CN115974717A

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

Info

Publication number: CN115974717A
Application number: CN202211560250.1A
Authority: CN
Inventors: 沈新良; 吴华龙; 曹端祥; 曹后红; 潘丽英; 黄文超; 沈浩; 王海涛
Original assignee: Zhejiang Yulong Pharmaceutical Co ltd
Current assignee: Zhejiang Yulong Pharmaceutical Co ltd
Priority date: 2021-12-22
Filing date: 2022-12-07
Publication date: 2023-04-18

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

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

The invention requests two priorities of our country, namely, the priority date is 22/12/2021, the priority number is CN 2021115835066, the invention patent application with the title of 'a compound of bisamide containing heptafluoroisopropyl, and the preparation method and application thereof', and the priority date is 24/10/2022, the priority number is CN

2022113037189, entitled "a bis-amide compound containing heptafluoroisopropyl and its intermediate compound, its preparation method and application".

[ technical field ] A method for producing a semiconductor device

The invention belongs to the field of pesticides, and relates to a heptafluoroisopropyl-containing bisamide compound and an intermediate compound thereof, a preparation method of the compounds, an x-ray powder diffraction characteristic of a heptafluoroisopropyl-containing bisamide compound crystal, and application of the compounds.

[ technical background ] A method for producing a semiconductor device

Due to the frequent use of a large amount of pesticides, the pesticide causes serious resistance problems in most regions of the world at present, the original effect can be achieved only by increasing the dosage, some diseases can not be cured by medicines, and certain problems are caused to agricultural production, environment and ecology. There is a need to provide new pesticides with better activity, lower dosage, and more environmentally friendly properties. Scientific research institutions and enterprises at home and abroad continuously increase the investment on pesticide creation, and a plurality of novel pesticides with high activity, low dosage and environmental friendliness appear.

The m-diamide insecticide Broflanilide (structural formula: 01) developed by the cooperation of Japan Sanjing chemical company and Pasteur company is commercialized at present, the Chinese name is bromofenoxanil, and the bromofenoxanil is mainly used for fruits, vegetables, beans, cotton, corn, grains, flowers and non-crop application, and has very good effect on controlling pests such as lepidoptera, coleoptera, termites, ants, cockroaches, flies and the like, and the invention is shown in Chinese patent CN102119173B, an amide derivative, a pest control agent containing the amide derivative and a use method thereof. However, a plurality of domestic enterprises and research institutions optimize and improve the structure on the basis of the above steps, and a series of novel insecticides with higher activity, lower dosage and more environment-friendly property are discovered. Chinese patent CN 109497062B is a compound of m-diamide compound, its preparation method and application, representative structure, cyclopropyl flubendiamide (structural formula: 02); we find that the compound of bisamide containing heptafluoro isopropyl has higher insecticidal activity with a general structural formula (II), and a representative structure (structural formula: 03); so that more medicine selection and medication schemes are provided in the production of crops such as agriculture and gardening.

Wherein R is ¹ The substituents are independently selected from H, fluoro, trifluoromethyl, cyano or nitro;

R ² the substituents are independently selected from the group consisting of 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 the related compounds has the defects of complex route, harsh chemical reaction conditions, poor selectivity, unfriendly environment, low total yield, difficult purification or high process cost and the like, and is not beneficial to industrial production and large-scale application. For details, reference may be made to the relevant documents or patents, such as: liubaiping, etc. Synthesis and bioactivity of Brofenamide, fine chemical intermediate journal, 12 months in 2020, volume 50, 6 th, pages 16-20.

[ summary of the invention ]

Aiming at the defects of the prior art, the invention aims to provide the bisamide compound containing the heptafluoroisopropyl and the preparation method thereof, which have the advantages of simple preparation process operation, mild chemical reaction conditions, environmental friendliness, high total yield, high final product content, low cost and easy industrial production, and also relates to an intermediate compound for preparing the bisamide compound containing the heptafluoroisopropyl and the preparation method thereof through the optimized design of the preparation process and the optimized improvement of reaction conditions.

To achieve the purpose, the invention provides a preparation method of an intermediate compound for preparing a heptafluoroisopropyl-containing bisamide compound, which is shown as the following general formula (I),

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.

The preparation method 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 shown as the formula (1) or the formula (2):

wherein R is ³ Is C1-C5 alkyl;

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

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

the N-alkylation reaction bromoalkane in the formula (1) or the formula (2) is selected from: 2-methoxy bromoethane, 2-ethoxy bromoethane, 3-methoxy bromopropane, 3-ethoxy bromopropane, 2-n-propoxy bromoethane, 2-isopropoxybromoethane, 2-n-butoxy bromoethane, bromomethylcyclopropane, bromomethane, or bromoethane;

the N-alkylation reaction catalyst in formula (1) or formula (2) is selected from: one or more of cetyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, polyethylene glycol 400-800, tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium hydrogen sulfate, 15-crown-5-ether, 18-crown-6-ether or 4-Dimethylaminopyridine (DMAP);

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

For the preparation method of the intermediate compound, the following technical scheme is adopted in the invention for achieving the purpose.

Firstly, 2-fluoro-3-nitrobenzoic acid raw material and corresponding alcohol are used for esterification reaction in the presence of a catalyst to obtain corresponding 2-fluoro-3-nitrobenzoic acid ester, and the reaction formula is as follows:

wherein R is ³ Is C1-C5 alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, particularly preferably methyl or ethyl, and is prepared from the corresponding alcohols by esterification.

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

The 2-fluoro-3-nitrobenzoic acid is an important intermediate of medicines and pesticides, is realized by a plurality of synthetic routes, can be generally purchased or synthesized by markets, and has the content of over 95 percent of industrial grade. The present invention, if not specified otherwise, is generally obtained by market procurement and can be carried out by those skilled in the art by the following classical synthetic reaction scheme:

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

wherein, the reaction solvent generally adopts alcohols, such as: methanol, ethanol, n-propanol, isopropanol, tert-butanol; ethers, such as: tetrahydrofuran, methyl t-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 solvent is used in an amount of 2 to 20 times, preferably 2 to 10 times, the weight of 2-fluoro-3-nitrobenzoate. The catalyst is generally employed in a mass concentration

1 to 5 percent of palladium carbon or Raney nickel, preferably 5 percent of palladium carbon catalyst is used, the amount of the catalyst used on a dry basis is 0.1 to 10 percent of the weight of the 2-fluoro-3-nitrobenzoate, preferably 1 to 5 percent of the catalyst, and the catalyst can be recycled for 5 to 10 times from the economic viewpoint. The hydrogen is over 99 percent of industrial grade, the reaction pressure is 0-2MPa, the preferred pressure is 0-0.5MPa, and the reaction is particularly preferred to be close to normal pressure.

The reaction temperature is 0 to 100 ℃, preferably 5 to 50 ℃. The reaction time is generally from 2 to 24 hours, until the catalyst does not absorb hydrogen.

The resulting 2-fluoro-3-aminobenzoate (or one that can be obtained directly from the market) is then reacted with a series of benzoyl chlorides in the presence of a solvent to give the amide intermediate. The reaction formula is as follows:

wherein R is ¹ The substituents are independently selected from H, fluoro, trifluoromethyl, cyano or nitro; r is ³ The definition is the same as before.

Here, the benzoyl chloride series starting material used for the amidation reaction is generally prepared from the corresponding benzoic acid series starting material and thionyl chloride by means of an acylchlorination reaction in an inert solvent followed by desolvation, and the amount used is generally 1.0 to 1.2 times, preferably 1.0 to 1.05 times the molar amount of 2-fluoro-3-aminobenzoate.

The acid-removing agent generally used in the amidation reaction is triethylamine, pyridine, N-diisopropylethylamine, 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 is used, the molar amount is 0.1-5.0 times of that of the benzoyl chloride series raw material, and the preferred economic amount is 0.1-2.0 times; the amidation reaction uses dichloromethane, chloroform, dichloroethane, tetrahydrofuran, dioxane, dimethyl sulfoxide, acetonitrile, toluene, xylene, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, 1, 3-dimethyl-2-imidazolidinone, etc., preferably uses dichloroethane, toluene, acetonitrile, N-dimethylformamide, N-dimethylacetamide, 1, 3-dimethyl-2-imidazolidinone, etc., and the amount of the solvent is 1-20 times of the weight of the raw materials of benzoyl chloride series, preferably 2-5 times of the economic amount; the amidation reaction temperature is generally from-5 to 150 ℃ and preferably from 0 to 130 ℃; the reaction time is generally 1 to 5 hours, preferably 1 to 2 hours.

The obtained product can be used for realizing the preparation method of the intermediate compound of the invention, and the flow of the method is as the formula (1)

Shown in the specification:

wherein R is ³ Selected from C1-C5 alkyl;

the solvent in the N-alkylation reaction is selected from: one or more of N, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, 1, 3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dichloroethane, cyclohexane, methylcyclohexane, toluene, ethylbenzene and xylene; preferred solvents are: one or more of N, N-dimethylformamide, N-dimethylacetamide, acetonitrile, cyclohexane, methylcyclohexane and toluene are used in an amount of 2 to 10 times, preferably 2 to 5 times, the weight of the raw material amide or 2-fluoro-3-aminobenzoate.

The base in the N-alkylation reaction is selected from potassium carbonate, sodium hydroxide, potassium hydroxide and sodium hydride, and is preferably: the dosage of the potassium carbonate, the sodium carbonate and the sodium hydride is 1 to 3 times of the molar weight of the raw materials of the amide or the 2-fluoro-3-aminobenzoate, and the preferred dosage is 1 to 2 times.

The alkyl bromides in the N-alkylation reaction are selected from: 2-methoxy bromoethane, 2-ethoxy bromoethane, 3-methoxy bromopropane, 3-ethoxy bromopropane, 2-n-propoxy bromoethane, 2-isopropoxybromoethane, 2-n-butoxy bromoethane, bromomethylcyclopropane, bromomethane, or bromoethane; generally, it is commercially available or synthetically available, and the present invention is not specifically described and generally refers to the market acquisition. The dosage is 1 to 3 times, preferably 1 to 2 times of the molar weight of the raw material of the amide or the 2-fluoro-3-aminobenzoate. The invention adopts alkyl bromide to avoid using alkyl iodide, which has high activity, but high industrialization cost and is not beneficial to industrialization, while alkyl bromide has low activity, poor selectivity and low yield, and can achieve better effect only in the presence of a catalyst and under optimized process conditions.

The catalyst in the N-alkylation reaction is selected from: cetyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, polyethylene glycol 400-800, tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium hydrogen sulfate, 15-crown-5-ether, 18-crown-6-ether or 4-Dimethylaminopyridine (DMAP). In addition, the catalyst may also employ iodide salts, such as: potassium iodide, sodium iodide, etc., but the catalytic effect is inferior to that of phase transfer catalyst or 4-dimethylamino pyridine (DMAP), tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium hydrogen sulfate, 18-crown-6-ether or 4-dimethylamino pyridine (DMAP) are preferably used, the dosage of the catalyst is 1-10 percent, preferably 1-5 percent of the weight of the raw material of amide or 2-fluoro-3-aminobenzoate.

The invention also provides another preparation method of the intermediate compound, and the flow of the method is shown as the formula (2):

similar to the first preparation method, R ³ Selected from C1-C5 alkyl;

The alkali in the N-alkylation reaction is selected from potassium carbonate, sodium hydroxide, potassium hydroxide and sodium hydride, preferably potassium carbonate, sodium carbonate or sodium hydride, and the dosage of the alkali is 1 to 3 times, preferably 1 to 2 times of the molar weight of the raw material of amide or 2-fluoro-3-aminobenzoate.

The alkyl bromide in the N-alkylation reaction is selected from: 2-methoxy bromoethane, 2-ethoxy bromoethane, 3-methoxy bromopropane, 3-ethoxy bromopropane, 2-n-propoxy bromoethane, 2-isopropoxybromoethane, 2-n-butoxy bromoethane, bromomethylcyclopropane, bromomethane, or bromoethane; generally, it is commercially available or synthetically available, and the present invention is not specifically described and generally refers to the market acquisition. The dosage is 1 to 3 times, preferably 1 to 2 times of the molar weight of the raw material of the amide or the 2-fluoro-3-aminobenzoate. The invention adopts alkyl bromide to avoid using alkyl iodide, which is because the alkyl iodide has high activity, but causes high industrialization cost and is not beneficial to industrialization, while the alkyl bromide has low activity, poor selectivity and low yield, and can achieve better effect only in the presence of a catalyst and under optimized process conditions.

The catalyst in the N-alkylation reaction is selected from: cetyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, polyethylene glycol 400-800, tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium hydrogen sulfate, 15-crown-5-ether, 18-crown-6-ether or 4-Dimethylaminopyridine (DMAP). In addition, the catalyst may also employ iodide salts, such as: potassium iodide, sodium iodide, etc., but the catalytic effect is inferior to that of phase transfer catalyst or 4-dimethylamino pyridine (DMAP), tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium hydrogen sulfate, 15-crown-5-ether, 18-crown-6-ether or 4-dimethylamino pyridine (DMAP) are preferably used, the amount of the catalyst is 1-10%, preferably 1-5% of the weight of the raw material of amide or 2-fluoro-3-aminobenzoate.

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

Wherein, DMAP catalyst can be added in the amidation reaction, the dosage is 1-10 percent of the weight of the benzoic acid series acyl chloride raw material, preferably 1-5 percent, and when the catalyst is not added, the reaction yield and the reaction time under the process condition of the invention are acceptable, so the invention is not necessarily used; in the preparation method of the intermediate compound, no acid-removing agent is needed in amidation reaction, and the conversion yield and the reaction time can be accepted under the process condition of the invention. Wherein the temperature of the amidation reaction is 0-200 deg.C, preferably 0-150 deg.C

The hydrolysis reaction conditions in the preparation methods of the two intermediate compounds are generally normal conditions, and generally alcohol solvents such as methanol, ethanol, isopropanol and the like or ether solvents such as 1, 4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether and the like are adopted, preferably methanol and ethanol, and the using amount is generally 2-10 times, preferably 2-5 times of the weight of the corresponding ester; the alkali is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, preferably sodium hydroxide, the concentration is 1-35% by mass, and the molar amount is 1.1-3.0 times of the corresponding ester. The reaction temperature is generally 5 to 50 ℃ and preferably 20 to 30 ℃. The reaction time is generally 1 to 5 hours, preferably 1 to 2 hours.

In the above two intermediate compound preparation methods, the N-alkylation reaction temperature is 50-200 deg.C, preferably 50-150 deg.C, when the solvent is a solvent that can produce azeotropy with water, the reaction temperature is preferably azeotropic temperature, and the water produced by the reaction can be removed by azeotropy, so that the reaction time can be shortened; the reaction pressure is generally normal pressure, when the bromoalkane is methyl bromide or ethyl bromide, because the boiling point of the bromoalkane is low, volatilization is avoided, and the closed reaction is preferred, and the pressure is 0-0.2MPa. And the N-alkylation reaction time is usually 2 to 12 hours, preferably 2 to 8 hours.

Furthermore, the invention also provides a diamide compound containing heptafluoro-isopropyl, the structure of the compound is shown as the general formula (II),

The invention also provides a preparation method of the heptafluoroisopropyl-containing bisamide compound, and the flow of the method is shown as the formula (3):

wherein, the acyl chlorination reaction is generally carried out by reacting the raw material with thionyl chloride in an inert solvent, desolventizing, and carrying out the next reaction. The solvent adopted in the acyl chlorination reaction is dichloromethane, chloroform, dichloroethane, toluene or xylene, etc., and the preferred solvent is dichloroethane or toluene, etc.; the reaction temperature of acyl chlorination is generally 20-150 ℃, and the reaction temperature is preferably 40-100 ℃; the time for the acid chlorination reaction is generally 1 to 5 hours, preferably 2 to 3 hours.

The solvent in the amidation reaction is one or more of dichloromethane, dichloroethane, cyclohexane, methylcyclohexane, toluene, ethylbenzene, xylene, ethyl acetate, tetrahydrofuran and acetonitrile; preference is given to using dichloroethane, cyclohexane, methylcyclohexane, toluene, ethyl acetate or acetonitrile as solvent, generally in amounts of from 2 to 10 times, preferably from 3 to 8 times, by weight, based on the weight of the starting materials of the formula (I). The reaction time can be shortened by using 4-Dimethylaminopyridine (DMAP) as a catalyst for amidation, but the present invention does not necessarily require the use of a catalyst or an acid-removing agent for amidation under the preferable conditions of the present invention, and the reaction yield and the reaction time are acceptable. The other raw material of 4-heptafluoro isopropyl-2-trifluoromethyl aniline in amidation reaction can be obtained by synthesis or market purchase, the synthesis method is that the o-trifluoromethyl aniline raw material and 2-bromo heptafluoro propane or 2-iodo heptafluoro propane are subjected to alkylation reaction in the presence of sodium hydrosulfite, and the synthesis details are disclosed in the Chinese invention patent CN 102119173B. The starting 4-heptafluoroisopropyl-2-trifluoromethylaniline is used in an amount of 1.0 to 1.3 times, preferably 1.0 to 1.05 times, the molar amount of the starting material of the general formula (I). Liquid bromine is used as a brominating agent in the bromination reaction, the price is low, the raw materials are easy to obtain, a byproduct bromide salt is easy to recycle, the cost is low compared with that of an N-bromosuccinimide brominating agent, the N-bromosuccinimide brominating agent is also beneficial to environmental protection, the using amount is 1-2 times of the molar amount of the raw materials in the general formula (I), the preferable using amount is 1-1.5 times, the preferable using mode is dripping reaction, the dripping reaction can also be carried out under the ultraviolet illumination condition, and the preferable reaction can be carried out without illumination.

The bromination reaction can also reduce the use amount of bromine, and an oxidant is added shortly after the reaction, so that the generated bromide salt is oxidized into elemental bromine to be used for the bromination reaction again, the use amount of the bromine can be reduced, but the operation of a reaction system is complicated and related side reaction impurities are brought, and the invention is not necessarily adopted.

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, and preferably one or more mixtures of dichloroethane, methanol, ethanol, isopropanol and tert-butanol are used. The amount used is generally 2 to 10 times, preferably 3 to 8 times, the weight of the starting material corresponding to formula (I).

The alkali in the bromination reaction is selected from sodium hydroxide, potassium carbonate, sodium carbonate or any concentration water solution thereof, or any concentration sodium methoxide methanol solution, sodium ethoxide ethanol solution, sodium isopropoxide isopropanol solution and sodium tert-butanol solution thereof, preferably solid sodium hydroxide, potassium hydroxide and potassium carbonate are used; the amount used is generally 1 to 2 times, preferably 1 to 1.5 times, the molar amount of the starting material of the formula (I). The bromination reaction temperature is from 0 to 100 ℃ and the use temperature is preferably from 20 to 80 ℃.

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 Is methyl.

The invention also provides a crystal of the diamide compound containing heptafluoro isopropyl, when R is ¹ Is H and R ² Is 2-methoxyethyl, and the crystalline 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 ¹ Is fluorine and R2 is 2-methoxyethyl, and the crystalline 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 ¹ Is fluorine and R ² The crystal is 2-ethoxyethyl, and the diffraction of the crystal X-ray powder 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 invention, the crystal is obtained by crystallizing a crystallization solvent, wherein the solvent is one or a mixture of more 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.

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.

In the present invention, the operations of distillation, distillation under reduced pressure, filtration, drying, extraction, delamination, crystallization, recrystallization, and the like involved in the operation of the production method are conventional operations, and are not described in detail again.

[ description of the drawings ]

FIG. 1 is a result of X-ray powder crystal diffraction analysis of a sample of the compound of Synthesis example 17;

FIG. 2 shows the results of X-ray powder crystal diffraction analysis of a sample of the compound of Synthesis example 18;

FIG. 3 shows the results of X-ray powder crystal diffraction analysis of a sample of the compound of Synthesis example 20.

[ detailed description ] embodiments

The following examples are intended to illustrate the technical solutions of the present invention without limiting them and should not be construed as specifically limiting the present invention.

The raw materials in the synthetic examples of the invention are generally obtained by market purchase except special instructions, the content specification is usually more than or equal to 95%, the content is not accurately corrected, the percentage concentration in the synthetic examples is generally weight percentage concentration except special instructions, the HPLC content data is area normalized content, the HPLC content is not accurately corrected, the yield is molar yield, and the HPLC content data is not accurately corrected.

Preparation of Synthesis example 1

Methanol 100g, 2-fluoro-3-nitrobenzoic acid 50g and 98% sulfuric acid 2.5g are put into a 250ml four-mouth glass reaction bottle, the temperature is increased for reflux reaction for 24 hours, the temperature is reduced to about 0-5 ℃, crystallization is carried out, filtration is carried out, drying is carried out at 50 ℃ to obtain 51g of 2-fluoro-3-nitrobenzoic acid methyl ester solid, the HPLC content is 98%, the yield is 94.8%, and the solid is used for synthesis reaction.

Synthesis preparation example 2

Ethanol 100g, 2-fluoro-3-nitrobenzoic acid 50g and 98% sulfuric acid 2.5g are put into a 250ml four-mouth glass reaction bottle, the mixture is heated up for reflux reaction for 24 hours, the temperature is reduced to about 0-5 ℃, crystallization is carried out, filtration is carried out, and drying is carried out at 50 ℃ to obtain 54.5g of solid of 2-fluoro-3-nitrobenzoic acid ethyl ester, the HPLC content is 98%, the yield is 94.6%, and the solid is used for synthesis reaction.

Synthesis preparation example 3

250g of methanol, 2g of 5% palladium carbon and 2g of dried palladium carbon (the water content is 50%) are put into a 500ml hydrogenation reaction kettle, 51g of solid 2-fluoro-3-nitrobenzoic acid methyl ester obtained in synthesis preparation example 1 is put into the reaction kettle, the reaction kettle is sealed, after air is replaced by nitrogen, the nitrogen is replaced by hydrogen twice, hydrogen is introduced for reaction for 12 hours under the condition that the temperature is 5-15 ℃ and the pressure is 0-0.05MPa, HPLC detection reaction is finished, the reaction kettle is taken out, a catalyst is filtered out (can be recycled and reused), and the filtrate is decompressed and desolventized to obtain 43g of oily liquid, namely 2-fluoro-3-methyl aminobenzoate, the HPLC content is 97%, and the yield is 98.3% for synthesis reaction.

Synthetic preparation example 4

In a 500ml hydrogenation reaction kettle, 250g of methanol, 2g of 5% palladium carbon and 2g of dried palladium carbon (water content is 50%), 54.5g of solid of ethyl 2-fluoro-3-nitrobenzoate obtained in synthesis preparation example 2 is added, the reaction kettle is sealed, after air is replaced by nitrogen, hydrogen is used for replacing nitrogen twice, hydrogen is introduced for reaction for 12 hours under the condition that the pressure is maintained at 5-15 ℃ and 0-0.05MPa, HPLC detection reaction is completed, the reaction kettle is taken out, a catalyst is filtered out (can be recycled and applied), filtrate is decompressed and desolventized to obtain 46g of oily liquid, namely ethyl 2-fluoro-3-aminobenzoate, the normalized content of HPLC is 96%, and the yield is 96.3%, and the oily liquid is used for synthesis reaction.

Synthesis preparation example 5

25g (0.20 mol) of benzoic acid and 72g (0.60 mol) of thionyl chloride, heating and refluxing for 2-5 hours, cooling to room temperature, performing rotary evaporation on reaction liquid, performing desolvation under reduced pressure to 80 ℃ to obtain benzoyl chloride oily liquid, cooling to about 25 ℃, and adding 25g of new dichloroethane for dissolving for later use.

In another 250ml four-mouth glass reaction bottle, 100g of dichloroethane, 35g (0.20 mol) of 3-amino-2-fluorobenzoic acid methyl ester and 24g (0.30 mol) of pyridine are added, the temperature is reduced to 5-25 ℃ in an ice bath, the benzoyl chloride standby liquid is dripped in within 1 hour, the reaction is carried out for 1-2 hours at the temperature of 5-25 ℃,50 ml of water is added after the reaction is finished, the mixture is stirred for 0.5 hour, a solvent layer is obtained by layering, the solvent layer is transferred to a 500ml rotary evaporator, the reduced pressure is used for desolventizing to 80 ℃ to obtain 53g of 2-fluoro-3- [ (phenylcarbonyl) amino ] benzoic acid methyl ester off-white solid, the normalized content of HPLC is 94% (the yield is 91.2%) for later use, and the product is directly used for synthesis reaction without further treatment.

Synthesis preparation example 6

By following a similar operation as in preparation example 5, in which 35g (0.20 mol) of methyl 3-amino-2-fluorobenzoate as the starting material was replaced with 38g (0.20 mol) of ethyl 3-amino-2-fluorobenzoate obtained in preparation example 4, and the remainder was unchanged, 55g of ethyl 2-fluoro-3- [ (phenylcarbonyl) amino ] benzoate was obtained as an off-white solid, which was used in the synthesis without further treatment and which was normalized by HPLC to 94% (yield 90%) for use.

Synthesis preparation example 7

Following the procedure of synthetic preparation example 5, 25g (0.20 mol) of benzoic acid was replaced with 28g (0.20 mol) of p-fluorobenzoic acid and the other procedures were the same to give 56g of methyl 2-fluoro-3- [ (4-fluorophenylcarbonyl) amino ] benzoate as an off-white solid, which was used in the synthesis reaction without further treatment and had a normalized HPLC content of 94% (yield 90.2%).

Synthesis example 1

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

200g of N, N-dimethylformamide as a solvent and 15g (0.10 mol) of potassium carbonate as an alkali were put into a 250ml four-necked glass reaction flask, 25g (0.086 mol) of methyl 2-fluoro-3- [ (phenylcarbonyl) amino ] benzoate synthesized in preparation example 5 as a synthesis catalyst and 1g of tetrabutylammonium bromide were added, the temperature was raised to 55 to 65 ℃ and 15.8g (0.11 mol) of 1-bromo-2-methoxyethane was dropped within 1 hour, the reaction was allowed to keep warm for about 2 hours, water was cooled to room temperature, and then the reaction mixture was filtered, and the filtrate was desolventized under reduced pressure to obtain a residual material, methanol 50g,10% of liquid alkali 60g (0.15 mol) was added, the temperature was raised to 25 ℃ and the reaction was kept warm for about 2 hours, and then water was added 150g,30% of hydrochloric acid was added to adjust the pH to 1 to 2, the reaction mixture to 10 to 25 ℃ to crystallize, and the mixture was filtered, washed with water, and dried to obtain 26.5g of a white solid having a melting point: 155.8-157.9 ℃, the HPLC normalized content is about 95 percent, the yield is 92.3 percent, and the product is 2-fluoro-3- [ (2-methoxyethyl) (phenylcarbonyl) amino ] benzoic acid. The reaction formula is as follows:

synthesis examples 2 to 4

According to the procedure of Synthesis example 1, 1g of tetrabutylammonium bromide as a catalyst was replaced with 1g of tetrabutylammonium chloride, 1g of tetrabutylammonium hydrogen sulfate and 1g of 18-crown-6-ether, respectively, and the results obtained were similar without changing the other feeds and procedures.

Synthesis example 5

100g of toluene as a solvent, 15g (0.10 mol) of potassium carbonate as an alkali, 25g (0.086 mol) of methyl 2-fluoro-3- [ (phenylcarbonyl) amino ] benzoate synthesized in preparation example 5, 1g (0.11 mol) of tetrabutylammonium bromide as a catalyst, 15.8g (0.11 mol) of 1-bromo-2-methoxyethane, a reflux water separator, heating to reflux reaction, removing water produced by the reaction, refluxing for about 2 hours until no water is produced, cooling water to room temperature, filtering, removing the filtrate under reduced pressure to obtain a residue, adding 50g of methanol, 60g (0.15 mol) of 10% aqueous alkali, heating to 25-35 ℃, keeping the temperature for about 2 hours, adding 150g of water, 30% of hydrochloric acid to adjust the pH to 1-2, crystallizing at about 10-25 ℃, filtering, washing with water, and drying to obtain 27g of a beige white solid, having a HPLC (yield of about 95%, 94%, and a value of 2-fluoro-3-methoxyethyl) (phenyl) amino ] benzoic acid.

Synthesis examples 6 to 7

According to the procedure of Synthesis example 5, 100g of toluene as a solvent was replaced with 100g of methylcyclohexane and 100g of xylene, respectively, and the results obtained were similar to each other without changing the charge and the procedure.

Synthesis example 8

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

A250 ml four-mouth glass reaction bottle is charged with 100g of dichloroethane solvent, 12.5g (0.088 mol) of 4-fluorobenzoic acid and 25g (0.20 mol) of thionyl chloride, heated for reflux reaction for 2-5 hours, and decompressed for desolventizing to obtain 4-fluorobenzoyl chloride as oily liquid for later use.

In another 250ml four-mouth glass reaction bottle, 200g of solvent N, N-dimethylformamide, under nitrogen protection, 3.5g (0.091 mol) of alkali 60% sodium hydride, 15g (0.086 mol) of methyl 2-fluoro-3-aminobenzoate synthesized in preparation example 3, 1g of tetrabutylammonium bromide as a catalyst, 16.8g (0.11 mol) of 1-bromo-2-ethoxyethane, heating to 110-120 ℃, carrying out a heat preservation reaction for about 8 hours, cooling water to room temperature, filtering, carrying out desolventization of the filtrate under reduced pressure, extracting the residue with 100ml of dichloroethane, washing with water (after the product nuclear magnetic hydrogen spectrum and mass spectrum data are attached), drying the filtrate obtained by drying the solvent layer with anhydrous magnesium sulfate, filtering the obtained filtrate at 25-35 ℃, adding 4-fluorobenzoyl chloride synthesized above, heating to reflux reaction for 2-5 hours, carrying out desolventization under reduced pressure to obtain an oily residue (after the product nuclear hydrogen spectrum and mass spectrum data are attached), adding 50g of methanol, 60g (0.15 mol) of 10% liquid alkali, heating to 25-35 hours, carrying out a heat preservation reaction for about 25-5 hours, filtering, carrying out a heat preservation reaction for about 25-30 hours to obtain a yellow crystal, drying, carrying out a crystallization for about 25-29 hours, carrying out a crystallization for about 25-30 hours to obtain a yellow crystal with water, heating, and carrying out a crystallization temperature for about 25-29 ℃ to obtain a crystal, wherein: 77.3-79.2 ℃, the HPLC normalized content is about 92 percent, the yield is 90.1 percent, and the product is 2-fluoro-3- [ (2-ethoxyethyl) (phenylcarbonyl) amino ] benzoic acid (after the nuclear magnetic hydrogen spectrum and mass spectrum data of the product are attached). The reaction formula is as follows:

nuclear magnetic hydrogen spectroscopy was performed using a Bruker AV-400spectrometer (400 MHz), TMS as an internal standard, and CDCl as a solvent ₃ or DMSO-d6 (the same applies below, unless otherwise specified); high resolution mass spectra were determined using a UHR-TOF maXis (ESI) mass spectrometer (same below, unless otherwise specified).

The nuclear magnetic hydrogen spectrum and mass spectrum data of the methyl 2-fluoro-3- [ (2-ethoxyethyl) amino ] benzoate 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。

the nuclear magnetic hydrogen spectrum and mass spectrum data of the 2-fluoro-3- (4-fluoro-N- (2-ethoxyethyl) benzoylamino) methyl benzoate 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。

the nuclear magnetic hydrogen spectrum and mass spectrum data of the 2-fluoro-3- [ (2-ethoxyethyl) (phenylcarbonyl) amino ] benzoic acid are as follows:

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

Similar results were obtained by following the procedure of Synthesis example 8 and adding 1g of 4-Dimethylaminopyridine (DMAP) in the second amidation step, without changing the other feeds and operations.

Synthesis example 10

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

100g of dichloroethane as a solvent, 12.5g (0.088 mol) of p-fluorobenzoic acid and 25g (0.20 mol) of thionyl chloride are put into a 250ml four-mouth glass reaction bottle, heated and refluxed for 2 to 5 hours, and decompressed and desolventized to obtain the p-fluorobenzoyl chloride as an oily liquid for standby.

In another 250ml four-mouth glass reaction bottle, 100g of toluene solvent is added, 15g (0.10 mol) of alkali potassium carbonate is added, 15g (0.086 mol) of methyl 2-fluoro-3-aminobenzoate synthesized in preparation example 3 is added, 1g of tetrabutylammonium bromide is added, 15.8g (0.11 mol) of 1-bromo-2-methoxyethane is added, the temperature is raised to 100-120 ℃, reflux dehydration reaction is carried out for about 5 hours, water is cooled to room temperature, filtration, washing and decompression desolvation are carried out to obtain a material (after the nuclear magnetic hydrogen spectrum and mass spectrum data of a product are attached), 100g of dichloroethane is added for dissolution, the p-fluorobenzoyl chloride synthesized above is added at 25-35 ℃, and the temperature is raised for reflux reaction for 2-5 hours. Cooling, adding 100ml of water, layering, washing, decompressing and desolventizing to obtain a residual oily material (after nuclear magnetic hydrogen spectrum and mass spectrum data of a product are attached), adding 50g of methanol and 60g (0.15 mol) of 10% liquid caustic soda, heating to 25-35 ℃, keeping the temperature for reaction for about 2 hours, adding 150g of water, adjusting the pH to 1-2 by 30% of hydrochloric acid, crystallizing at about 10-25 ℃, filtering, washing with water, and drying to obtain 28g of beige solid with a melting point: 120.5-122.5 ℃, the HPLC normalized content is about 93 percent, the yield is 90.3 percent, and the product is 2-fluoro-3- [ (2-methoxyethyl) (4-fluorophenylcarbonyl) amino ] benzoic acid (after the nuclear magnetic hydrogen spectrum and mass spectrum data of the product are attached). The reaction formula is as follows:

the nuclear magnetic hydrogen spectrum and mass spectrum data of the methyl 2-fluoro-3- [ (2-methoxyethyl) amino ] benzoate 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＝3.9Hz,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。

the nuclear magnetic hydrogen spectrum and mass spectrum data of the 2-fluoro-3- (4-fluoro-N- (2-methoxyethyl) benzoylamino) methyl benzoate 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。

the nuclear magnetic hydrogen spectrum and mass spectrum data of the 2-fluoro-3- [ (2-methoxyethyl) (4-fluorophenylcarbonyl) amino ] benzoic acid 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。

synthesis example 11

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

In a 500ml pressure reaction vessel, 200g of N, N-dimethylformamide as a solvent, 15g (0.10 mol) of potassium carbonate as a base, 25g (0.086 mol) of methyl 2-fluoro-3- [ (phenylcarbonyl) amino ] benzoate synthesized in preparation example 5 as a catalyst, 1g of tetrabutylammonium bromide, 20g (0.21 mol) of methyl bromide introduced at room temperature, the reaction vessel sealed and heated to 55-65 ℃ for a reaction at a temperature of about 2 hours, cooled to room temperature, filtered, and desolventized under reduced pressure to obtain an oily liquid, 50g of methanol, 60g (0.15 mol) of 10% liquid base, heated to 25-35 ℃ for a reaction at a temperature of about 2 hours, added with 150g of water, 30% of hydrochloric acid to adjust the pH to 1-2, crystallized at a temperature of about 10-25 ℃, filtered, washed with water, and dried to obtain 23g of a beige-white solid with a content of about 95% by HPLC, a yield of 93%, which is 2-fluoro-3- [ (methyl) (phenylcarbonyl) amino ] benzoic acid. The reaction formula is as follows:

synthesis example 12

According to the procedure of synthetic example 11, 20g (0.21 mol) of methyl bromide was replaced with 22g (0.20 mol) of ethyl bromide, and the mixture was charged into an autoclave, and the operation was similar, to thereby obtain 24g of an off-white solid having an HPLC normalized content of about 95% and a yield of 92.3% as 2-fluoro-3- [ (ethyl) (phenylcarbonyl) amino ] benzoic acid. The reaction formula is as follows:

synthesis example 13

100g of toluene as a solvent, 15g (0.10 mol) of potassium carbonate as an alkali, 26.7g (0.086 mol) of methyl 2-fluoro-3- [ (4-fluorophenylcarbonyl) amino ] benzoate synthesized in preparation example 7, 1g (0.11 mol) of tetrabutylammonium bromide as a catalyst, 15.8g (0.11 mol) of 1-bromo-2-methoxyethane, a reflux water separator, heating to reflux reaction, removing water produced by the reaction, refluxing for about 2 hours until no water is produced, cooling water to room temperature, filtering, and removing solvent under reduced pressure to obtain a residual material, 50g of methanol, 60g (0.15 mol) of 10% aqueous alkali, heating to 25-35 ℃, keeping the temperature for about 2 hours, adding 150g of water, adjusting pH to 1-2 with 30% hydrochloric acid, crystallizing at about 10-25 ℃, filtering, washing with water, and drying to obtain 28.5g of a beige-yellow solid, a melting point: 122.5-123.4 ℃, the HPLC normalized content is about 95 percent, the yield is 93.9 percent, and the product is 2-fluoro-3- [ (2-methoxyethyl) (4-fluorophenylcarbonyl) amino ] benzoic acid. The nuclear magnetic hydrogen spectrum and mass spectrum 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。

synthesis example 14

According to the procedure of synthetic example 13, 15.8g (0.11 mol) of 1-bromo-2-methoxyethane was replaced with 16.5g (0.12 mol) of bromomethylcyclopropane, and the same was repeated except for using the above-mentioned solvent to obtain 28g of an off-white solid, which was 2-fluoro-3- [ (cyclopropylmethyl) (4-fluorophenylcarbonyl) amino ] benzoic acid with a HPLC normalized content of about 95% and a yield of 93.3%.

Synthesis examples 15 to 16

According to the procedures of Synthesis examples 1 and 5, respectively, 25g (0.086 mol) of methyl 2-fluoro-3- [ (phenylcarbonyl) amino ] benzoate as a starting material was replaced with 26.3g (0.086 mol) of ethyl 2-fluoro-3- [ (phenylcarbonyl) amino ] benzoate obtained in preparation example 6, and similar results were obtained in the same procedures as in the other examples.

Synthesis comparative example 1

According to synthetic example 1, wherein 1g of tetrabutylammonium bromide as a catalyst was not added, and the other charge and operation were the same, 24g of an off-white solid was obtained, and the target product, 2-fluoro-3- [ (2-methoxyethyl) (phenylcarbonyl) amino ] benzoic acid, had an HPLC normalized content of about 55%, a yield of 48.3%, and was mainly 2-fluoro-3- [ (phenylcarbonyl) amino ] benzoic acid.

Synthesis of comparative example 2

According to synthetic example 5, wherein 1g of tetrabutylammonium bromide as a catalyst was not added, and the other charge and operation were the same, 21g of an off-white solid was obtained, and the target product, 2-fluoro-3- [ (2-methoxyethyl) (phenylcarbonyl) amino ] benzoic acid, had an HPLC normalized content of about 5%, a yield of 3.8%, and was mainly 2-fluoro-3- [ (phenylcarbonyl) amino ] benzoic acid.

Synthesis of comparative example 3

According to the operation of the synthesis example 8, 1g of tetrabutylammonium bromide as a catalyst is not added, other feeding materials and the operation are all the same, and finally, the oily material with the normalized content of about 45 percent is obtained, and the solid crystals of the target product are not obtained.

Synthesis example 17

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

200g of dichloroethane and 23.7g (0.071 mol) of 2-fluoro-3- [ (2-methoxyethyl) (phenylcarbonyl) amino ] benzoic acid obtained in Synthesis example 1 and 24g (0.20 mol) of thionyl chloride were put into a 250ml four-neck glass reaction flask, heated and refluxed for 3 to 5 hours, cooled to room temperature, the reaction solution was transferred to a 500ml rotary evaporator, desolvated to 80 ℃ under reduced pressure to obtain an acid chloride oily liquid, cooled to about 25 ℃, dissolved in 150g of acetonitrile, transferred to the reaction flask, and added with 27.8g (0.08 mol) of 4- (1, 2, 3-heptafluoropropane-2-yl) -2- (trifluoromethyl) aniline as a starting material, and refluxed for 5 to 10 hours.

Cooling to room temperature, adding 20g of powdery potassium carbonate, dripping 13.5g of liquid bromine at 25-45 ℃ for 2 hours for reaction, preserving heat for 2 hours, filtering out inorganic salts, carrying out decompression and desolventizing on the filtrate to obtain a residual material, adding 120g of ethanol, heating and refluxing for 1 hour, cooling for crystallization, crystallizing for 1 hour at 0-5 ℃, filtering and drying to obtain 42g of white crystalline powder solid, which is a target compound and has a melting point: 179.5-180.5 deg.c, HPLC normalized content of about 98% and total yield of 81.9%. The reaction formula is as follows:

the nuclear magnetic hydrogen spectrum and mass spectrum data are as follows:

nuclear magnetic hydrogen spectroscopy was performed using a Bruker AV-400spectrometer (400 MHz), TMS as an internal standard, and DMSO-d6 as a solvent (the same applies below unless otherwise specified); high resolution mass spectra were determined using a UHR-TOF maXis (ESI) mass spectrometer (same below, unless otherwise specified).

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) ⁺ ]。

A sample of the objective compound was subjected to X-ray powder crystal diffraction analysis using a Japanese SmartLab diffractometer (unless otherwise specified, the same shall apply hereinafter), and the crystals had characteristic peaks at the following positions, 2 theta =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 °, 26.2 °, 26.420 ± 0.2 °, 27.420 ± 0.2 °, 22.239 ± 0.239 ± 0.461 ± 0.32 °, 23.32 ± 0.32 °, 24.32 ± 0.32 °, 33 ± 2 °, 33.32 ± 2 ° 32.32 °, 33 ± 0.32 °, 33.32 ± 0.32 °.

The sample obtained in the synthesis example is recrystallized by using isopropyl ether with 3 times of weight, and the characteristic peak of the crystal is completely consistent with the upper surface of the finally obtained sample through X-ray powder crystal diffraction analysis.

The sample obtained in the synthesis example is recrystallized by using 3 times of the weight of ethylene glycol monomethyl ether, and the characteristic peak of the crystal is completely consistent with the characteristic peak of the crystal by X-ray powder crystal diffraction analysis of the finally obtained sample.

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

Synthesis example 18

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

200g of dichloroethane and 25g (0.071 mol) of 2-fluoro-3- [ (2-methoxyethyl) (4-fluorophenylcarbonyl) amino ] benzoic acid obtained in Synthesis example 13 and 24g (0.20 mol) of thionyl chloride were put into a 250ml four-neck glass reaction flask, heated and refluxed for 3 to 5 hours, cooled to room temperature, the reaction mixture was transferred to a 500ml rotary evaporator, desolvated under reduced pressure to 80 ℃ to obtain an acid chloride oily liquid, cooled to about 25 ℃, and then 150g of fresh dichloroethane was added to dissolve the oily liquid, and transferred to the reaction flask, and 27.8g (0.08 mol) of 4- (1, 2, 3-heptafluoropropane-2-yl) -2- (trifluoromethyl) aniline as a starting material was added thereto, and refluxed for 5 to 10 hours. Cooling to room temperature, adding 5g of sodium hydroxide, dropwise adding 13.5g of liquid bromine at 35-55 ℃ for 2 hours for reaction, preserving heat for 2 hours, adding 50ml of water, layering and removing a water layer to obtain a solvent layer, performing reduced pressure desolventization to obtain a residual material, adding 120g of ethylene glycol monomethyl ether, heating and refluxing for 1 hour, cooling for crystallization, crystallizing for 1 hour at 0-5 ℃, filtering and drying to obtain 44g of white crystalline powder solid, which is a target compound and has a melting point: 152.4-153.2 ℃, the normalized HPLC content is about 98 percent, and the total yield of the three steps is 83.7 percent. The reaction formula is as follows:

the nuclear magnetic hydrogen spectrum and mass spectrum 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 6.8Hz,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)。

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, 2 theta

± 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 °, 22.22.22.818 ± 0.23.999 ± 0.2 °,2 ± 0.25 ± 0.2 °,2 ± 0.22.22.22 ± 0.2 °,2 ± 0.25 ± 0.2 °, 2.2 ± 0.2 °,2 °, 2.7 ± 0.2 °, 2.2 °, 2.2.2 ± 0.2.2 °, 27.2.2 °, 27.2 °,2 °, 2.2.2.2 ± 0.2.2.2 ° 2 °, 2.2 ° 20.2 °, 2.

The sample obtained in the synthesis example is recrystallized by using ethanol with the weight 3 times that of the sample, and the characteristic peak of the crystal is completely consistent with the upper surface of the sample obtained finally through X-ray powder crystal diffraction analysis.

Synthetic example 19

According to the procedure of Synthesis example 18, in which 25g (0.071 mol) of 2-fluoro-3- [ (2-methoxyethyl) (4-fluorophenylcarbonyl) amino ] benzoic acid was replaced with 25.6g (0.071 mol) of 2-fluoro-3- [ (2-methoxyethyl) (4-fluorophenylcarbonyl) amino ] benzoic acid obtained in Synthesis example 10, 42g of a white crystalline powdery solid was finally obtained as the objective compound, melting point: 152.4-153.2 ℃, the normalized HPLC content is about 98 percent, and the total yield of the three steps is 79.9 percent. The results of the samples are completely consistent after nuclear magnetism, mass spectrum and X-ray powder crystal diffraction analysis.

Synthesis example 20

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

200g of dichloroethane, 26g (0.071 mol) of 2-fluoro-3- [ (2-ethoxyethyl) (4-fluorophenylcarbonyl) amino ] benzoic acid obtained in Synthesis example 8, and 24g (0.20 mol) of thionyl chloride were put into a 250ml four-necked glass reaction flask, and the mixture was refluxed for 3 to 5 hours, cooled to room temperature, transferred to a 500ml rotary evaporator, desolventized under reduced pressure to 80 ℃ to obtain an acid chloride oily liquid, cooled to about 25 ℃, dissolved in 150g of toluene, transferred to the reaction flask, and added with 27.8g (0.08 mol) of a 4- (1, 2, 3-heptafluoropropane-2-yl) -2- (trifluoromethyl) aniline as a starting material, heating up and refluxing for 5-10 hours, carrying out decompression desolventizing to obtain a residual material, adding 120g of methanol, cooling to room temperature, adding 5g of sodium hydroxide, dropwise adding 13.5g of liquid bromine at 35-55 ℃ for about 2 hours for reaction, keeping the temperature for 2 hours, adding 50ml of water, layering and removing a water layer to obtain a solvent layer, carrying out decompression desolventizing to obtain a residual material, adding 120g of isopropyl ether, heating up and refluxing for 1 hour, cooling for crystallization, crystallizing for 1 hour at 0-5 ℃, filtering and drying to obtain 44.5g of white crystalline powder solid, which is a target compound and has a melting point: 168.2-169.2 ℃, the normalized HPLC content is about 98 percent, and the total yield of the three steps is 83.1 percent. The reaction formula is as follows:

the nuclear magnetic hydrogen spectrum and mass spectrum 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 6.8Hz,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)。

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) ⁺ ]。

=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 degrees, 23.400 +/-0.2 degrees, 23.882 +/-0.2 degrees, 24.383 +/-0.2 degrees, 24.579 +/-0.2 degrees, 25.001 +/-0.2 degrees, 25.160 +/-0.2 degrees, 25.459 +/-0.2 degrees, 26.780 +/-0.2 degrees, 26.920 +/-0.2 degrees, 27.199 +/-0.2 degrees, 27.378 +/-0.2 degrees, 28.742 +/-0.2 degrees, 29.319 +/-0.2 degrees, 29.998 +/-0.2 degrees, 31.339 +/-0.2 degrees, 31.939 +/-0.2 degrees, 32.140 +/-0.2 degrees, 32.522 +/-0.2 degrees, 33.479 +/-0.2 degrees, 36.400 +/-0.2 degrees, 43.039 +/-0.2 degrees, 31.939 +/-0.2 degrees, and the like see figure 3 for details.

The sample obtained in the synthesis example is recrystallized by using ethanol with the weight being 3 times that of the sample, and the characteristic peak of the crystal is completely consistent with the upper surface of the sample obtained finally through X-ray powder crystal diffraction analysis.

The sample obtained in the synthesis example is recrystallized by using 3 times of ethylene glycol dimethyl ether, and the characteristic peak of the crystal is completely consistent with the characteristic peak of the crystal by X-ray powder crystal diffraction analysis of the finally obtained sample.

The crystal obtained by crystallizing the compound in ethanol, isopropyl ether, ethylene glycol monomethyl ether and ethylene glycol dimethyl ether solvents respectively has consistent crystal types, easy obtainment and good stability.

And recrystallizing the sample obtained in the synthesis example by using 3 times of methanol, isopropanol, tetrahydrofuran, ethylene glycol monoethyl ether, ethylene glycol diethyl ether and methyl tert-butyl ether respectively, and analyzing the finally obtained sample by X-ray powder crystal diffraction to ensure that the characteristic peak of the crystal is completely consistent with the characteristic peak of the crystal.

The crystal 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 and the like is consistent in crystal type, easy to obtain and good in stability.

Synthesis example 21

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

The procedure of Synthesis example 18 was followed, in which 25g (0.071 mol) of the starting material 2-fluoro-3- [ (2-methoxyethyl) (4-fluorophenylcarbonyl) amino ] benzoic acid was replaced with 20.4g (0.071 mol) of 2-fluoro-3- [ (methyl) (phenylcarbonyl) amino ] benzoic acid obtained in Synthesis example 11. The same other operations were carried out, to obtain 40.1g of a white crystalline powdery solid as the objective compound, melting point: 155.1-156.4 ℃, the normalized HPLC content is about 98 percent, and the total yield of the three steps is 83.4 percent. The reaction formula is as follows:

the nuclear magnetic hydrogen spectrum and mass spectrum 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)+]。

synthesis example 22

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

The procedure of Synthesis example 18 was followed, in which 25g (0.071 mol) of the starting material 2-fluoro-3- [ (2-methoxyethyl) (4-fluorophenylcarbonyl) amino ] benzoic acid was replaced with 21.4g (0.071 mol) of 2-fluoro-3- [ (ethyl) (phenylcarbonyl) amino ] benzoic acid obtained in Synthesis example 12. The same other operations were carried out, to obtain 40g of a white crystalline powdery solid as the objective compound, melting point: 166.1-167.8 ℃, the normalized HPLC content is about 98 percent, and the total yield of the three steps is 81.5 percent. The reaction formula is as follows:

synthesis example 23

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

The procedure of Synthesis example 18 was followed, wherein 25g (0.071 mol) of the starting 2-fluoro-3- [ (2-methoxyethyl) (4-fluorophenylcarbonyl) amino ] benzoic acid was replaced with 23.4g (0.071 mol) of 2-fluoro-3- [ (cyclopropylmethyl) (4-fluorophenylcarbonyl) amino ] benzoic acid obtained in Synthesis example 14. The same other operations were carried out to obtain 43g of a white crystalline powdery solid as the objective compound, melting point: 152.5-153.3 ℃, the HPLC normalization content is about 98 percent, and the total yield of the three steps is 82.3 percent. The reaction formula is as follows:

synthesis example 24

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

According to the procedure of reference Synthesis preparation example 5 in which 25g (0.20 mol) of benzoic acid was replaced with 29.5g (0.20 mol) of p-cyanobenzoic acid and the other operations were the same, methyl 2-fluoro-3- [ (4-cyanophenylcarbonyl) amino ] benzoate was synthesized, and 27.2g (0.086 mol) was taken in place of 26.7g (0.086 mol) of the methyl 2-fluoro-3- [ (4-fluorophenylcarbonyl) amino ] benzoate material as the raw material in Synthesis example 13, while 16.8g (0.11 mol) of 1-bromo-2-ethoxyethane was taken in place of 15.8g (0.11 mol) of the 1-bromo-2-methoxyethane as the raw material in Synthesis example 13 and the other operations were the same, 2-fluoro-3- [ (2-ethoxyethyl) (4-cyanophenylcarbonyl) amino ] benzoic acid was synthesized, and 26.6g (0.071 mol) was taken in place of the raw material 2-fluoro-3- [ (2-methoxyethyl) (4-cyanophenylcarbonyl) amino ] benzoic acid in Synthesis example 18, and the other operations were the same, whereby 25g (25.071) of the objective compound was obtained as a white crystalline solid, and the melting point of the final product was obtained: 150.1-152.2 ℃, the HPLC normalization content is about 98 percent, and the total yield of the last three steps is 80.3 percent. The reaction formula is as follows:

the nuclear magnetic hydrogen spectrum and mass spectrum 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 procedure of Synthesis example 13, wherein 15.8g (0.11 mol) of 1-bromo-2-methoxyethane was replaced with 18.7g (0.11 mol) of 1-bromo-2-n-propoxyethane, the yield and content of 2-fluoro-3- [ (2-n-propoxyethyl) (4-fluorophenylcarbonyl) amino ] benzoic acid as an intermediate were obtained in the same manner with the other feeds and operations. Synthesis of target Compound according to a similar operation to that of Synthesis example 20, in which 26g (0.071 mol) of the starting material 2-fluoro-3- [ (2-ethoxyethyl) (4-fluorophenylcarbonyl) amino ] benzoic acid was replaced with 27g (0.071 mol) of the above-obtained 2-fluoro-3- [ (2-n-propoxyethyl) (4-fluorophenylcarbonyl) amino ] benzoic acid, the other operation was similar, and the target compound was finally obtained: 2-fluoro-3- [ (4-fluorophenylcarbonyl) (2-N-propoxyethyl) amino ] -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropan-2-yl) -6- (trifluoromethyl) phenyl ] benzamide, melting point: 156.5 to 156.8, and the yield and the content result are similar.

Other compounds of formula (I) or (II) of the present invention may be synthesized by reference to the above examples.

Examples of biological Activity test

A part of the compound of the general formula (II) obtained by the invention is used for testing various pests.

Preparing a compound: weighing a certain mass of original drug by using a balance (0.001 g), preparing 1% mother liquor by using DMF (dimethyl formamide), and diluting the mother liquor into test concentration for later use by using distilled water containing 0.1% Tween-80; if the preparation is prepared, a certain mass of preparation sample is weighed by a balance (0.001 g) according to the content of the active ingredients of the preparation, and the preparation sample is diluted into the test concentration by distilled water for later use.

Table 1: part of the compound of the formula (II)

Test example 1 partial Compounds of general formula (II) in the determination of the indoor biological Activity of Plutella xylostella

A Plutella xylostella (Plutella xylostella) sensitive population and a chlorantraniliprole resistant population are bred indoors with radish seedlings;

the test method comprises the following steps: and (3) measuring the activity of the plutella xylostella: soaking folium Raphani in the solution for 30s by soaking method, drying in the shade in a plastic culture dish filled with filter paper, inoculating 10 heads of 2-year-old diamond back moth, and placing in an observation room at 22 deg.C under illumination (16/8 h). After 2 days, the body was observed with a brush pen, no response was observed as dead, and the procedure was repeated 3 times with a blank control without any drug.

The test results show that the activity of some compounds of general formula (II) such as SYN101 and the like on diamond back moth is determined as shown in Table II:

the results show that: at the tested concentrations of 0.2mg/L,0.1mg/L and 0.05mg/L, the compounds SYN101, SYN102, SYN103, SYN104, SYN105, SYN106 and SYN107 show excellent insecticidal activity on the activity of diamondback moth sensitive population and the activity of diamondback moth chlorantraniliprole resistant population, wherein the insecticidal activities are all more than 80%, and at the low concentration of 0.05mg/L, the activities of SYN104, SYN105, SYN106 and SYN107 on the diamondback moth sensitive population and the activity of diamondback moth chlorantraniliprole resistant population still show excellent insecticidal activity, wherein the insecticidal activities are all 100%.

Table 2: the activity determination result of part of the compound with the general formula (II) on diamond back moth

Test example 2 part of the general formula (II) Compounds for the determination of the indoor biological Activity of Spodoptera frugiperda

Spodoptera frugiperda activity assay: soaking appropriate amount of corn leaf in the solution for 30s by soaking method, placing in plastic culture dish filled with filter paper, naturally drying in the shade, inoculating 10 heads of Spodoptera frugiperda of 2 years, and placing in an observation room at 26 deg.C under illumination (16/8 h). After 2 days, the body was observed with a brush pen, no response was observed as dead, and the procedure was repeated 3 times with a blank control without any drug.

And (3) test results: the results of the indoor bioactivity assay of some compounds of general formula (II) such as SYN101 against Spodoptera frugiperda are shown in Table 3:

the results show that: compounds SYN101, SYN102 and SYN103 all had better activity at the tested concentration of 0.2mg/L, reaching 100%, at the tested concentration of 0.1mg/L, the activity was slightly poor, but all were more than 80%, at the tested concentration of 0.05mg/L, the activity was poor. At the tested concentration of 0.2mg/L,0.1mg/L and 0.05mg/L, the compounds SYN104, SYN105, SYN106 and SYN107 all showed excellent insecticidal activity, all reaching 100%.

Table 3: the activity of partial compound of the general formula (II) on Spodoptera frugiperda

The applicant states that the invention is illustrated by the above representative examples to be a method for preparing a heptafluoroisopropyl-containing bisamide compound and an intermediate thereof, but the invention is not limited to the above examples, and does not mean that the invention is realized by relying on the above examples. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.

Claims

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

The method 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 shown as the formula (1) or the formula (2):

wherein R is ³ Is C1-C5 alkyl;

the N-alkylation reaction solvent is selected from: one or more of N, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, 1, 3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dichloroethane, cyclohexane, methylcyclohexane, toluene, ethylbenzene and xylene;

the N-alkylation reaction base is selected from: potassium carbonate, sodium hydride;

the N-alkylation reaction bromoalkane is selected from: 2-methoxy bromoethane, 2-ethoxy bromoethane, 3-methoxy bromopropane, 3-ethoxy bromopropane, 2-n-propoxy bromoethane, 2-isopropoxybromoethane, 2-n-butoxy bromoethane, bromomethylcyclopropane, bromomethane, or bromoethane;

the N-alkylation reaction catalyst is selected from: one or more of cetyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, polyethylene glycol 400-800, tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium hydrogen sulfate, 15-crown-5 ether, 18-crown-6-ether or 4-Dimethylaminopyridine (DMAP);

the amidation reaction solvent is selected from: one or more of N, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, 1, 3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, ethyl acetate, dichloromethane, dichloroethane, cyclohexane, methylcyclohexane, toluene, ethylbenzene and xylene.

2. A preparation method of a heptafluoroisopropyl-containing bisamide compound has a structure shown in a general formula (II),

The method is characterized in that the process flow of the preparation method of the compound with the structure shown in the general formula (II) is as shown in the formula (3):

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 orAn ethyl group;

the amidation reaction solvent is selected from: one or more of dichloromethane, dichloroethane, cyclohexane, methylcyclohexane, toluene, ethylbenzene, xylene, ethyl acetate, tetrahydrofuran or acetonitrile;

the bromination reaction solvent is selected from: one or more of dichloromethane, dichloroethane, methanol, ethanol, isopropanol and tert-butanol;

the bromination reaction base is selected from: sodium hydroxide, potassium carbonate, sodium carbonate or their aqueous solutions.

3. The method according to claim 1, wherein R is ³ Is methyl or ethyl.

4. The method according to claim 1, wherein R is ³ Is methyl.

5. The method according to claim 1 or 2, wherein R is ¹ The substituents are independently selected from H or fluorine; r is ² The substituents are independently selected from 2-methoxyethyl, 2-ethoxyethyl, 2-n-propoxyethyl, 2-isopropoxyethyl, 2-n-butoxyethyl, cyclopropylmethyl, methyl or ethyl.

6. The process according to claim 1, wherein the N-alkylation catalyst is selected from the group consisting of: tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, 15-crown-5-ether, 18-crown-6-ether or 4-Dimethylaminopyridine (DMAP).

7. The method of claim 1, wherein the N-alkylation reaction temperature is 50 ℃ to 150 ℃; the temperature of the amidation reaction is 0-150 ℃.

8. The process according to claim 2, wherein the amidation reaction temperature is 20 ℃ to 180 ℃; the bromination reaction temperature is 0-100 ℃.

9. The process according to claim 2 or 8, characterized in that the amidation reaction solvent is selected from: one or more mixtures of dichloroethane, cyclohexane, methylcyclohexane, toluene or acetonitrile; the bromination reaction solvent is selected from: one or more of dichloroethane, methanol, ethanol, isopropanol and tert-butanol; the bromination reaction base is selected from: sodium hydroxide, potassium carbonate or aqueous solutions thereof.

10. The crystalline compound of claim 2, wherein R is a moiety of formula (II) ¹ Is H and R ² Is 2-methoxyethyl, which is characterized in that the x-ray powder diffraction of the crystal has characteristic peaks at the following positions, 2 theta =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 °, 26.561 ± 0.2 °, 27.420 ± 0.2 °, 28.239 ± 0.461 ± 0.32 °, 33.32 ± 0.32 °, 33 ± 0.32 °.

11. The crystalline compound of claim 2, wherein R is a moiety of formula (II) ¹ Is fluorine and R ² The compound is a 2-methoxyethyl group, and is characterized in that a crystalline x-ray powder diffraction has characteristic peaks at the following positions, namely 2 theta =7.376 +/-0.2 degrees, 9.897 +/-0.2 degrees, 10.940 +/-0.2 degrees, 12.015 +/-0.2 degrees, 12.303 +/-0.2 degrees, 14.398 +/-0.2 degrees, 14.578 +/-0.2 degrees, 15.561 +/-0.2 degrees, 15.839 +/-0.2 degrees, 17.163 +/-0.2 degrees, 18.257 +/-0.2 degrees, 18.463 +/-0.2 degrees, 18.737 +/-0.2 degrees, 18.922 +/-0.2 degrees, 19.219 +/-0.2 degrees, 19.518 +/-0.2 degrees, 19.137 +/-0.2 degrees, 20.137 +/-0.2 degrees, 20.379 +/-0.2 degrees and 20.600 +/-0 degrees.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. A crystal of the compound prepared by the process according to claim 2, wherein the compound has a structure represented by the general formula (II) wherein R is ¹ Is fluorine and R ² Is 2-ethoxyethyl, and is characterized in that the diffraction of crystalline X-ray powder has characteristic peaks at the following positions, 2 theta =7.318 plus or minus 0.2 degrees, 9.697 plus or minus 0.2 degrees, 10.940 plus or minus 0.2 degrees, 11.981 plus or minus 0.2 degrees, 12.136 plus or minus 0.2 degrees, 14.142 plus or minus 0.2 degrees, 14.461 plus or minus 0.2 degrees, 15.240 plus or minus 0.2 degrees, 15.561 plus or minus 0.2 degrees, 16.304 plus or minus 0.2 degrees, 17.161 plus or minus 0.2 degrees, 17.979 plus or minus 0.2 degrees, 18.562 plus or minus 0.2 degrees, 19.138 plus or minus 0.2 degrees, 19.698 plus or minus 0.2 degrees, 20.039 plus or minus 0.2 degrees, 20.220 plus or minus 0.2 degrees, 20.442 plus or minus 0.2 degrees, 20.784 plus or minus 0.2 degrees, 20.998 plus or minus 0.2 degrees, 21.819 plus or minus 0.2 degrees, 22.039 plus or minus 0.2 degrees 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 ° and 43.039 +/-0.2 °.

13. The crystalline solid according to any one of claims 10 to 12, wherein the crystallization solvent is one or more 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.