Preparation method for high-content 2-trifluoromethyl-4-heptafluoroisopropyl aniline

Abstract

The present invention provides a preparation method for high-content 2-trifluoromethyl-4-heptafluoroisopropyl aniline. In the presence of dithionous acid, a solvent, and a catalyst, 2-trifluoromethyl aniline and 2-bromoheptafluoropropane undergo a reaction and post-treatment to obtain high-content 2-trifluoromethyl-4-heptafluoroisopropyl aniline, wherein the catalyst is selected from phosphoric acid, pyrophosphoric acid, hypophosphorous acid, metaphosphoric acid, phosphorous acid, pyrophosphorous acid, hydrobromic acid, hydrogen bromide gas, hydrogen chloride gas or sodium bisulfite. The preparation method of the present invention is simple to operate, has mild chemical reaction conditions, achieves a primary reaction conversion content of 96% or above under good reaction conditions, has few post-treatment steps, requires no rectification, achieves a final product content of 98% or above, achieves a total reaction yield of 93% or above, is easy for industrial production, and has good prospects for application.

Description

A method for preparing high-content 2-trifluoromethyl-4-heptafluoroisopropylaniline

[0001] The present invention claims two domestic priorities, namely, a Chinese invention patent application with a priority date of 2023-08-31, priority number CN 2023111154144, and invention name: A method for preparing high-content 2-trifluoromethyl-4-heptafluoroisopropylaniline; and a Chinese invention patent application with a priority date of 2023-10-13, priority number CN 2023113280512, and invention name: A method for preparing high-content 2-trifluoromethyl-4-heptafluoroisopropylaniline. Technical Field

[0002] The invention belongs to the technical field of compound synthesis and relates to the preparation of a novel heptafluoroisopropyl-containing bisamide insecticide intermediate 2-trifluoromethyl-4-heptafluoroisopropylaniline. Technical Background

[0003] Due to the extensive and frequent use of pesticides, serious resistance has now developed in much of the world. Increased dosages are necessary to achieve their intended effects, and some diseases are now untreatable. This has inevitably created challenges for agricultural production, the environment, and the ecosystem. New pesticides with greater activity, lower dosages, and improved environmental friendliness are urgently needed. Research institutions and companies both domestically and internationally are continuously increasing their investment in pesticide development, resulting in the emergence of several new pesticides with high activity, low dosages, and environmental friendliness.

[0004] Brofenac (Structural Formula: 01), a meta-diamide insecticide jointly developed by Mitsui Chemicals and BASF, has been commercialized and is primarily used for the control of pests such as Lepidoptera, Coleoptera, termites, ants, cockroaches, and flies in fruits, vegetables, beans, cotton, corn, grains, flowers, and non-crop applications. It is highly effective. For details, see Chinese Patent CN 102119143B, which covers amide derivatives, pest control agents containing such amide derivatives, and methods of use. However, several domestic companies and research institutions have optimized and improved these structures, discovering a series of new insecticides with higher activity, lower dosages, and improved environmental friendliness. Chinese patent CN 109497062 B discloses a diamide compound, its preparation method, and application. Its representative structure is cycloflumizone (Structural Formula: 02). 2-Trifluoromethyl-4-heptafluoroisopropylaniline is an important intermediate in this new class of insecticides and is used to synthesize 2-bromo-6-trifluoromethyl-4-heptafluoroisopropylaniline (Structural Formula: 03), which is also used in this new class of insecticides and has huge market potential.

[0005] Early public data indicate that the synthesis of 2-trifluoromethyl-4-heptafluoroisopropylaniline typically involves using 2-trifluoromethylaniline and 2-iodoheptafluoropropane as raw materials, reacting and post-processing in the presence of sodium dithionite, a solvent, water, and a phase-transfer catalyst to obtain 2-trifluoromethyl-4-heptafluoroisopropylaniline. The overall reaction yield is approximately 30%, resulting in high costs and unsuitable for industrial production. CN114478264A discloses a method for preparing 2-trifluoromethyl-4-heptafluoroisopropylaniline, which utilizes amines and a phase-transfer catalyst, followed by post-reaction treatment to obtain a high-purity product. However, the disadvantage is that the primary conversion rate and overall reaction yield remain low, at only approximately 70-80%. CN111032617A also discloses a method for preparing 2-trifluoromethyl-4-heptafluoroisopropylaniline, which uses sodium bisulfate as a catalyst. However, the method has the disadvantages of low utilization of 2-bromoheptafluoropropane, high consumption, low primary conversion rate and low overall yield, with a maximum of about 70-84%.

[0006] Summary of the Invention

[0007] In view of the shortcomings of the prior art and to solve the above problems, the present invention provides a method for preparing 2-trifluoromethyl-4-heptafluoroisopropylaniline with high content and high yield by optimizing the design of the preparation process and optimizing the reaction conditions.

[0008] The invention provides a preparation method of 2-trifluoromethyl-4-heptafluoroisopropylaniline. The method comprises the following steps: using 2-trifluoromethylaniline and 2-bromoheptafluoropropane as raw materials, reacting and post-treating in the presence of sodium dithionite, a solvent and a catalyst to obtain 2-trifluoromethyl-4-heptafluoroisopropylaniline with high content and high yield.

[0009] The reaction formula is as follows:

[0010] In the present invention, the main raw materials 2-trifluoromethylaniline and 2-bromoheptafluoropropane have been commercialized, are in sufficient supply, and are reasonably priced. In the preparation method of the present invention, industrial-grade raw materials are generally used, generally with a content of ≥98%. The 2-bromoheptafluoropropane is generally packaged in steel cylinders or iron cans, and the feeding method is to introduce the 2-bromoheptafluoropropane into the reaction system, either by adding it all at once or in portions, and the reaction can be performed at normal pressure or in a closed reaction. A closed reaction is advantageous in reducing the volatilization of the 2-bromoheptafluoropropane, thereby improving its utilization rate, while a cryogenic condenser can be used when reacting at normal pressure.

[0011] In the present invention, the amount of 2-bromoheptafluoropropane added is 1.0-5.0 times, preferably 1.0-2.0 times, and more preferably 1.0-1.5 times, the molar amount of 2-trifluoromethylaniline. If the amount of 2-bromoheptafluoropropane exceeds this range, the reaction is uneconomical and the excess 2-bromoheptafluoropropane needs to be recovered, which is difficult and wasteful.

[0012] The preparation method of the present invention uses sodium dithionite (Na2S2O4) as an initiator (also known as hydrosulfite). The sodium dithionite can be used at an industrial standard content of 85%. The hydrosulfite is added in an amount of 0.5-2.0 times, preferably 0.5-1.5 times, and more preferably 0.5-1.2 times, based on the molar amount of 2-trifluoromethylaniline. The hydrosulfite can be added to the reaction system all at once or in multiple additions.

[0013] The preparation method of the present invention is carried out in a solvent selected from the group consisting of: amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, and N-methylpyrrolidone; ethers such as ethylene glycol dimethyl ether, ethylene glycol diethyl ether, methyl tert-butyl ether, tetrahydrofuran, and 1,4-dioxane; esters such as ethyl acetate, n-butyl acetate, and isobutyl acetate; ketones such as acetone, methyl ethyl ketone, and butanone; and nitriles such as acetonitrile and propionitrile; or mixtures thereof. Preferred solvents are selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, methyl tert-butyl ether, ethyl acetate, n-butyl acetate, isobutyl acetate, acetone, methyl ethyl ketone, acetonitrile, and propionitrile, or mixtures thereof. The amount of solvent used is generally 2-20 times, preferably 5-10 times, the weight of the 2-trifluoromethylaniline raw material. The catalyst used in the preparation method of the present invention is selected from the group consisting of phosphoric acid, pyrophosphoric acid, hypophosphoric acid, metaphosphoric acid, phosphorous acid, pyrophosphoric acid, hydrobromic acid, hydrogen bromide gas, hydrogen chloride gas, sodium bisulfite, or mixtures thereof. The catalyst may also be selected from polymeric compounds of the aforementioned phosphoric acid, hypophosphoric acid, metaphosphoric acid, and phosphorous acid, or mixtures thereof. Generally, each molecule of the polymeric compound contains ≥3 phosphorus atoms. Phosphoric acid, hypophosphoric acid, metaphosphoric acid, phosphorous acid, and hydrobromic acid may be used in aqueous solutions, not necessarily in anhydrous or high-concentration forms. Phosphoric acid, hypophosphoric acid, metaphosphoric acid, and phosphorous acid may also be used in polymeric forms, with high content and low water content, with the content being >100% based on the corresponding monomeric acid content. A concentration of 20-100% may also be used, and the corresponding acids may be prepared into various concentrations by dilution with water, depolymerization with water, or depolymerization by heating with water. Hydrobromic acid can be used at an industrial concentration of 20-60%. Hydrogen bromide gas and hydrogen chloride gas can be obtained through laboratory preparation or commercially. When the catalyst is used at a low concentration, the water content in the reaction system increases, promoting the hydrolysis of 2-bromoheptafluoropropane and reducing the utilization of the raw materials. Therefore, although an aqueous solution of the catalyst can also effectively proceed with the reaction, it is preferred to use an anhydrous or high-concentration catalyst to reduce the hydrolysis of 2-bromoheptafluoropropane and improve utilization.

[0014] On the other hand, phosphoric acid and its derivatives (i.e., pyrophosphoric acid, hypophosphorous acid, metaphosphoric acid, phosphorous acid, and pyrophosphorous acid), including their polymeric compounds, have higher catalytic activity, can reduce the usage and consumption of 2-bromoheptafluoropropane, achieve better reaction effects, and the content of the obtained products is higher than that of other catalysts.

[0015] The molar amount of the catalyst (calculated based on the corresponding monomer acid if the compound is in polymer form) is 0.01-0.5 times, preferably 0.01-0.2 times, more preferably 0.05-0.1 times, of 2-trifluoromethylaniline. The catalyst can be added all at once.

[0016] The reaction temperature can generally be 20-150°C. When the reaction temperature is low, the reaction time will be prolonged. When the reaction temperature is too high, side reactions will increase, resulting in a decrease in yield. The preferred reaction temperature is 50-100°C, and particularly preferably 50-85°C.

[0017] The reaction time is generally 5-24 hours, preferably 5-12 hours. The reaction can be monitored by HPLC and the reaction can be stopped when the product no longer increases.

[0018] After the reaction is completed, carry out post-processing operation, generally comprise conventional operation steps such as filtration, distillation, extraction, washing, acidification, neutralization, distillation.The reaction system is cooled to room temperature, the inorganic salt in the system is filtered out, and the filtrate is distilled to recover the solvent. The solvent of recovery gain does not need to be handled separately, and can be directly used in the next batch reaction.The distillation residue is added with extraction solvent and dissolved. After conventional washing, pickling and neutralization, the extraction solvent is distilled back and directly high vacuum distilled out product to obtain high content, high yield 2-trifluoromethyl-4-heptafluoroisopropylaniline.

[0019] In the post-treatment extraction step, the extraction solvent is not particularly limited and is generally a conventional water-insoluble solvent, such as a mixture of one or more of toluene, ethylbenzene, xylene, cyclohexane, methylcyclohexane, petroleum ether, n-hexane, n-heptane, ethyl acetate, n-butyl acetate, isobutyl acetate, dichloromethane, and dichloroethane. The amount used is 2-20 times, preferably 5-10 times, the weight of the 2-trifluoromethylaniline raw material. The operating temperature is generally 20-100°C, preferably 20-30°C. Post-treatment operations are basic operating techniques mastered by those skilled in the art and will not be described in detail here.

[0020] The preparation method of the present invention, under preferred reaction conditions, can achieve a conversion content of more than 96% in a single reaction, and the post-processing steps of the obtained product are simple. Only ordinary distillation operation is required to obtain 2-trifluoromethyl-4-heptafluoroisopropylaniline with a content of more than 98% and a yield of more than 93%, without the need for rectification and purification. Therefore, the method is easy to industrialize and has a high application prospect.

[0021] In the present invention, the operations involved in the preparation method, such as distillation, vacuum distillation, filtration, extraction, and layering, are conventional operations and basic unit operations for general chemists and will not be described in detail here. For details, please refer to the synthesis examples.

[0022] Compared with the prior art, the preparation method of the present invention is simple to operate, has mild chemical reaction conditions, fewer post-processing steps, and does not require distillation. Under optimal reaction conditions, the total yield is above 93%, the final product content is above 98%, the cost is low, and it is easy to industrialize and produce, and has high application prospects. DETAILED DESCRIPTION

[0023] The technical solutions of the present invention are further described below through specific implementation methods. Those skilled in the art should understand that the embodiments are only used to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0024] The raw materials described in the synthesis examples of the present invention, unless otherwise specified, are generally purchased from the market, and are usually of industrial or reagent grade content. Sodium dithionite, also known as hydrosulfite, has a content of ≥85%, phosphoric acid has a content of ≥85%, metaphosphoric acid has a content of ≥99%, phosphorous acid has a content of ≥99%, and pyrophosphoric acid has a content of ≥99% (110% as phosphoric acid). The above contents are not precisely calibrated.

[0025] The percentage concentrations described in the synthesis examples are generally referred to as weight percent concentrations unless otherwise specified. The HPLC content data are generally area-normalized contents, without precise calibration, unless otherwise specified. The content data of the present invention are area-normalized contents, which are accurately calibrated by weighing standard products. Yield refers to molar yield, which is generally the yield calculated based on the raw material 2-trifluoromethylaniline, and the yield data are not accurately calibrated.

[0026] Synthesis Example 1

[0027] In a 500ml four-necked glass reaction bottle, 200g of N,N-dimethylformamide, 39.5g (0.24 mol) of 2-trifluoromethylaniline were added, 49.2g (0.24 mol) of sodium dithionite were added, 1.38g (0.012 mol) of phosphoric acid as a catalyst was added dropwise, a condenser with a reflux condensing temperature of about -10°C was installed, the reaction temperature was controlled at 55-65°C, 73.6g (0.29 mol) of 2-bromoheptafluoropropane was added for 5 hours to react, and after the reaction was completed, the reaction was kept at 55-65°C for 2 hours, the temperature was lowered, the inorganic salts were filtered out, the filtrate was distilled under reduced pressure, the solvent was recovered, and the residue was obtained. The liquid was sampled for HPLC analysis, and the area-normalized content was 96.4%. 400 ml of toluene and 50 ml of water were added to the resulting residue, and the mixture was stirred at room temperature to dissolve. The acidic aqueous layer was separated, and the solvent layer was washed with 50 ml of 10% hydrochloric acid. The pH was then adjusted to near neutral with a small amount of 5% sodium bicarbonate. The aqueous layer was separated, dried over anhydrous MgSO4, and filtered to obtain a toluene solution containing 2-trifluoromethyl-4-heptafluoroisopropylaniline. The solvent was distilled off under reduced pressure, and the 2-trifluoromethyl-4-heptafluoroisopropylaniline was removed under high vacuum to obtain 75 g of the finished product, with an HPLC content of greater than 98% and a GC content of greater than 98%. The molar yield based on the starting 2-trifluoromethylaniline was 93.1%.

[0028] The NMR data are as follows:

[0029] 1 H-NMR (400MHz, CDCl3) δ (ppm): 4.50 (2H, br s), 6.84 (1H, d, J = 8.2Hz), 7.50 (1H, d, J = 8.2Hz), 7.66 (1H, br s,).

[0030] Synthesis Example 2

[0031] The same procedures were followed as in Synthesis Example 1, except that 200 g of N,N-dimethylformamide was replaced with 200 g of acetonitrile. After post-treatment, 2-trifluoromethyl-4-heptafluoroisopropylaniline was distilled off under high vacuum to yield 76 g of the finished product, with an HPLC content exceeding 98% and a GC content exceeding 98%. The molar yield, calculated as 2-trifluoromethylaniline, was 94.4%.

[0032] Synthesis Example 3

[0033] In a 500ml autoclave, 200g of acetonitrile, 39.5g (0.24 mol) of 2-trifluoromethylaniline, 49.2g (0.24 mol) of sodium dithionite and 1.38g (0.012 mol) of phosphoric acid as a catalyst were added. 73.6g (0.29 mol) of 2-bromoheptafluoropropane was introduced at room temperature within 10 minutes. The autoclave was sealed and the temperature was raised to 55-65°C. The reaction was kept at 55-65°C for 6-8 hours. The temperature was lowered, the inorganic salts were filtered out, and the filtrate was distilled under reduced pressure to recover the solvent. The residual liquid was sampled and analyzed by HPLC. The corrected area was normalized to 0.05%. A content of 96.1%, and to the obtained residue, 400 ml of methylcyclohexane and 50 ml of water were added, stirred at room temperature, dissolved, and the acidic aqueous layer was separated. The solvent layer was washed with 50 ml of 10% hydrochloric acid and the layer was separated. The pH value was adjusted to nearly neutral with a small amount of 5% sodium bicarbonate. After separating the aqueous layer, it was dried over anhydrous MgSO4 and filtered to obtain a methylcyclohexane solution containing 2-trifluoromethyl-4-heptafluoroisopropylaniline. After the solvent was distilled off under reduced pressure, 2-trifluoromethyl-4-heptafluoroisopropylaniline was distilled off under high vacuum to obtain 76.5 g of the finished product. The HPLC content was greater than 98%, and the GC content was greater than 98%.

[0034] The molar yield was 94.8% based on the raw material 2-trifluoromethylaniline.

[0035] Synthesis Example 4

[0036] The procedure of Synthesis Example 3 was followed, except that 61 g (0.24 mole) of 2-bromoheptafluoropropane was introduced, and other operations were the same. After the reaction, the distilled residue obtained by filtration and distillation was sampled and analyzed by HPLC. The corrected area-normalized content was 92.1%. After the same treatment, 2-trifluoromethyl-4-heptafluoroisopropylaniline was distilled off under high vacuum to obtain 73.3 g of the finished product. The HPLC content was greater than 98%, and the GC content was greater than 98%. The molar yield was 90.9% based on the raw material 2-trifluoromethylaniline.

[0037] Synthesis Example 5-6-7

[0038] The synthesis was carried out in accordance with the procedures of Example 3, except that 1.38 g (0.012 mol) of phosphoric acid as the catalyst was replaced by 0.8 g (0.012 mol) of phosphorous acid, 1.6 g (0.024 mol) of phosphorous acid, and 1.07 g (0.06 mol) of pyrophosphoric acid, respectively. The other procedures were the same, and the yield and content data were similar.

[0039] Comparison of Synthesis Implementation Examples 8-18 Conversion Content of Different Catalysts

[0040] The operation was carried out according to Synthesis Example 1, wherein 200 g of N,N-dimethylformamide was replaced with 200 g of acetonitrile, and the catalyst phosphoric acid 1.38 g (0.012 mol) was replaced with equimolar amounts of phosphoric acid, 50% phosphoric acid, metaphosphoric acid, phosphorous acid, sodium bisulfate, 40% hydrobromic acid, hydrogen bromide gas, hydrogen chloride gas, 98% concentrated sulfuric acid, sodium bisulfite, and no catalyst. 58.5 g (0.24 mol) of 2-bromoheptafluoropropane was used, and the other operations were identical. After completion of the reaction, the reaction was filtered, and the filtrate was analyzed by HPLC to detect the corrected normalized content of the raw material 2-trifluoromethylaniline peak and the product 2-trifluoromethyl-4-heptafluoroisopropylaniline peak, reflecting the conversion content after the reaction. The specific data are compared as follows:

[0041] Comparison of data results shows that under the catalyst and process conditions of the present invention, phosphoric acid and phosphoric acid-derived catalysts, in particular, have high reactivity. Under the same conditions, the conversion content of the first reaction is greatly improved, making it possible to reduce the amount of 2-bromoheptafluoropropane used, improve the reaction utilization rate of raw materials, increase the yield, and simplify the process.

[0042] The present invention illustrates the preparation method of high-content 2-trifluoromethyl-4-heptafluoroisopropylaniline through the above representative examples. However, the present invention is not limited to these examples, nor does it mean that the present invention must rely on these examples to be implemented. Those skilled in the art will understand that any improvements to the present invention, equivalent substitutions of raw materials in the process of the present invention, addition of auxiliary components, and selection of specific methods, etc., are all within the scope of protection and disclosure of the present invention.

Claims

1. A method for preparing high-content 2-trifluoromethyl-4-heptafluoroisopropylaniline, characterized in that In the presence of dithionite, solvent and catalyst, the raw material 2-trifluoromethylaniline and 2-bromoheptafluoropropane are reacted and post-treated to obtain high-content 2-trifluoromethyl-4-heptafluoroisopropylaniline; the reaction formula is as follows: The solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, methyl tert-butyl ether, ethyl acetate, n-butyl acetate, isobutyl acetate, acetone, methyl ethyl ketone, acetonitrile, propionitrile or a mixture thereof; The catalyst is selected from phosphoric acid, pyrophosphoric acid, hypophosphorous acid, metaphosphoric acid, phosphorous acid, pyrophosphorous acid, hydrobromic acid, hydrogen bromide gas, hydrogen chloride gas, sodium bisulfite or a mixture thereof, or is selected from a polymer compound of phosphoric acid, hypophosphorous acid, metaphosphoric acid, phosphorous acid or a mixture thereof.

2. The method for preparing high-content 2-trifluoromethyl-4-heptafluoroisopropylaniline according to claim 1, characterized in that The solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, methyl tert-butyl ether, ethyl acetate, n-butyl acetate, isobutyl acetate, acetone, methyl ethyl ketone, acetonitrile, propionitrile or a mixture thereof; The catalyst is selected from phosphoric acid, pyrophosphoric acid, polyphosphoric acid, hypophosphorous acid, metaphosphoric acid, phosphorous acid, pyrophosphorous acid, hydrobromic acid, hydrogen bromide gas, sodium bisulfite or a mixture thereof.

3. The method for preparing high-content 2-trifluoromethyl-4-heptafluoroisopropylaniline according to claim 1 or 2, characterized in that The molar amount of the catalyst is 1-20% of 2-trifluoromethylaniline.

4. The method for preparing high-content 2-trifluoromethyl-4-heptafluoroisopropylaniline according to claim 1 or 2, characterized in that The concentrations of phosphoric acid, hypophosphorous acid, metaphosphoric acid and phosphorous acid are 20-100%, and the concentration of hydrobromic acid is 20-60%.

5. The method for preparing high-content 2-trifluoromethyl-4-heptafluoroisopropylaniline according to claim 1 or 2, characterized in that The concentration of the phosphoric acid, hypophosphorous acid, metaphosphoric acid and phosphorous acid is 100%.

6. The method for preparing high-content 2-trifluoromethyl-4-heptafluoroisopropylaniline according to claim 1 or 2, characterized in that The molar amount of 2-bromoheptafluoropropane raw material is 100-200% of 2-trifluoromethylaniline.

7. The method for preparing high-content 2-trifluoromethyl-4-heptafluoroisopropylaniline according to claim 1 or 2, characterized in that The molar amount of sodium dithionite is 50-150% of 2-trifluoromethylaniline.

8. The method for preparing high-content 2-trifluoromethyl-4-heptafluoroisopropylaniline according to claim 1 or 2, characterized in that The reaction temperature is 20-150°C.

9. The method for preparing high-content 2-trifluoromethyl-4-heptafluoroisopropylaniline according to claim 1 or 2, characterized in that The weight ratio of the solvent to 2-trifluoromethylaniline is 5-10:1.

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