A process for the preparation of 4-trifluoromethylaniline

Abstract

The application provides a preparation method of 4-trifluoromethylaniline, comprising the following steps: introducing ammonia into a raw material system comprising 4-chlorobenzotrifluoride, formaldehyde and a dehydrating agent to perform a first reaction; after the 4-chlorobenzotrifluoride is completely converted, the introduction of ammonia is stopped, and a dilute acid solution is added to the reaction system to perform a second reaction, thereby obtaining 4-trifluoromethylaniline. The preparation method of 4-trifluoromethylaniline provided by the application does not need to use expensive copper salt catalysts and trifluoromethylation reagents, and 4-trifluoromethylaniline can be prepared in a high yield by one-pot method with low-cost 4-trifluoromethylaniline as a raw material, thereby greatly reducing the preparation cost.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and relates to a method for preparing 4-trifluoromethylaniline. Background Technology

[0002] Fipronil, chemically known as 5-amino-1-(2,6-dichloro-4-trifluorotoluyl)-4-trifluoromethyl-sulfinylpyrazole-3-onitrile (structural formula shown in Formula I), is the first benzylpyrazole insecticide used for pest control. Its mechanism of action involves blocking Cl- channels in the nerve membrane controlled by γ-aminobutyric acid receptors, inducing Cl- flow, causing extreme excitation of the nervous system, and leading to insect death. This achieves effective control of various economic pests and has been widely used in agriculture and veterinary medicine. Compared with traditional organophosphates, pyrethroids, and carbamates, it has advantages such as broad spectrum and high efficiency.

[0003]

[0004] 2,6-Dichloro-4-trifluoromethylbenzene is an important intermediate in the synthesis of fipronil, and various methods for synthesizing 2,6-dichloro-4-trifluoromethylaniline have been reported in the literature and patents.

[0005] Patent CN101289401A discloses a method for preparing 2,6-dichloro-4-trifluoromethylaniline by directly reacting 3,4,5-trichlorotrifluorotoluene with ammonia. However, this method has three chlorine atoms in the raw material, resulting in low reaction selectivity, the formation of multiple isomers, and difficulty in purifying the product.

[0006] Patent CN100534975C discloses a method for preparing 2,6-dichloro-4-trifluoromethylaniline from 4-trifluoromethylaniline using chlorine chlorination. This method is simple, easy to purify, and yields a high-purity, high-quality product. However, the raw material for 4-trifluoromethylaniline is currently expensive, and its synthesis mainly involves the following methods: 1. Using copper salt as a catalyst, reacting 4-trifluoromethyl halobenzene with ammonia to obtain 4-trifluoromethylaniline. This is currently the mainstream method, but it requires the use of copper salt catalysts at equivalent levels, significantly increasing the synthesis cost of 4-trifluoromethylaniline. 2. Using 4-chlorotrifluorotoluene as a raw material, sodium amide reacts with 4-chlorotrifluorotoluene at ultra-low temperatures using liquid ammonia solvent to generate 4-trifluoromethylaniline and its meta-isomer. In this reaction, the strong basicity of sodium amide causes 4-chlorotrifluorotoluene to first form benzyne. The reaction between benzyne and sodium amide lacks selectivity, resulting in a near 1:1 ratio of 4-trifluoromethylaniline to the meta-isomer. This method leads to poor product selectivity, difficulty in purification, and low yield. Furthermore, the reaction involves ultra-low temperatures and liquid ammonia solvent, placing high demands on equipment and resulting in high energy consumption. 3. Using aniline as a raw material, trifluoromethylating reagents can be used to directly trifluoromethylate aniline. However, commonly used trifluoromethylating reagents such as trifluoromethyliodomethane and 1-(trifluoromethyl)-1,2-benzyliodo-3(1H)-one are relatively expensive. This method also suffers from poor selectivity, producing a large number of isomers, making product purification difficult.

[0007] Therefore, it is of great significance to develop a low-cost, simple, and highly selective method for preparing 4-trifluoromethylaniline. Summary of the Invention

[0008] To address the shortcomings of existing technologies, this invention provides a method for preparing 4-trifluoromethylaniline. This method uses inexpensive 4-trifluoromethylaniline as a raw material, without the need for expensive copper salt catalysts and trifluoromethylation reagents. By adding formaldehyde and a dehydrating agent to the raw material, auxiliary groups are introduced to enhance the nucleophilicity of ammonia N, and the auxiliary groups are simply removed by hydrolysis. 4-trifluoromethylaniline is then prepared in high yield using a one-pot method.

[0009] This invention provides a method for preparing 4-trifluoromethylaniline, comprising the following steps:

[0010] Ammonia gas was introduced into a raw material system comprising 4-chlorotrifluorotoluene, formaldehyde, and a dehydrating agent to carry out the first reaction. After the 4-chlorotrifluorotoluene was completely converted, the ammonia gas was stopped and a dilute acid solution was added to the reaction system to carry out the second reaction, yielding 4-trifluoromethylaniline.

[0011] In one alternative embodiment, the dehydrating agent is selected from one or more of trimethyl orthoformate, triethyl orthoformate, alumina, p-toluenesulfonic acid, aluminum chloride, silica gel, and 732 cation exchange resin.

[0012] In one optional embodiment, the raw material system further includes a solvent selected from one or more of N-methylpyrrolidone, N,N-dimethylformamide, nitrobenzene, dimethyl sulfoxide, sulfolane, and ethylene glycol.

[0013] In one optional embodiment, the amount of ammonia introduced is 3 to 10 times the molar amount of 4-chlorotrifluorotoluene.

[0014] In one optional embodiment, the molar ratio of 4-chlorotrifluorotoluene to formaldehyde in the raw material system is 1:(1-5); and / or, the molar ratio of 4-chlorotrifluorotoluene to dehydrating agent is 1:(1-6).

[0015] In one alternative embodiment, the formaldehyde is derived from one of paraformaldehyde, anhydrous formaldehyde, or a formaldehyde solution.

[0016] In one optional embodiment, the temperature of the first reaction is 80–160°C, and the time is 4–36 h.

[0017] In one alternative embodiment, the pressure of the first reaction is 0.2 to 1.0 MPa.

[0018] In one optional embodiment, the dilute acid solution is selected from a dilute hydrochloric acid solution with a mass concentration of 10%.

[0019] In one optional embodiment, the temperature of the second reaction is 25±10℃ and the time is 20 to 120 min.

[0020] The implementation of this invention has at least the following advantages:

[0021] The preparation method of this invention, through ingenious design, incorporates formaldehyde and a dehydrating agent as auxiliary reagents into the raw material system to promote the conversion of ammonia into a highly nucleophilic intermediate. Following nucleophilic attack, the intermediate can then undergo simple hydrolysis under acidic conditions to remove the auxiliary group, yielding an amino group, thereby achieving the synthesis of 4-trifluoromethylaniline. This method eliminates the need for expensive copper salt catalysts and trifluoromethylating reagents, and the one-pot synthesis of 4-trifluoromethylaniline in high yield significantly reduces preparation costs. Attached Figure Description

[0022] Figure 1 The 4-trifluoromethylaniline prepared in Example 1 of this invention 1 H NMR spectrum. Detailed Implementation

[0023] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions in the embodiments of this invention will be clearly and completely described below in conjunction with the embodiments of this invention. Obviously, the described embodiments are only some embodiments of this invention, not all embodiments. 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.

[0024] The inventors discovered that, without a catalyst, N,N-dimethyl-4-(trifluoromethyl)aniline can be prepared in high yield from dimethylamine and 4-chlorotrifluorotoluene in N-methylpyrrolidone solvent at 140°C and 3 MPa. The reaction route is as follows:

[0025]

[0026] Based on the above reaction, the inventors attempted to react ammonia with 4-chlorotrifluoromethyl without a catalyst. However, under the same reaction conditions, the expected 4-trifluoromethylaniline was not obtained. The actual reaction was that the chlorine atom in 4-chlorotrifluorotoluene was reduced by ammonia, thereby generating trifluorotoluene.

[0027] The inventors analyzed that the reason why dimethylamine can replace chlorine atoms while ammonia cannot may be that dimethylamine has two electron-donating methyl groups, which increases the electron density of the nitrogen atom in dimethylamine, thereby increasing its nucleophilicity. This allows it to nucleophilically substitute for the chlorine atom on the benzene ring, while the nitrogen atom in ammonia has too weak a nucleophilicity to substitute. However, if 4-trifluoromethylaniline is prepared from dimethylamine and 4-chlorotrifluorotoluene, the methyl groups need to be reduced after the reaction, which is extremely difficult.

[0028] Therefore, the inventors envisioned that if an auxiliary reagent with electron-donating properties could react with ammonia to enhance the nucleophilicity of nitrogen atoms, and if the auxiliary group formed by the auxiliary reagent after nucleophilic substitution was easily removed, then it would be possible to prepare 4-chlorotrifluorotoluene at low cost without the need for copper salt catalysis.

[0029] Based on the above concept, the present invention provides a method for preparing 4-trifluoromethylaniline, the method comprising the following steps:

[0030] Ammonia gas was introduced into a raw material system comprising 4-chlorotrifluorotoluene, formaldehyde, and a dehydrating agent to carry out the first reaction. After the 4-chlorotrifluorotoluene was completely converted, the ammonia gas was stopped and a dilute acid solution was added to the reaction system to carry out the second reaction, yielding 4-trifluoromethylaniline.

[0031] The inventors hypothesize the mechanism of the above reaction process as follows:

[0032] When ammonia is introduced into the raw material system, it reacts with formaldehyde to produce hydroxymethylamine. Under the action of a dehydrating agent, hydroxymethylamine is dehydrated to obtain methyleneimine. Methyleneimine can be converted into diaminomethane under the nucleophilic attack of ammonia. Diaminomethane can be further polymerized to obtain intermediate A (the reaction process is represented by the reaction formula below). In intermediate A, n is an integer ≥ 0, and its value can be 0. When it is 0, it is diaminomethane.

[0033]

[0034] In intermediate A, the secondary amine structure has N atom connected to alkylene groups on both sides. The electron-donating effect of the alkylene groups enhances the nucleophilicity of the N atom. Intermediate A performs nucleophilic attack on 4-trifluoromethylaniline to obtain intermediate B. Intermediate B has a structure similar to acetal. Its methylene amino group can be removed by hydrolysis under acidic conditions to obtain 4-trifluoromethylaniline (the reaction process is represented by the following reaction formula).

[0035]

[0036] In summary, this invention, through ingenious design, incorporates formaldehyde and a dehydrating agent as auxiliary reagents into the raw material system to promote the conversion of ammonia into a highly nucleophilic intermediate A. After nucleophilic attack, intermediate A can then undergo simple hydrolysis under acidic conditions to remove the auxiliary group, yielding an amino group, thereby achieving the synthesis of 4-trifluoromethylaniline. The preparation method of this invention eliminates the need for expensive copper salt catalysts and trifluoromethylation reagents, and the one-pot method achieves high yields of 4-trifluoromethylaniline, significantly reducing preparation costs.

[0037] The present invention does not specifically limit the type of dehydrating agent, which can be a dehydrating agent commonly used in the art, including but not limited to one or more of trimethyl orthoformate, triethyl orthoformate, alumina, p-toluenesulfonic acid, aluminum chloride, silica gel, and 732 cation exchange resin.

[0038] It is understood that the raw material system also includes a solvent, which is used to promote the complete dissolution and mixing of 4-chlorotrifluorotoluene, formaldehyde, and dehydrating agent. This invention does not specifically limit the type of solvent, but it should be able to fully dissolve the above raw materials without participating in the reaction, including but not limited to one or more of N-methylpyrrolidone, N,N-dimethylformamide, nitrobenzene, dimethyl sulfoxide, sulfolane, and ethylene glycol.

[0039] Considering the limited solubility of ammonia as a gaseous component in the solvent, to ensure complete reaction, the amount of ammonia introduced can be controlled to be 3 to 10 times the molar amount of 4-chlorotrifluorotoluene.

[0040] In a preferred embodiment, the molar ratio of 4-chlorotrifluorotoluene to formaldehyde in the raw material system is 1:(1 to 5). For example, the molar ratio of 4-chlorotrifluorotoluene to formaldehyde can be 1:1, 1:2, 1:3, 1:4, 1:5, or any combination thereof.

[0041] In a preferred embodiment, the molar ratio of 4-chlorotrifluorotoluene to the dehydrating agent in the raw material system is 1:(1-6).

[0042] The formaldehyde in the raw material system can be derived from paraformaldehyde, anhydrous formaldehyde, or formaldehyde solution. Considering storage and reducing wastewater volume, paraformaldehyde is preferred.

[0043] Research has shown that the first reaction can be carried out at temperatures between 80 and 160°C. Monitoring has shown that within this temperature range, the reaction can be completed within 4 to 36 hours.

[0044] To ensure that ammonia gas is fully dissolved in the raw material system and thoroughly mixed with the raw materials for reaction, the first reaction can be carried out under a certain pressure. In a preferred embodiment, the pressure of the first reaction is 0.2–1.0 MPa. Conducting the reaction under this pressure helps to increase the concentration of ammonia gas in the reaction, accelerates the reaction, and prevents ammonia gas from overflowing during the reaction, thus avoiding unnecessary losses.

[0045] The first reaction is considered complete when the conversion of 4-chlorotrifluorotoluene is detected. Commonly used detection methods in the field can be used to monitor the conversion of 4-chlorotrifluorotoluene, including but not limited to HPLC, NMR, etc. The conversion of 4-chlorotrifluorotoluene is considered complete when it disappears or ceases to react.

[0046] After the first reaction is complete, stop introducing ammonia gas into the reaction system and add a dilute acid solution to initiate the second reaction. The dilute acid solution can be a 10% hydrochloric acid solution.

[0047] The second reaction is a process of hydrolysis to remove auxiliary groups under acidic conditions, which can be completed at a temperature of 25±10℃ for 20 to 120 minutes.

[0048] After the second reaction is completed, the reaction system needs to be post-processed to obtain high-purity 4-trifluoromethylaniline. Specifically, the post-processing operations include: allowing the reaction solution to stand and then separating the liquids, collecting the organic phase, and distilling the organic phase to obtain 4-trifluoromethylaniline.

[0049] The preparation method of 4-trifluoromethylaniline provided by the present invention will be further described below with reference to specific embodiments.

[0050] Unless otherwise specified, the experimental methods used in the following embodiments can be conventional methods in the art.

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

[0052] Example 1

[0053] This embodiment provides a method for preparing 4-trifluoromethylaniline, including the following steps:

[0054] 1) Add 180g of 4-chlorotrifluorotoluene (1mol), 33g of paraformaldehyde (1.1mol), and 106g of trimethyl orthoformate (1mol) to a high-pressure reactor, and then add 900g of N-methylpyrrolidone to completely dissolve the raw materials. After dissolution, introduce 85g of ammonia gas (5mol) into the high-pressure reactor, raise the temperature to 100℃ and react for 10h. Maintain the reactor pressure at 0.2MPa during the reaction process. HPLC detects the disappearance of the 4-chlorotrifluorotoluene raw material. Cool the reaction solution to room temperature and add 2700g of 10% dilute hydrochloric acid melt dropwise. After the addition is complete, continue stirring at room temperature for 30min.

[0055] 2) After stirring, the reaction solution was allowed to stand and separated. The organic phase was collected and distilled to obtain 137g of 4-trifluoromethylaniline, with a yield of 85% and HPLC purity >99%.

[0056] The obtained 4-trifluoromethylaniline was characterized by proton nuclear magnetic resonance spectroscopy. Figure 1 The above is the 1H NMR spectrum of 4-trifluoromethylaniline prepared in Example 1. Figure 1 The assignment analysis of the proton NMR spectrum yielded the following proton NMR data for 4-trifluoromethylaniline:

[0057] 1 H NMR (400MHz, CDCl3) δ7.46 (d, J = 8.6 Hz, 2H), 6.68 (d, J = 8.6 Hz, 2H), 3.94 (s, 2H).

[0058] Example 2

[0059] This embodiment provides a method for preparing 4-trifluoromethylaniline, including the following steps:

[0060] 1) Add 180g of 4-chlorotrifluorotoluene (1mol), 33g of paraformaldehyde (1.1mol), and 102g of alumina (1mol) to a high-pressure reactor, and then add 900g of N-methylpyrrolidone to completely dissolve the raw materials. After dissolution, introduce 85g of ammonia gas (5mol) into the high-pressure reactor, raise the temperature to 120℃ and react for 18h. Maintain the reactor pressure at 0.2MPa during the reaction process. HPLC detects the disappearance of the 4-chlorotrifluorotoluene raw material. Cool the reaction solution to room temperature and add 2700g of 10% dilute hydrochloric acid melt dropwise. After the addition is complete, continue stirring at room temperature for 30min.

[0061] 2) After stirring, the reaction solution was allowed to stand and separated. The organic phase was collected and distilled to obtain 130g of 4-trifluoromethylaniline, with a yield of 81% and HPLC purity >99%.

[0062] Example 3

[0063] This embodiment provides a method for preparing 4-trifluoromethylaniline, including the following steps:

[0064] 1) Add 180g of 4-chlorotrifluorotoluene (1mol), 33g of paraformaldehyde (1.1mol), and 172g of p-toluenesulfonic acid (1mol) to a high-pressure reactor, and then add 900g of N-methylpyrrolidone to completely dissolve the raw materials. After dissolution, introduce 85g of ammonia gas (5mol) into the high-pressure reactor, raise the temperature to 80℃ and react for 5h. Maintain the reactor pressure at 0.2MPa during the reaction process. HPLC detects the disappearance of the 4-chlorotrifluorotoluene raw material. Cool the reaction solution to room temperature and add 2700g of 10% dilute hydrochloric acid melt dropwise. After the addition is complete, continue stirring at room temperature for 30min.

[0065] 2) After stirring, the reaction solution was allowed to stand and separated. The organic phase was collected and distilled to obtain 121g of 4-trifluoromethylaniline, with a yield of 75% and HPLC purity >99%.

[0066] Example 4

[0067] This embodiment provides a method for preparing 4-trifluoromethylaniline, including the following steps:

[0068] 1) Add 180g of 4-chlorotrifluorotoluene (1mol), 33g of paraformaldehyde (1.1mol), and 180g of silica gel (3mol) to a high-pressure reactor, and then add 900g of N-methylpyrrolidone to completely dissolve the raw materials. After dissolution, introduce 85g of ammonia gas (5mol) into the high-pressure reactor, raise the temperature to 140℃ and react for 20h. Maintain the reactor pressure at 0.2MPa during the reaction process. HPLC detects the disappearance of the 4-chlorotrifluorotoluene raw material. Cool the reaction solution to room temperature and add 2700g of 10% dilute hydrochloric acid melt dropwise. After the addition is complete, continue stirring at room temperature for 30min.

[0069] 2) After stirring, the reaction solution was allowed to stand and separated. The organic phase was collected and distilled to obtain 113g of 4-trifluoromethylaniline, with a yield of 70% and HPLC purity >99%.

[0070] Example 5

[0071] This embodiment provides a method for preparing 4-trifluoromethylaniline, including the following steps:

[0072] 1) Add 180g of 4-chlorotrifluorotoluene (1mol), 33g of paraformaldehyde (1.1mol), and 100g of 732 cation exchange resin to a high-pressure reactor, and then add 900g of N-methylpyrrolidone to completely dissolve the raw materials. After dissolution, introduce 85g of ammonia gas (5mol) into the high-pressure reactor, raise the temperature to 80℃ and react for 10h. Maintain the reactor pressure at 0.2MPa during the reaction process. HPLC detects the disappearance of the 4-chlorotrifluorotoluene raw material. Cool the reaction solution to room temperature and add 2700g of 10% dilute hydrochloric acid melt dropwise. After the addition is complete, continue stirring at room temperature for 30min.

[0073] 2) After stirring, the reaction solution was allowed to stand and separated. The organic phase was collected and distilled to obtain 129g of 4-trifluoromethylaniline, with a yield of 80% and HPLC purity >99%.

[0074] Example 6

[0075] This embodiment provides a method for preparing 4-trifluoromethylaniline, including the following steps:

[0076] 1) Add 180g of 4-chlorotrifluorotoluene (1mol), 33g of paraformaldehyde (1.1mol), and 106g of trimethyl orthoformate (1mol) to a high-pressure reactor, and then add 900g of N,N-dimethylformamide to completely dissolve the raw materials. After dissolution, introduce 85g of ammonia gas (5mol) into the high-pressure reactor, raise the temperature to 100℃ and react for 10h. Maintain the reactor pressure at 0.2MPa during the reaction process. HPLC detects the disappearance of the 4-chlorotrifluorotoluene raw material. Cool the reaction solution to room temperature and add 2700g of 10% dilute hydrochloric acid melt dropwise. After the addition is complete, continue stirring at room temperature for 30min.

[0077] 2) After stirring, the reaction solution was allowed to stand and separated. The organic phase was collected and distilled to obtain 135g of 4-trifluoromethylaniline, with a yield of 84% and HPLC purity >99%.

[0078] Example 7

[0079] This embodiment provides a method for preparing 4-trifluoromethylaniline, including the following steps:

[0080] 1) Add 180g of 4-chlorotrifluorotoluene (1mol), 33g of paraformaldehyde (1.1mol), and 106g of trimethyl orthoformate (1mol) to a high-pressure reactor, and then add 900g of nitrobenzene to completely dissolve the raw materials. After dissolution, introduce 85g of ammonia gas (5mol) into the high-pressure reactor, raise the temperature to 100℃ and react for 9h. Maintain the reactor pressure at 0.2MPa during the reaction process. HPLC detects the disappearance of the 4-chlorotrifluorotoluene raw material. Cool the reaction solution to room temperature and add 2700g of 10% dilute hydrochloric acid melt dropwise. After the addition is complete, continue stirring at room temperature for 30min.

[0081] 2) After stirring, the reaction solution was allowed to stand and separated. The organic phase was collected and distilled to obtain 127g of 4-trifluoromethylaniline, with a yield of 79% and HPLC purity >99%.

[0082] Example 9

[0083] This embodiment provides a method for preparing 4-trifluoromethylaniline, including the following steps:

[0084] 1) Add 180g of 4-chlorotrifluorotoluene (1mol), 33g of paraformaldehyde (1.1mol), and 106g of trimethyl orthoformate (1mol) to a high-pressure reactor, and then add 900g of dimethyl sulfoxide to completely dissolve the raw materials. After dissolution, introduce 85g of ammonia gas (5mol) into the high-pressure reactor, raise the temperature to 100℃ and react for 10h. Maintain the reactor pressure at 0.2MPa during the reaction process. HPLC detects the disappearance of the 4-chlorotrifluorotoluene raw material. Cool the reaction solution to room temperature and add 2700g of 10% dilute hydrochloric acid melt dropwise. After the addition is complete, continue stirring at room temperature for 30min.

[0085] 2) After stirring, the reaction solution was allowed to stand and separated. The organic phase was collected and distilled to obtain 129g of 4-trifluoromethylaniline, with a yield of 80% and HPLC purity >99%.

[0086] Example 10

[0087] This embodiment provides a method for preparing 4-trifluoromethylaniline, including the following steps:

[0088] 1) Add 180g of 4-chlorotrifluorotoluene (1mol), 33g of paraformaldehyde (1.1mol), and 106g of trimethyl orthoformate (1mol) to a high-pressure reactor, and then add 900g of ethylene glycol to completely dissolve the raw materials. After dissolution, introduce 85g of ammonia gas (5mol) into the high-pressure reactor, raise the temperature to 100℃ and react for 10h. Maintain the reactor pressure at 0.2MPa during the reaction process. HPLC detects the disappearance of the 4-chlorotrifluorotoluene raw material. Cool the reaction solution to room temperature and add 2700g of 10% dilute hydrochloric acid melt dropwise. After the addition is complete, continue stirring at room temperature for 30min.

[0089] 2) After stirring, the reaction solution was allowed to stand and separated. The organic phase was collected and distilled to obtain 105g of 4-trifluoromethylaniline, with a yield of 65% and HPLC purity >99%.

[0090] Example 11

[0091] This embodiment provides a method for preparing 4-trifluoromethylaniline, including the following steps:

[0092] 1) Add 180g of 4-chlorotrifluorotoluene (1mol), 33g of paraformaldehyde (1.1mol), and 106g of trimethyl orthoformate (1mol) to a high-pressure reactor, and then add 900g of N-methylpyrrolidone to completely dissolve the raw materials. After dissolution, introduce 85g of ammonia gas (5mol) into the high-pressure reactor, raise the temperature to 80℃ and react for 30h. Maintain the reactor pressure at 0.2MPa during the reaction process. HPLC detects the disappearance of the 4-chlorotrifluorotoluene raw material. Cool the reaction solution to room temperature and add 2700g of 10% dilute hydrochloric acid melt dropwise. After the addition is complete, continue stirring at room temperature for 30min.

[0093] 2) After stirring, the reaction solution was allowed to stand and separated. The organic phase was collected and distilled to obtain 122g of 4-trifluoromethylaniline, with a yield of 76% and HPLC purity >99%.

[0094] Example 12

[0095] This embodiment provides a method for preparing 4-trifluoromethylaniline, including the following steps:

[0096] 1) Add 180g of 4-chlorotrifluorotoluene (1mol), 33g of paraformaldehyde (1.1mol), and 106g of trimethyl orthoformate (1mol) to a high-pressure reactor, and then add 900g of N-methylpyrrolidone to completely dissolve the raw materials. After dissolution, introduce 85g of ammonia gas (5mol) into the high-pressure reactor, raise the temperature to 160℃ and react for 4h. Maintain the reactor pressure at 0.2MPa during the reaction process. HPLC detects the disappearance of the 4-chlorotrifluorotoluene raw material. Cool the reaction solution to room temperature and add 2700g of 10% dilute hydrochloric acid melt dropwise. After the addition is complete, continue stirring at room temperature for 30min.

[0097] 2) After stirring, the reaction solution was allowed to stand and separated. The organic phase was collected and distilled to obtain 119g of 4-trifluoromethylaniline, with a yield of 74% and HPLC purity >99%.

[0098] Example 13

[0099] This embodiment provides a method for preparing 4-trifluoromethylaniline, including the following steps:

[0100] 1) Add 180g of 4-chlorotrifluorotoluene (1mol), 60g of paraformaldehyde (2mol), and 212g of trimethyl orthoformate (2mol) to a high-pressure reactor, and then add 900g of N-methylpyrrolidone to completely dissolve the raw materials. After dissolution, introduce 85g of ammonia gas (5mol) into the high-pressure reactor, raise the temperature to 100℃ and react for 8h. Maintain the reactor pressure at 0.2MPa during the reaction process. HPLC detects the disappearance of the 4-chlorotrifluorotoluene raw material. Cool the reaction solution to room temperature and add 2700g of 10% dilute hydrochloric acid melt dropwise. After the addition is complete, continue stirring at room temperature for 30min.

[0101] 2) After stirring, the reaction solution was allowed to stand and separated. The organic phase was collected and distilled to obtain 138g of 4-trifluoromethylaniline, with a yield of 86% and HPLC purity >99%.

[0102] Example 14

[0103] This embodiment provides a method for preparing 4-trifluoromethylaniline, including the following steps:

[0104] 1) Add 180g of 4-chlorotrifluorotoluene (1mol), 33g of paraformaldehyde (1.1mol), and 106g of trimethyl orthoformate (1mol) to a high-pressure reactor, and then add 900g of N-methylpyrrolidone to completely dissolve the raw materials. After dissolution, introduce 119g of ammonia gas (7mol) into the high-pressure reactor, raise the temperature to 100℃ and react for 8h. During the reaction, maintain the reactor pressure at 0.8-1.0MPa. HPLC detects the disappearance of the 4-chlorotrifluorotoluene raw material. Cool the reaction solution to room temperature and add 2700g of 10% dilute hydrochloric acid melt dropwise. After the addition is complete, continue stirring at room temperature for 30min.

[0105] 2) After stirring, the reaction solution was allowed to stand and separated. The organic phase was collected and distilled to obtain 140g of 4-trifluoromethylaniline, with a yield of 87% and HPLC purity >99%.

[0106] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A process for the preparation of 4-trifluoromethylaniline, characterized in that, Includes the following steps: Ammonia gas was introduced into a raw material system comprising 4-chlorotrifluorotoluene, formaldehyde, and a dehydrating agent to carry out the first reaction. After the 4-chlorotrifluorotoluene was completely converted, the ammonia gas was stopped and a dilute acid solution was added to the reaction system to carry out the second reaction, yielding 4-trifluoromethylaniline.

2. The production method according to claim 1, characterized by, The dehydrating agent is selected from one or more of trimethyl orthoformate, triethyl orthoformate, alumina, p-toluenesulfonic acid, aluminum chloride, silica gel, and 732 cation exchange resin.

3. The production method according to claim 1 or 2, characterized by, The raw material system further includes a solvent, which is selected from one or more of N-methylpyrrolidone, N,N-dimethylformamide, nitrobenzene, dimethyl sulfoxide, sulfolane, and ethylene glycol.

4. The preparation method according to claim 1, characterized in that, The amount of ammonia introduced is 3 to 10 times the molar amount of 4-chlorotrifluorotoluene.

5. The preparation method according to claim 1, characterized in that, In the raw material system, the molar ratio of 4-chlorotrifluorotoluene to formaldehyde is 1:(1-5); and / or, the molar ratio of 4-chlorotrifluorotoluene to dehydrating agent is 1:(1-6).

6. The preparation method according to claim 1 or 5, characterized in that, The formaldehyde is derived from one of paraformaldehyde, anhydrous formaldehyde, or formaldehyde solution.

7. The preparation method according to claim 1, characterized in that, The temperature of the first reaction is 80–160°C, and the time is 4–36 h.

8. The production method according to claim 1 or 7, characterized by, The pressure of the first reaction is 0.2 to 1.0 MPa.

9. The method of claim 1, wherein, The dilute acid solution is selected from a dilute hydrochloric acid solution with a mass concentration of 10%.

10. The preparation method according to claim 1 or 9, characterized in that, The temperature of the second reaction is 25±10℃, and the time is 20 to 120 min.

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