 Hz), 124.0, 112.3 (t, J = 3.9 Hz), 109.4 (d, J = 3.9 Hz), 105.6–102.9 (m), 96.43 (ddd, J = 22.2, 15.6, 3.9 Hz), 49.9, 48.6.

[0061] 19 19F NMR (471 MHz, DMSO-d6) δ -106.07–-106.91 (m), -135.99 (dd, J = 21.8, 13.2 Hz), -140.25 (d, J = 21.5 Hz).

[0062] Hydrolysis: 50 g of the fluorinated product obtained above and 200 g of an aqueous sulfuric acid solution with a mass concentration of 35% were added to a 500 mL single-necked flask, and the reaction was carried out at 100 °C for 4 h. Monitored by HPLC, the raw materials were completely reacted. After the reaction mixture was cooled to room temperature (25 °C), the hydrolysis product precipitated from the hydrolysis reaction solution. After adding water for pulping, centrifugal filtration, and drying, the hydrolysis product (pale yellow solid, 45.8 g, yield 92.5%, purity 98.9%) was obtained. The 1H NMR, 13C NMR, and 19F NMR information of the hydrolysis product is as follows:

[0063] 1 1H NMR (500 MHz, DMSO-d6) δ 10.88 (br, 3H), 3.73 (s, 2H).

[0064] 13 13C NMR (126 MHz, DMSO-d6) δ 171.0, 166.7–159.4 (m), 156.2–149.8 (m), 147.7 (dd, J = 15.3, 7.4 Hz), 146.2–144.8 (m), 143.6 (dd, J = 13.7, 3.4 Hz), 126.6 (dd, J = 15.3, 3.4 Hz), 119.3 (dd, J = 19.5, 3.4 Hz), 115.2 (dd, J = 23.9, 16.7 Hz), 31.9.

[0065] 19F NMR (471 MHz, DMSO-d6) δ -118.0 (d, J = 15.3 Hz), -136.5 (d, J = 23.6 Hz), -142.3 (dd, J = 23.5, 15.3 Hz).

[0066] Decarboxylation: 40 g of the above-mentioned hydrolyzate was mixed and stirred with 1 g of potassium carbonate and 160 g of the third organic solvent DMF. The mixture was stirred and heated to 90 °C for 4 h of decarboxylation reaction. Monitored by HPLC, the raw materials were completely reacted. The DMF was recovered by solvent evaporation, and then water was added for pulping, filtration, acidification with dilute sulfuric acid, and then filtered, washed with water and dried to obtain the decarboxylated product 2,4,5-trifluorophenylacetic acid (white solid, 26.4 g, yield 96.8%, purity 99.2%). The 1H NMR spectrum of 2,4,5-trifluorophenylacetic acid is as Figure 1 shown, and the 13C NMR spectrum is as Figure 2 shown, and the 19F NMR spectrum is as Figure 3 shown. The 1H NMR, 13C NMR and 19F NMR information are as follows:

[0067] 1 H NMR (500 MHz, DMSO-d6) δ 12.63 (s, 1H), 7.81–7.08 (m, 2H), 3.61 (s, 2H).

[0068] 13 C NMR (126 MHz, DMSO-d6) δ 171.9, 157.6 (dd, J = 9.9, 2.2 Hz), 155.6 (dd, J = 9.9, 2.2 Hz), 150.3–147.7 (m), 146.4 (ddd, J = 241.3, 12.4, 3.5 Hz), 124.3–113.8 (m), 106.1 (dd, J = 28.7, 21.2 Hz), 34.1.

[0069] 19 F NMR (471 MHz, DMSO-d6) δ -118.24 (dd, J = 15.5, 3.6 Hz), -136.51 (dd, J = 22.6, 3.7 Hz), -144.18 (dd, J = 22.6, 15.5 Hz).

[0070] Example 2

[0071] Substitution: 100 g of tetrachloroterephthalonitrile, 57 g of sodium carbonate and 350 g of the first organic solvent DMF were added to a 500 mL single-necked flask. 48 g of methyl cyanoacetate was added dropwise under stirring. After the addition was completed, the reaction was carried out at 50 °C for 9 h. Monitored by HPLC, the raw materials were completely reacted. The organic solvent was removed under reduced pressure, and then water was added for pulping, centrifugal filtration and drying to obtain the substitution product (red solid, 120.1 g, yield 95.7%, purity 98.4%).

[0072] Fluorination: Take 100 g of the above-obtained substitution product and add it to a 1000 mL single-necked flask. Add 63.8 g of potassium fluoride and 500 g of the second organic solvent DMF. Stir and heat up to 150 °C and keep the reaction for 4 h. Monitor by HPLC. After the raw materials are completely reacted. After the reaction mixture is cooled to room temperature (25 °C), remove the organic solvent under reduced pressure. Then, add water for pulping, centrifugal filtration, and drying to obtain the fluorinated product (red solid, 81.6 g, yield 96.3%, purity 98.6%).

[0073] Hydrolysis: Take 50 g of the above-obtained fluorinated product and 200 g of a sulfuric acid aqueous solution with a mass concentration of 35% and add them to a 500 mL single-necked flask. React at 100 °C for 5 h. Monitor by HPLC. After the raw materials are completely reacted. After the reaction mixture is cooled to room temperature (25 °C), the hydrolysis product precipitates from the hydrolysis reaction solution. Add water for pulping, centrifugal filtration, and drying to obtain the hydrolysis product (light yellow solid, 45.9 g, yield 92.1%, purity 98.6%).

[0074] Decarboxylation: Mix 40 g of the above-obtained hydrolysis product with 1.2 g of potassium carbonate and 160 g of the third organic solvent DMF and stir. Stir and heat up to 100 °C and carry out the decarboxylation reaction for 5 h. Monitor by HPLC. After the raw materials are completely reacted. Remove the solvent to recover DMF, then add water for pulping, filtration, acidify with dilute sulfuric acid, and then filter, wash with water, and dry to obtain the decarboxylated product 2,4,5-trifluorophenylacetic acid (white solid, 26.4 g, yield 97.4%, purity 99.4%).

[0075] Example 3

[0076] Substitution: Add 100 g of tetrachloroterephthalonitrile, 29.5 g of sodium methoxide, and 350 g of the first organic solvent N-methylpyrrolidone to a 500 mL single-necked flask. While stirring, dropwise add 55 g of methyl cyanoacetate. After the addition is complete, react at 60 °C for 8 h. Monitor by HPLC. After the raw materials are completely reacted. Remove the organic solvent under reduced pressure. Then, add water for pulping, centrifugal filtration, and drying to obtain the substitution product (red solid, 119.8 g, yield 95.8%, purity 98.8%).

[0077] Fluorination: Take 100 g of the above-obtained substitution product and add it to a 1000 mL single-necked flask. Add 65 g of potassium fluoride and 500 g of the second organic solvent DMF. Stir and heat up to 160 °C and keep the reaction for 5 h. Monitor by HPLC. After the raw materials are completely reacted. After the reaction mixture is cooled to room temperature (25 °C), remove the organic solvent under reduced pressure. Then, add water for pulping, centrifugal filtration, and drying to obtain the fluorinated product (red solid, 81.1 g, yield 95.4%, purity 98.7%).

[0078] Hydrolysis: 50 g of the above-obtained fluorinated product and 210 g of a sulfuric acid aqueous solution with a mass concentration of 40% were added to a 500 mL single-necked flask, and the reaction was carried out at 110 °C for 5 h. Monitored by HPLC, the raw materials were completely reacted. After the reaction mixture was cooled to room temperature (25 °C), the hydrolysis product precipitated from the hydrolysis reaction solution, and the hydrolysis product was obtained by adding water for pulping, centrifugal filtration, and drying (pale yellow solid, 46.6 g, yield 93.3%, purity 98.4%).

[0079] Decarboxylation: 40 g of the above-obtained hydrolysis product, 1.2 g of potassium carbonate, and 160 g of the third organic solvent DMF were mixed and stirred, and the temperature was raised to 90 °C with stirring for decarboxylation reaction for 6 h. Monitored by HPLC, the raw materials were completely reacted. The DMF was recovered by solvent stripping, then water was added for pulping, filtration, acidification with dilute sulfuric acid, and then filtration, washing with water, and drying to obtain the decarboxylated product 2,4,5-trifluorophenylacetic acid (white solid, 26.6 g, yield 97.8%, purity 99.1%).

[0080] Example 4

[0081] Substitution: 100 g of tetrachloroterephthalonitrile, 57.2 g of potassium carbonate, and 300 g of the first organic solvent acetonitrile were added to a 500 mL single-necked flask. 44.7 g of methyl cyanoacetate was added dropwise under stirring. After the addition was completed, the reaction was carried out at 40 °C for 12 h. Monitored by HPLC, the raw materials were completely reacted. The organic solvent was removed under reduced pressure, and then water was added for pulping, centrifugal filtration, and drying to obtain the substitution product (red solid, 120.1 g, yield 95.8%, purity 98.5%).

[0082] Fluorination: 100 g of the above-obtained substitution product was added to a 1000 mL single-necked flask, 52.1 g of potassium fluoride and 400 g of the second organic solvent DMF were added, and the temperature was raised to 100 °C with stirring and kept for reaction for 5 h. Monitored by HPLC, the raw materials were completely reacted. After the reaction mixture was cooled to room temperature (25 °C), the organic solvent was removed under reduced pressure, and then water was added for pulping, centrifugal filtration, and drying to obtain the fluorinated product (red solid, 80.4 g, yield 94.7%, purity 98.5%).

[0083] Hydrolysis: 50 g of the above-obtained fluorinated product and 200 g of a sulfuric acid aqueous solution with a mass concentration of 10% were added to a 500 mL single-necked flask, and the reaction was carried out at 50 °C for 6 h. Monitored by HPLC, the raw materials were completely reacted. After the reaction mixture was cooled to room temperature (25 °C), the hydrolysis product precipitated from the hydrolysis reaction solution, and the hydrolysis product was obtained by adding water for pulping, centrifugal filtration, and drying (pale yellow solid, 46.2 g, yield 93.1%, purity 98.9%).

[0084] Decarboxylation: 40 g of the above-obtained hydrolysis product was mixed and stirred with 2.0 g of potassium carbonate and 120 g of the third organic solvent DMF. The mixture was stirred and heated to 120 °C for 4 h of decarboxylation reaction. Monitored by HPLC, the raw materials were completely reacted. The DMF was recovered by solvent evaporation. Then, water was added for pulping, filtration, acidification with dilute sulfuric acid, and then filtration, washing with water, and drying to obtain the decarboxylation product 2,4,5-trifluorophenylacetic acid (white solid, 26.4 g, yield 96.9%, purity 99.3%).

[0085] Example 5

[0086] Substitution: 100 g of tetrachloroterephthalonitrile, 166.3 g of potassium carbonate, and 600 g of the first organic solvent acetonitrile were added to a 500 mL single-necked flask. 130.4 g of methyl cyanoacetate was added dropwise under stirring. After the addition was completed, the reaction was carried out at 120 °C for 12 h. Monitored by HPLC, the raw materials were completely reacted. The organic solvents were removed under reduced pressure. Then, water was added for pulping, centrifugal filtration, and drying to obtain the substitution product (red solid, 120.3 g, yield 95.9%, purity 98.5%).

[0087] Fluorination: 100 g of the above-obtained substitution product was added to a 1000 mL single-necked flask, and 123.4 g of potassium fluoride and 900 g of the second organic solvent DMF were added. The mixture was stirred and heated to 180 °C for 3 h of heat preservation reaction. Monitored by HPLC, the raw materials were completely reacted. After the reaction mixture was cooled to room temperature (25 °C), the organic solvents were removed under reduced pressure. Then, water was added for pulping, centrifugal filtration, and drying to obtain the fluorination product (red solid, 80.6 g, yield 94.8%, purity 98.4%).

[0088] Hydrolysis: 50 g of the above-obtained fluorination product and 200 g of a 60% sulfuric acid aqueous solution were added to a 500 mL single-necked flask. The reaction was carried out at 150 °C for 4 h. Monitored by HPLC, the raw materials were completely reacted. After the reaction mixture was cooled to room temperature (25 °C), the hydrolysis product precipitated from the hydrolysis reaction solution. Water was added for pulping, centrifugal filtration, and drying to obtain the hydrolysis product (light yellow solid, 46.1 g, yield 93.0%, purity 98.8%).

[0089] Decarboxylation: 40 g of the above-obtained hydrolysis product was mixed and stirred with 0.6 g of potassium carbonate and 200 g of the first organic solvent DMF. The mixture was stirred and heated to 110 °C for 6 h of decarboxylation reaction. Monitored by HPLC, the raw materials were completely reacted. The DMF was recovered by solvent evaporation. Then, water was added for pulping, filtration, acidification with dilute sulfuric acid, and then filtration, washing with water, and drying to obtain the decarboxylation product 2,4,5-trifluorophenylacetic acid (white solid, 26.2 g, yield 96.3%, purity 99.4%).

[0090] Example 6

[0091] Substitution: Add 100 g of tetrachloroterephthalonitrile, 62.4 g of potassium carbonate, and 300 g of the first organic solvent acetonitrile into a 500 mL single-necked flask. While stirring, add 55.9 g of methyl cyanoacetate dropwise. After the addition is complete, react at 45 °C for 12 h. Monitored by HPLC, the raw materials have reacted completely. Remove the organic solvent under reduced pressure, and then obtain the substitution product through adding water for pulping, centrifugal filtration, and drying (red solid, 120.5 g, yield 96.2%, purity 98.6%).

[0092] Fluorination: Take 100 g of the substitution product obtained above and add it into a 1000 mL single-necked flask. Add 61.7 g of potassium fluoride and 800 g of the second organic solvent DMF. Stir and heat up to 140 °C and keep the reaction for 5 h. Monitored by HPLC, the raw materials have reacted completely. After the reaction mixture solution is cooled to room temperature (25 °C), remove the organic solvent under reduced pressure, and then obtain the fluorination product through adding water for pulping, centrifugal filtration, and drying (red solid, 81.7 g, yield 96.2%, purity 98.5%).

[0093] Hydrolysis: Take 50 g of the fluorination product obtained above and 200 g of a sulfuric acid aqueous solution with a mass concentration of 25% and add them into a 500 mL single-necked flask. React at 100 °C for 6 h. Monitored by HPLC, the raw materials have reacted completely. After the reaction mixture solution is cooled to room temperature (25 °C), the hydrolysis product precipitates from the hydrolysis reaction solution, and the hydrolysis product is obtained through adding water for pulping, centrifugal filtration, and drying (light yellow solid, 46.6 g, yield 93.7%, purity 98.7%).

[0094] Decarboxylation: Mix and stir 40 g of the hydrolysis product obtained above, 1 g of potassium carbonate, and 160 g of the third organic solvent DMF. Stir and heat up to 120 °C, and carry out the decarboxylation reaction for 6 h. Monitored by HPLC, the raw materials have reacted completely. Remove and recover DMF by evaporation, then add water for pulping, filtration, acidification with dilute sulfuric acid, and then filter, wash with water, and dry to obtain the decarboxylation product 2,4,5-trifluorophenylacetic acid (white solid, 26.6 g, yield 98.3%, purity 99.6%).

[0095] Example 7

[0096] Substitution: Add 100 g of tetrachloroterephthalonitrile, 114.3 g of potassium carbonate, and 300 g of the first organic solvent acetonitrile into a 500 mL single-necked flask. While stirring, add 111.8 g of methyl cyanoacetate dropwise. After the addition is complete, react at 80 °C for 12 h. Monitored by HPLC, the raw materials have reacted completely. Remove the organic solvent under reduced pressure, and then obtain the substitution product through adding water for pulping, centrifugal filtration, and drying (red solid, 120.6 g, yield 96.2%, purity 98.5%).

[0097] Fluorination: Take 100 g of the above-obtained substituted product, add it to a 1000 mL single-necked flask, add 88.2 g of potassium fluoride and 500 g of the second organic solvent DMF, stir and heat up to 160 °C, keep the temperature for reaction for 6 h. After monitoring by HPLC, the raw materials are completely reacted. After the reaction mixture is cooled to room temperature (25 °C), the organic solvent is removed under reduced pressure, and then water is added for pulping, centrifugal filtration, and drying to obtain the fluorinated product (red solid, 81.8 g, yield 96.3%, purity 98.5%).

[0098] Hydrolysis: Take 50 g of the above-obtained fluorinated product and 200 g of a sulfuric acid aqueous solution with a mass concentration of 40% and add them to a 500 mL single-necked flask. React at 120 °C for 5 h. After monitoring by HPLC, the raw materials are completely reacted. After the reaction mixture is cooled to room temperature (25 °C), the hydrolysis product precipitates from the hydrolysis reaction solution, and water is added for pulping, centrifugal filtration, and drying to obtain the hydrolysis product (light yellow solid, 46.8 g, yield 94.3%, purity 98.9%).

[0099] Decarboxylation: Mix and stir 40 g of the above-obtained hydrolysis product, 1 g of potassium carbonate, and 160 g of the third organic solvent DMF, stir and heat up to 100 °C, and carry out the decarboxylation reaction for 4 h. After monitoring by HPLC, the raw materials are completely reacted. The DMF is recovered by solvent evaporation, then water is added for pulping, filtration, acidification with dilute sulfuric acid, and then filtration, washing with water, and drying to obtain the decarboxylation product 2,4,5-trifluorophenylacetic acid (white solid, 26.6 g, yield 98.0%, purity 99.6%).

[0100] The following will show in tabular form the differences in the reaction conditions of the substitution reaction, fluorination reaction, hydrolysis reaction, and decarboxylation reaction in Examples 8 to 23 and Example 1, as well as the reaction yields and other situations. Among them, Table 1 is for the substitution reaction part, Table 2 is for the fluorination reaction part, Table 3 is for the hydrolysis reaction part, and Table 4 is for the decarboxylation reaction part.

[0101] Table 1

[0102]

[0103]

[0104] Table 2

[0105]

[0106]

[0107] Table 3

[0108]

[0109]

[0110] Table 4

[0111]

[0112] Comparative Example 1

[0113] The difference between Comparative Example 1 and Example 1 is that fluorination is carried out first and then substitution, and a strong acid is used for decarboxylation in the decarboxylation step. The specific steps are as follows:

[0114] Fluorination: Take 100 g of tetrachloroterephthalonitrile, add it to a 2000 mL single-necked flask, add 218.5 g of potassium fluoride and 700 g of the organic solvent DMF, stir and heat to 150 °C for heat preservation reaction for 10 h. After monitoring by HPLC, the raw materials have reacted completely. After the reaction mixture solution is cooled to room temperature (25 °C), the organic solvent is removed under reduced pressure, and then water is added for pulping, centrifugal filtration, and drying to obtain the fluorinated product (red solid, 69.4 g, yield 89.4%, purity 97.0%).

[0115] Substitution: Add 50 g of the above-mentioned fluorinated product, 41.4 g of potassium carbonate, and 200 g of the first organic solvent acetonitrile to a 500 mL single-necked flask. While stirring, add 29.7 g of methyl cyanoacetate dropwise. After the addition is complete, react at 60 °C for 12 h. After monitoring by HPLC, the raw materials have reacted completely. The organic solvent is removed under reduced pressure, and then water is added for pulping, centrifugal filtration, and drying to obtain the substituted product (red solid, 65.8 g, yield 94.9%, purity 97.5%).

[0116] Hydrolysis: Take 50 g of the above-obtained substituted product and 200 g of a sulfuric acid aqueous solution with a mass concentration of 40% and add them to a 500 mL single-necked flask. React at 120 °C for 8 h. After monitoring by HPLC, the raw materials have reacted completely. After the reaction mixture solution is cooled to room temperature (25 °C), the hydrolysis product precipitates from the hydrolysis reaction solution, and water is added for pulping, centrifugal filtration, and drying to obtain the hydrolysis product (light yellow solid, 46.3 g, yield 92.6%, purity 97.2%).

[0117] Decarboxylation: Mix 40 g of the above-obtained hydrolysis product with 200 g of a sulfuric acid aqueous solution with a mass concentration of 40% in an autoclave, stir and heat to 180 °C, and carry out decarboxylation reaction for 8 h. After monitoring by HPLC, the raw materials have reacted completely. After filtration, washing with water, and drying, the decarboxylated product 2,4,5-trifluorophenylacetic acid is obtained (white solid, 24.8 g, yield 90.9%, purity 97.5%).

[0118] The parameters of the fluorination reaction part in Examples 1 to 23 and Comparative Example 1, as well as the purity and total molar yield of 2,4,5-trifluorophenylacetic acid, etc. are summarized, and the results are shown in Table 5 as follows.

[0119] Table 5

[0120]

[0121]

[0122] It should be further noted here that, since the synthesis sequence of "fluorination first, then substitution" was not adopted in Comparative Example 1, the amount of potassium fluoride added in Comparative Example 1 was expressed in terms of the molar ratio of potassium fluoride to tetrachloroterephthalonitrile, which was 10:1. The total molar yield in Table 5 was the result of multiplying the yields of each step in the synthesis of 2,4,5-trifluorophenylacetic acid in the corresponding examples or comparative examples.

[0123] From the above description, it can be seen that the above embodiments of the present invention achieved the following technical effects:

[0124] According to the data in the table, Examples 1 to 23 were used to prepare 2,4,5-trifluorophenylacetic acid by the preparation method of the present invention. The total molar yields of the prepared 2,4,5-trifluorophenylacetic acid were all above 80%. In particular, by controlling the parameters in the preparation process within the preferred range, the total molar yield of the prepared 2,4,5-trifluorophenylacetic acid was even higher, up to 88.0% at most. Moreover, the purity of the 2,4,5-trifluorophenylacetic acid prepared by the preparation method of the present invention was also higher, all reaching more than 99%.

[0125] On the contrary, in Comparative Example 1, the traditional method of fluorination first and then substitution was used to prepare 2,4,5-trifluorophenylacetic acid. The total molar yield of 2,4,5-trifluorophenylacetic acid was only 71.4%, and the purity was only 97.5%. And the molar ratio of potassium fluoride to tetrachloroterephthalonitrile was 10:1. It can be seen that the specific synthesis sequence of substitution first and then fluorination proposed by the present invention can not only effectively improve the selectivity of the reaction, greatly increase the total molar yield of 2,4,5-trifluorophenylacetic acid, but also further reduce the usage amount of potassium fluoride and further reduce the preparation cost.

[0126] In short, using the method for preparing 2,4,5-trifluorophenylacetic acid provided by the present invention can not only make the yields of each reaction step within a good range, but also reduce the raw material cost and the cost in the preparation process. The optimization of the above synthesis method, especially for the large-scale production of 2,4,5-trifluorophenylacetic acid, has important significance.

[0127] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention can have various changes and modifications. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for preparing 2,4,5-trifluorophenylacetic acid, characterized in that: The preparation method comprises: Substitution: dissolving tetrachloroterephthalonitrile, a first base and a substitution reagent in a first organic solvent to carry out a substitution reaction, and subjecting the obtained substitution reaction solution to a first separation to obtain a substitution product; Fluorination: mixing the substituted product with a fluoride salt and a second organic solvent to carry out a fluorination reaction, and the resulting fluorination reaction solution is subjected to a second separation to obtain a fluorinated product; Hydrolysis: hydrolyzing the fluorinated product in an acid aqueous solution, and subjecting the obtained hydrolysis reaction solution to a third separation to obtain a hydrolysis product; Decarboxylation: mixing the hydrolyzate with a decarboxylating agent and a third organic solvent to carry out a decarboxylation reaction, and subjecting the resulting decarboxylation reaction solution to a fourth separation to obtain the 2,4,5-trifluorophenylacetic acid product; The substitution reagent has a structure shown in the following formula (I): Among them, R1 is C1~C 10 R2 is -CN or -COOR3, and R3 is H or C1~C 10 of alkyl.

2. The method for preparing 2,4,5-trifluorophenylacetic acid according to claim 1, characterized in that: In the formula (I), R1 is at least one of methyl, ethyl or isopropyl; Preferably, R3 is at least one of methyl, ethyl or isopropyl; Preferably, the molar ratio of the fluoride salt to the substitution product is (3-7):1; more preferably, the molar ratio of the fluoride salt to the substitution product is (3.5-5):

1.

3. The method for preparing 2,4,5-trifluorophenylacetic acid according to claim 1, characterized in that: The decarboxylating agent is a carbonate; Preferably, the decarboxylating agent is one or more of potassium carbonate, sodium bicarbonate, potassium bicarbonate or sodium carbonate; Preferably, the molar ratio of the decarboxylating agent to the hydrolyzate is (0.03-0.1):1; Preferably, the fluoride salt is potassium fluoride.

4. The method for preparing 2,4,5-trifluorophenylacetic acid according to any one of claims 1 to 3, characterized in that: The temperature of the substitution reaction is 40 to 120° C., and the time of the substitution reaction is 8 to 12 hours; Preferably, the temperature of the substitution reaction is 45 to 80°C; Preferably, the first base is one or more of potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide; Preferably, the molar ratio of the first base, the substitution reagent and the tetrachloroterephthalonitrile is (1.1 to 3.2): (1.2~3.5):1; More preferably, the molar ratio of the first base, the substitution reagent and the tetrachloroterephthalonitrile is (1.2~2.2):(1.5~3):

1.

5. The method for preparing 2,4,5-trifluorophenylacetic acid according to any one of claims 1 to 3, characterized in that: The temperature of the fluorination reaction is 100-180°C, and the time of the fluorination reaction is 3-5 hours; more preferably, the temperature of the fluorination reaction is 140-160°C.

6. The method for preparing 2,4,5-trifluorophenylacetic acid according to any one of claims 1 to 3, characterized in that: The temperature of the hydrolysis reaction is 50-150°C, and the time of the hydrolysis product is 4-6h; preferably, the temperature of the hydrolysis reaction is 100-120°C; Preferably, the aqueous acid solution is an aqueous sulfuric acid solution; Preferably, the mass concentration of the aqueous acid solution is 10-60%; more preferably, the mass concentration of the acid solution is 25-40%.

7. The method for preparing 2,4,5-trifluorophenylacetic acid according to any one of claims 1 to 3, characterized in that: The temperature of the decarboxylation reaction is 90-120° C., and the time of the decarboxylation reaction is 4-6 hours.

8. The method for preparing 2,4,5-trifluorophenylacetic acid according to any one of claims 1 to 7, characterized in that: The first organic solvent is one or more of acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, ethyl acetate and dimethyl sulfoxide; Preferably, the second organic solvent is an aprotic organic solvent; further preferably, the second organic solvent is one or more of N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and N,N-dimethylacetamide; Preferably, the third organic solvent is N,N-dimethylformamide.

9. The method for preparing 2,4,5-trifluorophenylacetic acid according to any one of claims 1 to 7, characterized in that: The first separation comprises: removing the first organic solvent in the substitution reaction solution, adding water thereto, and sequentially performing first slurrying and first filtration to obtain the substitution product; and / or, The second separation comprises: removing the second organic solvent in the fluorination reaction solution, adding water thereto, and sequentially performing second slurrying and second filtration to obtain the fluorinated product; and / or, The third separation comprises: cooling the hydrolysis reaction solution to 25-35° C., the hydrolysis product is precipitated from the hydrolysis reaction solution, and then centrifuging and washing in sequence to obtain the hydrolysis product; and / or, The fourth separation comprises: removing the third organic solvent in the decarboxylation reaction solution, adding water thereto, sequentially performing a third pulping and a third filtration, and acidifying the obtained second solid material to obtain the decarboxylation product; Preferably, the acid used in the acidification process is sulfuric acid.

10. The method for preparing 2,4,5-trifluorophenylacetic acid according to any one of claims 1 to 7, characterized in that: The weight ratio of the first organic solvent to the tetrachloroterephthalonitrile is (3-6):1; Preferably, the weight ratio of the second organic solvent to the substitution product is (4-9):1; more preferably, the weight ratio of the second organic solvent to the substitution product is (5-8):1; Preferably, the weight ratio of the third solvent to the hydrolyzate is (3-5):1; Preferably, the weight ratio of the aqueous acid solution to the fluorinated product is (4-7):1.

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