Preparation method of 2-methyl-3-(trifluoromethyl) aniline and flunixin meglumine

Abstract

The invention provides a preparation method of 2-methyl-3-(trifluoromethyl) aniline and flunixin meglumine, which comprises the following steps: taking 3, 4, 5-trichlorotoluene as a raw material, and carrying out trichloromethylation reaction under the action of a first catalyst to obtain a trichloromethylation intermediate; carrying out halogen exchange reaction on the trichloromethylation intermediate under the action of a fluorinating agent to obtain a trifluoromethylation intermediate; carrying out nitration reaction on the trifluoromethylation intermediate under the action of a nitration reagent to obtain a nitration intermediate; and carrying out hydrogenation reduction reaction on the nitration intermediate under the action of a reducing agent and a second catalyst to obtain 2-methyl-3-(trifluoromethyl) aniline. According to the invention, 3, 4, 5-trichlorotoluene is taken as a starting raw material, the selectivity of trichloromethylation reaction is obviously improved, so that the yield of 2-methyl-3-(trifluoromethyl) aniline can be improved, and the method has the advantages of high selectivity, few byproducts, low cost and the like.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic synthesis, in particular to a preparation method of 2-methyl-3-(trifluoromethyl) aniline and flunixin meglumine. BACKGROUND

[0002] 2-methyl-3-(trifluoromethyl) aniline is a key synthetic intermediate of flunixin meglumine, a non-steroidal anti-inflammatory drug for veterinary use. Flunixin meglumine, as a cyclooxygenase inhibitor, is widely used in veterinary clinical applications. It can relieve inflammation, pain and fever symptoms in animals, and is particularly useful for treating equine muscle inflammation, visceral colic and diarrhea in young horses, and is also used for the adjuvant treatment of respiratory diseases in ruminants, endotoxin mastitis, and the treatment of arthritis in dogs, ophthalmic infections, and diarrhea in pigs and non-lactating syndrome in sows.

[0003] Currently, there are mainly three typical routes for the synthesis of 2-methyl-3-(trifluoromethyl) aniline. According to the different starting materials and reaction steps, it can be divided into the following three categories: (1) a multi-step synthesis route using 3,4-dichlorotoluene as the starting material. This route requires four steps of trichloromethylation, fluorination, nitration and hydrogenation reduction to prepare the target product. However, this route is limited by the poor selectivity of the first step of trichloromethylation and the presence of many by-products. The total yield reported in the literature is only 32.9%. At the same time, the low utilization rate of 3,4-dichlorotoluene leads to high raw material costs, and the multi-step reaction process has high energy consumption and complicated operation, which is not suitable for industrialization. (2) A protection-methylation route using 2-chloro-5-(trifluoromethyl) aniline as the starting material. This route synthesizes the target product through four steps of pivaloyl protection, methylation, hydrogenation reduction and hydrolysis. However, the methylation step needs to be carried out at a low temperature of -25℃, which requires high equipment material requirements and significantly increases energy consumption. More importantly, the methylation reaction uses the highly toxic reagent dimethyl sulfate, which poses a serious safety hazard. In addition, the key reagent pivaloyl chloride is in short supply and expensive on the market. Although the total yield can reach 61.7%, the overall safety and cost issues still cannot meet the requirements of industrialization. (3) A simplified route using 3-(trifluoromethyl) aniline as the starting material. This route synthesizes the target product through three steps of pivaloyl protection, methylation and hydrolysis. However, the core defect of this route is the low selectivity of the methylation reaction, with an intermediate yield of only 38.9%. Although the yield of the subsequent steps is high, the overall process stability is poor, making it difficult to achieve stable scale-up production.

[0004] Therefore, the existing technology has low yield, high cost, harsh reaction conditions and poor safety, which cannot meet the requirements of high efficiency, safety and economy for industrialization. Therefore, it is urgent to develop a new synthesis method. SUMMARY

[0005] The application provides a preparation method of 2-methyl-3-(trifluoromethyl) aniline and flunixin meglumine, which can improve the yield of 2-methyl-3-(trifluoromethyl) aniline, has the advantages of high safety and low cost, and can effectively overcome the defects in the prior art.

[0006] In a first aspect, the application provides a preparation method of 2-methyl-3-(trifluoromethyl) aniline, which comprises the following steps:

[0007] The 3,4,5-trichloromethylbenzene is used as a raw material, and a trichloromethylated intermediate is obtained by performing a trichloromethylation reaction under the action of a first catalyst.

[0008] The trichloromethylated intermediate is subjected to a halogen exchange reaction under the action of a fluorinating agent to obtain a trifluoromethylated intermediate.

[0009] The trifluoromethylated intermediate is subjected to a nitration reaction under the action of a nitration reagent to obtain a nitration intermediate.

[0010] The nitration intermediate is subjected to a hydrogenation reduction reaction under the action of a reducing agent and a second catalyst to obtain 2-methyl-3-(trifluoromethyl) aniline.

[0011] In a possible implementation, the first catalyst is a Lewis acid catalyst, the Lewis acid catalyst comprises at least one of aluminum chloride, FeCl3 / SiO2, TiCl4 and SnCl4; and / or, the fluorinating agent comprises at least one of HF and KF / 18-crown-6; and / or, the nitration reagent comprises sulfuric acid and nitric acid; and / or, the second catalyst comprises at least one of Pd / C, Pt / C and Raney nickel.

[0012] In a possible implementation, the trichloromethylation reaction under the action of the first catalyst comprises: adding 3,4,5-trichloromethylbenzene into carbon tetrachloride solvent containing the first catalyst to perform the reaction; and the molar ratio of aluminum chloride to carbon tetrachloride is (0.05-0.5):1.

[0013] In a possible implementation, the trichloromethylation reaction is performed at a temperature of 60-80°C for 2-3h.

[0014] In a possible implementation, the halogen exchange reaction of the trichloromethylated intermediate under the action of the fluorinating agent comprises: placing the trichloromethylated intermediate into a reaction kettle, adding the fluorinating agent into the reaction kettle, and performing the reaction at 60-90°C for 4-6h to obtain the trifluoromethylated intermediate; and the molar ratio of the trichloromethylated intermediate to the fluorinating agent is 1:(4-10).

[0015] In a possible implementation, the nitration reaction of the trifluoromethylated intermediate under the action of a nitration reagent comprises: mixing the trifluoromethylated intermediate with the nitration reagent, and reacting at 40-70°C for 4-6h; the molar ratio of the trifluoromethylated intermediate to the nitration reagent is 1:(7-15); and / or the sulfuric acid comprises at least one of 98% sulfuric acid, 20% fuming sulfuric acid, and 50% fuming sulfuric acid; and / or the nitric acid comprises at least one of 65% nitric acid, 70% nitric acid, and 98% fuming nitric acid.

[0016] In a possible implementation, the hydrogenation reduction reaction of the nitration intermediate under the action of a reducing agent and a second catalyst comprises: mixing the nitration intermediate, a buffer, water, and the second catalyst in a reaction kettle, introducing hydrogen into the reaction kettle to a pressure of 0.8-1.2MPa in the reaction kettle, and reacting at 80-90°C for 6-8h.

[0017] In a possible implementation, the buffer comprises at least one of sodium acetate, sodium carbonate, sodium bicarbonate, and sodium hydroxide; and / or the mass ratio of the nitration intermediate, the buffer, water, and the second catalyst is (4-6):3:15:(1-2).

[0018] In a possible implementation, the method further comprises: after the reaction is completed, performing rectification treatment on the obtained product to obtain the 2-methyl-3-(trifluoromethyl) aniline.

[0019] In a second aspect, the application provides a preparation method of flunixin meglumine, comprising: preparing 2-methyl-3-(trifluoromethyl) aniline according to the preparation method of 2-methyl-3-(trifluoromethyl) aniline described above, and preparing the flunixin meglumine from the 2-methyl-3-(trifluoromethyl) aniline.

[0020] The preparation method of 2-methyl-3-(trifluoromethyl) aniline provided by the application realizes high yield, low cost, and high safety of 2-methyl-3-(trifluoromethyl) aniline synthesis by using 3,4,5-trichlorotoluene as a starting material and optimizing process parameters of trichloromethylation, fluorination, nitration, and hydrogenation reduction. BRIEF DESCRIPTION OF DRAWINGS

[0021] The accompanying drawings, which are incorporated into and form a part of the specification, illustrate one embodiment consistent with the application and, together with the description, serve to explain the principles of the application.

[0022] Figure 1 The preparation method of 2-methyl-3-(trifluoromethyl) aniline in Example 1 of the application is as follows: 1 H-NMR chart. DETAILED DESCRIPTION

[0023] In order to make the skilled in the art better understand the scheme of the present application, the present application is further described in detail below. The following specific embodiments are only to describe the principles and characteristics of the present application, and the examples are only used to explain the present application, not to limit the scope of the present application. Based on the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0024] In order to solve the problems of low yield, high cost, harsh conditions and the like in the existing synthesis technology, the inventors have found that the total yield of the existing technology is insufficient, the raw materials rely on high-priced scarce products, the reaction requires low temperature and high energy consumption, the reaction selectivity is poor, there are many by-products, and toxic reagents are used and the process is complex. The contradiction is that increasing the yield is easy to cause the cost to rise or the conditions to be more severe, and optimizing the selectivity will increase the process complexity. Therefore, it is necessary to optimize the reaction path to increase the yield to a higher level, use low-cost raw materials, develop mild reaction conditions, optimize the catalyst to improve the selectivity, replace the toxic reagent, and simplify the process to solve the problems.

[0025] Based on this, the preparation method of 2-methyl-3-(trifluoromethyl) aniline provided by the present application comprises: taking 3,4,5-trichloromethylbenzene as a raw material, and performing a trichloromethyl reaction under the action of a first catalyst to obtain a trichloromethyl intermediate;

[0026] Performing a halogen exchange reaction on the trichloromethyl intermediate under the action of a fluorinating agent to obtain a trifluoromethyl intermediate;

[0027] Performing a nitration reaction on the trifluoromethyl intermediate under the action of a nitration reagent to obtain a nitration intermediate;

[0028] Performing a hydrogenation reduction reaction on the nitration intermediate under the action of a reducing agent and a second catalyst to obtain 2-methyl-3-(trifluoromethyl) aniline.

[0029] The above preparation method can be represented by the following reaction formula:

[0030]

[0031] The preparation method of the present application takes 3,4,5-trichloromethylbenzene as a starting raw material, first reacts in a carbon tetrachloride solvent under a catalyst, realizes trichloromethylation through a Friedel-Crafts alkylation mechanism, performs a halogen exchange reaction under the action of a fluorinating agent, promotes the exchange of chlorine atoms and fluorine atoms in the trichloromethyl through the strong nucleophilicity of the fluorinating agent, then performs a nitration reaction under the action of a nitration reagent, provides a nitro group through the nitration reagent and uses the nitration reagent as a dehydrating agent to maintain the acidity of the reaction system, and finally performs a hydrogenation reduction reaction under the action of a reducing agent and a second catalyst, reduces the nitro group to an amino group through a hydrogen transfer mechanism.

[0032] In one embodiment, the first catalyst is a Lewis acid catalyst, the Lewis acid catalyst includes at least one of aluminum trichloride, FeCl3 / SiO2, TiCl4, SnCl4; the fluorination agent includes at least one of HF, KF / 18-crown-6; the nitration agent includes sulfuric acid and nitric acid; the second catalyst includes at least one of Pd / C, Pt / C, Raney nickel.

[0033] Specifically, the present application selects a Lewis acid catalyst (such as aluminum trichloride) as the catalyst for the trichloromethylation reaction: aluminum trichloride, as a strong Lewis acid, can form a coordination bond with the chlorine atoms in the carbon tetrachloride molecule through its empty orbital, weaken the C-Cl bond polarity and promote its homolytic cleavage, generating a trichloromethyl cation (+CCl3) intermediate and a tetrachloroaluminate (AlCl4 - ) anion; the +CCl3 intermediate has strong electrophilicity and will preferentially attack the sites with relatively high electron cloud density on the 3,4,5-trichlorotoluene aromatic ring, i.e., the methyl ortho position (2, 6, 3, 4, 5 positions are occupied by chlorine atoms). At the same time, the strong acidity of aluminum trichloride can stabilize the aryl cation transition state generated during the reaction, reduce the activation energy of the electrophilic substitution reaction, and reduce the substitution side reactions at non-target sites (such as the chlorine atom ortho position), ultimately achieving high-selectivity trichloromethylation.

[0034] In one embodiment, the trichloromethylation reaction under the action of the first catalyst includes: adding 3,4,5-trichlorotoluene to carbon tetrachloride solvent containing the first catalyst to react, wherein the molar ratio of aluminum trichloride to carbon tetrachloride is (0.05-0.5):1. In detail, carbon tetrachloride, aluminum trichloride are put into a reaction device, then heated, and 3,4,5-trichlorotoluene is added dropwise to react. The inventors found that controlling the molar ratio of aluminum trichloride to carbon tetrachloride in the above range can ensure that aluminum trichloride fully activates carbon tetrachloride to generate a trichloromethyl cation, while avoiding side reactions caused by excessive catalyst, thereby significantly improving the efficiency and selectivity of the trichloromethylation reaction.

[0035] In addition, the above preparation process further includes, after the reaction is completed, treating the obtained system, including cooling, extraction, washing, and concentration, to obtain the trichloromethylated intermediate. The present application does not limit the specific operation of extraction, which is basically the same as the extraction method at the present stage in the art, for example, water can be added to 60-90% of the mass of carbon tetrachloride, and the system is allowed to stand and separate into layers, the upper organic phase is collected, and the lower aqueous phase is extracted again with carbon tetrachloride, and the combined organic phase is collected.

[0036] The present application does not limit the specific reaction device for the trichloromethylation reaction, for example, it can be a reaction kettle; the present application does not limit the washing solvent after extraction, for example, it can be 5% sodium hydroxide aqueous solution.

[0037] In one embodiment, the temperature of the trichloromethylation reaction is 60-80℃, and the time is 2-3h. The inventors have found that controlling the heating temperature as described above ensures that the reaction system proceeds under thermodynamic and kinetic equilibrium, avoiding side reactions caused by high temperature or insufficient reaction rate at low temperature; controlling the reaction time as described above ensures that the trichloromethylation reaction proceeds sufficiently, while avoiding excessive reaction that leads to waste of raw materials.

[0038] In one embodiment, the halogen exchange reaction of the trichloromethylated intermediate under the action of the fluorinating agent comprises: placing the trichloromethylated intermediate into a reaction kettle, adding the fluorinating agent thereto, and reacting at 60-90℃ for 4-6h to obtain a trifluoromethylated intermediate, wherein the molar ratio of the trichloromethylated intermediate to the fluorinating agent is 1:(4-10). The inventors have found that controlling the reaction temperature and time within the above ranges can accelerate the fluorination reaction, while avoiding decomposition of the fluorinating agent caused by high temperature; controlling the above molar ratio can ensure sufficient fluorinating agent, thereby promoting complete exchange of chlorine atoms with fluorine atoms in the trichloromethyl group.

[0039] In addition, the above preparation process further comprises, after the reaction is completed, subjecting the obtained system to rectification treatment, and the present application does not limit the specific way of rectification treatment, which is basically the same as the rectification method at the present stage in the art.

[0040] In one embodiment, the nitration reaction under the action of the nitration agent comprises: mixing the trifluoromethylated intermediate with the nitration agent (sulfuric acid), adding the nitration agent (nitric acid) dropwise, and reacting at 40-70℃ for 4-6h, wherein the molar ratio of the trifluoromethylated intermediate to the nitration agent is 1:(7-15). The inventors have found that controlling the above reaction temperature and time can balance the control of reaction rate and side reactions; controlling the above molar ratio range can ensure excess nitric acid, promoting complete substitution of the nitro group.

[0041] Further, the sulfuric acid comprises at least one of 98% sulfuric acid, 20% oleum, and 50% oleum; and the nitric acid comprises at least one of 65% nitric acid, 70% nitric acid, and 98% oleum.

[0042] In an embodiment, the hydrogenation reduction of the nitration intermediate in the presence of the reducing agent and the second catalyst (Pd / C) comprises: placing the nitration intermediate, a buffer (sodium acetate), water and Pd / C into a reaction kettle, introducing the reducing agent (hydrogen) into the reaction kettle to a pressure of 0.8-1.2 MPa, and reacting at 80-90°C for 6-8 h. It should be noted that the addition of the buffer can neutralize the acidic substances generated during the reaction, maintain the pH stability of the reaction system, and thus improve the activity of the palladium-carbon catalyst; the reducing agent (hydrogen) provides active hydrogen species under the catalysis of the palladium-carbon catalyst, and reduces the nitro group to an amino group through a hydrogen transfer mechanism; controlling the heating temperature and time can accelerate the reduction reaction and avoid catalyst deactivation caused by high temperature; and controlling the pressure range can stabilize the reaction environment, improve the selectivity and conversion rate of the hydrogenation reaction, and avoid problems such as an increase in side reactions and a slow reaction rate caused by excessively high or low pressure, thereby ensuring efficient and orderly reaction.

[0043] In addition, the preparation process further comprises filtration, extraction, and concentration. The present application does not limit the specific solvent for extraction. For example, dichloromethane can be used as long as the product is completely extracted.

[0044] In an embodiment, the buffer comprises at least one of sodium acetate, sodium carbonate, sodium bicarbonate, and sodium hydroxide.

[0045] Further, the mass ratio of the nitration intermediate, the buffer, water, and the second catalyst is (4-6):3:15:(1-2). Controlling the mass ratio can ensure sufficient contact of the components and promote efficient reduction reaction.

[0046] In an embodiment, the method further comprises: after the reaction is completed, performing rectification treatment on the obtained product to obtain 2-methyl-3-(trifluoromethyl) aniline. That is, 2-methyl-3-(trifluoromethyl) aniline is distilled out of the product system, which is conducive to improving the purity of 2-methyl-3-(trifluoromethyl) aniline. The inventors have found that controlling the temperature and time of the rectification treatment can accurately regulate the vaporization and condensation efficiency of the fraction, avoid side reactions such as oxidation and decomposition of the product caused by high temperature, and reduce the entrainment of low-boiling-point impurities (such as unreacted raw materials) and high-boiling-point impurities (such as polysubstituted by-products), thereby ultimately improving the product purity of 2-methyl-3-(trifluoromethyl) aniline.

[0047] The second aspect of the present application provides a preparation method of flunixin meglumine, which comprises: preparing 2-methyl-3-(trifluoromethyl) aniline according to the above preparation process; and preparing flunixin meglumine from 2-methyl-3-(trifluoromethyl) aniline.

[0048] In the present application, 2-methyl-3-(trifluoromethyl) aniline is used as a raw material for synthesizing flunixin meglumine, and flunixin meglumine can be synthesized through a conventional process, without special limitation. The present application first prepares 2-methyl-3-(trifluoromethyl) aniline through the above-mentioned preparation process, can prepare flunixin meglumine with high purity and yield, and further can improve the yield and purity of flunixin meglumine, simplify the preparation process of flunixin meglumine, and be beneficial to industrialized production and application.

[0049] Hereinafter, the preparation method of 2-methyl-3-(trifluoromethyl) aniline provided by the present application will be further introduced in combination with specific examples.

[0050] In the following examples, the experimental methods used, unless otherwise specified, can adopt conventional methods in the art.

[0051] In the following examples, unless otherwise specified, all raw materials can be prepared by commercial purchase or conventional methods.

[0052] Example 1

[0053] 1) Trichloromethylation reaction

[0054] Put 3 kg of carbon tetrachloride and 1 kg of aluminum trichloride into a reaction kettle, heat to 60°C, and drop 1 kg of 3,4,5-trichloromethylbenzene. After the drop is completed, heat for 2 h, then cool to 15°C, add 1.8 kg of water, cool to 3°C, stir for 1 h, and then separate the layers. Wash the combined organic phase with 5% sodium hydroxide aqueous solution once, and then wash with water once. Then, concentrate the washed organic phase to collect the concentrate, to obtain 1.5 kg of trichloromethyl intermediate (2-trichloromethyl-3,4,5-trichloromethylbenzene) with a HPLC purity of 99.0% and a yield of 93.7%;

[0055] 2) Halogen exchange reaction

[0056] Put 5 kg of the trichloromethyl intermediate into a high-pressure reaction kettle, charge hydrogen fluoride to 0.8 MPa, heat to 60°C, and stir for 4 h. Distill to obtain 4.1 kg of trifluoromethyl intermediate (2-trifluoromethyl-3,4,5-trichloromethylbenzene) with a HPLC purity of 99.0% and a yield of 97.4%;

[0057] 3) Nitration reaction

[0058] 4 kg of the trifluoromethylation intermediate was mixed with 12 kg of 98% sulfuric acid, heated to 40 °C, and 1 kg of 65% nitric acid was added dropwise. The mixture was kept at this temperature for 4 h. After the reaction was completed, 12 kg of dichloromethane was added for dilution, and the mixture was washed and concentrated in layers to obtain 4.6 kg of the nitration intermediate (2-trifluoromethyl-6-nitro-3,4,5-trichlorotoluene), with an HPLC purity of 99.0% and a yield of 98.5%.

[0059] 4) Hydrogenation reduction reaction

[0060] 4 kg of nitration intermediate (2-nitro-3-(trifluoromethyl)toluene), 3 kg of sodium acetate, 15 kg of water, and 1 kg of palladium on carbon catalyst were added to a reactor. After nitrogen purging, hydrogen purging was performed, and hydrogen was introduced into the reactor to 1.0 MPa. The temperature was raised to 80 °C and reacted for 5-6 h. The mixture was cooled and discharged, filtered under pressure, extracted with dichloromethane, dried, concentrated, and then distilled under a vacuum of (-0.095)-(-0.1 MPa) at 70-80 °C to obtain 2.2 kg of pure 2-methyl-3-(trifluoromethyl)aniline with an HPLC purity of 99.5% and a yield of 96.9%.

[0061] The total yield of 2-methyl-3-(trifluoromethyl)aniline synthesized in the above four steps was 87.1%, and the HPLC purity was 99.5%.

[0062] The obtained 2-methyl-3-(trifluoromethyl)aniline was characterized by 1H NMR spectroscopy. Figure 1 The 1H NMR spectrum of 2-methyl-3-(trifluoromethyl)aniline prepared in Example 1 is shown below. Figure 1 As shown, for Figure 1 The assignment analysis of the proton NMR spectrum yielded the following proton NMR data for 2-methyl-3-(trifluoromethyl)aniline:

[0063] 1H NMR (500MHz, DMSO-d6): δ7.22~7.26 (t, 1.0H), 6.73~6.78 (t, 3.0H), 6.09~6.11 (m, 1.0H), 2.67~2.68 (d, 3.0H)

[0064] Example 2

[0065] The method for 2-methyl-3-(trifluoromethyl)aniline in this embodiment is basically the same as that in Example 1, except that the heating temperature in step 1) is 65°C, the yield of 2-methyl-3-(trifluoromethyl)aniline is 88.5%, and the HPLC purity is 99.5%.

[0066] Example 3

[0067] The present example 2-methyl-3-(trifluoromethyl) aniline method is basically identical with example 1, the difference is that the heating temperature in step 1) is 70℃, the yield of 2-methyl-3-(trifluoromethyl) aniline is 89.8%, and the HPLC purity is 99.5%.

[0068] Comparative example 1

[0069] 2-methyl-3-(trifluoromethyl) aniline is obtained from 3,4-dichlorotoluene as raw material through electrophilic substitution, fluorination, nitration and hydrogenation reduction, and the total yield of 2-methyl-3-(trifluoromethyl) aniline is 32.9%.

[0070] Comparative example 2

[0071] 2-methyl-3-(trifluoromethyl) aniline is obtained from 2-chloro-5-(trifluoromethyl) aniline as raw material through pivaloyl protection, methylation, hydrogenation reduction and hydrolysis, and the total yield of 2-methyl-3-(trifluoromethyl) aniline is 61.7%.

[0072] Comparative example 3

[0073] 2-methyl-3-(trifluoromethyl) aniline is obtained from 3-(trifluoromethyl) aniline as raw material through pivaloyl protection, methylation and hydrolysis, and the total yield of 2-methyl-3-(trifluoromethyl) aniline is 38.9%.

[0074] Finally, it should be noted that: the above examples are only used to illustrate the technical solutions of the present application, and not to limit them; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that: it can still modify the technical solutions recorded in the foregoing examples, or make equivalent replacement for part or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application, and they should be covered in the scope of the claims and the description of the present application.

Claims

1. A method for preparing 2-methyl-3-(trifluoromethyl)aniline, characterized in that, Includes the following steps: Using 3,4,5-trichlorotoluene as a raw material, a trichloromethylation reaction was carried out under the action of a first catalyst to obtain a trichloromethylation intermediate; The trichloromethylated intermediate was subjected to a halogen exchange reaction in the presence of a fluorinating agent to obtain a trifluoromethylated intermediate. The trifluoromethylated intermediate was subjected to a nitration reaction in the presence of a nitrating agent to obtain a nitrated intermediate. The nitration intermediate was subjected to hydrogenation reduction reaction in the presence of a reducing agent and a second catalyst to obtain 2-methyl-3-(trifluoromethyl)aniline.

2. The method according to claim 1, characterized in that, The first catalyst is a Lewis acid catalyst, wherein the Lewis acid catalyst comprises at least one of aluminum trichloride, FeCl3 / SiO2, TiCl4, and SnCl4; and / or, The fluorinating agent includes at least one of HF and KF / 18-crown-6; and / or, The nitrating agent includes sulfuric acid and nitric acid; and / or, The second catalyst includes at least one of Pd / C, Pt / C, and Raney nickel.

3. The method according to claim 1 or 2, characterized in that, The trichloromethylation reaction under the action of the first catalyst includes: adding 3,4,5-trichlorotoluene to a carbon tetrachloride solvent containing the first catalyst for reaction; The molar ratio of aluminum trichloride to carbon tetrachloride is (0.05-0.5):

1.

4. The method according to any one of claims 1-3, characterized in that, The trichloromethylation reaction is carried out at a temperature of 60-80℃ for 2-3 hours.

5. The method according to any one of claims 1-4, characterized in that, The halogen exchange reaction of the trichloromethylated intermediate under the action of a fluorinating agent includes: placing the trichloromethylated intermediate into a reaction vessel, adding the fluorinating agent thereto, and reacting at 60-90°C for 4-6 hours to obtain the trifluoromethylated intermediate; The molar ratio of the trichloromethylation intermediate to the fluorinating agent is 1:(4-10).

6. The method according to claim 2, characterized in that, The nitration reaction of the trifluoromethylated intermediate under the action of the nitrating agent includes: mixing the trifluoromethylated intermediate with the nitrating agent and reacting at 40-70°C for 4-6 hours; The molar ratio of the trifluoromethylation intermediate to the nitrating agent is 1:(7-15); and / or, The sulfuric acid includes at least one selected from 98% sulfuric acid, 20% fuming sulfuric acid, and 50% fuming sulfuric acid; and / or, The nitric acid includes at least one of 65% nitric acid, 70% nitric acid, and 98% fuming nitric acid.

7. The method according to any one of claims 1-6, characterized in that, The hydrogenation reduction reaction of the nitration intermediate under the action of a reducing agent and a second catalyst includes mixing the nitration intermediate, buffer, water, and second catalyst in a reaction vessel, introducing hydrogen gas into the reaction vessel to a pressure of 0.8-1.2 MPa, and reacting at 80-90°C for 6-8 hours.

8. The method according to claim 7, characterized in that, The buffer includes at least one of sodium acetate, sodium carbonate, sodium bicarbonate, and sodium hydroxide; and / or, The mass ratio of the nitration intermediate, buffer, water, and second catalyst is (4-6):3:15:(1-2).

9. The method according to any one of claims 1-8, characterized in that, Also includes: After the hydrogenation reduction reaction is completed, the product is subjected to distillation to obtain the 2-methyl-3-(trifluoromethyl)aniline.

10. A method for preparing flunixin meglumine, characterized in that, The method for preparing 2-methyl-3-(trifluoromethyl)aniline according to any one of claims 1-9 includes the preparation of 2-methyl-3-(trifluoromethyl)aniline, and the preparation of the flunixin meglumine using the 2-methyl-3-(trifluoromethyl)aniline as a raw material.

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