A heptafluoroisopropyl-containing bisamide compound and its intermediate compound, and its preparation method and use

Abstract

The present invention provides a method for preparing an intermediate compound for preparing a heptafluoroisopropyl-containing bisamide compound, and a method for preparing the heptafluoroisopropyl-containing bisamide compound, wherein the method flow is shown in formula (3). The heptafluoroisopropyl-containing bisamide compound obtained by the present invention has excellent insecticidal activity, and the chemical reaction conditions are mild, environmentally friendly, high in total yield, high in final product content, low in cost, easy to produce industrially, and has high application prospects.

Description

[0001] The present invention claims two domestic priorities, namely, the invention patent application with the priority date of December 22, 2021 and the priority number of CN2021115835066, entitled "A bisamide compound containing heptafluoroisopropyl group, preparation method and application thereof" and the invention patent application with the priority date of October 24, 2022 and the priority number of CN

[0002] 2022113037189, invention patent application entitled "A bisamide compound containing heptafluoroisopropyl and its intermediate compound, preparation method and use thereof". [Technical field]

[0003] The invention belongs to the field of insecticides and relates to a heptafluoroisopropyl-containing bisamide compound and an intermediate compound thereof, a preparation method thereof, an X-ray powder diffraction characteristic of a crystal of the heptafluoroisopropyl-containing bisamide compound, and uses thereof.

Technical Background

[0004] Due to the frequent and extensive use of pesticides, serious resistance problems have been caused in most parts of the world. The dosage must be increased to achieve the original effect. Some diseases are no longer treatable, which will inevitably cause certain problems for agricultural production, environment, and ecology. It is necessary to introduce new pesticides with better activity, lower dosage, and more environmental friendliness. Domestic and foreign research institutions and enterprises continue to increase their investment in pesticide creation, and a number of new pesticides with high activity, low dosage, and environmental friendliness have emerged.

[0005] Broflanilide (structural formula: 01), a diamide insecticide jointly developed by Mitsui Chemicals and BASF, has been commercialized. Its Chinese name is brofenac, which is mainly used for fruits, vegetables, beans, cotton, corn, grains, flowers and non-crop purposes to control lepidoptera, coleoptera, termites, ants, cockroaches, flies and other pests. It has very good effects. For details, see Chinese patent CN102119173B, amide derivatives, pest control agents containing the amide derivatives and methods of use thereof. However, many domestic companies and research institutions have optimized and improved the structure on this basis and discovered a series of new insecticides with higher activity, lower dosage and more environmentally friendly. Chinese patent CN 109497062B discloses a diamide compound and its preparation method and application, with a representative structure of cyclopentadienil (structural formula: 02). We have discovered a diamide compound containing a heptafluoroisopropyl group, with a general structural formula (II) having high insecticidal activity, with a representative structure (structural formula: 03). This provides more drug selection and drug use options in crop production such as agriculture and horticulture.

[0006]

[0007] Among them, R 1 The substituents are independently selected from H, fluorine, trifluoromethyl, cyano or nitro;

[0008] R 2 The substituents are independently selected from 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 2-n-propoxyethyl, 2-isopropoxyethyl, 2-n-butoxyethyl, cyclopropylmethyl, methyl or ethyl.

[0009] However, the preparation process of related compounds has the disadvantages of complex routes, harsh chemical reaction conditions, poor selectivity, environmental unfriendliness, low total yield, difficult purification or high process cost, which is not conducive to industrial production and large-scale application. For details, please refer to relevant literature or patents, such as: Liu Aiping, et al. Synthesis and biological activity of broflanilide, Journal of Fine Chemical Intermediates, December 2020, Vol. 50, No. 6, pp. 16-20. [Summary of the invention]

[0010] In view of the deficiencies in the prior art, the present invention aims to provide a heptafluoroisopropyl-containing bisamide compound and a preparation method thereof, which has simple operation of the preparation process, mild chemical reaction conditions, environmental friendliness, high total yield, high final product content, low cost, and easy industrial production, through the optimization design of the preparation process and the optimization and improvement of the reaction conditions. It also relates to an intermediate compound for preparing the heptafluoroisopropyl-containing bisamide compound and a preparation method thereof.

[0011] To achieve this object, the present invention provides a method for preparing an intermediate compound for preparing a heptafluoroisopropyl-containing bisamide compound, wherein the intermediate is represented by the following general formula (I):

[0012]

[0013] Among them, R 1 The substituents are independently selected from H, fluorine, trifluoromethyl, cyano or nitro;

[0014] R 2 The substituents are independently selected from 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 2-n-propoxyethyl, 2-isopropoxyethyl, 2-n-butoxyethyl, cyclopropylmethyl, methyl or ethyl.

[0015] It is characterized in that the process flow of the preparation method of the intermediate compound of the structure represented by the general formula (I) is as follows:

[0016]

[0017] Among them, R 3 is a C1-C5 alkyl group;

[0018] The N-alkylation reaction solvent in formula (1) or formula (2) is selected from the group consisting of: N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dichloroethane, cyclohexane, methylcyclohexane, toluene, ethylbenzene, and one or more mixtures of xylene;

[0019] The N-alkylation reaction base in formula (1) or formula (2) is selected from: potassium carbonate, sodium carbonate, sodium hydride;

[0020] The N-alkylated bromoalkane in formula (1) or (2) is selected from the group consisting of 2-methoxybromoethane, 2-ethoxybromoethane, 3-methoxybromopropane, 3-ethoxybromopropane, 2-n-propoxybromoethane, 2-isopropoxybromoethane, 2-n-butoxybromoethane, bromomethylcyclopropane, methyl bromide and ethyl bromide;

[0021] The N-alkylation reaction catalyst in formula (1) or formula (2) is selected from the group consisting of hexadecyltrimethylammonium chloride, benzyltriethylammonium chloride, polyethylene glycol 400-800, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, 15-crown-5-ether, 18-crown-6-ether or a mixture of one or more of 4-dimethylaminopyridine (DMAP);

[0022] The amidation reaction solvent in formula (2) is selected from: one or more mixtures of N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, ethyl acetate, dichloromethane, dichloroethane, cyclohexane, methylcyclohexane, toluene, ethylbenzene and xylene.

[0023] For the preparation method of the above intermediate compound, in order to achieve this purpose, the present invention adopts the following technical scheme.

[0024] First, 2-fluoro-3-nitrobenzoic acid raw material and corresponding alcohols are used to carry out esterification reaction in the presence of a catalyst to obtain the corresponding 2-fluoro-3-nitrobenzoate. The reaction formula is as follows:

[0025]

[0026] Among them, R 3 It is a C1-C5 alkyl group, preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, and particularly preferably a methyl group or an ethyl group, and is prepared by an esterification reaction of the corresponding alcohols.

[0027] The catalyst for the esterification reaction is concentrated sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid. Concentrated sulfuric acid is preferred, with a preferred mass concentration of 80-100%, and an amount of 0.5%-20% of the weight of the 2-fluoro-3-nitrobenzoic acid raw material, preferably 1-5%. Alcohols are generally selected from C1-C5 alcohols, preferably methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and particularly preferably methanol or ethanol; the amount is 2-10 times the weight of the 2-fluoro-3-nitrobenzoic acid raw material, preferably 3-5 times; the reaction temperature is generally 50-200°C, preferably the boiling point reflux reaction temperature of the corresponding alcohol; the reaction time is generally 5-48 hours, preferably 5-24 hours.

[0028] Among them, 2-fluoro-3-nitrobenzoic acid is an important intermediate for medicine and pesticides. There are many synthetic routes. It can generally be obtained through market purchase or synthesis. The content is generally more than 95% of industrial grade. If there is no special explanation in the present invention, it generally refers to being obtained through market purchase. Those skilled in the art can also achieve it through the following classic synthetic reaction route:

[0029]

[0030] Then, the obtained 2-fluoro-3-nitrobenzoate is subjected to a hydrogenation reduction reaction in a solvent in the presence of palladium carbon or Raney nickel catalyst to reduce the nitro group to the corresponding amino group to obtain the corresponding 2-fluoro-3-aminobenzoate. The reaction formula is as follows:

[0031]

[0032] Among them, the reaction solvent generally uses alcohols, such as methanol, ethanol, n-propanol, isopropanol, tert-butanol; ethers, such as tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, etc., preferably alcohols, such as methanol, ethanol, isopropanol, tert-butanol. The amount of solvent used is 2-20 times the weight of 2-fluoro-3-nitrobenzoate, preferably 2-10 times. The catalyst generally uses a mass concentration of

[0033] 1-5% palladium carbon or Raney nickel, preferably 5% palladium carbon catalyst, the catalyst is used in an amount of 0.1%-10% by weight of 2-fluoro-3-nitrobenzoate on a dry basis, preferably 1%-5%, and can be recycled 5-10 times for economic considerations. Hydrogen is more than 99% of industrial grade, the reaction pressure is 0-2Mpa, preferably 0-0.5Mpa, and particularly preferably close to normal pressure reaction.

[0034] The reaction temperature is 0-100° C., preferably 5-50° C. The reaction time is generally 2-24 hours until the catalyst stops absorbing hydrogen.

[0035] Next, the obtained 2-fluoro-3-aminobenzoic acid ester (or can be directly purchased from the market) is reacted with a series of benzoyl chlorides in the presence of a solvent to obtain an amide intermediate. The reaction formula is as follows:

[0036]

[0037] Among them, R 1 The substituents are independently selected from H, fluorine, trifluoromethyl, cyano or nitro; R 3 Same definition as above.

[0038] Here, the benzoyl chloride series raw materials used in the amidation reaction are generally prepared by chlorinating the corresponding benzoic acid series raw materials and thionyl chloride in an inert solvent followed by desolventizing, and the amount used is generally 1.0-1.2 times the molar amount of 2-fluoro-3-aminobenzoate, preferably 1.0-1.05 times.

[0039] The acidifying agent commonly used in the amidation reaction is triethylamine, pyridine, N,N-diisopropylethylamine, N,N-dimethylaniline, tetramethylethylenediamine, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium methoxide, sodium tert-butoxide or potassium tert-butoxide, etc., preferably triethylamine or pyridine, the molar amount is 0.1-5.0 times of the benzoyl chloride series raw material, and the preferred economic amount is 0.1-2.0 times; the solvent used in the amidation reaction is dichloromethane, chloroform, dichloroethane, tetrahydrofuran, dioxane, dimethyl sulfoxide, acetonitrile, toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone or 1,3-dimethyl-2-imidazolidinone, etc., preferably the solvent is dichloroethane, toluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide or 1,3-dimethyl-2-imidazolidinone, etc., the dosage is 1-20 times the weight of the benzoyl chloride series raw materials, and the preferred economic dosage is 2-5 times; the amidation reaction temperature is generally -5-150°C, and the preferred reaction temperature is 0-130°C; the reaction time is generally 1-5 hours, preferably 1-2 hours.

[0040] The obtained product can be used to implement the preparation method of the intermediate compound of the present invention, and the process flow of the method is as follows:

[0041] As shown:

[0042]

[0043] Among them, R 3 An alkyl group selected from C1-C5;

[0044] The solvent in the N-alkylation reaction is selected from: one or more mixtures of N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dichloroethane, cyclohexane, methylcyclohexane, toluene, ethylbenzene, and xylene; the preferred solvent is: one or more mixtures of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, cyclohexane, methylcyclohexane, and toluene, and the amount used is 2-10 times the weight of the amide or 2-fluoro-3-aminobenzoic acid ester raw material, preferably 2-5 times.

[0045] The base in the N-alkylation reaction is selected from potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, preferably potassium carbonate, sodium carbonate, sodium hydride, and the amount used is 1-3 times the molar amount of the amide or 2-fluoro-3-aminobenzoate raw material, preferably 1-2 times.

[0046] The bromoalkane in the N-alkylation reaction is selected from: 2-methoxybromoethane, 2-ethoxybromoethane, 3-methoxypropane bromide, 3-ethoxypropane bromide, 2-n-propoxybromoethane, 2-isopropoxybromoethane, 2-n-butoxybromoethane, bromomethylcyclopropane, methyl bromide or ethyl bromide; it can usually be obtained from the market or synthesized. The present invention does not specifically specify that it generally refers to obtaining from the market. The dosage is 1-3 times the molar amount of the amide or 2-fluoro-3-aminobenzoate raw material, preferably 1-2 times. The present invention uses bromoalkane and avoids the use of iodoalkane. This is because iodoalkane has high activity, but it causes high industrialization cost and is not conducive to industrialization. Bromoalkane is usually less active, poor selectivity, and low yield. It is necessary to have a catalyst in the presence of and optimize the process conditions to achieve a better effect.

[0047] The catalyst in the N-alkylation reaction is selected from one or more mixtures of hexadecyltrimethylammonium chloride, benzyltriethylammonium chloride, polyethylene glycol 400-800, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, 15-crown-5-ether, 18-crown-6-ether or 4-dimethylaminopyridine (DMAP). In addition, the catalyst may also be an iodide salt, such as potassium iodide, sodium iodide, etc., but the catalytic effect is not as good as that of a phase transfer catalyst or 4-dimethylaminopyridine (DMAP). Preferably, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, 18-crown-6-ether or 4-dimethylaminopyridine (DMAP) is used. The amount of the catalyst is 1-10% of the weight of the amide or 2-fluoro-3-aminobenzoic acid ester raw material, preferably 1-5%. The use of the catalyst in the present invention can reduce the reaction temperature, improve the reaction selectivity and the product yield.

[0048] The present invention also provides another method for preparing the above intermediate compound, the process of which is shown in formula (2):

[0049]

[0050] Similar to the first preparation method, R 3 An alkyl group selected from C1-C5;

[0051] The solvent in the N-alkylation reaction is selected from: one or more mixtures of N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dichloroethane, cyclohexane, methylcyclohexane, toluene, ethylbenzene, and xylene; the preferred solvent is: one or more mixtures of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, cyclohexane, methylcyclohexane, and toluene, and the amount used is 2-10 times the weight of the amide or 2-fluoro-3-aminobenzoic acid ester raw material, preferably 2-5 times.

[0052] The base in the N-alkylation reaction is selected from potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, preferably potassium carbonate, sodium carbonate or sodium hydride, and the amount used is 1-3 times the molar amount of the amide or 2-fluoro-3-aminobenzoate raw material, preferably 1-2 times.

[0053] The bromoalkane in the N-alkylation reaction is selected from: 2-methoxybromoethane, 2-ethoxybromoethane, 3-methoxypropane bromide, 3-ethoxypropane bromide, 2-n-propoxybromoethane, 2-isopropoxybromoethane, 2-n-butoxybromoethane, bromomethylcyclopropane, methyl bromide or ethyl bromide; it can usually be obtained from the market or synthesized. The present invention does not specifically specify that it generally refers to obtaining from the market. The dosage is 1-3 times the molar amount of the amide or 2-fluoro-3-aminobenzoate raw material, preferably 1-2 times. The present invention uses bromoalkane and avoids the use of iodoalkane. This is because iodoalkane has high activity, but it causes high industrialization cost and is not conducive to industrialization. Bromoalkane is usually less active, poor selectivity, and low yield. It is necessary to have a catalyst in the presence of and optimize the process conditions to achieve a better effect.

[0054] The catalyst in the N-alkylation reaction is selected from one or more mixtures of hexadecyltrimethylammonium chloride, benzyltriethylammonium chloride, polyethylene glycol 400-800, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, 15-crown-5-ether, 18-crown-6-ether or 4-dimethylaminopyridine (DMAP). In addition, the catalyst may also be an iodide salt, such as potassium iodide, sodium iodide, etc., but the catalytic effect is not as good as that of a phase transfer catalyst or 4-dimethylaminopyridine (DMAP). Preferably, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, 15-crown-5-ether, 18-crown-6-ether or 4-dimethylaminopyridine (DMAP) is used. The amount of the catalyst is 1-10% of the weight of the amide or 2-fluoro-3-aminobenzoic acid ester raw material, preferably 1-5%. The use of the catalyst in the present invention can reduce the reaction temperature, improve the reaction selectivity and the product yield.

[0055] The amidation reaction solvent is selected from: one or more mixtures of N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, ethyl acetate, dichloromethane, dichloroethane, cyclohexane, methylcyclohexane, toluene, ethylbenzene, and xylene. The preferred solvent is: one or more mixtures of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, tetrahydrofuran, ethyl acetate, dichloromethane, dichloroethane, and toluene. The amount used is 2-10 times the weight of the benzoic acid series acyl chloride raw material, preferably 2-5 times.

[0056] Among them, the amidation reaction can be carried out by adding DMAP catalyst, the amount of which is 1-10% by weight of the benzoic acid series acyl chloride raw material, preferably 1-5%. When no catalyst is added, the reaction yield and reaction time under the process conditions of the present invention are acceptable, so the present invention does not necessarily have to use it; in the preparation method of the intermediate compound of the present invention, the amidation reaction does not need to use an acidifying agent, and under the process conditions of the present invention, the conversion yield and reaction time are acceptable. Among them, the amidation reaction temperature is 0-200°C, preferably 0-150°C

[0057] In the preparation methods of the above two intermediate compounds, the hydrolysis reaction conditions are generally normal conditions, generally using alcohol solvents such as methanol, ethanol, isopropanol, etc., or ether solvents such as 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, etc., preferably methanol and ethanol, and the amount used is generally 2-10 times the weight of the corresponding ester, preferably 2-5 times; the base generally uses sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, preferably sodium hydroxide, and the concentration generally uses a mass concentration of 1-35%, and the molar amount is 1.1-3.0 times the corresponding ester. The reaction temperature is generally 5-50°C, and the preferred temperature is 20-30°C. The reaction time is generally 1-5 hours, preferably 1-2 hours.

[0058] In the preparation methods of the above two intermediate compounds, the N-alkylation reaction temperature is 50-200°C, preferably 50-150°C. When the solvent is an azeotropic solvent that can produce azeotropy with water, the reaction temperature is preferably the azeotropic temperature, and the water produced by the reaction can be removed by azeotropy, which can shorten the reaction time; the reaction pressure is generally normal pressure reaction. When the bromoalkane is methyl bromide or ethyl bromide, due to the low boiling point of the bromoalkane, to avoid volatilization, it is preferably a closed reaction with a pressure of 0-0.2MPa. The N-alkylation reaction time is usually 2-12 hours, preferably 2-8 hours.

[0059] Furthermore, the present invention also provides a heptafluoroisopropyl-containing bisamide compound, the structure of which is shown in general formula (II):

[0060]

[0061] Among them, R 1 The substituents are independently selected from H, fluorine, trifluoromethyl, cyano or nitro;

[0062] R 2 The substituents are independently selected from 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 2-n-propoxyethyl, 2-isopropoxyethyl, 2-n-butoxyethyl, cyclopropylmethyl, methyl or ethyl.

[0063] The present invention also provides a method for preparing the above-mentioned heptafluoroisopropyl-containing bisamide compound, and the process flow of the method is shown in formula (3):

[0064]

[0065]

[0066] The usual method of the acyl chloride reaction is that the raw material of the general formula (I) reacts with thionyl chloride in an inert solvent, and then undergoes a desolventizing treatment to enter the next step of the reaction. The solvent used in the acyl chloride reaction is dichloromethane, chloroform, dichloroethane, toluene or xylene, etc., preferably dichloroethane or toluene, etc.; the acyl chloride reaction temperature is generally 20-150°C, preferably 40-100°C; the acyl chloride reaction time is generally 1-5 hours, preferably 2-3 hours.

[0067] The solvent in the amidation reaction is selected from one or more mixtures of dichloromethane, dichloroethane, cyclohexane, methylcyclohexane, toluene, ethylbenzene, xylene, ethyl acetate, tetrahydrofuran or acetonitrile; preferably, the solvent is dichloroethane, cyclohexane, methylcyclohexane, toluene, ethyl acetate or acetonitrile, and the amount used is generally 2-10 times, preferably 3-8 times, of the weight of the raw material of the corresponding general formula (I). The amidation can also use a catalyst 4-dimethylaminopyridine (DMAP), which can shorten the reaction time, but under the preferred conditions of the present invention, the amidation does not require the use of a catalyst and a succinic acid agent, and the reaction yield and reaction time are acceptable, so the present invention does not necessarily have to use it. Another raw material of the amidation reaction, 4-heptafluoroisopropyl-2-trifluoromethylaniline, can be obtained by synthesis or market purchase. The synthesis method is prepared by alkylation reaction of o-trifluoromethylaniline raw material and 2-bromoheptafluoropropane or 2-iodoheptafluoropropane in the presence of hydrosulfur powder. The synthesis is detailed in the disclosure of Chinese invention patent CN 102119173B. The amount of the raw material 4-heptafluoroisopropyl-2-trifluoromethylaniline used is 1.0-1.3 times the molar amount of the raw material of the general formula (I), and the preferred amount is 1.0-1.05 times. The bromination reaction uses liquid bromine as a brominating agent, which is cheap, the raw material is easily available, and the byproduct bromide salt is easy to recycle. Compared with N-bromosuccinimide, the brominating agent has low cost and is environmentally friendly. The amount used is 1-2 times the molar amount of the raw material of the general formula (I), and the preferred amount is 1-1.5 times. The preferred method of use is dropwise reaction, and the dropwise reaction can also be carried out under ultraviolet light conditions. Preferably, the reaction can be carried out without light.

[0068] The bromination reaction can also be carried out to reduce the amount of bromine used. An oxidant is added shortly after the reaction so that the generated bromide salt is oxidized into elemental bromine and is used again in the bromination reaction. This can reduce the amount of bromine used, but it will lead to complex operation of the reaction system and related side reaction impurities, which is not necessarily required in the present invention.

[0069] The solvent in the bromination reaction is selected from one or more mixtures of dichloromethane, dichloroethane, methanol, ethanol, n-propanol, isopropanol, n-butanol, and tert-butanol, preferably one or more mixtures of dichloroethane, methanol, ethanol, isopropanol, and tert-butanol. The amount used is generally 2-10 times, preferably 3-8 times, the weight of the raw material corresponding to the general formula (I).

[0070] The base in the bromination reaction is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or any concentration of aqueous solution thereof, or any concentration of sodium methoxide methanol solution, sodium ethoxide ethanol solution, sodium isopropanol isopropanol solution, sodium tert-butoxide tert-butanol solution, preferably solid sodium hydroxide, potassium hydroxide, potassium carbonate; the amount used is generally 1-2 times the molar amount of the raw material of general formula (I), preferably 1-1.5 times. The bromination reaction temperature is 0-100°C, preferably 20-80°C.

[0071] In the present invention, preferably, R 1 The substituents are independently selected from H or fluorine; R 2 The substituents are independently selected from 2-methoxyethyl, 2-ethoxyethyl, 2-n-propoxyethyl, 2-isopropoxyethyl, 2-n-butoxyethyl, cyclopropylmethyl, methyl or ethyl; R 3 It is methyl.

[0072] The present invention also provides a bisamide compound crystal containing heptafluoroisopropyl, when R 1 H and R 2 is 2-methoxyethyl, and the crystalline x-ray powder diffraction has characteristic peaks at the following positions:

[0073] 2θ=3.521±0.2°, 7.041±0.2°, 8.238±0.2°, 10.260±0.2°, 10.578±0.2°, 12.142±0.2°, 12.941±0.2°, 13.601±0.2°, 14.922±0. 2°, 15.980±0.2°, 17.417±0.2°, 17.681±0.2°, 18.321±0.2°, 18.801±0.2°, 19.241±0.2°, 19.721±0.2°, 20.420±0.2°, 20.658 ±0.2°, 21.218±0.2°, 22.541±0.2°, 23.379±0.2°, 24.478±0.2°, 24.898±0.2°, 26.499±0.2°, 27.420±0.2°, 28.239±0.2°, 29.461±0.2°, 30.040±0.2°, 30.839±0.2°, 32.119±0.2°, 32.318±0.2°, 33.419±0.2°, 33.741±0.2°, 35.561±0.2°, 37.720±0.2°.

[0074] When R 1 is fluorine and R2 is 2-methoxyethyl, and the crystalline x-ray powder diffraction has characteristic peaks at the following positions:

[0075] 2θ=7.376±0.2°, 9.897±0.2°, 10.940±0.2°, 12.015±0.2°, 12.303±0.2°, 14.398±0.2°, 14.578±0.2°, 15.561±0.2°, 15.839±0.2°, 17 .163±0.2°, 18.257±0.2°, 18.463±0.2°, 18.737±0.2°, 18.922±0.2°, 19.219±0.2°, 19.518±0.2°, 19.823±0.2°, 20.137±0.2°, 20.37 9±0.2°, 20.600±0.2°, 20.861±0.2°, 21.023±0.2°, 21.722±0.2°, 22.021±0.2°, 22.218±0.2°, 22.818±0.2°, 23.999±0.2°, 24.738±0.2°, 25.077±0.2°, 25.481±0.2°, 25.860±0.2°, 27.161±0.2°, 27.682±0.2°, 29.058±0.2°, 29.323±0.2°, 29.760±0.2°, 29.940±0.2°.

[0076] When R 1 is fluorine and R 2 It is 2-ethoxyethyl, and the crystalline x-ray powder diffraction has characteristic peaks at the following positions:

[0077] 2θ=7.318±0.2°, 9.697±0.2°, 10.940±0.2°, 11.981±0.2°, 12.136±0.2°, 14.14 2±0.2°, 14.461±0.2°, 15.240±0.2°, 15.561±0.2°, 16.304±0.2°, 17.161±0.2° , 17.979±0.2°, 18.562±0.2°, 19.138±0.2°, 19.698±0.2°, 20.039±0.2°, 20.220±0.2°, 20.442±0.2°, 20.784±0.2°, 20.998±0.2°, 21.819±0.2°, 22.039±0.2° , 22.401±0.2°, 23.400±0.2°, 23.882±0.2°, 24.383±0.2°, 24.579±0.2°, 25.001±0.2°, 25.160±0.2°, 25.459±0.2°, 26.780±0.2°, 26.920±0.2°, 27.199±0.2° , 27.378±0.2°, 28.742±0.2°, 29.319±0.2°, 29.998±0.2°, 31.339±0.2°, 31.939±0.2°, 32.140±0.2°, 32.522±0.2°, 33.479±0.2°, 36.400±0.2°, 43.039±0.2°.

[0078] In the present invention, the crystals are obtained by crystallization with a crystallization solvent, and the solvent is selected from one or more mixtures of methanol, ethanol, isopropanol, tetrahydrofuran, isopropyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, and methyl tert-butyl ether.

[0079] The heptafluoroisopropyl-containing bisamide compounds obtained by the invention have excellent insecticidal activity, and the chemical reaction conditions are mild, environmentally friendly, high in total yield, high in final product content, low in cost, easy in industrial production, and have high application prospects.

[0080] In the present invention, operations such as distillation, reduced pressure distillation, filtration, drying, extraction, stratification, crystallization, and recrystallization involved in the preparation method are conventional operations and will not be described in detail again.

Brief Description of the Drawings

[0081] Figure 1 The X-ray powder crystal diffraction analysis results of the compound sample of Synthesis Example 17;

[0082] Figure 2 The X-ray powder crystal diffraction analysis results of the compound sample of Synthesis Example 18;

[0083] Figure 3 This is the X-ray powder crystal diffraction analysis result of the compound sample of Synthesis Example 20. [Specific implementation method]

[0084] The following examples are used to explain the technical solutions of the present invention in a non-limiting manner and should not be regarded as specific limitations of the present invention.

[0085] The raw materials described in the synthesis examples of the present invention are generally purchased from the market unless otherwise specified, and the content specification is usually ≥95%, and the content is not accurately calibrated. The percentage concentration described in the synthesis examples generally refers to the weight percentage concentration unless otherwise specified. The HPLC content data is the area-normalized content and is not accurately calibrated. The yield refers to the molar yield, and the yield data is not accurately calibrated.

[0086] Synthesis Preparation Example 1

[0087] In a 250 ml four-necked glass reaction bottle, add 100 g of methanol, 50 g of 2-fluoro-3-nitrobenzoic acid, and 2.5 g of 98% sulfuric acid, heat and reflux for 24 hours, cool to about 0-5°C for crystallization, filter, and dry at 50°C to obtain 51 g of solid methyl 2-fluoro-3-nitrobenzoate with an HPLC content of 98% and a yield of 94.8%, which is used for synthesis reactions.

[0088] Synthesis Preparation Example 2

[0089] In a 250 ml four-necked glass reaction bottle, add 100 g of ethanol, 50 g of 2-fluoro-3-nitrobenzoic acid, and 2.5 g of 98% sulfuric acid, heat and reflux for 24 hours, cool to about 0-5°C for crystallization, filter, and dry at 50°C to obtain 54.5 g of solid 2-fluoro-3-nitrobenzoic acid ethyl ester with HPLC content of 98% and yield of 94.6%, which is used for synthesis reaction.

[0090] Synthesis Preparation Example 3

[0091] In a 500ml hydrogenation reactor, 250g of methanol and 2g of 5% palladium on carbon (water content 50%) were added, and 51g of solid methyl 2-fluoro-3-nitrobenzoate obtained in Synthesis Preparation Example 1 was added. The reactor was sealed, and the air was replaced with nitrogen. The nitrogen was replaced twice with hydrogen, and hydrogen was introduced at 5-15°C to maintain the pressure of 0-0.05MPa for 12 hours. HPLC detected that the reaction was complete, and the catalyst was taken out and filtered out (recyclable). The filtrate was decompressed and desolventized to obtain 43g of an oily liquid, which was methyl 2-fluoro-3-aminobenzoate with an HPLC content of 97% and a yield of 98.3%, which was used for the synthesis reaction.

[0092] Synthesis Preparation Example 4

[0093] In a 500ml hydrogenation reactor, 250g of methanol and 2g of 5% palladium on carbon (water content 50%) were added, and 54.5g of solid 2-fluoro-3-nitrobenzoic acid ethyl ester obtained in Synthesis Preparation Example 2 was added. The reactor was sealed, and the air was replaced by nitrogen. The nitrogen was replaced twice with hydrogen, and hydrogen was introduced at 5-15°C to maintain the pressure of 0-0.05MPa for 12 hours. HPLC detected that the reaction was complete, and the catalyst was taken out and filtered out (recyclable). The filtrate was decompressed and desolvated to obtain 46g of oily liquid, which was 2-fluoro-3-aminobenzoic acid ethyl ester. The HPLC normalized content was 96%, and the yield was 96.3%, which was used for the synthesis reaction.

[0094] Synthesis Preparation Example 5

[0095] Benzoic acid 25g (0.20mol), thionyl chloride 72g (0.60mol), heat and reflux for reaction for 2-5 hours, cool to room temperature, rotary evaporate the reaction solution, decompress and desolventize to 80°C to obtain benzoyl chloride oily liquid, cool to about 25°C, add new dichloroethane 25g to dissolve and set aside.

[0096] In another 250ml four-necked glass reaction bottle, 100g of dichloroethane, 35g (0.20mol) of methyl 3-amino-2-fluorobenzoate, and 24g (0.30mol) of pyridine were added, and the mixture was cooled to 5-25°C in an ice bath. The above benzoyl chloride reserve solution was added dropwise within 1 hour, and the mixture was reacted at 5-25°C for 1-2 hours. After the reaction was completed, 50ml of water was added, and the mixture was stirred for 0.5 hour. The solvent layer was separated and transferred to a 500ml rotary evaporator, and the solvent was removed under reduced pressure to 80°C to obtain 53g of methyl 2-fluoro-3-[(phenylcarbonyl)amino]benzoate as an off-white solid with a HPLC normalized content of 94% (yield 91.2%). The solid was used for standby use without further treatment and directly used in the synthesis reaction.

[0097] Synthesis Preparation Example 6

[0098] The similar operation was carried out according to Synthesis Preparation Example 5, wherein 35 g (0.20 mol) of methyl 3-amino-2-fluorobenzoate was replaced by 38 g (0.20 mol) of ethyl 3-amino-2-fluorobenzoate obtained in Synthesis Preparation Example 4, and the other ingredients remained unchanged, to obtain 55 g of off-white solid ethyl 2-fluoro-3-[(phenylcarbonyl)amino]benzoate with a HPLC normalized content of 94% (yield 90%) for standby use and used directly in the synthesis reaction without further treatment.

[0099] Synthesis Preparation Example 7

[0100] The synthesis preparation example 5 was followed except that 25 g (0.20 mol) of benzoic acid was replaced by 28 g (0.20 mol) of p-fluorobenzoic acid. Other operations were the same to obtain 56 g of off-white solid methyl 2-fluoro-3-[(4-fluorophenylcarbonyl)amino]benzoate with a HPLC normalized content of 94% (yield 90.2%) for standby use and used directly in the synthesis reaction without further treatment.

[0101] Synthesis Example 1

[0102] Synthesis of 2-fluoro-3-[(2-methoxyethyl)(phenylcarbonyl)amino]benzoic acid.

[0103] In a 250ml four-necked glass reaction bottle, add 200g of solvent N,N-dimethylformamide, 15g (0.10mol) of potassium carbonate, and then add 25g (0.086mol) of methyl 2-fluoro-3-[(phenylcarbonyl)amino]benzoate obtained in Synthesis Preparation Example 5 and 1g of catalyst tetrabutylammonium bromide. Heat to 55-65°C, drop 15.8g (0.11mol) of 1-bromo-2-methoxyethane within 1 hour, keep warm and react for about 2 hours, cool to room temperature, filter, The filtrate was decompressed and desolventized to obtain a residual material, 50 g of methanol and 60 g (0.15 mol) of 10% liquid caustic soda were added, the temperature was raised to 25-35°C, and the reaction was kept warm for about 2 hours. 150 g of water was added, and the pH was adjusted to 1-2 with 30% hydrochloric acid. Crystallization was carried out at about 10-25°C, and the mixture was filtered, washed with water, and dried to obtain 26.5 g of an off-white solid with a melting point of 155.8-157.9°C, a HPLC normalized content of about 95%, and a yield of 92.3%, which was 2-fluoro-3-[(2-methoxyethyl)(phenylcarbonyl)amino]benzoic acid. The reaction formula is as follows:

[0104]

[0105] Synthesis Example 2-4

[0106] According to the operation of Synthesis Example 1, 1 g of the catalyst tetrabutylammonium bromide was replaced by 1 g of tetrabutylammonium chloride, 1 g of tetrabutylammonium hydrogen sulfate, and 1 g of 18-crown-6-ether, respectively, and other materials and operations remained unchanged, and similar results were obtained.

[0107] Synthesis Example 5

[0108] In a 250 ml four-necked glass reaction bottle, 100 g of toluene solvent, 15 g (0.10 mol) of potassium carbonate, 25 g (0.086 mol) of methyl 2-fluoro-3-[(phenylcarbonyl)amino]benzoate obtained in Synthesis Preparation Example 5, 1 g of tetrabutylammonium bromide catalyst, 15.8 g (0.11 mol) of 1-bromo-2-methoxyethane were added, a reflux water separator was installed, the temperature was raised to reflux reaction, the reaction water was removed, and the reflux reaction was carried out for about 2 hours. Anhydrous is generated, the temperature is reduced to room temperature, filtered, and the filtrate is decompressed to obtain a residual material, 50 g of methanol and 60 g (0.15 mol) of 10% liquid alkali are added, the temperature is raised to 25-35°C, and the reaction is kept warm for about 2 hours, 150 g of water is added, and 30% hydrochloric acid is used to adjust the pH to 1-2, and crystallization is carried out at about 10-25°C. The solid is filtered, washed with water, and dried to obtain 27 g of an off-white solid with an HPLC normalized content of about 95% and a yield of 94%, which is 2-fluoro-3-[(2-methoxyethyl)(phenylcarbonyl)amino]benzoic acid.

[0109] Synthesis Example 6-7

[0110] According to the operation of Synthesis Example 5, 100 g of the solvent toluene was replaced by 100 g of methylcyclohexane and 100 g of xylene respectively, and other materials and operations remained unchanged, and similar results were obtained.

[0111] Synthesis Example 8

[0112] Synthesis of 2-fluoro-3-[(2-ethoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid.

[0113] In a 250ml four-necked glass reaction bottle, add 100g of dichloroethane solvent, 12.5g (0.088mol) of 4-fluorobenzoic acid, and 25g (0.20mol) of thionyl chloride. Heat and reflux for 2-5 hours. Desolventize under reduced pressure to obtain an oily liquid, 4-fluorobenzoyl chloride, for later use.

[0114] In another 250ml four-necked glass reaction bottle, add 200g of solvent N,N-dimethylformamide, protect with nitrogen, add 3.5g (0.091mol) of 60% sodium hydride as a base, then add 15g (0.086mol) of methyl 2-fluoro-3-aminobenzoate synthesized in Synthesis Preparation Example 3, 1g of catalyst tetrabutylammonium bromide, 16.8g (0.11mol) of 1-bromo-2-ethoxyethane, raise the temperature to 110-120°C, keep the reaction for about 8 hours, cool to room temperature, filter, desolventize the filtrate under reduced pressure, extract the residual material with 100ml of dichloroethane, wash with water (the product nuclear magnetic hydrogen spectrum and mass spectrum data are attached), dry the solvent layer with anhydrous magnesium sulfate and filter the filtrate to obtain 25-35 ℃, add the 4-fluorobenzoyl chloride synthesized above, heat to reflux reaction for 2-5 hours, reduce pressure and desolventize to obtain residual oily material (the product nuclear magnetic hydrogen spectrum and mass spectrum data are attached), add 50g methanol, 60g (0.15mol) of 10% liquid alkali, heat to 25-35 ℃, keep warm for about 2 hours, add 150g water, adjust the pH to 1-2 with 30% hydrochloric acid, crystallize at about 10-25 ℃, filter, wash with water, and dry to obtain 29.4g of beige solid, melting point: 77.3-79.2 ℃, HPLC normalized content is about 92%, yield 90.1%, which is 2-fluoro-3-[(2-ethoxyethyl)(phenylcarbonyl)amino]benzoic acid (the product nuclear magnetic hydrogen spectrum and mass spectrum data are attached). The reaction formula is as follows:

[0115]

[0116] The H-NMR spectra were measured using a Bruker AV-400 spectrometer (400 MHz), TMS was used as the internal standard, and the solvent was CDCl3 or DMSO-d6 (unless otherwise specified, the same below); the high-resolution mass spectra were measured using a UHR-TOF maXis (ESI) mass spectrometer (unless otherwise specified, the same below).

[0117] The H NMR and mass spectrometry data of methyl 2-fluoro-3-[(2-ethoxyethyl)amino]benzoate are as follows:

[0118] 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 7.10-6.90 (m, 3H, ArH), 5.49 (s, 1H, NH), 3.80 (s, 3H, CH3O), 3.50 (t, J=6.0Hz ,2H,OCH2),3.41(q,J=6.2Hz,2H,OCH2CH3),3.25(dd,J1=J2=6.0Hz,2H,NCH2),1.08(t,J=6.8Hz,3H,OCH2CH3).

[0119] HRMS(ESI)calcd.for C 12 H 16 FNNaO3[(M+Na)+]:264.1012; Found:264.0988.

[0120] The H NMR and mass spectrometry data of methyl 2-fluoro-3-(4-fluoro-N-(2-ethoxyethyl)benzamido)benzoate are as follows:

[0121] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):7.78-7.70(m,2H,ArH),7.48-7.20(m,3H,ArH),7.18-6.90(m,2H,ArH),4.10-3.80(m, 2H,OCH2),3.75(s,3H,CH3O),3.65-3.40(m,2H,NCH2),3.28(q,J=6.2Hz,2H,OCH2CH3),0.92(t,J=6.8Hz,3H,OCH2CH3).

[0122] HRMS(ESI)calcd.for C 19 H 19 F2NNaO4[(M+Na)+]:386.1180; Found:386.1173.

[0123] The H NMR and mass spectrometry data of 2-fluoro-3-[(2-ethoxyethyl)(phenylcarbonyl)amino]benzoic acid are as follows:

[0124] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.20(s,1H,COOH),7.75-7.60(m,2H,ArH),7.38-7.15(m,3H,ArH),7.12-6.90(m,2H, ArH), 4.10-3.82 (m, 2H, OCH2), 3.68-3.49 (m, 2H, NCH2), 3.30 (q, J = 6.2Hz, 2H, OCH2CH3), 0.94 (t, J = 6.8Hz, 3H, OCH2CH3).

[0125] HRMS(ESI)calcd.for C 18 H 17 F2NNaO4[(M+Na)+]:372.1023; Found:372.1024.

[0126] Synthesis Example 9

[0127] The operation of Synthesis Example 8 was followed, except that 1 g of 4-dimethylaminopyridine (DMAP) was added during the second step of amidation, and other materials and operations remained unchanged, and similar results were obtained.

[0128] Synthesis Example 10

[0129] Synthesis of 2-fluoro-3-[(2-methoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid.

[0130] In a 250ml four-necked glass reaction bottle, add 100g of solvent ethylene dichloride, 12.5g (0.088mol) of p-fluorobenzoic acid, and 25g (0.20mol) of thionyl chloride. Heat and reflux for 2-5 hours. Desolventize under reduced pressure to obtain an oily liquid, p-fluorobenzoyl chloride, for later use.

[0131] In another 250ml four-necked glass reaction bottle, add 100g of toluene solvent, 15g (0.10mol) of potassium carbonate, 15g (0.086mol) of methyl 2-fluoro-3-aminobenzoate synthesized in Synthesis Preparation Example 3, 1g of tetrabutylammonium bromide as catalyst, 15.8g (0.11mol) of 1-bromo-2-methoxyethane, raise the temperature to 100-120°C, reflux and dehydrate for about 5 hours, cool to room temperature, filter, wash with water, and desolventize to obtain the material (the product nuclear magnetic hydrogen spectrum and mass spectrum data are attached), add 100g of dichloroethane to dissolve, add the p-fluorobenzoyl chloride synthesized above at 25-35°C, and heat to reflux for 2-5 hours. Cool down and add 100 ml of water, separate and wash, desolventize under reduced pressure to obtain residual oily material (product NMR hydrogen spectrum, mass spectrum data attached), add 50 g of methanol, 60 g (0.15 mol) of 10% liquid alkali, raise the temperature to 25-35°C, keep warm for about 2 hours, add 150 g of water, adjust the pH to 1-2 with 30% hydrochloric acid, crystallize at about 10-25°C, filter, wash with water, and dry to obtain 28 g of beige solid, melting point: 120.5-122.5°C, HPLC normalized content of about 93%, yield 90.3%, 2-fluoro-3-[(2-methoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid (product NMR hydrogen spectrum, mass spectrum data attached). The reaction formula is as follows:

[0132]

[0133] The H NMR and mass spectrometry data of methyl 2-fluoro-3-[(2-methoxyethyl)amino]benzoate are as follows:

[0134] 1H-NMR (400MHz, CDCl3) δ (ppm): 7.00-6.91 (m, 3H, ArH), 5.50 (s, 1H, NH), 3.80 (s, 3H, OCH3), 4.45 (t, J = 3.9Hz, 2H, OCH2), 3.25-7.24 (m, 5H, NCH2 and OCH3).

[0135] HRMS(ESI)calcd.for C 11 H 14 FNNaO3[(M+Na)+]:250.0855; Found:250.0836.

[0136] The H NMR and mass spectrometry data of methyl 2-fluoro-3-(4-fluoro-N-(2-methoxyethyl)benzamido)benzoate are as follows:

[0137] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):7.74-7.71(m,2H,ArH),7.48-7.20(m,3H,ArH),7.18-6.80(m,2 H,ArH),4.20-3.80(m,2H,OCH2),3.79(s,3H,CH3O),3.62-3.40(m,2H,NCH2),3.13(s,3H,CH3O). HRMS(ESI)calcd.for C 18 H 17 F2NNaO4[(M+Na)+]:372.1023; Found:372.1024.

[0138] The H NMR and mass spectrometry data of 2-fluoro-3-[(2-methoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid are as follows:

[0139] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.32(s,1H,COOH),7.70-7.60(m,2H,ArH),7.38-7.20(m,3H,A rH),7.15-6.90(m,2H,ArH),4.15-3.82(m,2H,OCH2),3.53-3.40(m,2H,NCH2),3.14(s,3H,OCH3).

[0140] HRMS(ESI)calcd.for C 17 H 15 F2NNaO4[(M+Na)+]:358.0867; Found:358.0858.

[0141] Synthesis Example 11

[0142] Synthesis of 2-fluoro-3-[(methyl)(phenylcarbonyl)amino]benzoic acid.

[0143] In a 500 ml pressure reactor, 200 g of N,N-dimethylformamide solvent, 15 g (0.10 mol) of potassium carbonate, 25 g (0.086 mol) of methyl 2-fluoro-3-[(phenylcarbonyl)amino]benzoate obtained in Synthesis Preparation Example 5, 1 g of tetrabutylammonium bromide catalyst, 20 g (0.21 mol) of methyl bromide were introduced at room temperature, the reactor was sealed, the temperature was raised to 55-65°C, and the reaction was kept warm for about 2 hours. Cool to room temperature, filter, decompress the filtrate to obtain an oily liquid, add 50g methanol, 60g (0.15mol) of 10% liquid caustic soda, raise the temperature to 25-35°C, keep warm for about 2 hours, add 150g water, adjust the pH to 1-2 with 30% hydrochloric acid, crystallize at about 10-25°C, filter, wash with water, and dry to obtain 23g of off-white solid, HPLC normalized content of about 95%, yield 93%, which is 2-fluoro-3-[(methyl)(phenylcarbonyl)amino]benzoic acid. The reaction formula is as follows:

[0144]

[0145] Synthesis Example 12

[0146] According to the operation of Synthesis Example 11, 20 g (0.21 mol) of methyl bromide was replaced by 22 g (0.20 mol) of ethyl bromide, and the autoclave was added. Other operations were similar, and finally 24 g of off-white solid was obtained. The HPLC normalized content was about 95%, and the yield was 92.3%, which was 2-fluoro-3-[(ethyl)(phenylcarbonyl)amino]benzoic acid. The reaction formula is as follows:

[0147]

[0148] Synthesis Example 13

[0149] In a 250ml four-necked glass reaction bottle, 100g of toluene solvent, 15g (0.10mol) of potassium carbonate, 26.7g (0.086mol) of methyl 2-fluoro-3-[(4-fluorophenylcarbonyl)amino]benzoate synthesized in Synthesis Preparation Example 7, 1g of tetrabutylammonium bromide catalyst, 15.8g (0.11mol) of 1-bromo-2-methoxyethane were added, a reflux water separator was installed, the temperature was raised to reflux reaction, the reaction water was removed, the reflux reaction was carried out for about 2 hours, until no water was generated, and the temperature was lowered. To room temperature, filter, desolventize under reduced pressure to obtain residual material, add 50g methanol, 60g (0.15mol) of 10% liquid alkali, raise the temperature to 25-35°C, keep warm for about 2 hours, add 150g water, adjust the pH to 1-2 with 30% hydrochloric acid, crystallize at about 10-25°C, filter, wash with water, and dry to obtain 28.5g of beige solid, melting point: 122.5-123.4°C, HPLC normalized content of about 95%, yield 93.9%, 2-fluoro-3-[(2-methoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid. The reaction formula and the nuclear magnetic hydrogen spectrum and mass spectrum data of the product are as follows:

[0150]

[0151] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.32(s,1H,COOH),7.70-7.60(m,2H,ArH),7.38-7.20(m,3H,A rH),7.15-6.90(m,2H,ArH),4.15-3.82(m,2H,OCH2),3.53-3.40(m,2H,NCH2),3.14(s,3H,OCH3). HRMS(ESI)calcd.for C 17 H 15 F2NNaO4[(M+Na)+]:358.0867; Found:358.0858.

[0152] Synthesis Example 14

[0153] According to the synthesis example 13, 15.8 g (0.11 mol) of 1-bromo-2-methoxyethane was replaced by 16.5 g (0.12 mol) of bromomethylcyclopropane, and other operations were the same, and finally 28 g of off-white solid was obtained. The HPLC normalized content was about 95%, and the yield was 93.3%, which was 2-fluoro-3-[(cyclopropylmethyl)(4-fluorophenylcarbonyl)amino]benzoic acid.

[0154]

[0155] Synthesis Examples 15-16

[0156] The operations were performed according to Synthesis Example 1 and Synthesis Example 5, respectively, except that 25 g (0.086 mol) of methyl 2-fluoro-3-[(phenylcarbonyl)amino]benzoate material was replaced by 26.3 g (0.086 mol) of ethyl 2-fluoro-3-[(phenylcarbonyl)amino]benzoate obtained in Synthesis Preparation Example 6, and other operations were the same, and similar results were obtained.

[0157] Synthesis Comparative Example 1

[0158] According to Synthesis Example 1, except that 1 g of tetrabutylammonium bromide as catalyst was not added, other materials and operations were the same, and finally 24 g of off-white solid was obtained. The target product 2-fluoro-3-[(2-methoxyethyl)(phenylcarbonyl)amino]benzoic acid had an HPLC normalized content of about 55% and a yield of 48.3%. The rest was mainly 2-fluoro-3-[(phenylcarbonyl)amino]benzoic acid.

[0159] Synthesis Comparative Example 2

[0160] According to Synthesis Example 5, except that 1 g of tetrabutylammonium bromide as catalyst was not added and other materials and operations were the same, 21 g of off-white solid was obtained. The target product 2-fluoro-3-[(2-methoxyethyl)(phenylcarbonyl)amino]benzoic acid had a HPLC normalized content of about 5% and a yield of 3.8%. The rest was mainly 2-fluoro-3-[(phenylcarbonyl)amino]benzoic acid.

[0161] Synthesis Comparative Example 3

[0162] The operation of Synthesis Example 8 was followed, except that 1 g of the catalyst tetrabutylammonium bromide was not added, and other materials and operations were the same. Finally, an oily material with a normalized content of about 45% was obtained, but no solid crystals of the target product were obtained.

[0163] Synthesis Example 17

[0164] Synthesis of 2-fluoro-3-[(phenylcarbonyl)(2-methoxyethyl)amino]-N-[2-bromo-4-(1,1,1,2,3,3,3-heptafluoropropane-2-yl)-6-(trifluoromethyl)phenyl]benzamide.

[0165] In a 250ml four-necked glass reaction bottle, 200g of dichloroethane, 23.7g (0.071mol) of 2-fluoro-3-[(2-methoxyethyl)(phenylcarbonyl)amino]benzoic acid obtained in Synthesis Example 1, 24g (0.20mol) of thionyl chloride were added, and the mixture was heated to reflux for 3-5 hours, cooled to room temperature, and the reaction solution was transferred to a 500ml rotary evaporator, desolvated to 80°C under reduced pressure to obtain an acyl chloride oily liquid, cooled to about 25°C, 150g of acetonitrile was added to dissolve, and the mixture was transferred to a reaction bottle, and 27.8g (0.08mol) of 4-(1,1,1,2,3,3,3-heptafluoropropane-2-yl)-2-(trifluoromethyl)aniline raw material was added, and the mixture was heated to reflux for 5-10 hours.

[0166] Cool to room temperature, add 20g of powdered potassium carbonate, and drop 13.5g of liquid bromine at 25-45°C for about 2 hours to react, keep warm for 2 hours, filter, filter out inorganic salts, decompress the filtrate to obtain residual material, add 120g of ethanol, heat and reflux for 1 hour, cool and crystallize, crystallize at 0-5°C for 1 hour, filter and dry to obtain 42g of white crystalline powder solid, which is the target compound, melting point: 179.5-180.5°C, HPLC normalized content is about 98%, and the total yield of three steps is 81.9%. The reaction formula is as follows:

[0167]

[0168]

[0169] The H NMR spectrum and mass spectrum data are as follows:

[0170] The H-NMR spectrum was measured using a Bruker AV-400 spectrometer (400 MHz), TMS was used as the internal standard, and DMSO-d6 was used as the solvent (unless otherwise specified, the same below); the high-resolution mass spectrum was measured using a UHR-TOF maXis (ESI) mass spectrometer (unless otherwise specified, the same below).

[0171] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.57(s,1H,CONH),8.39(s,1H),7.92(s,1H),7.61 -7.51(m,3H),7.34-7.24(m,5H),4.32-3.70(m,2H),3.68-3.45(m,2H),3.19(s,3H).

[0172] HRMS(ESI)calcd.for C 27 H 18 F 11 N2NaO3[(M+Na) +]:729.0223[(M+Na) + ],731.0202[(M+2+Na) + ]; Found:729.0213[(M+Na) + ],731.0196[(M+2+Na) + ].

[0173] The target compound sample was analyzed by X-ray powder crystal diffraction using a Japanese Rigaku SmartLab diffractometer (the same below unless otherwise specified). The crystals had characteristic peaks at the following positions: 2θ = 3.521 ± 0.2°, 7.041 ± 0.2°, 8.238 ± 0.2°, 10.260 ± 0.2°, 10.578 ± 0.2°, 12.142 ± 0.2°, 12.941 ± 0.2°, 13.601 ± 0.2°, 14.922 ± 0.2°, 15.980 ± 0.2°, 17.417 ± 0.2°, 17.681 ± 0.2°, 18.321 ± 0.2°, 18.801 ± 0.2°, 19.241 ± 0.2 °, 19.721±0.2°, 20.420±0.2°, 20.658±0.2°, 21.218±0.2°, 22.541±0.2°, 23.379±0.2°, 24.478±0.2°, 24.898±0.2°, 26.499±0.2°, 27.420±0.2°, 28.239±0.2°, 29.461±0.2°, 30.040±0.2°, 30.839±0.2°, 32.119±0.2°, 32.318±0.2°, 33.419±0.2°, 33.741±0.2°, 35.561±0.2°, 37.720±0.2°, see the attached Figure 1 .

[0174] The sample obtained in this synthesis example was recrystallized with 3 times the weight of isopropyl ether. The X-ray powder crystal diffraction analysis of the finally obtained sample showed that the characteristic peaks of the crystals were exactly the same as above.

[0175] The sample obtained in this synthesis example was recrystallized with 3 times the weight of ethylene glycol monomethyl ether. The X-ray powder crystal diffraction analysis of the finally obtained sample showed that the characteristic peaks of the crystals were exactly the same as above.

[0176] The above results indicate that the crystals obtained by crystallizing the obtained compound in ethanol, isopropyl ether and ethylene glycol monomethyl ether solvents, respectively, have the same crystal type, are easy to obtain and have good stability.

[0177] Synthesis Example 18

[0178] Synthesis of 2-fluoro-3-[(4-fluorophenylcarbonyl)(2-methoxyethyl)amino]-N-[2-bromo-4-(1,1,1,2,3,3,3-heptafluoropropane-2-yl)-6-(trifluoromethyl)phenyl]benzamide.

[0179] In a 250ml four-necked glass reaction bottle, 200g of dichloroethane, 25g (0.071mol) of 2-fluoro-3-[(2-methoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid obtained in Synthesis Example 13 and 24g (0.20mol) of thionyl chloride were added, and the mixture was heated to reflux for 3-5 hours. The mixture was cooled to room temperature, and the reaction solution was transferred to a 500ml rotary evaporator and desolvated to 80°C under reduced pressure to obtain an acyl chloride oily liquid. The mixture was cooled to about 25°C, 150g of new dichloroethane was added to dissolve the mixture, and the mixture was transferred to a reaction bottle. 27.8g (0.08mol) of 4-(1,1,1,2,3,3,3-heptafluoropropane-2-yl)-2-(trifluoromethyl)aniline raw material was added, and the mixture was heated to reflux for 5-10 hours. Cool to room temperature, add 5g of sodium hydroxide, and drop 13.5g of liquid bromine at 35-55°C for about 2 hours to react, keep warm for 2 hours, add 50ml of water, separate the water layer, and decompress the solvent layer to obtain the residual material, add 120g of ethylene glycol monomethyl ether, heat and reflux for 1 hour, cool and crystallize, crystallize at 0-5°C for 1 hour, filter and dry to obtain 44g of white crystalline powder solid, which is the target compound, melting point: 152.4-153.2°C, HPLC normalized content is about 98%, and the total yield of three steps is 83.7%. The reaction formula is as follows:

[0180]

[0181] The H NMR spectrum and mass spectrum data are as follows:

[0182] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.56(s,1H,CONH),8.38(s,1H),7.92(s,1H),7.65(dd,J=7.6Hz,and 6.8Hz,1H),7.60-7.49(m,1H),7.42-7.20(m,3H),7.10-7.02(m,2H),4.10-3.70(m,2H),3.68-3.42(m,2H),3.19(s,3H,CH3O).

[0183] HRMS(ESI)calcd.for C 27 H 17BrF12N2NaO3[(M+Na)+]:747.0129[(M+Na)+],749.0108[(M+2+Na)+]; Found:747.0111[(M+Na)+],749.0094[(M+2+Na)+].

[0184] The target compound sample was analyzed by X-ray powder crystal diffraction, and the crystals had characteristic peaks at the following positions, 2θ

[0185] =7.376±0.2°, 9.897±0.2°, 10.940±0.2°, 12.015±0.2°, 12.303±0.2°, 14.398±0.2°, 14.578±0.2°, 15.561±0.2°, 15.839±0.2°, 17.163±0.2°, 18.257±0.2°, 18.463±0.2°, 18.737±0.2°, 18.922±0.2°, 19.219±0.2°, 19.518±0.2°, 19.823±0.2°, 20.137±0.2°, 20.379±0.2° .2°、20.600±0.2°、20.861±0.2°、21.023±0.2°、21.722±0.2°、22.021±0.2°、22.218±0.2°、22.818±0.2°、23.999±0.2°、24.738±0.2°、25.077±0.2°、25.481±0.2°、25.860±0.2°、27.161±0.2°、27.682±0.2°、29.058±0.2°、29.323±0.2°、29.760±0.2°、29.940±0.2°, see the attached Figure 2 .

[0186] The sample obtained in this synthesis example was recrystallized with 3 times the weight of ethanol. The X-ray powder crystal diffraction analysis of the finally obtained sample showed that the characteristic peaks of the crystals were exactly the same as above.

[0187] The sample obtained in this synthesis example was recrystallized with 3 times the weight of isopropyl ether. The X-ray powder crystal diffraction analysis of the finally obtained sample showed that the characteristic peaks of the crystals were exactly the same as above.

[0188] The above results indicate that the crystals obtained by crystallizing the obtained compound in ethanol, isopropyl ether and ethylene glycol monomethyl ether solvents, respectively, have the same crystal type, are easy to obtain and have good stability.

[0189] Synthesis Example 19

[0190] Synthesis of 2-fluoro-3-[(4-fluorophenylcarbonyl)(2-methoxyethyl)amino]-N-[2-bromo-4-(1,1,1,2,3,3,3-heptafluoropropane-2-yl)-6-(trifluoromethyl)phenyl]benzamide.

[0191] According to the operation of Synthesis Example 18, 25 g (0.071 mol) of 2-fluoro-3-[(2-methoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid was replaced by 25.6 g (0.071 mol) of 2-fluoro-3-[(2-methoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid obtained in Synthesis Example 10, and finally 42 g of white crystalline powder solid was obtained, which was the target compound, with a melting point of 152.4-153.2° C., an HPLC normalized content of about 98%, and a three-step total yield of 79.9%. The sample was analyzed by nuclear magnetic resonance, mass spectrometry, and X-ray powder crystal diffraction, and the results were completely consistent.

[0192] Synthesis Example 20

[0193] Synthesis of 2-fluoro-3-[(4-fluorophenylcarbonyl)(2-ethoxyethyl)amino]-N-[2-bromo-4-(1,1,1,2,3,3,3-heptafluoropropane-2-yl)-6-(trifluoromethyl)phenyl]benzamide.

[0194] In a 250ml four-necked glass reaction bottle, 200g of dichloroethane, 26g (0.071mol) of 2-fluoro-3-[(2-ethoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid obtained in Synthesis Example 8, and 24g (0.20mol) of thionyl chloride were added, and the mixture was heated to reflux for 3-5 hours, cooled to room temperature, and the reaction solution was transferred to a 500ml rotary evaporator, desolvated to 80°C under reduced pressure to obtain an acyl chloride oily liquid, cooled to about 25°C, and 150g of toluene was added to dissolve the mixture, and the mixture was transferred to a reaction bottle, and 27g of 4-(1,1,1,2,3,3,3-heptafluoropropane-2-yl)-2-(trifluoromethyl)aniline raw material was added. 8g (0.08mol), heated to reflux for 5-10 hours, decompressed to obtain residual material, added 120g methanol, cooled to room temperature, added 5g sodium hydroxide, at 35-55 ° C, 13.5g liquid bromine was added dropwise for about 2 hours, kept warm for 2 hours, added 50ml water, separated the water layer by stratification, obtained the solvent layer decompressed to obtain residual material, added 120g isopropyl ether, heated to reflux for 1 hour, cooled to crystallize, crystallized at 0-5 ° C for 1 hour, filtered and dried to obtain 44.5g white crystalline powder solid, which is the target compound, melting point: 168.2-169.2 ° C, HPLC normalized content of about 98%, three-step total yield of 83.1%. The reaction formula is as follows:

[0195]

[0196] The H NMR spectrum and mass spectrum data are as follows:

[0197] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.52(s,1H,CONH),8.38(s,1H),7.92(s,1H),7.67(dd,J=7.6Hz,and 6.8Hz,1H),7.60-7.50(m,1H),7.48-7.20(m,3H),7.18-6.95(m,2H),4.20-3 .72(m,2H),3.68-3.45(m,2H),3.42-3.32(m,2H),1.01(t,J=6.8Hz,3H,CH3).

[0198] HRMS(ESI)calcd.For C 28 H 19 F 12 N2NaO3[(M+Na) + ]:761.0285[(M+Na) + ],763.0265[(M+2+Na) + ]; Found:761.0263[(M+Na) + ],763.0248[(M+2+Na) + ].

[0199] The target compound sample was analyzed by X-ray powder crystal diffraction, and the crystals had characteristic peaks at the following positions, 2θ

[0200] =7.318±0.2°、9.697±0.2°、10.940±0.2°、11.981±0.2°、12.136±0.2°、14.142±0.2°、14.461±0.2°、15.240±0.2°、15.561±0.2°、16.304±0.2°、17.161±0.2°、1 7.979±0.2°, 18.562±0.2°, 19.138±0.2°, 19.698±0.2°, 20.039±0.2°, 20.220±0.2°, 20.442±0.2°, 20.784±0.2°, 20.998±0.2°, 21.819±0.2°, 22.039±0.2°, 22 .401±0.2°, 23.400±0.2°, 23.882±0.2°, 24.383±0.2°, 24.579±0.2°, 25.001±0.2°, 25.160±0.2°, 25.459±0.2°, 26.780±0.2°, 26.920±0.2°, 27.199±0.2°, 27 .378±0.2°, 28.742±0.2°, 29.319±0.2°, 29.998±0.2°, 31.339±0.2°, 31.939±0.2°, 32.140±0.2°, 32.522±0.2°, 33.479±0.2°, 36.400±0.2°, 43.039±0.2°, see the attached Figure 3 .

[0201] The sample obtained in this synthesis example was recrystallized with 3 times the weight of ethanol. The X-ray powder crystal diffraction analysis of the finally obtained sample showed that the characteristic peaks of the crystals were exactly the same as above.

[0202] The sample obtained in this synthesis example was recrystallized with 3 times the weight of ethylene glycol monomethyl ether. The X-ray powder crystal diffraction analysis of the finally obtained sample showed that the characteristic peaks of the crystals were exactly the same as above.

[0203] The sample obtained in this synthesis example was recrystallized with 3 times the weight of ethylene glycol dimethyl ether. The sample finally obtained was analyzed by X-ray powder crystal diffraction, and the characteristic peaks of the crystals were exactly the same as above.

[0204] It is shown that the crystals obtained by crystallizing the compound in ethanol, isopropyl ether, ethylene glycol monomethyl ether and ethylene glycol dimethyl ether solvents respectively have the same crystal type, are easy to obtain and have good stability.

[0205] The sample obtained in this synthesis example was recrystallized with 3 times the weight of methanol, isopropanol, tetrahydrofuran, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, and methyl tert-butyl ether, respectively. The X-ray powder crystal diffraction analysis of the finally obtained sample showed that the characteristic peaks of the crystals were exactly the same as above.

[0206] It is shown that the crystals obtained by crystallizing the compound in solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, isopropyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, methyl tert-butyl ether, etc., are of consistent crystal type, are easy to obtain and have good stability.

[0207] Synthesis Example 21

[0208] Synthesis of 2-fluoro-3-[(phenylcarbonyl)(methyl)amino]-N-[2-bromo-4-(1,1,1,2,3,3,3-heptafluoropropane-2-yl)-6-(trifluoromethyl)phenyl]benzamide.

[0209] According to the operation of Synthesis Example 18, the raw material 2-fluoro-3-[(2-methoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid 25g (0.071mol) was replaced by 2-fluoro-3-[(methyl)(phenylcarbonyl)amino]benzoic acid 20.4g (0.071mol) obtained in Synthesis Example 11. Other operations were the same, and finally 40.1g of white crystalline powder solid was obtained, which was the target compound, with a melting point of 155.1-156.4°C, an HPLC normalized content of about 98%, and a total yield of 83.4% in three steps. The reaction formula is as follows:

[0210]

[0211] The H NMR spectrum and mass spectrum data are as follows:

[0212] 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.65 (s, 1H, CONH), 8.39 (s, 1H), 7.93 (s, 1H), 7.61-7.51 (m, 2H), 7.45-7.15 (m, 6H), 3.32 (s, 3H).

[0213] HRMS(ESI)calcd.for C 25 H 14 F 11 N2NaO2[(M+Na)+]:684.9961[(M+Na)+],686.9940[(M+2+Na)+]; Found:684.9956[(M+Na)+],686.9940[(M+2+Na)+].

[0214] Synthesis Example 22

[0215] Synthesis of 2-fluoro-3-[(phenylcarbonyl)(ethyl)amino]-N-[2-bromo-4-(1,1,1,2,3,3,3-heptafluoropropane-2-yl)-6-(trifluoromethyl)phenyl]benzamide.

[0216] According to the operation of Synthesis Example 18, the raw material 2-fluoro-3-[(2-methoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid 25g (0.071mol) was replaced by 2-fluoro-3-[(ethyl)(phenylcarbonyl)amino]benzoic acid 21.4g (0.071mol) obtained in Synthesis Example 12. Other operations were the same, and finally 40g of white crystalline powder solid was obtained, which was the target compound, with a melting point of 166.1-167.8°C, an HPLC normalized content of about 98%, and a total yield of 81.5% in three steps. The reaction formula is as follows:

[0217]

[0218] Synthesis Example 23

[0219] Synthesis of 2-fluoro-3-[(4-fluorophenylcarbonyl)(cyclopropylmethyl)amino]-N-[2-bromo-4-(1,1,1,2,3,3,3-heptafluoropropane-2-yl)-6-(trifluoromethyl)phenyl]benzamide.

[0220] According to the operation of Synthesis Example 18, the raw material 2-fluoro-3-[(2-methoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid 25g (0.071mol) was replaced by 2-fluoro-3-[(cyclopropylmethyl)(4-fluorophenylcarbonyl)amino]benzoic acid 23.4g (0.071mol) obtained in Synthesis Example 14. Other operations were the same, and finally 43g of white crystalline powder solid was obtained, which was the target compound, with a melting point of 152.5-153.3°C, an HPLC normalized content of about 98%, and a total yield of 82.3% in three steps. The reaction formula is as follows:

[0221]

[0222] Synthesis Example 24

[0223] Synthesis of 2-fluoro-3-[(4-cyanophenylcarbonyl)(2-ethoxyethyl)amino]-N-[2-bromo-4-(1,1,1,2,3,3,3-heptafluoropropane-2-yl)-6-(trifluoromethyl)phenyl]benzamide.

[0224] The reference synthesis preparation example 5 was operated, wherein 25 g (0.20 mol) of benzoic acid was replaced by 29.5 g (0.20 mol) of p-cyanobenzoic acid, and the other operations were the same to synthesize 2-fluoro-3-[(4-cyanophenylcarbonyl)amino]methyl benzoate, and 27.2 g (0.086 mol) of the raw material 2-fluoro-3-[(4-fluorophenylcarbonyl)amino]methyl benzoate in Synthesis Example 13 was replaced by 26.7 g (0.086 mol) of methyl benzoate, and 16.8 g (0.11 mol) of 1-bromo-2-ethoxyethane was used to replace the raw material 1-bromo-2-methyl 15.8g (0.11mol) of oxyethane, other operations are the same, the synthesized 2-fluoro-3-[(2-ethoxyethyl)(4-cyanophenylcarbonyl)amino]benzoic acid is obtained, and 26.6g (0.071mol) is taken to replace 25g (0.071mol) of 2-fluoro-3-[(2-methoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid in Synthesis Example 18, and other operations are the same, and finally 43.4g of off-white crystalline powder solid is obtained, which is the target compound, with a melting point of 150.1-152.2°C, a HPLC normalized content of about 98%, and a total yield of 80.3% in the last three steps. The reaction formula is as follows:

[0225]

[0226] The H NMR spectrum and mass spectrum data are as follows:

[0227] 1H-NMR(400MHz,DMSO-d6)δ(ppm):10.48(s,1H,CONH),8.39(s,1H),7.92(s,1H) ,7.72-7.65(m,3H),7.58-7.50(m,1H),7.48-7.35(m,2H),7.32(dd,J=7.2Hz,and 7.2Hz,1H),4.15-3.85(m,2H),3.70-3.50(m,2H),3.44-3.32(m,2H),1.00(t,J=6.0Hz,3H,CH3).

[0228] HRMS(ESI)calcd.for C 29 H 19 F 11 N3NaO3[(M+Na)+]:768.0332[(M+Na)+],770.0311[(M+2+Na)+]; Found:768.0310[(M+Na)+],770.0293[(M+2+Na)+].

[0229] Synthesis Example 25

[0230] The operation of Synthesis Example 13 was followed, wherein 15.8 g (0.11 mol) of 1-bromo-2-methoxyethane was replaced by 18.7 g (0.11 mol) of 1-bromo-2-n-propoxyethane, and other materials and operations were the same. The yield and content of the intermediate 2-fluoro-3-[(2-n-propoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid were similar. The synthesis of the target compound was carried out according to the similar operation as in Synthesis Example 20, wherein the raw material 2-fluoro-3-[(2-ethoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid 26g (0.071mol) was replaced by 2-fluoro-3-[(2-n-propoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid 27g (0.071mol) obtained above, and other operations were similar to obtain the target compound: 2-fluoro-3-[(4-fluorophenylcarbonyl)(2-n-propoxyethyl)amino]-N-[2-bromo-4-(1,1,1,2,3,3,3-heptafluoropropane-2-yl)-6-(trifluoromethyl)phenyl]benzamide, melting point: 156.5-156.8, and the yield and content results were similar.

[0231] Other compounds of the general formula (I) or (II) of the present invention can be synthesized by referring to the methods of the above examples.

[0232] Biological Activity Test Example

[0233] Some of the compounds of general formula (II) obtained by the present invention were tested against various pests.

[0234] Compound preparation: Weigh a certain mass of the original drug with a balance (0.001 g), prepare it into a 1% mother solution with DMF, and then dilute it with distilled water containing 0.1% Tween-80 to the test concentration for use; if it is a preparation, weigh a certain mass of the preparation sample with a balance (0.001 g) according to the content of the active ingredient in the preparation, and dilute it with distilled water to the test concentration for use.

[0235] Table 1: Some compounds of general formula (II)

[0236]

[0237] Test Example 1 Indoor biological activity determination of some compounds of general formula (II) against Plutella xylostella

[0238] The sensitive population and chlorantraniliprole-resistant population of Plutella xylostella were reared indoors on radish seedlings;

[0239] Test method: Diamondback moth activity determination: Use the dipping method, take an appropriate amount of radish leaves and soak them in the medicine for 30 seconds, then place them in a plastic petri dish with filter paper to dry naturally in the shade, and inoculate 10 2-year-old diamondback moths in each dish, and place them in an observation room at 22°C and light (16 / 8h). Observe after 2 days, touch the insect body with a brush, and if there is no reaction, it is considered dead. Repeat 3 times, and set up a blank control without adding the medicine.

[0240] Test results: The results of the activity test of some compounds of general formula (II) such as SYN101 on Plutella xylostella are shown in Table 2:

[0241] The results showed that at the tested concentrations of 0.2 mg / L, 0.1 mg / L, and 0.05 mg / L, compounds SYN101, SYN102, SYN103, SYN104, SYN105, SYN106, and SYN107 showed excellent insecticidal activity against the sensitive population of Plutella xylostella and the population of Plutella xylostella resistant to chlorantraniliprole, all of which were greater than 80%. At the low concentration of 0.05 mg / L, SYN104, SYN105, SYN106, and SYN107 still showed excellent insecticidal activity against the sensitive population of Plutella xylostella and the population of Plutella xylostella resistant to chlorantraniliprole, all reaching 100%.

[0242] Table 2: Activity test results of some compounds of general formula (II) against Plutella xylostella

[0243]

[0244] Test Example 2 Indoor biological activity determination of some compounds of general formula (II) against fall armyworm

[0245] Activity determination of fall armyworm: Use the dipping method, take an appropriate amount of corn leaves and soak them in the drug for 30 seconds, then place them in a plastic petri dish lined with filter paper to dry naturally in the shade, and inoculate 10 2-year-old fall armyworms in each dish, and place them in an observation room at 26°C and light (16 / 8h). Observe after 2 days, touch the insect body with a brush, and if there is no reaction, it is considered dead. Repeat 3 times, and set up a blank control without adding the drug.

[0246] Test results: The indoor biological activity test results of some compounds of general formula (II), such as SYN101, on fall armyworm are shown in Table 3:

[0247] The results showed that compounds SYN101, SYN102, and SYN103 had good activity at a test concentration of 0.2 mg / L, reaching 100%. At a test concentration of 0.1 mg / L, the activity was slightly worse, but all greater than 80%. At a test concentration of 0.05 mg / L, the activity was poor. At test concentrations of 0.2 mg / L, 0.1 mg / L, and 0.05 mg / L, compounds SYN104, SYN105, SYN106, and SYN107 all showed excellent insecticidal activity, all reaching 100%.

[0248] Table 3: Activity test results of some compounds of general formula (II) against fall armyworm

[0249]

[0250] The applicant declares that the present invention illustrates a method for preparing a heptafluoroisopropyl-containing bisamide compound and an intermediate thereof through the above representative embodiments, but the present invention is not limited to the above embodiments, nor does it mean that the present invention must rely on the above embodiments to be realized. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing an intermediate compound for preparing a heptafluoroisopropyl-containing bisamide compound, wherein the intermediate is represented by the following general formula (I): in, R 1 The substituents are independently selected from H or fluorine, and R 2 The substituents are independently selected from 2-methoxyethyl or 2-ethoxyethyl; It is characterized in that the process flow of the preparation method of the intermediate compound of the structure represented by the general formula (I) is as follows: Among them, R 3 is methyl or ethyl; The N-alkylation reaction solvent is selected from: one or more mixtures of cyclohexane, methylcyclohexane, toluene, ethylbenzene, and xylene; The N-alkylation reaction base is selected from: potassium carbonate, sodium carbonate, sodium hydride; The N-alkylation reaction bromoalkane is selected from: 2-methoxyethyl bromide or 2-ethoxyethyl bromide; The N-alkylation reaction catalyst is selected from: one or more mixtures of tetrabutylammonium chloride, tetrabutylammonium bromide, and tetrabutylammonium hydrogen sulfate; The amidation reaction solvent is selected from: one or more mixtures of cyclohexane, methylcyclohexane, toluene, ethylbenzene and xylene.

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