Preparation method of 2-methyl-3-trifluoromethylaniline

Abstract

The invention provides a preparation method of 2-methyl-3-trifluoromethylaniline. The reaction comprises a nitration reaction, a fluorination reaction and a nitro group reduction reaction. In the synthesis process, a common chemical raw material o-bromotoluene is taken as a reaction starting point, green chemistry and environment friendliness are taken as a core concept, and the target product MTA is obtained through three steps of nitration reaction, nucleophilic substitution reaction and reduction reaction. In the second step of the reaction, trifluoromethylsilane is used for replacing the traditional gas-solid reaction of hydrogen fluoride. The reaction efficiency is improved, and the method is more environment-friendly. In addition, in the third step, SnCl2 and ethyl alcohol are used for reducing nitryl. The reaction not only increases the reaction efficiency, but also replaces the traditional palladium-carbon catalyst to reduce the production cost. The series of reactions are mild in temperature, environment-friendly and high in efficiency, and have a good industrial production prospect.

Description

Technical Field

[0001] The invention belongs to the technical field of fluorine chemical synthesis, and specifically relates to 2-methyl-3-trifluoromethylaniline, an intermediate for synthesizing tranquilizers and anti-inflammatory and analgesic drugs, flunixin meglumine. Background Art

[0002] Flunixin meglumine is a veterinary anti-inflammatory analgesic. It is an odorless white powder and is one of the non-steroidal drugs for veterinary use. This agent is mainly used to relieve visceral colic in horses and treat diarrhea, tremors, colitis, respiratory and other systemic diseases in foals. In terms of pharmacology, flunixin meglumine is an inhibitor of cyclooxygenase. The drug acts quickly and can generally relieve pain within 15 minutes. It is more effective than analgesic, pethidine, and codeine, and is four times more effective than phenylbutazone in treating horse lameness and joint swelling. This agent is widely used in various countries, and the compound structure is as follows: It can be found from the reported literature that if flunixin meglumine needs to be prepared efficiently, the intermediate 2-methyl-3-trifluoromethylaniline (MTA) must be introduced for synthesis. Among them, the structural formula of 2-methyl-3-trifluoromethylaniline is as follows: At present, there are several mainstream methods for synthesizing 2-methyl-3-trifluoromethylaniline.

[0003] A series of organic syntheses were carried out using trifluorotoluene as raw material, and 2-methyl-3-trifluoromethylaniline was obtained by Friedel-Crafts alkylation, nitric acid nitration, fluorination and hydrogenation reduction. The synthetic difficulty of this scheme lies in the methylation reaction in the second step of the process, and the raw materials used are sodium hydride, dimethyl sulfoxide, trimethyl sulfoxide iodine, etc. The sodium cyanide used in this step has the hidden danger of being flammable and explosive, and trimethyl sulfoxide iodine is expensive, and the reaction yield reported by the literature is only 32%, and the total yield of the reaction is only 26.8%. The process has a low yield and is generally environmentally friendly.

[0004] U.S. Patent No. 5,965,735 discloses a synthesis scheme using m-aminotrifluorotoluene as the starting point of the reaction. First, the amino group reacts with pivaloyl chloride, and the obtained amide is reacted with methyl iodide and butyl lithium or dimethyl sulfate at low temperature to obtain a methylated product, and then the protecting group is removed to obtain the target product MTA. The amount of butyl lithium used in this route must be greater than 2 eq. The price friendliness of butyl lithium is poor. Considering the toxicity problem, the toxicity of methyl iodide and dimethyl sulfate used cannot be ignored. In addition, the methylation reaction needs to be carried out under low temperature conditions, which creates resistance to industrial production. In view of the above conditions, this route is not suitable for large-scale industrial production needs, and its synthetic route is as follows: Chinese invention patent CN115073298A discloses a method for synthesizing 2-methyl-3-trifluoromethylaniline using 2-methylbenzoic acid as a starting material in a continuous flow microreactor, wherein the process is as follows: The method obtains the target product 2-methyl-3-trifluoromethylaniline through three steps of nitration, fluorination and hydrogenation reduction. The problems of low raw material conversion rate, high risk and environmental pollution in the process are solved. However, if the process of sulfur tetrafluoride fluorination is adopted, 3 mol of sulfur tetrafluoride is required for 1 mol of raw material, that is, 1.82 tons of sulfur tetrafluoride are consumed per ton of product, and the market price of sulfur tetrafluoride is as high as 500,000 yuan / ton, totaling 910,000 yuan. It is much higher than the market price of the target product of 800,000 yuan / ton. In addition, the nitration process of 2-methylbenzoic acid involves the problem of ortho-para selectivity, which is not explained in the patent, resulting in doubts about the yield of the target product. Overall, the industrial value is not high.

[0005] In summary, under the current policy of calling for green chemistry and environmentally friendly chemistry, it is particularly important to explore and realize a green and efficient synthesis scheme for 2-methyl-3-trifluoromethylaniline. Summary of the invention

[0006] The object of the present invention is to provide a method for preparing 2-methyl-3-trifluoromethylaniline (MTA). The reaction includes nitration reaction, fluorination reaction and nitro reduction reaction. In the synthesis process of the present invention, the common chemical raw material o-bromotoluene is used as the starting point of the reaction, and green chemistry and environmental friendliness are the core concepts. The target product MTA is obtained through a total of three steps: nitration reaction, nucleophilic substitution reaction and reduction reaction. In the second step of this reaction, trifluoromethylsilane is used to replace the traditional gas-solid reaction of hydrogen fluoride. It not only increases the efficiency of the reaction but also is more environmentally friendly. In addition, SnCl2 and ethanol are used in the third step to reduce the nitro group. This reaction not only increases the reaction efficiency but also replaces the traditional palladium carbon catalyst to reduce the production cost. This series of reactions has mild reaction temperature, environmental friendliness, high efficiency and good industrial production prospects.

[0007] To achieve the above object, the present invention adopts the following technical solution: A method for preparing 2-methyl-3-trifluoromethylaniline comprises the following steps: (1) Compound 1 is subjected to nitration reaction in an environment of concentrated nitric acid and concentrated sulfuric acid to obtain compound 2; (2) Compound 2 is reacted with triethyl(trifluoromethyl)silane to obtain compound 3; (3) Compound 3 is reduced by stannous chloride and ethanol to obtain the target product 2-methyl-3-trifluoromethylaniline; the compound 1 is o-bromotoluene.

[0008] The specific reaction process is as follows: Furthermore, the concentration of concentrated sulfuric acid in step (1) is 98 wt %, and the concentration of concentrated nitric acid is 68 wt %.

[0009] Furthermore, when triethyl(trifluoromethyl)silane is used for the reaction in step (2), the solvent of the system is a mixed solvent of N,N-dimethylformamide (DMF) and N-methylpyrrolidone (NMP) in a volume ratio of 1:1.

[0010] Furthermore, in step (2), KF and CuI are added to react.

[0011] Furthermore, in step (2), the molar ratio of KF to compound 2 is 1:1, the molar ratio of CuI to compound 2 is 1.5:1, and the molar ratio of triethyl (trifluoromethyl) silane to compound 2 is 1.2:1.

[0012] Furthermore, the reaction temperature of step (2) is 80°C and the reaction time is 24 hours.

[0013] Furthermore, in step (3), the molar ratio of stannous chloride to compound 3 is 1.2:1.

[0014] Furthermore, the reaction temperature of step (3) is 70°C and the reaction time is 2 hours.

[0015] The advantages of the present invention are: Compared with the existing synthesis technology of MTA, the experimental yield of MTA of the present invention reaches 92.1%. The compounds used in the reaction scheme adopted by the present invention are more environmentally friendly than the scheme described in Article 3 of this patent. The control of the properties of the drug in the present invention is mainly based on multiphase reactions, and the solid phase is more convenient for subsequent utilization and recovery in industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 is the compound 2 prepared in Example 1 1 HNMR spectrum.

[0017] Figure 2 It is the HPLC spectrum of compound 2 prepared in Example 1.

[0018] Figure 3 is the compound 3 prepared in Example 2 1 HNMR spectrum.

[0019] Figure 4 It is the HPLC spectrum of compound 3 prepared in Example 2.

[0020] Figure 5 is the compound 4 prepared in Example 3 1 HNMR spectrum.

[0021] Figure 6 It is the HPLC spectrum of compound 4 prepared in Example 3. DETAILED DESCRIPTION

[0022] In order to make the above features and advantages of the present invention more clearly understood, the following embodiments are given for detailed description. The methods of the present invention are all conventional methods in the art unless otherwise specified.

[0023] The present invention provides a novel, efficient and environmentally friendly synthesis scheme, the process of which comprises three steps, namely nitration, fluorination and hydrogenation reduction, as shown below.

[0024] The present invention will be further described below by means of specific examples.

[0025] Example 1 The synthetic route of compound 2 is as follows: In this reaction, the material data are shown in the following table.

[0026] The specific operation process is as follows Mix 34.6 g of 68 wt% concentrated nitric acid and 101.8 g of 98 wt% concentrated sulfuric acid for later use. Cool a 500 mL three-necked flask to 0-5 °C and add 58.6 g of o-bromotoluene, then drop the prepared mixed acid into the o-bromotoluene. After the mixed acid is added dropwise, heat to 45 °C and react for 3 hours.

[0027] The post-processing aspects are as follows The reaction mixture was cooled and allowed to stand to separate the upper oily substance. The oily layer was diluted with 150 mL of dichloromethane. The organic phase was washed three times with 50 mL of water and three times with 50 mL of saturated sodium carbonate. The organic phase was concentrated under reduced pressure to obtain 69.9 g (yield: 95.6%) of compound 2. After purification, it was sent for NMR detection. 1 HNMR spectrum is attached Figure 1 , and then the attached Figure 2 .

[0028] Example 2 The synthetic route of compound 3 is as follows: In this reaction, the material data are shown in the following table.

[0029] The specific operation process is as follows: In a 500 mL three-necked flask, 100 mL of DMF and 100 mL of NMP were added in sequence and stirred evenly. Then, 64.8 g of compound 2, 65.2 g of triethyl(trifluoromethyl)silane, 17.1 g of potassium fluoride, and 84.2 g of cuprous iodide were added and the temperature was raised to 80 °C for reaction for 24 hours.

[0030] The post-processing aspects are as follows: After the reaction is completed, the reaction system is allowed to stand until it reaches room temperature, and then washed three times with 100 mL of brine and three times with 100 mL of distilled water using a separatory funnel. After washing, it is dried with anhydrous sodium sulfate and then distilled under reduced pressure to obtain a crude product. After purification, a total of 58.4 g of compound 3 is obtained, with a yield of 97.6%. After purification, it is sent for nuclear magnetic resonance detection. Compound 3 1 HNMR spectrum is attached Figure 3 , and then the attached Figure 4 .

[0031] Example 3 The synthetic route of compound 3 is as follows: In this reaction, the material data are shown in the following table.

[0032] The specific operation process is as follows: Take a 500 mL three-necked flask, add 250 mL of ethanol, then add 65.8 g of SnCl2·2H2O and 50.0 g of compound 3. Stir the reaction system and heat it to 70 °C for 2 hours.

[0033] Post-processing: After the reaction is completed, cool to room temperature. Filter the reaction system to obtain a clear liquid and remove the ethanol solvent by vacuum distillation. Dissolve the solid obtained after vacuum distillation in about 150 mL of distilled water and extract it with 50 mL of dichloromethane. Take the organic phase and purify it by vacuum distillation to obtain the target product 2-methyl-3-trifluoromethylaniline, a total of 41.6 g, with a yield of 98.7%. After further purification, send it for nuclear magnetic resonance detection. Compound 4 1 HNMR spectrum is attached Figure 5 , and then the attached Figure 6.

[0034] The above description is only a preferred embodiment of the present invention. All equivalent changes and modifications made according to the scope of the patent application of the present invention should fall within the scope of the present invention.

Claims

1. A method for preparing 2-methyl-3-trifluoromethylaniline, characterized in that: The following steps are involved: (1) Compound 1 is subjected to nitration reaction in an environment of concentrated nitric acid and concentrated sulfuric acid to obtain compound 2; (2) Compound 2 is reacted with triethyl(trifluoromethyl)silane to obtain compound 3; (3) Compound 3 is reduced by stannous chloride and ethanol to obtain the target product 2-methyl-3-trifluoromethylaniline; the compound 1 is o-bromotoluene.

2. The method according to claim 1, characterized in that The structure of compound 2 is .

3. The method according to claim 1, characterized in that The structure of compound 3 is .

4. The method according to claim 1, characterized in that The concentration of concentrated sulfuric acid in step (1) is 98 wt %, and the concentration of concentrated nitric acid is 68 wt %.

5. The method according to claim 1, characterized in that When triethyl(trifluoromethyl)silane is used for the reaction in step (2), the solvent of the system is a mixed solvent of N,N-dimethylformamide and N-methylpyrrolidone in a volume ratio of 1:

1.

6. The method according to claim 1, characterized in that In step (2), KF and CuI are also added to react.

7. The method according to claim 6, characterized in that In step (2), the molar ratio of KF to compound 2 is 1:1, the molar ratio of CuI to compound 2 is 1.5:1, and the molar ratio of triethyl (trifluoromethyl) silane to compound 2 is 1.2:

1.

8. The method according to claim 1, characterized in that The reaction temperature of step (2) is 80°C and the reaction time is 24 hours.

9. The method according to claim 1, characterized in that: In step (3), the molar ratio of stannous chloride to compound 3 is 1.2:

1.

10. The method according to claim 1, characterized in that The reaction temperature of step (3) is 70°C and the reaction time is 2 hours.

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