CN115974717A - Heptafluoroisopropyl-containing bisamide compound and intermediate compound thereof, and preparation method and application thereof - Google Patents

Abstract

The invention provides a preparation method of an intermediate compound for preparing a bis-amide compound containing heptafluoro-isopropyl, a preparation method of the bis-amide compound containing heptafluoro-isopropyl, and a preparation method of the bis-amide compoundThe process flow of the method is shown as a formula (3). The heptafluoro-isopropyl-containing bisamide compound has excellent insecticidal activity, and the chemical reaction condition is mild, environment-friendly, high in total yield, high in final product content, low in cost, easy for industrial production and very high in application prospect.

Description

A bisamide compound containing heptafluoroisopropyl group and its intermediate compound, its preparation method and application

The present invention requests two domestic priority rights, namely, the priority date is December 22, 2021, the priority number is CN2021115835066, and the name is "a bisamide compound containing heptafluoroisopropyl group and its preparation method and application." "'s invention patent application and priority date is October 24, 2022, and the priority number is CN

2022113037189, an invention patent application titled "a bisamide compound containing heptafluoroisopropyl group and its intermediate compound, its preparation method and application".

【Technical field】

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, and a preparation of a heptafluoroisopropyl-containing bisamide compound crystal X-ray powder diffraction properties, and their uses.

【technical background】

Due to the large and frequent use of pesticides, serious resistance problems have been caused in most parts of the world at present, and the original effect must be achieved by increasing the dose. It is bound to cause certain problems. It is necessary to introduce new insecticides with better activity, lower consumption and more environmental friendliness. Domestic and foreign scientific research institutions and enterprises have continuously increased their investment in the development of pesticides, and many new pesticides with high activity, low dosage and environmental friendliness have emerged.

Broflanilide (structural formula: 01), an intermediate diamide insecticide jointly developed by Mitsui Chemicals Corporation of Japan and BASF, has been commercialized now. For corn, grain, flowers and non-crop purposes, it can prevent and control pests such as Lepidoptera, Coleoptera, termites, ants, cockroaches, flies, etc., and has very good effects. For details, see Chinese patent CN102119173B, amide derivatives, containing the amide Derivative pest control agents and methods of use thereof. However, many domestic enterprises and research institutions have optimized and improved the structure on this basis, and have discovered a series of new insecticides with higher activity, lower dosage, and more environmental friendliness. Chinese patent CN 109497062B is a kind of intermediate diamide compound and its preparation method and application, representative structure, ciprofluramid (structural formula: 02); we found a bisamide compound containing heptafluoroisopropyl, the structure The general formula (II) has high insecticidal activity, and the representative structure (structural formula: 03) provides more medication options and medication schemes in the production of crops such as agriculture and horticulture.

Wherein, the substituents ^of R are independently selected from H, fluorine, trifluoromethyl, cyano or nitro;

R 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.

However, the preparation process of related compounds has disadvantages such as complex routes, harsh chemical reaction conditions, poor selectivity, unfriendly environment, 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 related documents or patents, such as: Liu Aiping, etc. Synthesis and biological activity of broflanilide, Journal of Fine Chemical Intermediates, December 2020, Volume 50, Issue 6, pp. 16-20.

【Content of invention】

Aiming at the deficiencies of the prior art, the object of the present invention is to provide a preparation process with simple operation, mild chemical reaction conditions, environment-friendly, high total yield, and low final product content by optimizing the design of the preparation process and optimizing the reaction conditions. A heptafluoroisopropyl-containing bisamide compound that is high in cost, low in cost, and easy for industrial production and a preparation method thereof, and also relates to an intermediate compound and its preparation method for the preparation of the heptafluoroisopropyl-containing bisamide compound Preparation.

To achieve this purpose, the present invention provides a method for preparing an intermediate compound for the preparation of bisamide compounds containing heptafluoroisopropyl, the intermediate being shown in the following general formula (I):

Wherein, the substituents ^of R are independently selected from H, fluorine, trifluoromethyl, cyano or nitro;

R 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.

It is characterized in that the process flow of the preparation method of the intermediate compound with the structure shown in the general formula (I) is as formula (1) or formula (2):

Wherein, R ³ is an alkyl group of C1-C5;

The N-alkylation reaction solvent described in formula (1) or formula (2) is selected from: N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide Amide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolinone, dimethylsulfoxide, acetonitrile, tetrahydrofuran, dichloroethane, cyclohexane, methylcyclohexane, toluene, ethyl One or more mixtures of benzene and xylene;

The N-alkylation reaction alkali described in formula (1) or formula (2) is selected from: potassium carbonate, sodium carbonate, sodium hydride;

The N-alkylation bromoalkane described in formula (1) or formula (2) is selected from: 2-methoxy bromoethane, 2-ethoxy bromoethane, 3-methoxy bromopropane, 3-Ethoxybromopropane, 2-n-propoxybromoethane, 2-isopropoxybromoethane, 2-n-butoxybromoethane, bromomethylcyclopropane, bromomethyl or bromoethane;

The N-alkylation reaction catalyst described in formula (1) or formula (2) is selected from: hexadecyltrimethylammonium chloride, benzyltriethylammonium chloride, polyethylene glycol 400-800, One of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium bisulfate, 15-crown-5-ether, 18-crown-6-ether or 4-dimethylaminopyridine (DMAP) or multiple mixtures;

The amidation reaction solvent described in formula (2) is selected from: N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, 1,3-Dimethyl-2-imidazolinone, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, ethyl acetate, dichloromethane, dichloroethane, cyclohexane, methylcyclohexane, toluene, ethyl One or more mixtures of benzene and xylene.

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

First, use 2-fluoro-3-nitrobenzoic acid raw material and corresponding alcohols, carry out esterification reaction in the presence of catalyst, obtain corresponding 2-fluoro-3-nitrobenzoic acid ester, reaction formula is as follows:

Wherein, R ³ is C1-C5 alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, particularly preferably methyl or ethyl, from the corresponding alcohol Classes are prepared by esterification.

The esterification catalyst is concentrated sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid. It is preferably concentrated sulfuric acid, preferably with a mass concentration of 80-100%, and the dosage is 0.5%-20%, preferably 1-5%, of the weight of the 2-fluoro-3-nitrobenzoic acid raw material. Alcohols, generally choose C1-C5 alcohols, preferably methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, especially methanol or ethanol; the dosage is 2-fluoro-3-nitro 2-10 times of benzoic acid raw material weight, preferably 3-5 times; reaction temperature, generally 50-200 ℃, preferably the boiling point reflux reaction temperature of corresponding alcohol; reaction time, generally 5-48 hours, preferably reaction time 5-24 hours.

Among them, 2-fluoro-3-nitrobenzoic acid is an important intermediate of medicine and pesticide, which can be realized through various synthetic routes. It can generally be obtained through market purchase or synthesis, and its content is generally more than 95% of industrial grade. If the present invention has no special instructions, it generally refers to obtaining it through market purchase, and those skilled in the art can also realize it through the following classic synthesis reaction route:

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, and the nitro group is reduced to the corresponding amino group to obtain The corresponding 2-fluoro-3-aminobenzoate. The reaction formula is as follows:

Among them, the reaction solvent is generally used, 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, preferably 2-10 times, the weight of 2-fluoro-3-nitrobenzoate. Catalysts generally use a mass concentration of

1-5% palladium-carbon or Raney nickel, preferably 5% palladium-carbon catalyst, the amount of catalyst used on a dry basis is 0.1%-10% of the weight of 2-fluoro-3-nitrobenzoate, preferably 1%-5%, from economic considerations, can be recycled 5-10 times. The hydrogen is more than 99% of industrial grade, and the reaction pressure is 0-2Mpa, preferably 0-0.5Mpa, especially preferably near normal pressure.

The reaction temperature is 0-100°C, preferably 5-50°C. The reaction time is generally until the catalyst does not absorb hydrogen, generally 2-24 hours.

Next, the obtained 2-fluoro-3-aminobenzoic acid ester (or can be purchased directly 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:

Wherein, R ^substituents are independently selected from H, fluorine, trifluoromethyl, cyano or nitro; ^R is as defined above.

Here, the benzoyl chloride series raw materials used in the amidation reaction are generally prepared from the corresponding benzoic acid series raw materials and thionyl chloride through acid chloride reaction in an inert solvent, and the amount used is generally 2-fluoro-3- 1.0-1.2 times, preferably 1.0-1.05 times the molar weight of aminobenzoate.

Acidic agents commonly used in amidation reactions are 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., triethylamine or pyridine is preferably used, and the molar dosage is 0.1% of the benzoyl chloride series raw materials -5.0 times, the preferred economical amount is 0.1-2.0 times; the solvent used in the amidation reaction is dichloromethane, chloroform, dichloroethane, tetrahydrofuran, dioxane, dimethyl sulfoxide, acetonitrile, toluene, di Toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone or 1,3-dimethyl-2-imidazoline Ketones, etc., the preferred 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.

The resulting product can be used to realize the preparation method of the intermediate compound of the present invention, and the process flow is as shown in formula (1)

Shown:

Wherein, R ³ is selected from the alkyl group of C1-C5;

The solvent in the N-alkylation reaction is selected from: N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, 1, One or more of 3-dimethyl-2-imidazolinone, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dichloroethane, cyclohexane, methylcyclohexane, toluene, ethylbenzene, xylene The preferred solvent is: one or more mixtures of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, cyclohexane, methylcyclohexane, toluene, dosage It is 2-10 times, preferably 2-5 times, the weight of amide or 2-fluoro-3-aminobenzoate raw material.

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 is amide or 2-fluoro-3- 1-3 times, preferably 1-2 times the molar weight of aminobenzoic acid ester raw material.

Bromoalkane in the N-alkylation reaction is selected from: 2-methoxybromoethane, 2-ethoxybromoethane, 3-methoxybromopropane, 3-ethoxybromopropane, 2- n-propoxybromoethane, 2-isopropoxybromoethane, 2-n-butoxybromoethane, bromomethylcyclopropane, methyl bromide or bromoethane; usually commercially or synthetically available, this Inventions are not specifically stated, and generally refer to acquisition through the market. The dosage is 1-3 times, preferably 1-2 times, the molar weight of the amide or 2-fluoro-3-aminobenzoate raw material. The present invention adopts bromoalkane and avoids the use of iodoalkane, which is due to the high activity of iodoalkane, but causes high industrialization cost and is unfavorable for industrialization, while bromoalkane usually has low activity, poor selectivity, and low yield. Only in the presence of catalysts and optimized process conditions can better results be achieved.

The catalyst in the N-alkylation reaction is selected from: cetyltrimethylammonium chloride, benzyltriethylammonium chloride, polyethylene glycol 400-800, tetrabutylammonium chloride, tetrabutylammonium One or more mixtures of ammonium bromide, tetrabutylammonium bisulfate, 15-crown-5-ether, 18-crown-6-ether or 4-dimethylaminopyridine (DMAP). In addition, the catalyst can also use iodide salts, such as: potassium iodide, sodium iodide, etc., but the catalytic effect is not as good as phase transfer catalysts or 4-dimethylaminopyridine (DMAP), preferably tetrabutylammonium chloride, tetrabutylammonium chloride, etc. Ammonium bromide, tetrabutylammonium bisulfate, 18-crown-6-ether or 4-dimethylaminopyridine (DMAP), the catalyst dosage is 1- 10%, preferably 1-5%. The catalyst used in the present invention can reduce the reaction temperature and improve the reaction selectivity and product yield.

The present invention also provides another preparation method of the above-mentioned intermediate compound, the process flow of which is shown in formula (2):

Similar to the first preparation method, ^R3 is selected from C1-C5 alkyl groups;

The solvent in the N-alkylation reaction is selected from: N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, 1, One or more of 3-dimethyl-2-imidazolinone, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dichloroethane, cyclohexane, methylcyclohexane, toluene, ethylbenzene, xylene The preferred solvent is: one or more mixtures of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, cyclohexane, methylcyclohexane, toluene, dosage It is 2-10 times, preferably 2-5 times, the weight of amide or 2-fluoro-3-aminobenzoate raw material.

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 in an amount of amide or 2-fluoro-3-amino 1-3 times, preferably 1-2 times of the molar weight of benzoic acid ester raw material.

Bromoalkane in the N-alkylation reaction is selected from: 2-methoxybromoethane, 2-ethoxybromoethane, 3-methoxybromopropane, 3-ethoxybromopropane, 2- n-propoxybromoethane, 2-isopropoxybromoethane, 2-n-butoxybromoethane, bromomethylcyclopropane, methyl bromide or bromoethane; usually commercially or synthetically available, this Inventions are not specifically stated, and generally refer to acquisition through the market. The dosage is 1-3 times, preferably 1-2 times, the molar weight of the amide or 2-fluoro-3-aminobenzoate raw material. The present invention adopts bromoalkane and avoids the use of iodoalkane, which is due to the high activity of iodoalkane, but causes high industrialization cost and is unfavorable for industrialization, while bromoalkane usually has low activity, poor selectivity, and low yield. Only in the presence of catalysts and optimized process conditions can better results be achieved.

The catalyst in the N-alkylation reaction is selected from: cetyltrimethylammonium chloride, benzyltriethylammonium chloride, polyethylene glycol 400-800, tetrabutylammonium chloride, tetrabutylammonium One or more mixtures of ammonium bromide, tetrabutylammonium bisulfate, 15-crown-5-ether, 18-crown-6-ether or 4-dimethylaminopyridine (DMAP). In addition, the catalyst can also use iodide salts, such as: potassium iodide, sodium iodide, etc., but the catalytic effect is not as good as phase transfer catalysts or 4-dimethylaminopyridine (DMAP), preferably tetrabutylammonium chloride, tetrabutylammonium chloride, etc. Ammonium bromide, tetrabutylammonium bisulfate, 15-crown-5-ether, 18-crown-6-ether or 4-dimethylaminopyridine (DMAP), catalyst dosage is amide or 2-fluoro-3-aminobenzene 1-10%, preferably 1-5%, of the raw material weight of the formate ester, the catalyst used in the present invention can reduce the reaction temperature, improve the reaction selectivity and product yield.

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

Wherein, amidation reaction can adopt to add DMAP catalyst, and consumption is 1-10% of benzoic acid series acid chloride raw material weight, is preferably 1-5%, when not adding catalyzer, reaction yield and reaction time are both under the process conditions of the present invention. Acceptable, so the present invention does not necessarily have to be used; in the preparation method of the intermediate compound of the present invention, the amidation reaction does not need to use a fuacid agent, and under the process conditions of the present invention, the conversion yield and reaction time are acceptable. Wherein, the amidation reaction temperature is 0-200°C, preferably 0-150°C

In the preparation method of the aforementioned two intermediate compounds, the hydrolysis reaction conditions are generally the usual conditions, generally using alcohol solvents such as methanol, ethanol, isopropanol, etc., or ether solvents such as 1,4-dioxane, methyl tertiary Butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, etc., methanol and ethanol are preferred, and the amount used is generally 2-10 times the weight of the corresponding ester, preferably 2-5 times; the alkali generally uses sodium hydroxide, hydrogen Potassium oxide, sodium carbonate, potassium carbonate, preferably sodium hydroxide, the concentration generally adopts a mass concentration of 1-35%, and the molar dosage is 1.1-3.0 times of the corresponding ester. The reaction temperature is generally 5-50°C, preferably 20-30°C. The reaction time is generally 1-5 hours, preferably 1-2 hours.

In the preparation method of the above two intermediate compounds, the N-alkylation reaction temperature is 50-200°C, preferably the temperature is 50-150°C, and when the solvent is a solvent capable of producing azeotropy with water, the reaction temperature is preferably Boiling 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 bromoalkane is methyl bromide or bromoethane, due to the low boiling point of bromoalkane, avoid volatilization, preferably For closed reaction, the pressure is 0-0.2MPa. The N-alkylation reaction time is usually 2-12 hours, preferably 2-8 hours.

Further, the present invention also provides a heptafluoroisopropyl-containing bisamide compound, the structure of which is shown in the general formula (II),

Wherein, the substituents ^of R are independently selected from H, fluorine, trifluoromethyl, cyano or nitro;

R 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.

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

                             

Wherein, the general method of acyl chloride reaction is that the raw material of general formula (I) reacts with thionyl chloride in an inert solvent, and the precipitation treatment enters the next step of reaction. The solvent used in the acid chloride reaction is methylene chloride, chloroform, ethylene dichloride, toluene or xylene, etc., the preferred solvent is ethane dichloride or toluene, etc.; the acid chloride reaction temperature is generally 20-150 ° C, the preferred reaction temperature 40-100°C; acid chloride reaction time is generally 1-5 hours, preferably 2-3 hours.

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 The preferred solvent is ethylene dichloride, hexanaphthene, methylcyclohexane, toluene, ethyl acetate or acetonitrile, and the usage amount is generally 2-10 times of corresponding general formula (I) raw material weight, preferably 3-8 times. Amidation also can use catalyzer 4-dimethylaminopyridine (DMAP), can shorten reaction time, but under preferred condition of the present invention, amidation need not use catalyzer and acid agent, and reaction yield and reaction time are all acceptable, so The present invention does not necessarily have to be used. Another raw material of amidation reaction, 4-heptafluoroisopropyl-2-trifluoromethylaniline, can be obtained through synthesis or market purchase. The synthetic method is made of o-trifluoromethylaniline raw material and 2-bromoheptafluoropropane or 2-iodoheptafluoropropane It is prepared by alkylation reaction in the presence of sodium hydrosulfite, and the synthesis details are disclosed in the Chinese invention patent CN 102119173B. The amount of raw material 4-heptafluoroisopropyl-2-trifluoromethylaniline is 1.0-1.3 times, preferably 1.0-1.05 times, the molar amount of the raw material of general formula (I). The bromination reaction uses liquid bromine as the bromination agent, which is cheap, the raw materials are easy to obtain, and the by-product bromide salt is easy to recycle. Compared with N-bromosuccinimide bromination agent, the cost is lower, and it is also conducive to environmental protection. 1-2 times the molar amount of the raw material of general formula (I), the preferred usage is 1-1.5 times, the preferred way of use is drip reaction, and the drip reaction can also be adopted under the condition of ultraviolet light, preferably without light, it can be carried out reaction.

The bromination reaction can also be used to reduce the amount of bromine, adding an oxidizing agent shortly after the reaction, so that the generated bromide salt is oxidized into elemental bromine and used again for the bromination reaction, which can reduce the amount of bromine used, but it will cause a reaction The complex operation of the system and related side reaction impurities are not necessarily used in the present invention.

The solvent in the bromination reaction is selected from one or more mixtures in methylene dichloride, ethylene dichloride, methyl alcohol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, and the preferred solvent is di One or more mixtures of ethyl chloride, methanol, ethanol, isopropanol, tert-butanol. The amount used is generally 2-10 times, preferably 3-8 times, the weight of the raw material corresponding to general formula (I).

The alkali in the bromination reaction is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or their aqueous solutions of any concentration, or use any concentration of sodium methylate methanol solution, sodium ethylate ethanol solution, sodium isopropoxide isopropanol solution , sodium tert-butoxide tert-butanol solution, preferably solid sodium hydroxide, potassium hydroxide, potassium carbonate; the usage amount is generally 1-2 times of the molar weight of the raw material of general formula (I), preferably the usage amount is 1-1.5 times . The bromination reaction temperature is 0-100°C, preferably the use temperature is 20-80°C.

In the present invention, preferably, the ^R substituents are independently selected from H or fluorine; the ^R substituents are independently selected from 2-methoxyethyl, 2-ethoxyethyl, 2-n-propoxy Ethyl, 2-isopropoxyethyl, 2-n-butoxyethyl, cyclopropylmethyl, methyl or ethyl; R ³ is methyl.

The present invention also provides heptafluoroisopropyl-containing bisamide compound crystals. When ^R1 is H and ^R2 is 2-methoxyethyl, the crystal X-ray powder diffraction has 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°.

When R ^is fluorine and R is 2-methoxyethyl, the crystal x-ray powder diffraction has characteristic peaks at the following positions:

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°, 20.379±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°.

When R ^is fluorine and R is ² -ethoxyethyl, the crystal x-ray powder diffraction has characteristic peaks at the following positions:

2θ＝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°, 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°.

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

The bisamide compound containing heptafluoroisopropyl group obtained in the present invention has excellent insecticidal activity, the chemical reaction conditions are mild, the environment is friendly, the total yield is high, the final product content is high, the cost is low, it is easy for industrial production, and has great advantages. high application prospects.

In the present invention, operations such as distillation, vacuum distillation, filtration, drying, extraction, layering, crystallization, and recrystallization involved in the preparation method operations are conventional operations, and will not be described in detail again.

【Description of drawings】

Fig. 1 is the result of X-ray powder crystal diffraction analysis of the compound sample of Synthesis Example 17;

Fig. 2 is the result of X-ray powder crystal diffraction analysis of the compound sample of Synthesis Example 18;

Fig. 3 is the X-ray powder crystal diffraction analysis result of the compound sample of Synthesis Example 20.

【Detailed ways】

The following examples are used to explain the technical solutions of the present invention non-limitatively, and should not be regarded as specific limitations to the present invention.

The raw materials described in the synthesis examples of the present invention, unless otherwise specified, are generally purchased from the market, usually with a content specification ≥ 95%, and the content is not accurately corrected. Unless otherwise specified, the percentage concentrations described in the synthesis examples are Generally refers to the concentration by weight percentage, the HPLC content data is the area normalized content, without precise correction, and the yield refers to the molar yield, and the yield data is not precisely corrected.

Synthetic Preparation Example 1

In a 250ml four-necked glass reaction flask, put methanol 100g, 2-fluoro-3-nitrobenzoic acid 50g, 98% sulfuric acid 2.5g, heat up and reflux for 24 hours, cool down to about 0-5°C to crystallize, filter, 50 Dry at °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 was used for the synthesis reaction.

Synthetic Preparation Example 2

In a 250ml four-necked glass reaction flask, put 100g of ethanol, 50g of 2-fluoro-3-nitrobenzoic acid, 2.5g of 98% sulfuric acid, heat up and reflux for 24 hours, cool down to about 0-5°C to crystallize, filter, 50 After drying at ℃, 54.5 g of ethyl 2-fluoro-3-nitrobenzoate was obtained as a solid, with an HPLC content of 98% and a yield of 94.6%, which was used for the synthesis reaction.

Synthetic Preparation Example 3

In a 500ml hydrogenation reactor, drop into methanol 250g, 5% palladium charcoal and dry 2g (water content 50%), drop into the solid of 2-fluoro-3-nitrobenzoic acid methyl ester 51g that synthesis prepares embodiment 1 to obtain, airtight In the reaction kettle, after replacing the air with nitrogen, replace the nitrogen twice with hydrogen, maintain the pressure at 5-15°C at 0-0.05MPa, and feed hydrogen to react for 12 hours. HPLC detects that the reaction is complete, take it out, and filter out the catalyst (recoverable for mechanical use). The filtrate was precipitated under reduced pressure to obtain 43 g of 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.

Synthetic Preparation Example 4

In the 500ml hydrogenation reactor, drop into methyl alcohol 250g, 5% palladium charcoal is dried 2g (moisture content 50%), drop into the 2-fluoro-3-nitrobenzoic acid ethyl ester 54.5g solid that synthetic preparation embodiment 2 obtains, Close the reaction kettle, replace the air with nitrogen, replace the nitrogen with hydrogen twice, maintain the pressure at 5-15°C at 0-0.05MPa, feed hydrogen to react for 12 hours, HPLC detects that the reaction is complete, take it out, and filter out the catalyst (recoverable and applicable) , the filtrate was precipitated under reduced pressure to obtain 46 g of oily liquid, which was ethyl 2-fluoro-3-aminobenzoate, with an HPLC normalized content of 96%, and a yield of 96.3%, which was used for the synthesis reaction.

Synthetic Preparation Example 5

25g (0.20mol) of benzoic acid and 72g (0.60mol) of thionyl chloride were heated and refluxed for 2-5 hours, cooled to room temperature, the reaction solution was rotary evaporated, and the solvent was removed to 80°C under reduced pressure to obtain benzoyl chloride oily liquid. Cool down to about 25°C, add 25g of new dichloroethane to dissolve and set aside.

In another 250ml four-necked glass reaction bottle, put 100g of dichloroethane, 35g (0.20mol) of 3-amino-2-fluorobenzoic acid methyl ester, 24g (0.30mol) of pyridine, and cool down to 5-25°C in an ice bath , drop the above benzoyl chloride stock solution within 1 hour, react at 5-25°C for 1-2 hours, the reaction is completed, add 50ml of water, stir for 0.5 hours, separate layers to obtain a solvent layer, transfer to a 500ml rotary evaporator, and reduce pressure Precipitate to 80°C to obtain 53 g of off-white solid of methyl 2-fluoro-3-[(phenylcarbonyl)amino]benzoate, HPLC normalized content 94% (yield 91.2%) for later use, without further processing in the synthesis reaction.

Synthetic Preparation Example 6

According to the similar operation of synthesis preparation example 5, wherein 3-amino-2-fluorobenzoic acid methyl ester 35g (0.20mol) raw material is 3-amino-2-fluorobenzoic acid ethyl ester 38g (0.20mol) obtained in synthesis preparation example 4 Replacement, other unchanged, finally obtained 2-fluoro-3-[(phenylcarbonyl)amino]ethyl benzoate off-white solid 55g, HPLC normalized content 94% (yield 90%) standby, do not do further processing directly for synthesis reactions.

Synthetic Preparation Example 7

According to the synthesis preparation example 5, 25g (0.20mol) of benzoic acid was replaced by 28g (0.20mol) of p-fluorobenzoic acid, and the other operations were the same, and finally 2-fluoro-3-[(4-fluorophenylcarbonyl)amino] was obtained Methyl benzoate was 56 g of off-white solid, with HPLC normalized content of 94% (yield 90.2%) for later use, and was directly used in the synthesis reaction without further treatment.

Synthesis Example 1

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

In a 250ml four-necked glass reaction flask, add solvent N,N-dimethylformamide 200g, alkali potassium carbonate 15g (0.10mol), then drop into the 2-fluoro-3-[( Phenylcarbonyl)amino]methyl benzoate material 25g (0.086mol), catalyst tetrabutylammonium bromide 1g, warming up to 55-65°C, drop 1-bromo-2-methoxyethane 15.8 g in 1 hour g (0.11mol), heat preservation reaction for about 2 hours, cool the water to room temperature, filter, and desolvate the filtrate under reduced pressure to obtain the residual material, add methanol 50g, 10% liquid caustic soda 60g (0.15mol), heat up 25-35°C, keep warm React for about 2 hours, add 150g of water, 30% hydrochloric acid to adjust the pH to 1-2, crystallize at about 10-25°C, filter, wash with water, and dry to obtain 26.5g of off-white solid, melting point: 155.8-157.9°C, normalized content by HPLC About 95%, yield 92.3%, 2-fluoro-3-[(2-methoxyethyl)(phenylcarbonyl)amino]benzoic acid. The reaction formula is as follows:

Synthesis Example 2-4

According to the operation of Synthesis Example 1, the catalyst tetrabutylammonium bromide 1g is replaced with tetrabutylammonium chloride 1g, tetrabutylammonium bisulfate 1g, 18-crown-6-ether 1g respectively, and other materials and operations are not changed. changed, the results were similar.

Synthesis Example 5

In a 250ml four-necked glass reaction flask, drop into solvent toluene 100g, drop into alkali potassium carbonate 15g (0.10mol), drop into the 2-fluoro-3-[(phenylcarbonyl) amino] benzoic acid that synthetic preparation embodiment 5 synthesis obtains 25g (0.086mol) of methyl ester material, 1g of catalyst tetrabutylammonium bromide, 15.8g (0.11mol) of 1-bromo-2-methoxyethane was added, the reflux water separator was installed, the temperature was raised to reflux reaction, and the The reaction generates water, and the reflux reaction is about 2 hours until anhydrous is formed, the water is cooled to room temperature, filtered, the filtrate is desolvated under reduced pressure, and the residue is obtained. Add methanol 50g, 10% liquid caustic soda 60g (0.15mol), and heat up for 25- 35°C, heat preservation reaction for about 2 hours, add 150g of water, 30% hydrochloric acid to adjust the pH to 1-2, crystallize at about 10-25°C, filter, wash with water, and dry to obtain 27g of off-white solid, the normalized content of HPLC is about 95%. Yield 94%, 2-fluoro-3-[(2-methoxyethyl)(phenylcarbonyl)amino]benzoic acid.

Synthesis Example 6-7

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

Synthesis Example 8

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

In a 250ml four-necked glass reaction flask, drop into solvent dichloroethane 100g, 4-fluorobenzoic acid 12.5g (0.088mol), thionyl chloride 25g (0.20mol), heat up and reflux for 2-5 hours, reduce The oily liquid obtained by pressure precipitation is 4-fluorobenzoyl chloride, which is ready for use.

In another 250ml four-necked glass reaction bottle, put in 200g of N,N-dimethylformamide as a solvent, protect it under nitrogen, put in 3.5g (0.091mol) of alkali 60% sodium hydride, and then put it into synthesis preparation Example 3 to synthesize 15g (0.086mol) of methyl 2-fluoro-3-aminobenzoate, catalyst tetrabutylammonium bromide 1g, add 16.8g (0.11mol) of 1-bromo-2-ethoxyethane, and heat up to 110- 120°C, heat preservation reaction for about 8 hours, cool the water to room temperature, filter, and precipitate the filtrate under reduced pressure, add 100ml of dichloroethane to extract the residual material, wash with water (the H NMR spectrum and mass spectrum data of the product are attached), use the solvent layer The filtrate obtained by drying and filtering over anhydrous magnesium sulfate was added at 25-35°C with the 4-fluorobenzoyl chloride synthesized above, heated to reflux for 2-5 hours, and desolvated under reduced pressure to obtain the residual oily material (product NMR , mass spectrum data attached), add methanol 50g, 10% liquid caustic soda 60g (0.15mol), heat up 25-35 ℃, heat preservation reaction for about 2 hours, add water 150g, 30% hydrochloric acid to adjust the pH to 1-2, 10-25 Crystallize at about ℃, filter, wash with water, and dry to obtain 29.4g beige solid, melting point: 77.3-79.2℃, HPLC normalized content about 92%, yield 90.1%. It is 2-fluoro-3-[(2-ethoxy Ethyl)(phenylcarbonyl)amino]benzoic acid (the H NMR spectrum and mass spectrometry data of the product are attached). The reaction formula is as follows:

The H NMR spectrum was measured using Bruker AV-400spectrometer (400MHz), TMS was used as an internal standard, and the solvent was CDCl ₃ or DMSO-d6 (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).

2-Fluoro-3-[(2-ethoxyethyl)amino]benzoic acid methyl ester proton magnetic spectrum, mass spectral data are as follows:

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).

HRMS (ESI) calcd. for C ₁₂ H ₁₆ FNNaO ₃ [(M+Na)+]: 264.1012; Found: 264.0988.

2-Fluoro-3-(4-fluoro-N-(2-ethoxyethyl) benzamido) methyl benzoate H NMR spectrum, mass spectrometry data are as follows:

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).

HRMS (ESI) calcd. for C ₁₉ H ₁₉ F ₂ NNaO ₄ [(M+Na)+]: 386.1180; Found: 386.1173.

2-Fluoro-3-[(2-ethoxyethyl)(phenylcarbonyl)amino]benzoic acid has the following H NMR and mass spectrometry data:

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).

HRMS (ESI) calcd. for C ₁₈ H ₁₇ F ₂ NNaO ₄ [(M+Na)+]: 372.1023; Found: 372.1024.

Synthesis Example 9

According to the operation of Synthesis Example 8, 1 g of 4-dimethylaminopyridine (DMAP) was added in the second step of amidation, and the other materials and operations were unchanged, and the obtained results were similar.

Synthesis Example 10

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

In a 250ml four-necked glass reaction flask, put 100g of dichloroethane as solvent, 12.5g (0.088mol) of p-fluorobenzoic acid, 25g (0.20mol) of thionyl chloride, heat up and reflux for 2-5 hours, and depressurize The oily liquid obtained by precipitation is p-fluorobenzoyl chloride, which is ready for use.

In another 250ml four-necked glass reaction flask, drop into solvent toluene 100g, drop into alkali potassium carbonate 15g (0.10mol), drop into the 2-fluoro-3-aminobenzoic acid methyl ester 15g (0.086 mol), catalyst tetrabutylammonium bromide 1g, add 1-bromo-2-methoxyethane 15.8g (0.11mol), heat up to 100-120°C, reflux dehydration reaction, about 5 hours, water cooling to At room temperature, filter, wash with water, and desolvate under reduced pressure to obtain the material (product NMR, mass spectrometry data is attached) and add 100 g of dichloroethane to dissolve it. At 25-35 ° C, add the p-fluorobenzoyl chloride synthesized above, and heat up to reflux React for 2-5 hours. Cool down and add 100ml of water, separate layers, wash, and desolvate under reduced pressure to obtain residual oily material (product NMR, mass spectrometry data are attached), add methanol 50g, 10% liquid caustic soda 60g (0.15mol), heat up 25-35°C, Insulate and react for about 2 hours, add 150g of water, 30% hydrochloric acid to adjust the pH to 1-2, crystallize at about 10-25°C, filter, wash with water, and dry to obtain 28g of beige solid, melting point: 120.5-122.5°C, normalized content by HPLC About 93%, the yield is 90.3%, and it is 2-fluoro-3-[(2-methoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid (product NMR and mass spectrometry data are attached). The reaction formula is as follows:

2-Fluoro-3-[(2-methoxyethyl)amino]benzoic acid methyl ester proton magnetic spectrum, mass spectral data are as follows:

¹ H-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 = 3.9 Hz, 2H, OCH2), 3.25-7.24 (m, 5H, NCH2 and OCH3).

HRMS (ESI) calcd. for C ₁₁ H ₁₄ FNNaO ₃ [(M+Na)+]: 250.0855; Found: 250.0836.

2-Fluoro-3-(4-fluoro-N-(2-methoxyethyl) benzamido) methyl benzoate H NMR spectrum, mass spectrometry data are as follows:

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,2H,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 F ₂ NNaO ₄ [(M+Na)+]: 372.1023; Found: 372.1024.

2-Fluoro-3-[(2-methoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid has the following H NMR and mass spectrometry data:

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,ArH),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 F ₂ NNaO ₄ [(M+Na)+]: 358.0867; Found: 358.0858.

Synthetic Example 11

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

In a 500ml pressure reactor, put in 200g of solvent N,N-dimethylformamide, drop in 15g (0.10mol) of alkali potassium carbonate, and put in the 2-fluoro-3-[(phenyl Carbonyl)amino]methyl benzoate material 25g (0.086mol), catalyst tetrabutylammonium bromide 1g, bromide 20g (0.21mol) at room temperature, airtight reaction kettle, heat up to 55-65°C, heat preservation reaction for about 2 hours , cooled to room temperature, filtered, and the filtrate was desolvated under reduced pressure to obtain an oily liquid, added 50g of methanol, 60g (0.15mol) of 10% liquid caustic soda, raised the temperature to 25-35°C, kept the temperature for about 2 hours, added 150g of water, 30% hydrochloric acid to adjust pH is 1-2, crystallized at around 10-25°C, filtered, washed with water, dried to obtain 23g off-white solid, HPLC normalized content about 95%, yield 93%, is 2-fluoro-3-[(methyl) (Phenylcarbonyl)amino]benzoic acid. The reaction formula is as follows:

Synthetic Example 12

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 added to an autoclave. The 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 %, 2-fluoro-3-[(ethyl)(phenylcarbonyl)amino]benzoic acid. The reaction formula is as follows:

Synthetic Example 13

In a 250ml four-necked glass reaction flask, drop in 100g of solvent toluene, drop in 15g (0.10mol) of alkali potassium carbonate, and drop in the 2-fluoro-3-[(4-fluorophenylcarbonyl)amino synthesized in Preparation Example 7 ] methyl benzoate material 26.7g (0.086mol), catalyzer tetrabutylammonium bromide 1g, add 1-bromo-2-methoxyethane 15.8g (0.11mol), load back flow separator, be warming up to Reflux reaction, removal of reaction to generate water, reflux reaction for about 2 hours, until anhydrous is generated, water is cooled to room temperature, filtered, desolvated under reduced pressure, to obtain residual material, add methanol 50g, 10% liquid caustic soda 60g (0.15mol), Raise the temperature to 25-35°C, keep it warm for about 2 hours, add 150g 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 28.5g of beige solid, melting point: 122.5- 123.4°C, HPLC normalized content about 95%, yield 93.9%, 2-fluoro-3-[(2-methoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid. The H NMR spectrum and mass spectrometry data of the reaction formula and the product are as follows:

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,ArH),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 F ₂ NNaO ₄ [(M+Na)+]: 358.0867; Found: 358.0858.

Synthetic Example 14

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

Synthetic Examples 15-16

According to the operation of Synthesis Example 1 and Synthesis Example 5 respectively, 25 g (0.086 mol) of 2-fluoro-3-[(phenylcarbonyl) amino]methyl benzoate material was prepared from the 2-fluoro-3- [(phenylcarbonyl)amino]benzoic acid ethyl ester 26.3g (0.086mol) was replaced, other operations were the same, and the results obtained were similar.

Synthetic Comparative Example 1

According to Synthesis Example 1, wherein the catalyst tetrabutylammonium bromide 1g is not added, other materials and operations are all the same, and finally 24g off-white solid is obtained, the target product 2-fluoro-3-[(2-methoxyethyl) (Phenylcarbonyl)amino]benzoic acid HPLC normalized content is about 55%, the yield is 48.3%, and the others are mainly 2-fluoro-3-[(phenylcarbonyl)amino]benzoic acid.

Synthetic Comparative Example 2

According to Synthesis Example 5, wherein the catalyst tetrabutylammonium bromide 1g is not added, other materials and operations are all the same, and finally 21g off-white solid is obtained, the target product 2-fluoro-3-[(2-methoxyethyl) (Phenylcarbonyl)amino]benzoic acid HPLC normalized content of about 5%, yield 3.8%, the other is mainly 2-fluoro-3-[(phenylcarbonyl)amino]benzoic acid.

Synthetic Comparative Example 3

According to the operation of Synthesis Example 8, wherein catalyst tetrabutylammonium bromide 1g was not added, other feeding and operations were all the same, and finally the oily material was obtained with a normalized content of about 45%, and no solid crystal of the target product was obtained.

Synthetic Example 17

2-Fluoro-3-[(phenylcarbonyl)(2-methoxyethyl)amino]-N-[2-bromo-4-(1,1,1,2,3,3,3-heptafluoropropane-2 -Synthetic preparation of -6-(trifluoromethyl)phenyl]benzamide.

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

Cool down to room temperature, add 20g of powdered potassium carbonate, drop in 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, and desolvate the filtrate under reduced pressure to obtain the residual material, add Ethanol 120g, heat up and reflux for 1 hour, cool down to 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 about 98%, three steps The total yield is 81.9%. The reaction formula is as follows:

The H NMR and mass spectrometry data are as follows:

The proton nuclear magnetic spectrum uses Bruker AV-400spectrometer (400MHz), TMS is used as internal standard, the solvent uses DMSO-d6 (if no special instructions, the same below); high resolution mass spectrum is measured using UHR-TOF maXis (ESI) mass spectrometer (if no Special instructions, the same below).

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).

HRMS(ESI)calcd.for C ₂₇ H ₁₈ BrF ₁₁ N ₂ NaO ₃ [(M+Na) ⁺ ]: 729.0223[(M+Na) ⁺ ], 731.0202[(M+2+Na) ⁺ ]; Found: 729.0213[(M+Na) ⁺ ], 731.0196[(M+2+Na) ⁺ ].

The target compound sample was analyzed by X-ray powder crystal diffraction, and the instrument was analyzed by Rigaku SmartLab diffractometer (unless otherwise specified, the same below). The crystal has 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 attached drawing 1 for details.

The sample obtained in this synthesis example was recrystallized with 3 times the weight of isopropyl ether, and the finally obtained sample was analyzed by X-ray powder crystal diffraction, and the crystal characteristic peaks were completely consistent with the above.

The sample obtained in this synthesis example was recrystallized with 3 times the weight of ethylene glycol monomethyl ether, and the finally obtained sample was analyzed by X-ray powder crystal diffraction, and the crystal characteristic peaks were completely consistent with the above.

The above results show that the obtained compound is crystallized in ethanol, isopropyl ether, and ethylene glycol monomethyl ether solvents respectively, and the crystals are consistent in type, easy to obtain and good in stability.

Synthetic Example 18

2-fluoro-3-[(4-fluorophenylcarbonyl)(2-methoxyethyl)amino]-N-[2-bromo-4-(1,1,1,2,3,3,3- Synthetic preparation of heptafluoropropan-2-yl)-6-(trifluoromethyl)phenyl]benzamide.

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

The H NMR and mass spectrometry data are as follows:

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 6.8 Hz,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).

HRMS(ESI)calcd.for C ₂₇ H ₁₇ BrF12N ₂ NaO ₃ [(M+Na)+]:747.0129[(M+Na)+],749.0108[(M+2+Na)+]; Found:747.0111[ (M+Na)+], 749.0094[(M+2+Na)+].

The target compound sample is analyzed by X-ray powder crystal diffraction, and the crystal has characteristic peaks at the following positions, 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°, 20.379±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°.

The sample obtained in this synthesis example was recrystallized with 3 times the weight of ethanol, and the finally obtained sample was analyzed by X-ray powder crystal diffraction, and the crystal characteristic peaks were completely consistent with the above.

The sample obtained in this synthesis example was recrystallized with 3 times the weight of isopropyl ether, and the finally obtained sample was analyzed by X-ray powder crystal diffraction, and the crystal characteristic peaks were completely consistent with the above.

The above results show that the obtained compound is crystallized in ethanol, isopropyl ether, and ethylene glycol monomethyl ether solvents respectively, and the crystals are consistent in type, easy to obtain and good in stability.

Synthetic Example 19

2-fluoro-3-[(4-fluorophenylcarbonyl)(2-methoxyethyl)amino]-N-[2-bromo-4-(1,1,1,2,3,3,3- Synthetic preparation of heptafluoropropan-2-yl)-6-(trifluoromethyl)phenyl]benzamide.

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

Synthetic Example 20

2-fluoro-3-[(4-fluorophenylcarbonyl)(2-ethoxyethyl)amino]-N-[2-bromo-4-(1,1,1,2,3,3,3- Synthetic preparation of heptafluoropropan-2-yl)-6-(trifluoromethyl)phenyl]benzamide.

In the four-necked glass reaction bottle of 250ml, drop into dichloroethane 200g, the 2-fluoro-3-[(2-ethoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid 26g that synthesis embodiment 8 obtains (0.071mol), 24g (0.20mol) of thionyl chloride, heated and refluxed for 3-5 hours, cooled to room temperature, the reaction solution was transferred to a 500ml rotary evaporator, and desolvated to 80°C under reduced pressure to obtain an acid chloride oily liquid. Cool down to about 25°C, add 150g of toluene to dissolve, transfer to the reaction flask, and add 4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2-(trifluoromethyl ) 27.8g (0.08mol) of aniline raw material, heated and refluxed for 5-10 hours, desolvated under reduced pressure to obtain the residue, added 120g of methanol, cooled to room temperature, added 5g of sodium hydroxide, and dripped in about 2 hours at 35-55°C Put 13.5g of bromine into the liquid to react, keep warm for 2 hours, add 50ml of water, separate and separate the water layer, obtain the solvent layer and precipitate under reduced pressure to obtain the residual material, add 120g of isopropyl ether, heat up and reflux for 1 hour, cool down and crystallize, at 0 Crystallize at -5°C for 1 hour, filter and dry to obtain 44.5 g of white crystalline powder solid, which is the target compound, melting point: 168.2-169.2°C, HPLC normalized content of about 98%, and the total yield of three steps is 83.1%. The reaction formula is as follows:

The H NMR and mass spectrometry data are as follows:

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 6.8 Hz,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).

HRMS(ESI) calcd. For C ₂₈ H ₁₉ BrF ₁₂ N ₂ NaO ₃ [(M+Na) ⁺ ]: 761.0285[(M+Na) ⁺ ], 763.0265[(M+2+Na) ⁺ ]; Found: 761.0263[(M+Na) ⁺ ], 763.0248[(M+2+Na) ⁺ ].

The target compound sample is analyzed by X-ray powder crystal diffraction, and the crystal has characteristic peaks at the following positions, 2θ

=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°, 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°, see attached drawing 3 for details.

The sample obtained in this synthesis example was recrystallized with 3 times the weight of ethanol, and the finally obtained sample was analyzed by X-ray powder crystal diffraction, and the crystal characteristic peaks were completely consistent with the above.

The sample obtained in this synthesis example was recrystallized with 3 times the weight of ethylene glycol monomethyl ether, and the finally obtained sample was analyzed by X-ray powder crystal diffraction, and the crystal characteristic peaks were completely consistent with the above.

The sample obtained in this synthesis example was recrystallized with 3 times the weight of ethylene glycol dimethyl ether, and the finally obtained sample was analyzed by X-ray powder crystal diffraction, and the crystal characteristic peaks were completely consistent with the above.

It shows 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.

The samples obtained in this synthesis example were recrystallized with 3 times the weight of methanol, isopropanol, tetrahydrofuran, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, and methyl tert-butyl ether, and the finally obtained samples were subjected to X - X-ray powder crystal diffraction analysis, the crystal characteristic peaks are exactly the same as above.

Note that the compounds are respectively in 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 The crystals obtained by crystallization in solvents such as ether have consistent crystal types, are easy to obtain and have good stability.

Synthetic Example 21

2-Fluoro-3-[(phenylcarbonyl)(methyl)amino]-N-[2-bromo-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)- Synthetic preparation of 6-(trifluoromethyl)phenyl]benzamide.

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

The H NMR and mass spectrometry data are as follows:

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).

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

Synthetic Example 22

2-Fluoro-3-[(phenylcarbonyl)(ethyl)amino]-N-[2-bromo-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)- Synthetic preparation of 6-(trifluoromethyl)phenyl]benzamide.

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

Synthetic Example 23

2-Fluoro-3-[(4-fluorophenylcarbonyl)(cyclopropylmethyl)amino]-N-[2-bromo-4-(1,1,1,2,3,3,3-heptafluoropropane Synthetic preparation of -2-yl)-6-(trifluoromethyl)phenyl]benzamide.

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

Synthetic Example 24

2-fluoro-3-[(4-cyanophenylcarbonyl)(2-ethoxyethyl)amino]-N-[2-bromo-4-(1,1,1,2,3,3,3 Synthetic preparation of -heptafluoropropan-2-yl)-6-(trifluoromethyl)phenyl]benzamide.

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

The H NMR and mass spectrometry data are as follows:

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).

HRMS(ESI)calcd.for C ₂₉ H ₁₉ BrF ₁₁ N ₃ NaO ₃ [(M+Na)+]:768.0332[(M+Na)+],770.0311[(M+2+Na)+]; Found: 768.0310 [(M+Na)+], 770.0293 [(M+2+Na)+].

Synthetic Example 25

According to the operation of Synthesis Example 13, 15.8g (0.11mol) of 1-bromo-2-methoxyethane was replaced by 18.7g (0.11mol) of 1-bromo-2-n-propoxyethane, and other materials and The operation is the same, and the yield and content of the intermediate 2-fluoro-3-[(2-n-propoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid obtained are similar. The target compound was synthesized according to the similar operation of Synthesis Example 20, wherein the raw material 2-fluoro-3-[(2-ethoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid 26g (0.071mol) was obtained from above 2-fluoro-3-[(2-propoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid 27g (0.071mol) instead, other operations were similar, and finally the target compound was obtained: 2-fluoro-3- [(4-fluorophenylcarbonyl)(2-n-propoxyethyl)amino]-N-[2-bromo-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl )-6-(trifluoromethyl)phenyl]benzamide, melting point: 156.5-156.8, yield and content are similar.

Other compounds of general formula (I) or (II) of the present invention can be synthesized with reference to the methods in the above examples.

Example of biological activity test

A variety of pests have been tested with some compounds of the general formula (II) obtained in the present invention.

Compound preparation: take a certain quality of the original drug with a balance (0.001g), prepare a 1% mother solution with DMF, then dilute it with distilled water containing 0.1% Tween-80 to a test concentration for later use; For component content, take a certain quality preparation sample with a balance (0.001g), and dilute it with distilled water to a test concentration for later use.

Table 1: Some compounds of general formula (II)

Test embodiment 1 part general formula (II) compound is to diamondback moth indoor biological activity assay

The sensitive population of diamondback moth (Plutella xylostella) and the population resistant to chlorantraniliprole were reared with radish seedlings indoors;

Test method: Determination of Plutella xylostella activity: Using the dipping method, take an appropriate amount of radish leaves and soak them in the drug for 30 seconds, and then place them in a plastic petri dish lined with filter paper to dry naturally in the shade. Take 10 2-year-old Plutella xylostella in each dish, and place them at 22°C under light. (16/8h) Observation room. Observe after 2 days, lightly touch the worm body with a brush, if there is no response, it is regarded as a dead worm, repeat 3 times, and set up a blank control without adding medicine.

Result of the test: some general formula (II) compound SYN101 etc. are shown in table two to the active assay result of diamondback moth:

The results show that: at the test concentration of 0.2mg/L, 0.1mg/L, and 0.05mg/L, the activity of compounds SYN101, SYN102, SYN103, SYN104, SYN105, SYN106, and SYN107 on the sensitive populations of Plutella xylostella and the resistance of Plutella xylostella The amide population activity all showed excellent insecticidal activity, all greater than 80%. At a low concentration of 0.05mg/L, the activity of SYN104, SYN105, SYN106, and SYN107 on the sensitive population of Plutella xylostella and the activity of Plutella xylostella resistant to chlorantraniliprole remained the same. Exhibit excellent insecticidal activity, all up to 100%.

Table 2: The activity measurement result of some general formula (Ⅱ) compounds to Plutella xylostella

Test embodiment 2 part general formula (II) compound is to the indoor biological activity determination of Spodoptera frugiperda

Determination of the activity of Spodoptera frugiperda: Using the dipping method, take an appropriate amount of corn leaves to soak the drug for 30 seconds, put it in a plastic petri dish lined with filter paper and dry it naturally in the shade, pick up 10 2-year-old Spodoptera frugiperda in each dish, and place it at 26°C. Light (16/8h) observation room. Observe after 2 days, lightly touch the worm body with a brush, if there is no response, it is regarded as a dead worm, repeat 3 times, and set up a blank control without adding medicine.

Test results: some general formula (II) compounds SYN101 etc. are shown in Table 3 to the indoor biological activity assay test results of Spodoptera frugiperda:

The result shows: compound SYN101, SYN102, SYN103 all have good activity when test concentration 0.2mg/L, reach 100%, when test concentration 0.1mg/L, activity is slightly poor, but all greater than 80%, in When the test concentration is 0.05mg/L, the activity is poor. When the test concentration was 0.2mg/L, 0.1mg/L, and 0.05mg/L, the compounds SYN104, SYN105, SYN106, and SYN107 all showed excellent insecticidal activity, reaching 100%.

Table 3: The results of the activity assay of some general formula (II) compounds on Spodoptera frugiperda

The applicant declares that the present invention illustrates a preparation method of a heptafluoroisopropyl-containing bisamide compound and its intermediate through the above representative examples, but the present invention is not limited to the above examples, nor It means that the present invention can only be realized by relying on the above-mentioned embodiments. Those skilled in the art should understand that any improvement of the present invention, the equivalent replacement of each raw material of the product of the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within the scope of protection and disclosure of the present invention.

Claims (13)

1. A preparation method for an intermediate compound of a bisamide compound containing heptafluoroisopropyl, wherein the intermediate is shown in the following general formula (I),

Wherein, the substituents ^of R are independently selected from H, fluorine, trifluoromethyl, cyano or nitro; R 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. It is characterized in that the process flow of the preparation method of the intermediate compound with the structure shown in the general formula (I) is as formula (1) or formula (2):

Wherein, R ³ is an alkyl group of C1-C5; The N-alkylation reaction solvent is selected from: N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, 1, One or more of 3-dimethyl-2-imidazolinone, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dichloroethane, cyclohexane, methylcyclohexane, toluene, ethylbenzene, xylene a mixture; The N-alkylation reaction alkali is selected from: potassium carbonate, sodium carbonate, sodium hydride; The N-alkylation bromoalkane is selected from: 2-methoxybromoethane, 2-ethoxybromoethane, 3-methoxybromopropane, 3-ethoxybromopropane, 2- n-propoxybromoethane, 2-isopropoxybromoethane, 2-n-butoxybromoethane, bromomethylcyclopropane, bromomethyl or bromoethane; The N-alkylation reaction catalyst is selected from: cetyltrimethylammonium chloride, benzyltriethylammonium chloride, polyethylene glycol 400-800, tetrabutylammonium chloride, tetrabutylammonium chloride One or more mixtures of ammonium bromide, tetrabutylammonium bisulfate, 15-crown-5 ether, 18-crown-6-ether or 4-dimethylaminopyridine (DMAP); The amidation reaction solvent is selected from: N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, 1,3-di Methyl-2-imidazolinone, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, ethyl acetate, dichloromethane, dichloroethane, cyclohexane, methylcyclohexane, toluene, ethylbenzene, xylene one or more mixtures of . 2. A preparation method of a bisamide compound containing heptafluoroisopropyl, said compound having a structure shown in the following general formula (II),

Wherein, the substituents ^of R are independently selected from H, fluorine, trifluoromethyl, cyano or nitro; R 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. It is characterized in that the process flow of the preparation method of the compound represented by the general formula (II) is as shown in formula (3):

Wherein, the substituents ^of R are independently selected from H, fluorine, trifluoromethyl, cyano or nitro; R 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; The amidation reaction solvent is selected from one or more of dichloromethane, dichloroethane, cyclohexane, methylcyclohexane, toluene, ethylbenzene, xylene, ethyl acetate, tetrahydrofuran or acetonitrile mixture; The bromination reaction solvent is selected from: one or more mixtures in methylene chloride, ethylene dichloride, methanol, ethanol, isopropanol, and tert-butanol; The bromination reaction alkali is selected from: sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or their aqueous solutions. 3. The preparation method according to claim 1, characterized in that R is ^methyl or ethyl. 4. preparation method according to claim 1 is characterized in that R ³ is methyl. 5. according to the described preparation method of claim 1 or 2, it is characterized in that R ¹ substituent is independently selected from H or fluorine; R ² substituents are independently selected from 2-methoxyethyl, 2-ethoxy Ethyl, 2-n-propoxyethyl, 2-isopropoxyethyl, 2-n-butoxyethyl, cyclopropylmethyl, methyl or ethyl. 6. preparation method according to claim 1 is characterized in that N-alkylation reaction catalyst is selected from: tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium bisulfate, 15-crown- One or more mixtures of 5-ether, 18-crown-6-ether or 4-dimethylaminopyridine (DMAP). 7. The preparation method according to claim 1, characterized in that the N-alkylation reaction temperature is 50°C-150°C; the amidation reaction temperature is 0°C-150°C. 8. The preparation method according to claim 2, wherein the amidation reaction temperature is 20°C-180°C; the bromination reaction temperature is 0°C-100°C. 9. according to the described preparation method of claim 2 or 8, it is characterized in that amidation reaction solvent is selected from: one or more mixtures in dichloroethane, cyclohexane, methylcyclohexane, toluene or acetonitrile The bromination reaction solvent is selected from: one or more mixtures in ethylene dichloride, methyl alcohol, ethanol, Virahol, tert-butanol; The bromination reaction alkali is selected from: sodium hydroxide, potassium carbonate or their aqueous solution . 10. The crystal of the compound prepared by the preparation method according to claim 2, the compound has a structure as shown in general formula (II), when R ¹ is H and R ² is 2-methoxyethyl, its It is characterized in that the crystal X-ray powder diffraction has 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°. 11. The crystal of the compound prepared by the preparation method according to claim 2, the compound has a structure as shown in general formula (II), when R ¹ is fluorine and R ² is 2-methoxyethyl, its It is characterized in that the crystal X-ray powder diffraction has characteristic peaks at the following positions, 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°, 20.379±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 °. 12. The crystal of the compound prepared by the preparation method according to claim 2, the compound has a structure as shown in general formula (II), when R ¹ is fluorine and R ² is 2-ethoxyethyl, its It is characterized in that the crystal X-ray powder diffraction has characteristic peaks at the following positions, 2θ=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°, 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°. 13. The crystal according to any one of claims 10-12, characterized in that the crystallization solvent is methanol, ethanol, isopropanol, tetrahydrofuran, isopropyl ether, ethylene glycol monomethyl ether, ethylene glycol mono One or more mixtures of diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, and methyl tert-butyl ether.

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