A process for the preparation of 2,4,6-trifluorobenzoic acid

Abstract

The application provides a preparation method of 2,4,6-trifluorobenzoic acid, which comprises the following steps: 1) subjecting 1,3,5-trifluorobenzene to a bromination reaction to obtain 2,4,6-trifluorobromobenzene; and 2) subjecting the 2,4,6-trifluorobromobenzene to a Grignard reaction to obtain 2,4,6-trifluorobenzoic acid. The method has the advantages of short flow, simple process, high molar yield and high purity of 2,4,6-trifluorobromobenzene, low cost of 2,4,6-trifluorobenzoic acid prepared by the method, and relatively environmentally-friendly and safe operation process, and is suitable for large-scale production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and in particular to a method for preparing 2,4,6-trifluorobenzoic acid. Background Technology

[0002] Rasmidetan is a centrally penetrating, selective oral 5-HT1F agonist, approved by the FDA in October 2019, becoming the first FDA-approved drug for the treatment of acute migraine in adults in over 20 years. Compared to novel "ditan" class drugs with significant vasoconstrictive effects, lasmidetan's zero vasoconstrictive effect makes it safer for treating migraine sufferers with cardiovascular disease or at risk of cardiovascular disease. Therefore, the preparation of 2,4,6-trifluorobenzoic acid, a key intermediate for lasmidetan, is of significant research importance.

[0003] Currently, the synthesis of 2,4,6-trifluorobenzoic acid mainly uses trichlorobenzoyl chloride, pentachlorobenzonitrile, or trifluorobenzene as raw materials. Among these, using trichlorobenzoyl chloride as a raw material involves fluorination and hydrolysis to synthesize 2,4,6-trifluorobenzoic acid, but this method results in low molar yields and high production costs. Using pentachlorobenzonitrile as a raw material involves sequential fluorination, dechlorination, and hydrolysis to obtain 2,4,6-trifluorobenzoic acid, but this process... The process requires the use of large amounts of strong acids and bases, which generates toxic and highly corrosive waste liquids. The operation is dangerous and causes environmental pollution, limiting large-scale production. When using trifluorobenzene as a raw material, trifluorobenzene is added dropwise to a hexane solution of butyllithium, followed by the addition of solid carbon dioxide. Finally, 2,4,6-trifluorobenzoic acid is extracted using alkali. The butyllithium used in this process is hazardous, and the reaction needs to be carried out under anhydrous, oxygen-free, and low-temperature conditions, which places high demands on the reaction equipment and makes it difficult to achieve industrial production.

[0004] Therefore, how to provide a low-cost, relatively safe and environmentally friendly method for preparing 2,4,6-trifluorobenzoic acid that is suitable for large-scale production is a problem that urgently needs to be solved by those skilled in the art. Summary of the Invention

[0005] To address the problems existing in the prior art, this invention provides a method for preparing 2,4,6-trifluorobenzoic acid. This method has low preparation cost and safety risks, is relatively environmentally friendly, and is suitable for large-scale production.

[0006] This invention provides a method for preparing 2,4,6-trifluorobenzoic acid, comprising:

[0007] 1) Bromination of 1,3,5-trifluorobenzene yields 2,4,6-trifluorobromobenzene;

[0008] 2) The 2,4,6-trifluorobromobenzene is subjected to a Grignard reaction to obtain 2,4,6-trifluorobenzoic acid.

[0009] According to one embodiment of the present invention, step 1) includes: adding a bromine solution dropwise to a system comprising the 1,3,5-trifluorobenzene, a bromination solvent, and a bromination catalyst to carry out the bromination reaction, thereby obtaining the 2,4,6-trifluorobromobenzene;

[0010] The brominated solvent includes at least one of dichloromethane, chloroform, carbon tetrachloride, and toluene;

[0011] The bromination catalyst includes at least one of ferric chloride and ferric tribromide;

[0012] The bromine solution comprises bromine and the bromination solvent, and the molar ratio of 1,3,5-trifluorobenzene to the bromination solvent, bromination catalyst, and bromine is 1:(5-8):(0.02-0.07):(1-1.5).

[0013] According to one embodiment of the present invention, in the bromine solution, the mass-to-volume ratio of bromine to the brominating solvent is 1 g:(0.6-1.5) mL, and the dropping rate of the bromine solution is 1-3 g / min; and / or,

[0014] The bromine solution was added at a temperature of 20–30°C.

[0015] According to one embodiment of the present invention, after the bromination reaction is completed, the bromination reaction system is subjected to alkaline washing, water washing, and vacuum distillation in sequence to obtain the 2,4,6-trifluorobromobenzene.

[0016] According to one embodiment of the present invention, step 2) includes: adding the 2,4,6-trifluorobromobenzene dropwise to the Grignard reagent under an inert gas protection, and then passing carbon dioxide gas to carry out the Grignard reaction to obtain the 2,4,6-trifluorobenzoic acid;

[0017] The molar ratio of 2,4,6-trifluorobromobenzene to the Grignard reagent is 1:(1.0-1.5).

[0018] According to one embodiment of the present invention, the dropping rate of the 2,4,6-trifluorobromobenzene is 0.5-1.5 g / min; and / or,

[0019] The temperature for the Grignard reaction is -10℃ to 15℃.

[0020] According to one embodiment of the present invention, after the Grignard reaction is completed, the Grignard reaction system is quenched and then subjected to a first extraction treatment. The organic phase obtained from the first extraction treatment is concentrated, water is added, and the crude product is precipitated. After the crude product is dissolved, a second extraction treatment is performed. The aqueous phase of the second extraction treatment is filtered and the pH is adjusted to 0-2 to obtain the 2,4,6-trifluorobenzoic acid.

[0021] According to one embodiment of the present invention, before step 1), the method further includes: in a fluorination solvent, 1,3,5-trichlorobenzene and a fluorinating agent undergo a fluorination reaction under the action of a fluorination catalyst to obtain the 1,3,5-trifluorobenzene;

[0022] Wherein, the molar ratio of the 1,3,5-trichlorobenzene to the fluorinated solvent, fluorinated agent, and fluorinated catalyst is 1:(5-10):(3-5):(0.005-0.05);

[0023] The fluorinated solvent includes at least one of N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, dimethyl sulfoxide, and sulfolane;

[0024] The fluorinating agent includes at least one of potassium fluoride, sodium fluoride, and cesium fluoride;

[0025] The fluorination catalyst includes at least one of tetramethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, triphenylmethylphosphonium bromide, triphenylethylphosphonium bromide, and tetraphenylphosphonium bromide.

[0026] According to one embodiment of the present invention, the fluorination reaction is carried out under an inert gas atmosphere; and / or,

[0027] The fluorination reaction is carried out at a temperature of 130–180 °C.

[0028] According to one embodiment of the present invention, after the fluorination reaction is completed, the fluorination reaction system is subjected to vacuum distillation, and the fraction obtained by the vacuum distillation is subjected to vacuum rectification to obtain the 1,3,5-trifluorobenzene.

[0029] This invention prepares 2,4,6-trifluorobenzoic acid from 1,3,5-trifluorobenzene via bromination and Grignard reactions. This method is short, simple, and yields 2,4,6-trifluorobenzoic acid with a molar yield of up to 99.5% and a purity of up to 96.3%. It also features low production costs and a relatively safe and environmentally friendly process, making it suitable for large-scale production. Attached Figure Description

[0030] Figure 1 The proton nuclear magnetic resonance spectrum of the first product in Example 1 of this invention;

[0031] Figure 2 The 1H NMR spectrum of the second product of Example 1 of this invention;

[0032] Figure 3 The nuclear magnetic resonance hydrogen spectrum of the third product of Example 1 of the present invention. Detailed Implementation

[0033] To enable those skilled in the art to better understand the present invention, the present invention will be further described in detail below. The specific embodiments listed below are merely descriptions of the principles and features of the present invention, and the examples are only for explaining the present invention and are not intended to limit the scope of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0034] This invention provides a method for preparing 2,4,6-trifluorobenzoic acid, comprising:

[0035] 1) Bromination of 1,3,5-trifluorobenzene yields 2,4,6-trifluorobromobenzene;

[0036] 2) 2,4,6-trifluorobromobenzene undergoes a Grignard reaction to yield 2,4,6-trifluorobenzoic acid.

[0037] This invention uses 1,3,5-trifluorobenzene as a raw material and can prepare 2,4,6-trifluorobenzoic acid through only two steps: bromination and Grignard reaction. The process is short and simple to operate. Because the substitution sites for bromine are limited during the bromination reaction, it can only occur at positions 2, 4, and 6 of the benzene ring in 1,3,5-trifluorobenzene. Regardless of which position the bromine substitutes at, the product obtained is always 2,4,6-trifluorobromobenzene. Furthermore, by controlling the reaction conditions, it can be ensured that most of the bromine is substituted at one of the 2, 4, or 6 positions of the benzene ring, rather than multiple substitutions. Therefore, the yield and purity of 2,4,6-trifluorobromobenzene obtained by the bromination reaction are high. The Grignard reaction is a relatively conventional reaction, and by controlling the reaction conditions, the byproducts and impurities of the conversion of 2,4,6-trifluorobromobenzene to 2,4,6-trifluorobenzoic acid can be minimized. Therefore, the purity of 2,4,6-trifluorobenzoic acid prepared by the method of this invention can reach up to 99.5%, and the molar yield can reach up to 96.3%. Moreover, the method of this invention can also be used to prepare kilogram-level 2,4,6-trifluorobenzoic acid. Furthermore, this invention does not require the use of hard-to-obtain and highly dangerous raw materials, such as butyllithium, and does not require the use of large amounts of strong alkalis and strong acids, making it safer and more environmentally friendly, and suitable for large-scale production.

[0038] It should be noted that after the above bromination reaction is completed, a bromination reaction system is obtained, in which 2,4,6-trifluorobromobenzene is present. In order to avoid the influence of impurities in the bromination reaction system on step 2), the bromination reaction system needs to be post-treated to obtain 2,4,6-trifluorobromobenzene. Similarly, after the Grignard reaction is completed, 2,4,6-trifluorobenzoic acid is present in the Grignard reaction system. In order to obtain high-purity 2,4,6-trifluorobenzoic acid, the Grignard reaction system needs to be post-treated.

[0039] In step 1), the bromination reaction includes: adding a bromine solution dropwise to a system comprising 1,3,5-trifluorobenzene, a bromination solvent, and a bromination catalyst to produce 2,4,6-trifluorobromobenzene; wherein the bromination solvent comprises at least one of dichloromethane, chloroform, carbon tetrachloride, and toluene; the bromination catalyst comprises at least one of ferric chloride and ferric tribromide; the bromine solution comprises bromine and the bromination solvent, and the molar ratio of 1,3,5-trifluorobenzene to the bromination solvent, the bromination catalyst, and bromine is 1:(5-8):(0.02-0.07):(1-1.5).

[0040] Choosing the above-mentioned bromination solvent and bromination catalyst is beneficial for controlling the reaction rate, reducing by-products, and increasing the conversion rate of 1,3,5-trifluorobenzene, thereby increasing the molar yield and purity of 2,4,6-trifluorobromobenzene.

[0041] Furthermore, controlling the molar ratio of 1,3,5-trifluorobenzene to the bromination solvent, bromination catalyst, and bromine to 1:(5-8):(0.02-0.07):(1-1.5) is beneficial for obtaining 2,4,6-trifluorobromobenzene with high purity and high yield. Specifically, when the amount of bromine and bromination catalyst added is too high, it will lead to an increase in the byproducts of the bromination reaction, affecting the purity of 2,4,6-trifluorobromobenzene. Conversely, when the amount added is too low, the conversion of 1,3,5-trifluorobenzene is incomplete, which in turn leads to a decrease in the molar yield and purity of 2,4,6-trifluorobromobenzene.

[0042] When bromine is added dropwise directly to a system consisting of 1,3,5-trifluorobenzene, a bromination solvent, and a bromination catalyst, the reaction is too vigorous. Bromine may partially or completely replace the hydrogens at the 2, 4, and 6 positions of 1,3,5-trifluorobenzene, rather than just replacing one of the hydrogens, resulting in byproducts in the bromination reaction and consequently reducing the molar yield and purity of 2,4,6-trifluorobromobenzene. However, dissolving bromine in a bromination solvent can reduce the formation of byproducts, thereby improving the molar yield and purity of 2,4,6-trifluorobromobenzene.

[0043] To monitor the reaction progress in a timely manner, this invention uses GC (gas chromatography) to track the bromination reaction. When the GC detection shows that the content of 1,3,5-trifluorobenzene is less than 0.2%, it indicates that the bromination reaction is complete and 2,4,6-trifluorobromobenzene is obtained.

[0044] Through the inventors' research, when the mass-to-volume ratio of bromine to brominating solvent in the bromine solution is controlled at 1 g:(0.6-1.5) mL, and the dropping rate of the bromine solution is 1-3 g / min, 2,4,6-trifluorobromobenzene can be prepared at a relatively fast rate, and byproducts in the bromination reaction process are effectively reduced, thus improving the molar yield and purity of 2,4,6-trifluorobromobenzene. Those skilled in the art can, of course, adjust the mass-to-volume ratio of bromine to brominating solvent and the dropping rate of the bromine solution according to actual needs. For example, the concentration of bromine can be reduced to accelerate the dropping rate, or the concentration of bromine can be reduced and the dropping reaction rate slowed down to obtain 2,4,6-trifluorobromobenzene with higher molar yield and purity.

[0045] Furthermore, controlling the dropping temperature of the bromine solution to 20–30 °C can further improve the molar yield and purity of 2,4,6-trifluorobromobenzene.

[0046] The inventors discovered that both excessively high and low temperatures are unfavorable for the formation of 2,4,6-trifluorobromobenzene. At excessively high temperatures, the bromination reaction also becomes violent, producing byproducts; while at excessively low temperatures, the bromination reaction is difficult to proceed. Therefore, this invention controls the dropping temperature of the bromine solution to 20–30°C. Furthermore, at this temperature, the reaction conditions are relatively mild and easy to operate.

[0047] In the specific implementation process, after the bromination reaction is completed, the bromination reaction system is subjected to alkaline washing, water washing, and vacuum distillation in sequence to obtain 2,4,6-trifluorobromobenzene.

[0048] The present invention does not limit the type of alkaline solution, which may include at least one of sodium carbonate, sodium bicarbonate and sodium hydroxide.

[0049] By sequentially subjecting the bromination reaction system to alkaline washing, water washing, and vacuum distillation, 2,4,6-trifluorobromobenzene can be separated from the bromination reaction system, and its purity can be improved. Alkaline washing neutralizes acidic substances in the bromination reaction system, including unreacted bromine and hydrogen bromide gas produced during bromination. Water washing removes excess alkaline solution. Vacuum distillation of the organic phase obtained after water washing removes the bromination solvent, yielding 2,4,6-trifluorobromobenzene.

[0050] In this invention, step 2) includes: adding 2,4,6-trifluorobromobenzene dropwise to a Grignard reagent under an inert gas atmosphere, and then passing carbon dioxide gas through to carry out a Grignard reaction to obtain 2,4,6-trifluorobenzoic acid; wherein the molar ratio of 2,4,6-trifluorobromobenzene to the Grignard reagent is 1:(1.0-1.5).

[0051] The inert gas includes at least one of nitrogen, helium and argon, with nitrogen being preferred for cost reasons.

[0052] The Grignard reagent used in this invention includes at least one of methyl magnesium chloride solution, methyl magnesium bromide solution, methyl magnesium iodide solution, and isopropyl magnesium chloride solution. The solvent in the solution includes at least one of tetrahydrofuran, methyltetrahydrofuran, diethyl ether, and methyl tert-methyl ether. For cost considerations, tetrahydrofuran is preferred as the solvent. This invention does not limit the concentration of the Grignard reagent; in specific implementation, this invention uses a 2 mol / L Grignard reagent as the reaction raw material.

[0053] When the molar ratio of 2,4,6-trifluorobromobenzene to Grignard reagent is controlled at 1:(1.0-1.5), it is beneficial to obtain 2,4,6-trifluorobenzoic acid with high purity and high yield.

[0054] For safety, product yield, and purity considerations, the Grignard reaction is carried out under an inert gas atmosphere. During the Grignard reaction, the Grignard reagent first reacts with 2,4,6-trifluorobromobenzene to give benzyl magnesium halide or phenyl isopropyl magnesium halide; after carbon dioxide gas is introduced, the carbon dioxide reacts with the benzyl magnesium halide or phenyl isopropyl magnesium halide to give 2,4,6-trifluorobenzoic acid.

[0055] It is understandable that when the Grignard reagent is in excess relative to 2,4,6-trifluorobromobenzene, the content of 2,4,6-trifluorobromobenzene can be detected by HPLC (high performance liquid chromatography) to track the Grignard reaction. When the content of 2,4,6-trifluorobromobenzene is shown to be less than 0.2%, it indicates that the Grignard reaction is complete.

[0056] According to the inventors' research, when the dropping rate of 2,4,6-trifluorobromobenzene is controlled at 0.5-1.5 g / min, benzyl magnesium halide or phenyl isopropyl magnesium halide can be obtained at a faster rate with high molar yield and high purity, which is beneficial for obtaining 2,4,6-trifluorobenzoic acid with high purity and high molar yield.

[0057] Furthermore, when the Grignard reaction temperature is controlled at -10 to 15°C, the reaction is easy to operate and the generation of byproducts can be reduced, which is beneficial to improving the molar yield and purity of 2,4,6-trifluorobenzoic acid. Preferably, the Grignard reaction temperature is 0 to 10°C.

[0058] In the specific implementation process, after the Grignard reaction is completed, the Grignard reaction system is quenched and then subjected to a first extraction treatment. The organic phase obtained from the first extraction treatment is concentrated and then water is added to precipitate the crude product. After the crude product is dissolved, a second extraction treatment is performed. The aqueous phase from the second extraction treatment is filtered and the pH is adjusted to 0-2 to obtain 2,4,6-trifluorobenzoic acid.

[0059] The above process is a post-processing of the Grignard reaction system obtained after the Grignard reaction is completed. Specifically, it includes separating 2,4,6-trifluorobenzoic acid from the Grignard reaction system and then purifying it.

[0060] Because Grignard reagents are highly reactive and readily react with water to produce impurities, they affect the molar yield and purity of 2,4,6-trifluorobenzoic acid. Therefore, quenching is necessary. This invention quenches the Grignard reagent by adding acid (e.g., hydrochloric acid) dropwise to the system. Quenching is complete when the pH of the Grignard reaction system is less than 7. It should be noted that the temperature of the system should be controlled not to exceed the Grignard reaction temperature during acid addition to avoid the generation of impurities and byproducts. Preferably, the temperature during acid addition is controlled to be 0–10°C.

[0061] After quenching, the Grignard reaction system is subjected to a first extraction treatment using a first extractant. After the first extraction treatment, 2,4,6-trifluorobenzoic acid is present in the organic phase. This invention does not limit the type of the first extractant, as long as it can extract 2,4,6-trifluorobenzoic acid into the organic phase. For example, it can be methyl tert-butyl ether.

[0062] By concentrating the organic phase and then adding water, 2,4,6-trifluorobenzoic acid can be precipitated from the organic phase. After concentration, the first extractant can be removed, thereby obtaining a concentrated product containing 2,4,6-trifluorobenzoic acid. This invention does not limit the method of concentration; for example, rotary evaporation or condensation evaporation can be used. Adding water to the concentrated product containing 2,4,6-trifluorobenzoic acid allows 2,4,6-trifluorobenzoic acid to precipitate. Since a small amount of impurities are still present in the precipitated product, this step yields a crude product of 2,4,6-trifluorobenzoic acid.

[0063] To improve the purity of 2,4,6-trifluorobenzoic acid, this invention utilizes an alkaline aqueous solution (such as sodium hydroxide aqueous solution) to dissolve crude 2,4,6-trifluorobenzoic acid, obtaining a sodium 2,4,6-trifluorobenzoate solution. This solution is then subjected to a second extraction treatment using a second extractant. After the second extraction treatment, insoluble substances in the solution can be removed by filtration. This invention does not limit the type of the second extractant; it can be the same as or different from the first extractant. Exemplarily, it can be any one of methyl tert-butyl ether, ethyl acetate, dichloromethane, diethyl ether, and toluene.

[0064] Finally, the pH of the above solution was adjusted to 0-2 using an acid (e.g., hydrochloric acid) to convert sodium 2,4,6-trifluorobenzoate into 2,4,6-trifluorobenzoic acid crystals. The precipitated crystals were then filtered and dried to obtain pure 2,4,6-trifluorobenzoic acid.

[0065] In this invention, before step 1), the method further includes: reacting 1,3,5-trichlorobenzene with a fluorinating agent in a fluorinating solvent under the action of a fluorinating catalyst to obtain 1,3,5-trifluorobenzene; wherein the molar ratio of 1,3,5-trichlorobenzene to the fluorinating solvent, the fluorinating agent, and the fluorinating catalyst is 1:(5-10):(3-5):(0.005-0.05); the fluorinating solvent includes at least one of N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, dimethyl sulfoxide, and sulfolane; the fluorinating agent includes at least one of potassium fluoride, sodium fluoride, and cesium fluoride; and the fluorinating catalyst includes at least one of tetramethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, triphenylmethylphosphonium bromide, triphenylethylphosphonium bromide, and tetraphenylphosphonium bromide.

[0066] Considering the molar yield of 1,3,5-trifluorobenzene, the preferred fluorinating solvent is sulfolane; the preferred fluorinating agent is potassium fluoride; and the preferred fluorinating catalyst is tetraphenylphosphonium bromide. In specific implementations, the molar ratio of 1,3,5-trichlorobenzene to the fluorinating solvent, fluorinating agent, and fluorinating catalyst is 1:(5-10):(3-5):(0.005-0.05). When the amount of fluorinating solvent, fluorinating agent, and fluorinating catalyst added is too high, the amount of byproducts increases, affecting the yield and purity of 1,3,5-trifluorobenzene; when the content is too low, the conversion rate of 1,3,5-trichlorobenzene is low, which is not conducive to obtaining a high yield of 1,3,5-trifluorobenzene. Therefore, this invention controls the molar ratio of 1,3,5-trichlorobenzene to the fluorinating solvent, fluorinating agent, and fluorinating catalyst to be 1:(5-10):(3-5):(0.005-0.05).

[0067] Since 1,3,5-trichlorobenzene is inexpensive and widely available, using 1,3,5-trichlorobenzene as a raw material to prepare 1,3,5-trifluorobenzene, and then obtaining 2,4,6-trifluorobenzoic acid, can significantly reduce the preparation cost and is beneficial for industrial production. Therefore, this invention selects 1,3,5-trichlorobenzene as a raw material.

[0068] After the fluorination reaction is completed, the resulting 1,3,5-trifluorobenzene exists in the fluorination reaction system. The fluorination reaction system also contains fluorination solvent, fluorination catalyst, impurities, etc. Therefore, the system needs to be post-processed to obtain 1,3,5-trifluorobenzene.

[0069] This invention uses GC to track the fluorination reaction. When the GC detection shows that the content of 1,3,5-trichlorobenzene is less than 0.2%, it indicates that the reaction has ended.

[0070] In practice, the fluorination reaction is carried out under an inert gas atmosphere. The inert gas includes at least one of nitrogen, helium, and argon; nitrogen is preferred for cost reasons. Under inert gas protection, the fluorination catalyst and fluorinating agent are less hygroscopic, which is beneficial for improving the molar yield and purity of 1,3,5-trifluorobenzene.

[0071] According to research, the temperature for fluorination reaction is 130–180℃.

[0072] When the temperature is too low, the conversion rate of the fluorination reaction is low, resulting in a low molar yield and purity of 1,3,5-trifluorobenzene; while when the temperature is too high, it is difficult to operate and the reaction cost is high. Therefore, when the temperature of the fluorination reaction is controlled at 130–180 °C, 1,3,5-trifluorobenzene with high purity and high molar yield can be prepared at a lower cost, and the operation is convenient.

[0073] After the fluorination reaction is completed, the fluorination reaction system is subjected to vacuum distillation, and the fraction obtained from the vacuum distillation is subjected to vacuum rectification to obtain 1,3,5-trifluorobenzene.

[0074] The above process refers to the separation and purification of 1,3,5-trifluorobenzene from the fluorination reaction system after the fluorination reaction is completed. After vacuum distillation, the fluorinating solvent is removed, yielding a fraction containing 1,3,5-trifluorobenzene. This fraction is then subjected to vacuum distillation to remove impurities from the fluorination reaction process, resulting in 1,3,5-trifluorobenzene of higher purity.

[0075] The present invention will now be described in more detail through specific embodiments.

[0076] Example 1

[0077] The 2,4,6-trifluorobenzoic acid of the present invention is prepared by the following method:

[0078] 1) Under nitrogen protection, 18.15 g of 1,3,5-trichlorobenzene, 54.50 g of N,N-dimethylformamide, 18.6 g of potassium fluoride, and 0.32 g of tetrabutylammonium bromide were added to a reaction flask for fluorination. The fluorination reaction temperature was 150–160 °C. When the GC detection showed that the content of 1,3,5-trichlorobenzene was less than 0.2%, the reaction was complete, and the fluorination reaction system was obtained. The molar ratio of 1,3,5-trichlorobenzene, N,N-dimethylformamide, potassium fluoride, and tetrabutylammonium bromide was 1:7.46:3.20:0.01.

[0079] The fluorination reaction system was subjected to vacuum distillation, and the resulting fraction was subjected to vacuum rectification to obtain 12.53 g of the first product;

[0080] Figure 1The first product's 1H NMR spectrum confirms its structure as 1,3,5-trifluorobenzene. The GC purity of 1,3,5-trifluorobenzene is 99.3%, and the molar yield is 94.9%.

[0081] 2) Add 12.53g of 1,3,5-trifluorobenzene, 25mL of dichloromethane, and 0.50g of ferric chloride to a three-necked flask; dissolve 15.98g of bromine in 13mL of dichloromethane to form a bromine solution, with a mass-to-volume ratio of bromine to dichloromethane of 1g:0.81mL;

[0082] A bromination reaction was initiated by adding bromine solution dropwise to a three-necked flask at 30°C at a dropping rate of 1.66 g / min. The reaction ended when the content of the intermediate 1,3,5-trifluorobenzene was less than 0.2% as determined by GC, yielding the bromination reaction system. The molar ratio of 1,3,5-trifluorobenzene, dichloromethane, ferric chloride, and bromine was 1:6.25:0.03:1.05.

[0083] The bromination reaction system was successively washed with alkaline solution, washed with water, and the organic phase obtained after water washing was subjected to vacuum distillation to obtain 19.66 g of the second product.

[0084] Figure 2 The 1H NMR spectrum of the second product confirms its structure as 2,4,6-trifluorobromobenzene. The GC purity of 2,4,6-trifluorobromobenzene is 99.2%, and the molar yield is 98.2%.

[0085] 3) Under nitrogen protection, add 50 mL of 2 mol / L tetrahydrofuran solution (0.1 mol) of magnesium isopropyl chloride to a three-necked flask, and add 19.66 g of 2,4,6-trifluorobromobenzene dropwise at 0 °C with a dropping rate of 0.98 g / min, controlling the system temperature at 0-10 °C during the dropping process; wherein the molar ratio of 2,4,6-trifluorobromobenzene to magnesium isopropyl chloride is 1:1.07;

[0086] Dry carbon dioxide gas was introduced into the system at 0–10 °C. The reaction ended when the content of 2,4,6-trifluorobromobenzene was less than 0.2% as determined by HPLC.

[0087] At 0–10 °C, 10% hydrochloric acid was added dropwise to the Grignard reaction system, and the Grignard reaction system was extracted with 50 mL of methyl tert-butyl ether. The organic phase obtained by extraction was concentrated by rotary evaporation. 100 mL of water was added to the concentrated product to obtain the crude product. 10% sodium hydroxide aqueous solution was added to the crude product, followed by washing twice with 50 mL of methyl tert-butyl ether and filtration. The pH of the solution was adjusted to 1.0 using hydrochloric acid. 15.79 g of the third product was obtained by suction filtration and drying.

[0088] Figure 3The 1H NMR spectrum of the third product confirms its structure as 2,4,6-trifluorobenzoic acid. The HPLC purity of 2,4,6-trifluorobenzoic acid is 99.3%, the molar yield is 96.2%, and the total molar yield of the three-step reaction is 89.7%.

[0089] Example 2

[0090] The difference between this embodiment and Embodiment 1 is that the amounts of raw materials and solvents are increased tenfold, while the other conditions are the same as in Embodiment 1.

[0091] 1) The fluorination reaction raw materials include: 1815g 1,3,5-trichlorobenzene, 5450g N,N-dimethylformamide, 1860g potassium fluoride, and 32g tetrabutylammonium bromide; wherein the molar ratio of 1,3,5-trichlorobenzene, N,N-dimethylformamide, potassium fluoride, and tetrabutylammonium bromide is 1:7.46:3.20:0.01; in this example, 1280g of the first product was obtained.

[0092] The peak intensity and position of the first product in this embodiment are basically the same as those of the first product in Example 1, proving that its structure is 1,3,5-trifluorobenzene. The GC purity of 1,3,5-trifluorobenzene is 99.4%, and the molar yield is 96.9%.

[0093] 2) The bromination reaction raw materials include: 1280g 1,3,5-trifluorobenzene, 2500ml dichloromethane, and 50g ferric chloride; 1598g of bromine is dissolved in 1300ml dichloromethane to form a bromine solution; wherein, the molar ratio of 1,3,5-trifluorobenzene, dichloromethane, ferric chloride, and bromine is 1:6.12:0.03:1.03; in this example, 2028g of the second product was obtained.

[0094] The peak intensity and position of the second product in this embodiment are basically the same as those of the second product in Example 1, proving that its structure is 2,4,6-trifluorobromobenzene. The GC purity of 2,4,6-trifluorobromobenzene is 99.2%, and the molar yield is 99.2%.

[0095] 3) The Grignard reaction raw materials include: 2028g of 2,4,6-trifluorobromobenzene and 5000mL of 2mol / L tetrahydrofuran solution of isopropyl magnesium chloride; wherein, the molar ratio of 2,4,6-trifluorobromobenzene to isopropyl magnesium chloride is 1:1.04; in this example, 1652g of the third product was obtained.

[0096] The peak intensity and position of the third product in this embodiment are basically the same as those of the third product in Example 1, proving that its structure is 2,4,6-trifluorobenzoic acid. The HPLC purity of 2,4,6-trifluorobenzoic acid is 99.5%, the molar yield is 97.6%, and the total molar yield of the three-step reaction is 93.8%.

[0097] Example 3

[0098] The difference between this embodiment and Example 1 is that N,N-dimethylformamide in step 1) is replaced with sulfolane, while the other conditions are the same as in Example 1 (the reaction conditions in steps 1-3 and the molar ratio of the reaction raw materials are the same as in Example 1).

[0099] 1) In this example, 12.81 g of the first product was obtained. The peak intensity and position of the 1H NMR spectrum of the first product in this example are basically the same as those of the first product in Example 1, which proves that its structure is 1,3,5-trifluorobenzene. The GC purity of 1,3,5-trifluorobenzene is 99.4%, and the molar yield is 97.0%.

[0100] 2) In this example, 20.10 g of the second product was obtained. The peak intensity and position of the 1H NMR spectrum of the second product in this example are basically the same as those of the second product in Example 1, which proves that its structure is 2,4,6-trifluorobromobenzene. The GC purity of 2,4,6-trifluorobromobenzene is 99.2%, and the molar yield is 98.2%.

[0101] 3) In this embodiment, 16.13g of the third product was obtained;

[0102] The peak intensity and position of the third product in this embodiment are basically the same as those of the third product in Example 1, proving that its structure is 2,4,6-trifluorobenzoic acid. The HPLC purity of 2,4,6-trifluorobenzoic acid is 99.4%, the molar yield is 96.2%, and the total molar yield of the three-step reaction is 91.6%.

[0103] Example 4

[0104] The difference between this embodiment and Example 1 is that the amount of tetrabutylammonium bromide in step 1) is replaced from 0.32g to 0.64g, that is, the molar ratio of 1,3,5-trichlorobenzene, N,N-dimethylformamide, potassium fluoride, and tetrabutylammonium bromide is 1:7.46:3.20:0.02; the other conditions are the same as in Example 1 (the reaction conditions in steps 1-3 and the molar ratio of the reaction raw materials are the same as in Example 1).

[0105] 1) In this embodiment, 12.75g of the first product was obtained;

[0106] The peak intensity and position of the first product in this embodiment are basically the same as those of the first product in Example 1, proving that its structure is 1,3,5-trifluorobenzene. The GC purity of 1,3,5-trifluorobenzene is 99.3%, and the molar yield is 96.5%.

[0107] 2) In this embodiment, 19.99 g of the second product was obtained;

[0108] The peak intensity and position of the second product in this embodiment are basically the same as those of the second product in Example 1, proving that its structure is 2,4,6-trifluorobromobenzene. The GC purity of 2,4,6-trifluorobromobenzene is 99.2%, and the molar yield is 98.2%.

[0109] 3) In this embodiment, 16.06 g of the third product was obtained;

[0110] The peak intensity and position of the third product in this embodiment are basically the same as those of the third product in Example 1, proving that its structure is 2,4,6-trifluorobenzoic acid. The HPLC purity of 2,4,6-trifluorobenzoic acid is 99.4%, the molar yield is 96.2%, and the total molar yield of the three-step reaction is 91.2%.

[0111] Example 5

[0112] The difference between this embodiment and Example 1 is that tetrabutylammonium bromide in step 1) is replaced with tetraphenylphosphonium bromide, while the other conditions are the same as in Example 1 (the reaction conditions in steps 1-3 and the molar ratio of the reaction raw materials are the same as in Example 1).

[0113] 1) In this embodiment, 12.89 g of the first product was obtained;

[0114] The peak intensity and position of the first product in this embodiment are basically the same as those of the first product in Example 1, proving that its structure is 1,3,5-trifluorobenzene. The GC purity of 1,3,5-trifluorobenzene is 99.3%, and the molar yield is 97.6%.

[0115] 2) In this embodiment, 20.22 g of the second product was obtained;

[0116] The peak intensity and position of the second product in this embodiment are basically the same as those of the second product in Example 1, proving that its structure is 2,4,6-trifluorobromobenzene. The GC purity of 2,4,6-trifluorobromobenzene is 99.3%, and the molar yield is 98.2%.

[0117] 3) In this embodiment, 16.24 g of the third product was obtained;

[0118] The peak intensity and position of the third product in this embodiment are basically the same as those of the third product in Example 1, proving that its structure is 2,4,6-trifluorobenzoic acid. The HPLC purity of 2,4,6-trifluorobenzoic acid is 99.5%, the molar yield is 96.2%, and the total molar yield of the three-step reaction is 92.2%.

[0119] Example 6

[0120] The difference between this embodiment and Example 1 is that potassium fluoride in step 1) is replaced with sodium fluoride, while the other conditions are the same as in Example 1 (the reaction conditions in steps 1-3 and the molar ratio of the reaction raw materials are the same as in Example 1).

[0121] 1) In this embodiment, 12.07 g of the first product was obtained;

[0122] The peak intensity and position of the first product in this embodiment are basically the same as those of the first product in Example 1, proving that its structure is 1,3,5-trifluorobenzene. The GC purity of 1,3,5-trifluorobenzene is 99.1%, and the molar yield is 91.4%.

[0123] 2) In this embodiment, 18.94 g of the second product was obtained;

[0124] The peak intensity and position of the second product in this embodiment are basically the same as those of the second product in Example 1, proving that its structure is 2,4,6-trifluorobromobenzene. The GC purity of 2,4,6-trifluorobromobenzene is 99.0%, and the molar yield is 98.2%.

[0125] 3) In this embodiment, 15.20 g of the third product was obtained;

[0126] The peak intensity and position of the third product in this embodiment are basically the same as those of the third product in Example 1, proving that its structure is 2,4,6-trifluorobenzoic acid. The HPLC purity of 2,4,6-trifluorobenzoic acid is 99.0%, the molar yield is 96.2%, and the total molar yield of the three-step reaction is 86.3%.

[0127] Example 7

[0128] The difference between this embodiment and Example 1 is that the amount of ferric chloride in step 2) is replaced from 0.50g to 0.83g, that is, the molar ratio of 1,3,5-trifluorobenzene, dichloromethane, ferric chloride, and bromine is 1:6.25:0.05:1.05; the other conditions are the same as in Example 1 (the reaction conditions in steps 1-3 and the molar ratio of the reaction raw materials are the same as in Example 1);

[0129] 1) In this embodiment, 12.53 g of the first product was obtained;

[0130] The peak intensity and position of the first product in this embodiment are basically the same as those of the first product in Example 1, proving that its structure is 1,3,5-trifluorobenzene. The GC purity of 1,3,5-trifluorobenzene is 99.3%, and the molar yield is 94.9%.

[0131] 2) In this embodiment, 19.86 g of the second product was obtained;

[0132] The peak intensity and position of the second product in this embodiment are basically the same as those of the second product in Example 1, proving that its structure is 2,4,6-trifluorobromobenzene. The GC purity of 2,4,6-trifluorobromobenzene is 99.2%, and the molar yield is 99.2%.

[0133] 3) In this embodiment, 15.95g of the third product was obtained;

[0134] The peak intensity and position of the third product in this embodiment are basically the same as those of the third product in Example 1, proving that its structure is 2,4,6-trifluorobenzoic acid. The HPLC purity of 2,4,6-trifluorobenzoic acid is 99.3%, the molar yield is 96.2%, and the total molar yield of the three-step reaction is 90.6%.

[0135] Example 8

[0136] The difference between this embodiment and Example 1 is that the amount of bromine in step 2) is replaced from 15.98g to 16.78g, that is, the molar ratio of 1,3,5-trifluorobenzene, dichloromethane, ferric chloride, and bromine is 1:6.25:0.03:1.11; the other conditions are the same as in Example 1 (the reaction conditions in steps 1-3 and the molar ratio of the reaction raw materials are the same as in Example 1);

[0137] 1) In this embodiment, 12.53 g of the first product was obtained;

[0138] The peak intensity and position of the first product in this embodiment are basically the same as those of the first product in Example 1, proving that its structure is 1,3,5-trifluorobenzene. The GC purity of 1,3,5-trifluorobenzene is 99.3%, and the molar yield is 94.9%.

[0139] 2) In this embodiment, 19.86 g of the second product was obtained;

[0140] The peak intensity and position of the second product in this embodiment are basically the same as those of the second product in Example 1, proving that its structure is 2,4,6-trifluorobromobenzene. The GC purity of 2,4,6-trifluorobromobenzene is 99.3%, and the molar yield is 99.2%.

[0141] 3) In this embodiment, 15.95g of the third product was obtained;

[0142] The peak intensity and position of the third product in this embodiment are basically the same as those of the third product in Example 1, proving that its structure is 2,4,6-trifluorobenzoic acid. The HPLC purity of 2,4,6-trifluorobenzoic acid is 99.4%, the molar yield is 96.2%, and the total molar yield of the three-step reaction is 90.6%.

[0143] Example 9

[0144] The difference between this embodiment and Example 1 is that the 2 mol / L tetrahydrofuran solution of isopropyl magnesium chloride in step 3) is replaced with 0.105 mol instead of 0.1 mol, and the molar ratio of 2,4,6-trifluorobromobenzene to isopropyl magnesium chloride is 1:1.13; the other conditions are the same as in Example 1 (the reaction conditions in steps 1-3 and the molar ratio of the reaction raw materials are the same as in Example 1).

[0145] 1) In this embodiment, 12.53 g of the first product was obtained;

[0146] The peak intensity and position of the first product in this embodiment are basically the same as those of the first product in Example 1, proving that its structure is 1,3,5-trifluorobenzene. The GC purity of 1,3,5-trifluorobenzene is 99.3%, and the molar yield is 94.9%.

[0147] 2) In this embodiment, 19.66 g of the second product was obtained;

[0148] The peak intensity and position of the second product in this embodiment are basically the same as those of the second product in Example 1, proving that its structure is 2,4,6-trifluorobromobenzene. The GC purity of 2,4,6-trifluorobromobenzene is 99.2%, and the molar yield is 98.2%.

[0149] 3) In this embodiment, 15.99 g of the third product was obtained;

[0150] The peak intensity and position of the third product in this embodiment are basically the same as those of the third product in Example 1, which proves that its structure is 2,4,6-trifluorobenzoic acid. The HPLC purity of 2,4,6-trifluorobenzoic acid is 99.4%, the molar yield is 97.4%, and the total molar yield of the three-step reaction is 90.8%.

[0151] Example 10

[0152] The difference between this embodiment and Example 2 is that N,N-dimethylformamide in step 1) is replaced with sulfolane, and tetrabutylammonium bromide is replaced with tetraphenylphosphonium bromide; the amount of ferric chloride in step 2) is replaced from 50g to 83g, and the amount of bromine is replaced from 1598g to 1678g, with the molar ratio of 1,3,5-trifluorobenzene, dichloromethane, ferric chloride, and bromine being 1:6.25:0.05:1.07; the amount of 2mol / L tetrahydrofuran solution of isopropyl magnesium chloride in step 3) is replaced from 5468g to 5741g, with the molar ratio of 2,4,6-trifluorobromobenzene to isopropyl magnesium chloride being 1:1.07; the remaining conditions are the same as in Example 2.

[0153] 1) In this embodiment, 1300g of the first product was obtained;

[0154] The peak intensity and position of the first product in this embodiment are basically the same as those of the first product in Example 1, proving that its structure is 1,3,5-trifluorobenzene. The GC purity of 1,3,5-trifluorobenzene is 99.4%, and the molar yield is 98.4%.

[0155] 2) In this embodiment, 2064g of the second product was obtained;

[0156] The peak intensity and position of the second product in this embodiment are basically the same as those of the second product in Example 1, proving that its structure is 2,4,6-trifluorobromobenzene. The GC purity of 2,4,6-trifluorobromobenzene is 99.4%, and the molar yield is 99.4%.

[0157] 3) In this embodiment, 1696g of the third product was obtained;

[0158] The peak intensity and position of the third product in this embodiment are basically the same as those of the third product in Example 1, proving that its structure is 2,4,6-trifluorobenzoic acid. The HPLC purity of 2,4,6-trifluorobenzoic acid is 99.5%, the molar yield is 98.5%, and the total molar yield of the three-step reaction is 96.3%.

[0159] Example 11

[0160] The difference between this embodiment and Example 1 is that the fluorination temperature in step 1) is adjusted to 140-150℃, and 78.4g of N,N-dimethylacetamide, 16.8g of sodium fluoride, and 0.56g of tetrabutylammonium chloride are added, so that the molar ratio of 1,3,5-trichlorobenzene, N,N-dimethylacetamide, sodium fluoride, and tetrabutylammonium chloride is 1:9:4:0.02.

[0161] Replace 25 ml of dichloromethane with 25 ml of dichloroethane in step 2), and replace 0.50 g of ferric chloride with 0.89 g of ferric tribromide; in the bromine solution, the mass-to-volume ratio of bromine to dichloroethane is 1 g: 1.5 mL; control the dropping temperature of the bromine solution at 20 °C and the dropping rate at 1.6 g / min; make the molar ratio of 1,3,5-trifluorobenzene to dichloroethane, ferric tribromide, and bromine 1:5.33:0.03:1.07;

[0162] The dropping rate of 2,4,6-trifluorobromobenzene in step 3) was adjusted to 0.65 g / min, and the Grignard reaction temperature was adjusted to -10 to 0 °C; the aqueous phase obtained from the second extraction was filtered and the pH was adjusted to 0; the remaining conditions were the same as in Example 1.

[0163] 1) In this embodiment, 12.26 g of the first product was obtained;

[0164] The peak intensity and position of the first product in this embodiment are basically the same as those of the first product in Example 1, proving that its structure is 1,3,5-trifluorobenzene. The GC purity of 1,3,5-trifluorobenzene is 99.1%, and the molar yield is 92.8%.

[0165] 2) In this embodiment, 19.03 g of the second product was obtained;

[0166] The peak intensity and position of the second product in this embodiment are basically the same as those of the second product in Example 1, proving that its structure is 2,4,6-trifluorobromobenzene. The GC purity of 2,4,6-trifluorobromobenzene is 99.1%, and the molar yield is 97.2%.

[0167] 3) In this embodiment, 15.47 g of the third product was obtained;

[0168] The peak intensity and position of the third product in this embodiment are basically the same as those of the third product in Example 1, proving that its structure is 2,4,6-trifluorobenzoic acid. The HPLC purity of 2,4,6-trifluorobenzoic acid is 99.1%, the molar yield is 97.4%, and the total molar yield of the three-step reaction is 87.9%.

[0169] Example 12

[0170] The difference between this embodiment and Example 1 is that the amount of dichloromethane added to the bromine solution in step 2) is changed from 13 mL to 26 mL, that is, the mass-volume ratio of bromine to dichloromethane is changed from 1 g: 0.81 mL to 1 g: 1.63 mL. The other conditions are the same as in Example 1 (the reaction conditions in steps 1-3 and the molar ratio of the reaction raw materials are the same as in Example 1).

[0171] 1) In this embodiment, 12.53 g of the first product was obtained;

[0172] The peak intensity and position of the first product in this embodiment are basically the same as those of the first product in Example 1, proving that its structure is 1,3,5-trifluorobenzene. The GC purity of 1,3,5-trifluorobenzene is 99.3%, and the molar yield is 94.9%.

[0173] 2) In this embodiment, 19.58 g of the second product was obtained;

[0174] The peak intensity and position of the second product in this embodiment are basically the same as those of the second product in Example 1, which proves that its structure is 2,4,6-trifluorobromobenzene. The GC purity of 2,4,6-trifluorobromobenzene is 99.0%, and the molar yield is 97.8%.

[0175] 3) In this embodiment, 15.72 g of the third product was obtained;

[0176] The peak intensity and position of the third product in this embodiment are basically the same as those of the third product in Example 1, proving that its structure is 2,4,6-trifluorobenzoic acid. The HPLC purity of 2,4,6-trifluorobenzoic acid is 99.3%, the molar yield is 96.2%, and the total molar yield of the three-step reaction is 89.3%.

[0177] Example 13

[0178] The difference between this embodiment and Example 1 is that the dropping rate of the bromine solution in step 2) is changed from 1.66 g / min to 3.0 g / min, while the other conditions are the same as in Example 1 (the reaction conditions in steps 1-3 and the molar ratio of the reaction raw materials are the same as in Example 1).

[0179] 1) In this embodiment, 12.53 g of the first product was obtained;

[0180] The peak intensity and position of the first product in this embodiment are basically the same as those of the first product in Example 1, proving that its structure is 1,3,5-trifluorobenzene. The GC purity of 1,3,5-trifluorobenzene is 99.3%, and the molar yield is 94.9%.

[0181] 2) In this embodiment, 19.32 g of the second product was obtained;

[0182] The peak intensity and position of the second product in this embodiment are basically the same as those of the second product in Example 1, proving that its structure is 2,4,6-trifluorobromobenzene. The GC purity of 2,4,6-trifluorobromobenzene is 99.0%, and the molar yield is 96.5%.

[0183] 3) In this embodiment, 15.51g of the third product was obtained;

[0184] The peak intensity and position of the third product in this embodiment are basically the same as those of the third product in Example 1, proving that its structure is 2,4,6-trifluorobenzoic acid. The HPLC purity of 2,4,6-trifluorobenzoic acid is 99.1%, the molar yield is 96.2%, and the total molar yield of the three-step reaction is 88.1%.

[0185] Example 14

[0186] The difference between this embodiment and Example 1 is that the dropping temperature of the bromine solution in step 2) is changed from 20-30℃ to 40-50℃, while the other conditions are the same as in Example 1 (the reaction conditions in steps 1-3 and the molar ratio of the reaction raw materials are the same as in Example 1).

[0187] 1) In this embodiment, 12.53 g of the first product was obtained;

[0188] The peak intensity and position of the first product in this embodiment are basically the same as those of the first product in Example 1, proving that its structure is 1,3,5-trifluorobenzene. The GC purity of 1,3,5-trifluorobenzene is 99.3%, and the molar yield is 94.9%.

[0189] 2) In this embodiment, 18.98 g of the second product was obtained;

[0190] The peak intensity and position of the second product in this embodiment are basically the same as those of the second product in Example 1, proving that its structure is 2,4,6-trifluorobromobenzene. The GC purity of 2,4,6-trifluorobromobenzene is 99.0%, and the molar yield is 94.8%.

[0191] 3) In this embodiment, 15.24 g of the third product was obtained;

[0192] The peak intensity and position of the third product in this embodiment are basically the same as those of the third product in Example 1, proving that its structure is 2,4,6-trifluorobenzoic acid. The HPLC purity of 2,4,6-trifluorobenzoic acid is 99.1%, the molar yield is 96.2%, and the total molar yield of the three-step reaction is 86.5%.

[0193] Example 15

[0194] The difference between this embodiment and Example 1 is that the dropping rate of 2,4,6-trifluorobromobenzene in step 3) is changed from 1.0 g / min to 2.0 g / min, while the other conditions are the same as in Example 1 (the reaction conditions in steps 1-3 and the molar ratio of the reaction raw materials are the same as in Example 1).

[0195] 1) In this embodiment, 12.53 g of the first product was obtained;

[0196] The peak intensity and position of the first product in this embodiment are basically the same as those of the first product in Example 1, proving that its structure is 1,3,5-trifluorobenzene. The GC purity of 1,3,5-trifluorobenzene is 99.3%, and the molar yield is 94.9%.

[0197] 2) In this embodiment, 19.66 g of the second product was obtained;

[0198] The peak intensity and position of the second product in this embodiment are basically the same as those of the second product in Example 1, proving that its structure is 2,4,6-trifluorobromobenzene. The GC purity of 2,4,6-trifluorobromobenzene is 99.2%, and the molar yield is 98.2%.

[0199] 3) In this embodiment, 15.43 g of the third product was obtained;

[0200] The peak intensity and position of the third product in this embodiment are basically the same as those of the third product in Example 1, proving that its structure is 2,4,6-trifluorobenzoic acid. The HPLC purity of 2,4,6-trifluorobenzoic acid is 99.0%, the molar yield is 94.0%, and the total molar yield of the three-step reaction is 87.6%.

[0201] Example 16

[0202] The difference between this embodiment and Example 1 is that the temperature of the Grignard reaction in step 3) is changed from 0-10℃ to 16-25℃, while the other conditions are the same as in Example 1 (the reaction conditions in steps 1-3 and the molar ratio of the reactants are the same as in Example 1).

[0203] 1) In this embodiment, 12.53 g of the first product was obtained;

[0204] The peak intensity and position of the first product in this embodiment are basically the same as those of the first product in Example 1, proving that its structure is 1,3,5-trifluorobenzene. The GC purity of 1,3,5-trifluorobenzene is 99.3%, and the molar yield is 94.9%.

[0205] 2) In this embodiment, 19.66 g of the second product was obtained;

[0206] The peak intensity and position of the second product in this embodiment are basically the same as those of the second product in Example 1, proving that its structure is 2,4,6-trifluorobromobenzene. The GC purity of 2,4,6-trifluorobromobenzene is 99.2%, and the molar yield is 98.2%.

[0207] 3) In this embodiment, 15.34 g of the third product was obtained;

[0208] The peak intensity and position of the third product in this embodiment are basically the same as those of the third product in Example 1, proving that its structure is 2,4,6-trifluorobenzoic acid. The HPLC purity of 2,4,6-trifluorobenzoic acid is 99.1%, the molar yield is 93.5%, and the total molar yield of the three-step reaction is 87.1%.

[0209] Example 17

[0210] The difference between this embodiment and Example 1 is that 0.50g of ferric chloride in step 2) is replaced with 0.32g of ferric chloride, so that the molar ratio of 1,3,5-trifluorobenzene, dichloromethane, ferric chloride, and bromine is 1:6.25:0.02:1.05; the other conditions are the same as in Example 1 (the reaction conditions in steps 1-3 and the molar ratio of the reaction raw materials are the same as in Example 1).

[0211] 1) In this embodiment, 12.53 g of the first product was obtained;

[0212] The peak intensity and position of the first product in this embodiment are basically the same as those of the first product in Example 1, proving that its structure is 1,3,5-trifluorobenzene. The GC purity of 1,3,5-trifluorobenzene is 99.3%, and the molar yield is 94.9%.

[0213] 2) In this embodiment, 19.44 g of the second product was obtained;

[0214] The peak intensity and position of the second product in this embodiment are basically the same as those of the second product in Example 1, proving that its structure is 2,4,6-trifluorobromobenzene. The GC purity of 2,4,6-trifluorobromobenzene is 99.0%, and the molar yield is 97.1%.

[0215] 3) In this embodiment, 15.61 g of the third product was obtained;

[0216] The peak intensity and position of the third product in this embodiment are basically the same as those of the third product in Example 1, proving that its structure is 2,4,6-trifluorobenzoic acid. The HPLC purity of 2,4,6-trifluorobenzoic acid is 99.2%, the molar yield is 96.2%, and the total molar yield of the three-step reaction is 88.6%.

[0217] Example 18

[0218] The difference between this embodiment and Example 1 is that, in step 2), bromine solution is added dropwise to the three-necked flask at 40°C to carry out the bromination reaction; the other conditions are the same as in Example 1 (the reaction conditions in steps 1-3 and the molar ratio of the reaction raw materials are the same as in Example 1).

[0219] 1) In this embodiment, 12.53 g of the first product was obtained;

[0220] The peak intensity and position of the first product in this embodiment are basically the same as those of the first product in Example 1, proving that its structure is 1,3,5-trifluorobenzene. The GC purity of 1,3,5-trifluorobenzene is 99.3%, and the molar yield is 94.9%.

[0221] 2) In this embodiment, 19.38 g of the second product was obtained;

[0222] The peak intensity and position of the second product in this embodiment are basically the same as those of the second product in Example 1, proving that its structure is 2,4,6-trifluorobromobenzene. The GC purity of 2,4,6-trifluorobromobenzene is 98.8%, and the molar yield is 96.8%.

[0223] 3) In this embodiment, 15.56 g of the third product was obtained;

[0224] The peak intensity and position of the third product in this embodiment are basically the same as those of the third product in Example 1, proving that its structure is 2,4,6-trifluorobenzoic acid. The HPLC purity of 2,4,6-trifluorobenzoic acid is 99.0%, the molar yield is 96.2%, and the total molar yield of the three-step reaction is 88.4%.

[0225] Example 19

[0226] The difference between this embodiment and Example 1 is that the fluorination reaction temperature in step 1) is replaced by 110-120°C instead of 150-160°C. The other conditions are the same as in Example 1 (the reaction conditions in steps 1-3 and the molar ratio of the reaction raw materials are the same as in Example 1).

[0227] 1) In this embodiment, 12.10 g of the first product was obtained;

[0228] The peak intensity and position of the first product in this embodiment are basically the same as those of the first product in Example 1, proving that its structure is 1,3,5-trifluorobenzene. The GC purity of 1,3,5-trifluorobenzene is 98.6%, and the molar yield is 91.6%.

[0229] 2) In this embodiment, 18.98 g of the second product was obtained;

[0230] The peak intensity and position of the second product in this embodiment are basically the same as those of the second product in Example 1, proving that its structure is 2,4,6-trifluorobromobenzene. The GC purity of 2,4,6-trifluorobromobenzene is 99.0%, and the molar yield is 98.2%.

[0231] 3) In this embodiment, 15.25g of the third product was obtained;

[0232] The peak intensity and position of the third product in this embodiment are basically the same as those of the third product in Example 1, proving that its structure is 2,4,6-trifluorobenzoic acid. The HPLC purity of 2,4,6-trifluorobenzoic acid is 99.0%, the molar yield is 96.3%, and the total molar yield of the three-step reaction is 86.6%.

[0233] Example 20

[0234] The difference between this embodiment and Example 1 is that 0.32g of tetrabutylammonium bromide in step 1) is replaced with 3.2g of tetrabutylammonium bromide, so that the molar ratio of 1,3,5-trichlorobenzene to N,N-dimethylformamide, potassium fluoride and tetrabutylammonium bromide is 1:7.46:3.20:0.1. The other conditions are the same as in Example 1 (the reaction conditions in steps 1-3 and the molar ratio of the reaction raw materials are the same as in Example 1).

[0235] 1) In this embodiment, 12.12 g of the first product was obtained;

[0236] The peak intensity and position of the first product in this embodiment are basically the same as those of the first product in Example 1, proving that its structure is 1,3,5-trifluorobenzene. The GC purity of 1,3,5-trifluorobenzene is 98.6%, and the molar yield is 91.8%.

[0237] 2) In this embodiment, 19.04 g of the second product was obtained;

[0238] The peak intensity and position of the second product in this embodiment are basically the same as those of the second product in Example 1, proving that its structure is 2,4,6-trifluorobromobenzene. The GC purity of 2,4,6-trifluorobromobenzene is 99.0%, and the molar yield is 98.3%.

[0239] 3) In this embodiment, 15.30 g of the third product was obtained;

[0240] The peak intensity and position of the third product in this embodiment are basically the same as those of the third product in Example 1, proving that its structure is 2,4,6-trifluorobenzoic acid. The HPLC purity of 2,4,6-trifluorobenzoic acid is 99.0%, the molar yield is 96.3%, and the total molar yield of the three-step reaction is 86.9%.

[0241] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention have been clearly and completely described above in conjunction with specific embodiments. The described embodiments are only a part of the embodiments of this invention, not all of them. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

Claims

1. A process for the preparation of 2,4,6-trifluorobenzoic acid, characterized in that, The method comprises: 1) brominating 1,3,5-trifluorobenzene to obtain 2,4,6-trifluorobromobenzene; 2) subjecting the 2,4,6-trifluorobromobenzene to a Grignard reaction to obtain 2,4,6-trifluorobenzoic acid; Step 1) comprises: adding a bromine solution to a system comprising the 1,3,5-trifluorobenzene, a bromination solvent, a bromination catalyst to carry out the bromination reaction to obtain the 2,4,6-trifluorobromobenzene; wherein the bromination solvent comprises at least one of dichloromethane, chloroform, carbon tetrachloride, toluene; the bromination catalyst comprises at least one of ferric chloride and iron tribromide; the bromine solution comprises bromine and the bromination solvent, and the molar ratio of the 1,3,5-trifluorobenzene to the bromination solvent, bromination catalyst and bromine is 1:(5-8):(0.02-0.07):(1-1.5); in the bromine solution, the mass-volume ratio of the bromine to the bromination solvent is 1g:(0.6-1.5)mL, and the dropwise addition rate of the bromine solution is 1-3g / min; and / or, the dropwise addition temperature of the bromine solution is 20-30℃; Step 2) comprises: under the protection of inert gas, adding the 2,4,6-trifluorobromobenzene to a Grignard reagent, and then introducing carbon dioxide gas to carry out the Grignard reaction; the Grignard reagent comprises at least one of methylmagnesium chloride solution, methylmagnesium bromide solution, methylmagnesium iodide solution and isopropylmagnesium chloride solution; the dropwise addition rate of the 2,4,6-trifluorobromobenzene is 0.5-1.5g / min; and / or, the temperature of the Grignard reaction is -10-15℃; wherein the molar ratio of the 2,4,6-trifluorobromobenzene to the Grignard reagent is 1:(1.0-1.5); after the completion of the Grignard reaction, the Grignard reaction system is quenched, then subjected to a first extraction treatment, the organic phase obtained by the first extraction treatment is concentrated, then water is added to precipitate a crude product, the crude product is dissolved, then subjected to a second extraction treatment, the aqueous phase obtained by the second extraction treatment is filtered, then the pH is adjusted to 0-2 to obtain the 2,4,6-trifluorobenzoic acid.

2. The production method according to claim 1, characterized by, after the completion of the bromination reaction, the bromination reaction system is sequentially subjected to an alkali washing treatment, a water washing treatment and a reduced pressure distillation treatment to obtain the 2,4,6-trifluorobromobenzene.

3. The method of any one of claims 1-2, wherein, Before Step 1), it further comprises: in a fluorination solvent, subjecting 1,3,5-trichlorobenzene to a fluorination reaction with a fluorination agent in the presence of a fluorination catalyst to obtain the 1,3,5-trifluorobenzene; wherein the molar ratio of the 1,3,5-trichlorobenzene to the fluorination solvent, fluorination agent and fluorination catalyst is 1:(5-10):(3-5):(0.005-0.05); the fluorination solvent comprises at least one of N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, dimethyl sulfoxide and sulfolane; the fluorination agent comprises at least one of potassium fluoride, sodium fluoride and cesium fluoride; The fluorination catalyst comprises at least one of tetramethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, triphenylmethylphosphonium bromide, triphenylethylphosphonium bromide, and tetraphenylphosphonium bromide.

4. The production method according to claim 3, characterized by, The fluorination reaction is carried out under inert gas protection; and / or, The temperature of the fluorination reaction is 130-180°C.

5. The production method according to claim 3, characterized by, After the fluorination reaction is completed, the fluorination reaction system is subjected to vacuum distillation treatment, and the fraction obtained by the vacuum distillation treatment is subjected to vacuum rectification treatment to obtain the 1,3,5-trifluorobenzene.

Images