Process for the preparation of high content 2-trifluoromethyl-4-heptafluoroisopropylphenylamine

Abstract

The application provides a preparation method of high-content 2-trifluoromethyl-4-heptafluoroisopropylaniline, in which 2-trifluoromethyl aniline and 2-bromine heptafluoropropane are reacted in the presence of hydrosulfite, a solvent and a catalyst to obtain high-content 2-trifluoromethyl-4-heptafluoroisopropylaniline through reaction and post-treatment; 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 is simple in operation and mild in chemical reaction conditions; under the preferred reaction conditions, the conversion content reaches more than 96% in one reaction, the post-treatment steps are few, rectification is not needed, the content of the final product is more than 98%, the total reaction yield is more than 93%, the industrial production is easy, and the method has a high application prospect.

Description

[0001] The present application claims a domestic priority, the priority date is 2023 / 8 / 31, the priority number is CN2023111154144, and the invention name is a preparation method of high content 2-trifluoromethyl-4-heptafluoroisopropyl aniline. TECHNICAL FIELD

[0002] The present application belongs to the technical field of compound synthesis, and relates to the preparation of 2-trifluoromethyl-4-heptafluoroisopropyl aniline, a novel insecticide intermediate containing heptafluoroisopropyl. TECHNICAL BACKGROUND

[0003] Due to the large and frequent use of insecticides, serious resistance problems have occurred in most parts of the world at present, and the original effect can only be achieved by increasing the dosage. Some diseases have no medicine to cure, which will inevitably cause certain problems to agricultural production, environment and ecology. New insecticides with better activity, lower dosage and more environmentally friendly need to be developed. Domestic and foreign scientific research institutions and enterprises have continuously increased their investment in pesticide creation, and a number of new insecticides with high activity, low dosage and environmental friendliness have appeared.

[0004] The Japanese Mitsui Chemical Company and the BASF Company jointly developed the insecticide bromofluazuron (structure formula: 01) of m-diamide, which has been commercialized, and is mainly used for fruits and vegetables, beans, cotton, corn, cereals, flowers and non-crop purposes, to prevent and control Lepidoptera, Coleoptera, termites, ants, cockroaches, flies and other pests, and has very good effect. See Chinese patent CN 102119143B, amide derivatives, harmful organism control agents containing the amide derivatives, and methods of using the same. However, domestic enterprises and research institutions have optimized and improved the structure on this basis, and found a series of new insecticides with higher activity, lower dosage and more environmentally friendly. Chinese patent CN 109497062B, a m-diamide compound, a preparation method and application thereof, represent a structure, cyclopropane flumethrin (structure formula: 02); 2-trifluoromethyl-4-heptafluoroisopropyl aniline is an important intermediate of this new type of insecticide, and is used to synthesize 2-bromo-6-trifluoromethyl-4-heptafluoroisopropyl aniline (structure formula: 03), and is also applied to the field of this new type of insecticide, and has huge market potential.

[0005]

[0006]

[0007] Early data shows that the synthesis method of 2-trifluoromethyl-4-heptafluoroisopropyl aniline, generally, 2-trifluoromethyl aniline, 2-iodo heptafluoropropane is used as raw material, in the presence of sodium dithionite, solvent and water, phase transfer catalyst, through reaction, post-processing to obtain 2-trifluoromethyl-4-heptafluoroisopropyl aniline. The total yield of the reaction is about 30%, the cost is high, and it is not suitable for industrial production. CN114478264A discloses a preparation method of 2-trifluoromethyl-4-heptafluoroisopropyl aniline, which uses amine and phase transfer catalyst, and high-purity product is obtained after reaction and treatment. The disadvantage is that the conversion rate and the total yield of the reaction are still not high, only about 70-80%. CN111032617A also discloses a preparation method of 2-trifluoromethyl-4-heptafluoroisopropyl aniline, which uses sodium bisulfate as catalyst. The disadvantage is that the utilization of 2-bromoheptafluoropropane is not high, the consumption is large, the conversion rate and the total yield of the reaction are not high, and the highest is about 70-84%. SUMMARY

[0008] In view of the deficiencies of the prior art, to solve the above problems, the present application is characterized by optimizing the design of the preparation process and optimizing the reaction conditions to provide a preparation method of 2-trifluoromethyl-4-heptafluoroisopropyl aniline with high content and high yield.

[0009] The present application provides a preparation method of 2-trifluoromethyl-4-heptafluoroisopropyl aniline, which uses 2-trifluoromethyl aniline and 2-bromoheptafluoropropane as raw materials, in the presence of sodium dithionite, solvent and catalyst, through reaction and post-processing to obtain 2-trifluoromethyl-4-heptafluoroisopropyl aniline with high content and high yield.

[0010] The reaction formula is as follows:

[0011]

[0012] In the present application, the main raw materials 2-trifluoromethyl aniline and 2-bromoheptafluoropropane have been market industrialized, the market supply is sufficient, and the price is appropriate. In the preparation method of the present application, industrial grade raw materials are generally used, generally with a content of ≥98%. Among them, 2-bromoheptafluoropropane is generally packed in steel bottles or iron cans, and the feeding mode is to introduce or add at one time or in several times into the reaction system, which can be normal pressure reaction or closed reaction. Closed reaction is beneficial to reduce the volatilization of 2-bromoheptafluoropropane, thereby improving the utilization rate, and deep cooling condenser can be used when normal pressure reaction is adopted.

[0013] In the present application, the feeding amount of 2-bromoheptafluoropropane is 1.0-5.0 times, preferably 1.0-2.0 times, more preferably 1.0-1.5 times of the molar amount of 2-trifluoromethyl aniline. If the excess of 2-bromoheptafluoropropane is greater than the range, the reaction is not economical, the excess 2-bromoheptafluoropropane needs to be recovered, which is difficult to recover, causing waste.

[0014] The preparation method of the present application uses sodium hyposulfite Na2S2O4 as initiator (also known as sodium dithionite), which can be used in industrial specifications with 85% content. The amount of sodium dithionite is 0.5-2.0 times, preferably 0.5-1.5 times, more preferably 0.5-1.2 times the molar amount of 2-trifluoromethylaniline. It can be put into the reaction system at one time or in multiple times.

[0015] The preparation method of the present application is carried out in a solvent selected from: amides: N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, etc.; ethers: ethylene glycol dimethyl ether, ethylene glycol diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, etc.; esters: ethyl acetate, n-butyl acetate, isobutyl acetate, etc.; ketones: acetone, methyl ethyl ketone, butanone; nitriles: acetonitrile, propionitrile; or a mixture of these solvents. The preferred 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 amount of solvent is generally 2-20 times, preferably 5-10 times the weight of 2-trifluoromethylaniline raw material. The catalyst used in the preparation method of the present application is selected from: phosphoric acid, pyrophosphoric acid, hypophosphorous acid, metaphosphoric acid, phosphorous acid, pyrophosphorous acid, hydrobromic acid or hydrogen bromide gas, hydrogen chloride gas, sodium bisulfite or a mixture thereof; the catalyst can also be selected from the polymers of the aforementioned phosphoric acid, hypophosphorous acid, metaphosphoric acid, phosphorous acid or a mixture thereof, generally the number of phosphorus atoms in each molecule of the polymer compound is ≥3, wherein the phosphoric acid, hypophosphorous acid, metaphosphoric acid, phosphorous acid and hydrobromic acid can also be used in aqueous solution, and it is not necessary to use anhydrous or high-concentration, and the phosphoric acid, hypophosphorous acid, metaphosphoric acid, phosphorous acid can also be used in the form of polymer compound, with high content and low water content, if calculated according to the content of the corresponding monomer acid, the content is >100%. A 20-100% concentration can also be used, which can be obtained by dilution with water, hydrolysis or hydrolysis and depolymerization to obtain the corresponding acid to configure various concentrations. Hydrobromic acid can be used in 20-60% industrial concentration, hydrogen bromide gas and hydrogen chloride gas can be obtained by laboratory preparation or commercial acquisition; when the catalyst is used in low concentration, the water content in the reaction system increases, which can promote the hydrolysis of 2-bromoheptafluoropropane and reduce the utilization of raw materials. Therefore, although the catalyst can be used in aqueous solution form to make the reaction effective, it is preferred to use anhydrous or high-concentration to reduce the hydrolysis of 2-bromoheptafluoropropane and improve the utilization.

[0016] On the other hand, phosphoric acid and phosphoric acid derivatives (i.e. pyrophosphoric acid, hypophosphorous acid, metaphosphoric acid and phosphorous acid, pyrophosphorous acid) including their polymerized compounds have higher catalytic activity, which can reduce the use and consumption of 2-bromoheptafluoropropane, and achieve better reaction results, and the content of the obtained product is higher than that of other catalysts.

[0017] The molar amount of the catalyst (calculated as the corresponding monomeric acid if the compound is in a polymerized form) is 0.01-0.5 times, preferably 0.01-0.2 times, more preferably 0.05-0.1 times, the amount of 2-trifluoromethylaniline, and the feeding mode can be one-time feeding.

[0018] The reaction temperature can generally be 20-150℃, the reaction time will be prolonged when the reaction temperature is low, and the yield will be reduced when the reaction temperature is too high due to the increase of side reactions, and the preferred reaction temperature is 50-100℃, and the particularly preferred reaction temperature is 50-85℃.

[0019] The reaction time is generally 5-24 hours, and the preferred reaction time is generally 5-12 hours, and the reaction can be stopped when the product no longer increases by tracking the reaction by HPLC.

[0020] After the reaction is completed, the post-treatment operation is performed, which generally includes conventional operation steps such as filtration, distillation, extraction, water washing, acid washing, neutralization, and distillation. The reaction system is cooled to room temperature, and the inorganic salt in the system is filtered off, and the filtrate is distilled to recover the solvent. The recovered solvent does not need to be treated separately and can be directly used in the next batch of reactions. The distillation residue is dissolved in an extraction solvent, and after the conventional water washing, acid washing, and neutralization steps, the extraction solvent is recovered by distillation, and then the product is directly distilled under high vacuum to obtain 2-trifluoromethyl-4-heptafluoroisopropylaniline with high content and high yield.

[0021] In the extraction step of the post-treatment, the extraction solvent is not particularly limited and is generally a conventional solvent that is not soluble in water, such as one or a mixture of more than one of toluene, ethylbenzene, xylene, cyclohexane, methylcyclohexane, petroleum ether, n-hexane, n-heptane, ethyl acetate, n-butyl acetate, isobutyl acetate, dichloromethane, and dichloroethane. The amount is 2-20 times, preferably 5-10 times, the weight of 2-trifluoromethylaniline, and the operation temperature is generally 20-100℃, preferably 20-30℃. The post-treatment operation is a basic operation technique mastered by those skilled in the art, and will not be described here.

[0022] Under the preferred reaction conditions, the conversion content of the present preparation method is more than 96% in one reaction, and the post-treatment steps of the obtained product are simple, only ordinary distillation operation is needed 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, thus being easy to industrialize and having a high application prospect.

[0023] In the present application, the distillation, vacuum distillation, filtration, extraction, layering and other operations involved in the preparation method operation are conventional operations, the basic unit operations of general chemists, which will not be described in detail here, see the synthesis examples.

[0024] Compared with the prior art, the preparation method of the present application has simple operation, mild chemical reaction conditions, fewer post-processing steps, no need for rectification, and a total yield of more than 93% under the preferred reaction conditions, and the final product content is more than 98%, which is low in cost, easy to produce in industry, and has a high application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 HPLC spectrum of Example 8;

[0026] Figure 2 HPLC spectrum of Example 9;

[0027] Figure 3 HPLC spectrum of Example 12;

[0028] Figure 4 HPLC spectrum of Example 14;

[0029] Figure 5 HPLC spectrum of Example 17. DETAILED DESCRIPTION

[0030] The technical solutions of the present application will be further illustrated by specific embodiments, and those skilled in the art should understand that the embodiments are only to help understand the present application and should not be regarded as specific limitations of the present application.

[0031] The raw materials described in the synthesis examples of the present application are generally purchased from the market, usually with an industrial specification or a reagent grade specification, unless otherwise specified; sodium hydrosulfite, also known as safety powder, has a content specification of ≥85%, phosphoric acid has a content specification of ≥85%, metaphosphoric acid has a specification of ≥99%, phosphorous acid has a specification of ≥99%, and pyrophosphoric acid has a content specification of ≥99% (content of phosphoric acid is 110%), which are not accurately corrected.

[0032] The percentage concentration described in the synthesis examples generally refers to the weight percentage concentration, unless otherwise specified, and the HPLC content data, if not specified, generally refers to the area normalization content, which is not accurately corrected. The content data of the present application is the corrected area normalization content, which is accurately corrected by standard sample weighing. The yield refers to the molar yield, which is generally calculated based on the raw material 2-trifluoromethylaniline, and the yield data is not accurately corrected.

[0033] Synthesis Example 1

[0034] In a 500ml four-necked glass reaction flask, put in N,N-dimethylformamide 200g, 2-trifluoromethyl aniline 39.5g (0.24 mole), add sodium hydrosulfite 49.2g (0.24 mole), drop in catalyst phosphoric acid 1.38g (0.012 mole), install a condenser with a temperature of -10°C or so, control the reaction temperature at 55-65°C, pass in 2-bromoheptafluoropropane 73.6g (0.29 mole) for 5 hours, after the reaction, keep the temperature at 55-65°C for 2 hours, cool down, filter out the inorganic salt, distill off the solvent from the filtrate under reduced pressure, take a sample from the residue for HPLC analysis, and correct the area to 96.4% content, add toluene 400ml and water 50ml to the residue, stir at room temperature to dissolve, separate the acidic water layer, wash the solvent layer with 10% hydrochloric acid 50ml, separate the layers, adjust the pH to near neutral with a small amount of 5% sodium bicarbonate, separate the water layer, dry with anhydrous MgSO4, filter, and obtain a toluene solution of 2-trifluoromethyl-4-heptafluoroisopropylaniline, distill off the solvent under reduced pressure, and distill off 2-trifluoromethyl-4-heptafluoroisopropylaniline under high vacuum to obtain the finished product 75g, HPLC content greater than 98%, GC content greater than 98%. The molar yield is 93.1% based on the raw material 2-trifluoromethyl aniline.

[0035] NMR data are as follows:

[0036] 1 H-NMR (400MHz, CDC13) δ (ppm): 4.50 (2H, br s), 6.84 (1H, d, J = 8.2 Hz), 7.50 (1H, d, J = 8.2 Hz), 7.66 (1H, br s,).

[0037] Synthesis Example 2

[0038] According to the operation of Synthesis Example 1, except that N,N-dimethylformamide 200g is replaced with 200g acetonitrile, and other operations are the same. After work-up, distill off 2-trifluoromethyl-4-heptafluoroisopropylaniline under high vacuum to obtain the finished product 76g, HPLC content greater than 98%, GC content greater than 98%. The molar yield is 94.4% based on 2-trifluoromethyl aniline.

[0039] Synthesis Example 3

[0040] In a 500ml pressure vessel, put in acetonitrile 200g, 2-trifluoromethyl aniline 39.5g (0.24 mole), add sodium dithionite 49.2g (0.24 mole), add catalyst phosphoric acid 1.38g (0.012 mole), pass in 2-bromoheptafluoropropane 73.6g (0.29 mole) in 10 minutes at room temperature, seal the reaction vessel, control the reaction temperature at 55-65°C, keep the temperature at 55-65°C for 6-8 hours, cool down, filter off the inorganic salt, distill off the solvent from the filtrate, get the residue, take a sample for HPLC analysis, correct the area to unity, the content is 96.1%, add methylcyclohexane 400ml and water 50ml to the residue, stir at room temperature, dissolve, separate the acidic water layer, wash the solvent layer with 10% hydrochloric acid 50ml, separate the layer, adjust the pH value to near neutral with a small amount of 5% sodium bicarbonate, separate the water layer, dry with anhydrous MgSO4, filter, get the methylcyclohexane solution containing 2-trifluoromethyl-4-heptafluoroisopropyl aniline, distill off the solvent under reduced pressure, distill off 2-trifluoromethyl-4-heptafluoroisopropyl aniline under high vacuum to get the finished product 76.5g, HPLC content is greater than 98%, GC content is greater than 98%.

[0041] The molar yield is 94.8% based on the raw material 2-trifluoromethyl aniline.

[0042] Synthesis Example 4

[0043] According to the operation of synthesis example 3, pass in 2-bromoheptafluoropropane 61g (0.24 mole), and other operations are the same. After the reaction, filter and distill the residue after distillation, take a sample for HPLC analysis, correct the area to unity, the content is 92.1%, after the same treatment, distill off 2-trifluoromethyl-4-heptafluoroisopropyl aniline under high vacuum to get the finished product 73.3g, HPLC content is greater than 98%, GC content is greater than 98%. The molar yield is 90.9% based on the raw material 2-trifluoromethyl aniline.

[0044] Synthesis Examples 5-6-7

[0045] According to the operation of synthesis example 3, replace the catalyst phosphoric acid 1.38g (0.012 mole) with phosphorous acid 0.8g (0.012 mole), phosphorous acid 1.6g (0.024 mole) and pyrophosphoric acid 1.07g (0.06 mole) respectively, and other operations are the same, the yield and content data results are similar.

[0046] Synthesis Comparative Examples 8-18 Different catalysts reaction conversion content comparison

[0047] According to the operation of the synthesis example 1, wherein N, N-dimethylformamide 200 g is replaced by 200 g of acetonitrile, wherein the catalyst phosphoric acid 1.38 g (0.012 mole) is replaced by equimolar amount 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, no catalyst, etc. respectively. The amount of 2-bromoheptafluoropropane is 58.5 g (0.24 mole), and other operations are exactly the same. After the reaction is completed, filtration is performed, the filtrate is detected by HPLC, the corrected normalized content of the peaks of the raw material 2-trifluoromethylaniline and the product 2-trifluoromethyl-4-heptafluoroisopropylaniline is detected, the conversion content after the reaction is reflected, and the specific data comparison is as follows:

[0048]

[0049] The data result comparison shows that under the catalyst and process conditions of the present application, especially the phosphoric acid and the phosphoric acid derivative catalyst, the reaction activity is relatively high, the conversion content of one reaction is greatly improved under the same conditions, the use amount of 2-bromoheptafluoropropane is reduced, the reaction utilization rate of the raw material is improved, the yield is improved, and the process is simplified, which is possible.

[0050] The present application illustrates the preparation method of high content 2-trifluoromethyl-4-heptafluoroisopropylaniline through the above representative examples, but the present application is not limited to the above examples, and it does not mean that the present application must depend on the above examples to be realized. It should be understood by those skilled in the art that any improvement of the present application, equivalent replacement of each raw material of the process of the present application and addition of auxiliary ingredients, selection of specific modes, etc. fall within the protection scope and disclosure scope of the present application.

Claims

1. A process for the preparation of high content 2-trifluoromethyl-4- heptafluoroisopropylphenylamine, characterized in that In the presence of sodium hydrosulfite, solvent and catalyst, the starting material 2-trifluoromethyl aniline and 2-bromoheptafluoropropane are reacted and post-treated to obtain high content 2-trifluoromethyl-4-heptafluoroisopropyl aniline; 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, metaphosphoric acid, phosphorous acid or a mixture thereof.

2. Process for the preparation of high content 2-trifluoromethyl-4- heptafluoroisopropylphenylamine according to claim 1, characterized in that The molar amount of the catalyst is 1-20% of 2-trifluoromethyl aniline.

3. Process for the preparation of high content 2-trifluoromethyl-4- heptafluoroisopropylphenylamine according to claim 1, characterized in that The concentration of the phosphoric acid, metaphosphoric acid, phosphorous acid is 20-100%.

4. The process for the preparation of high content 2-trifluoromethyl-4- heptafluoroisopropylphenylamine according to claim 1, characterized in that The concentration of the phosphoric acid, metaphosphoric acid, phosphorous acid is 100%.

5. The process for the preparation of high content 2-trifluoromethyl-4- heptafluoroisopropylphenylamine according to claim 1, characterized in that The molar amount of the 2-bromoheptafluoropropane starting material is 100-200% of 2-trifluoromethyl aniline.

6. The process for the preparation of high content 2-trifluoromethyl-4- heptafluoroisopropylphenylamine according to claim 1, characterized in that The molar amount of sodium hydrosulfite is 50-150% of 2-trifluoromethyl aniline.

7. The process for the preparation of high content 2-trifluoromethyl-4- heptafluoroisopropylphenylamine according to claim 1, characterized in that The reaction temperature is 20-150°C.

8. The process for the preparation of high content 2-trifluoromethyl-4- heptafluoroisopropylphenylamine according to claim 1, characterized in that The weight ratio of the solvent to 2-trifluoromethyl aniline is 5-10:1.

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