WO2024087613A1 - 一种含七氟异丙基的双酰胺类化合物及其中间体化合物，其制备方法与用途 - Google Patents

一种含七氟异丙基的双酰胺类化合物及其中间体化合物，其制备方法与用途 Download PDF

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WO2024087613A1
WO2024087613A1 PCT/CN2023/096577 CN2023096577W WO2024087613A1 WO 2024087613 A1 WO2024087613 A1 WO 2024087613A1 CN 2023096577 W CN2023096577 W CN 2023096577W WO 2024087613 A1 WO2024087613 A1 WO 2024087613A1
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preparation
compound
reaction
ether
methyl
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French (fr)
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沈新良
吴华龙
曹端祥
曹后红
潘丽英
黄文超
沈浩
王海涛
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浙江宇龙药业有限公司
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
    • A01N37/46—N-acyl derivatives
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P7/00—Arthropodicides
    • A01P7/02—Acaricides
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P7/00—Arthropodicides
    • A01P7/04—Insecticides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated

Definitions

  • the invention patent application requested by this invention has a priority date of October 24, 2022, a priority number of CN 2022113037189, and is named “A bisamide compound containing heptafluoroisopropyl and its intermediate compound, preparation method and use thereof”.
  • the invention belongs to the field of insecticides and relates to a heptafluoroisopropyl-containing bisamide compound and an intermediate compound thereof, a preparation method thereof, an X-ray powder diffraction characteristic of a crystal of the heptafluoroisopropyl-containing bisamide compound, and uses thereof.
  • Broflanilide (structural formula: 01), a diamide insecticide jointly developed by Mitsui Chemicals and BASF, has been commercialized. Its Chinese name is brofenac, which is mainly used for fruits, vegetables, beans, cotton, corn, grains, flowers and non-crop purposes to control lepidoptera, coleoptera, termites, ants, cockroaches, flies and other pests. It has very good effects. For details, see Chinese patent CN102119173B, amide derivatives, pest control agents containing the amide derivatives and methods of use thereof. However, many domestic companies and research institutions have optimized and improved the structure on this basis and discovered a series of new insecticides with higher activity, lower dosage and more environmental friendliness.
  • Chinese patent CN 109497062 B discloses a diamide compound and its preparation method and application, with a representative structure of cyclopentadienil (structural formula: 02).
  • a diamide compound containing a heptafluoroisopropyl group with a general structural formula (II) having high insecticidal activity, with a representative structure (structural formula: 03). This provides more drug selection and drug use options in crop production such as agriculture and horticulture.
  • R1 substituents are independently selected from H, fluorine, trifluoromethyl, cyano or nitro;
  • R2 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 aims to provide a heptafluoroisopropyl-containing bisamide compound and a preparation method thereof, which has simple operation of the preparation process, mild chemical reaction conditions, environmental friendliness, high total yield, high final product content, low cost, and easy industrial production, through the optimization design of the preparation process and the optimization and improvement of the reaction conditions. It also relates to an intermediate compound for preparing the heptafluoroisopropyl-containing bisamide compound and a preparation method thereof.
  • the present invention provides a method for preparing an intermediate compound for preparing a heptafluoroisopropyl-containing bisamide compound, wherein the intermediate is represented by the following general formula (I):
  • R1 substituents are independently selected from H, fluorine, trifluoromethyl, cyano or nitro;
  • R2 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.
  • R 3 is a C1-C5 alkyl group
  • the N-alkylation reaction solvent in formula (1) or formula (2) is selected from: N,N-dimethylformamide, N,N-dimethyl A mixture of one or more of acetamide, N,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 carbonate, sodium hydride;
  • the N-alkylated bromoalkane in formula (1) or (2) is selected from the group consisting of 2-methoxybromoethane, 2-ethoxybromoethane, 3-methoxybromopropane, 3-ethoxybromopropane, 2-n-propoxybromoethane, 2-isopropoxybromoethane, 2-n-butoxybromoethane, bromomethylcyclopropane, methyl bromide or ethyl bromide;
  • the N-alkylation reaction catalyst in formula (1) or formula (2) is selected from the group consisting of hexadecyltrimethylammonium chloride, benzyltriethylammonium chloride, polyethylene glycol 400-800, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, 15-crown-5-ether, 18-crown-6-ether or a mixture of one or more of 4-dimethylaminopyridine (DMAP);
  • DMAP 4-dimethylaminopyridine
  • the amidation reaction solvent in formula (2) is selected from: one or more mixtures of N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, ethyl acetate, dichloromethane, dichloroethane, cyclohexane, methylcyclohexane, toluene, ethylbenzene and xylene.
  • R 3 is a C1-C5 alkyl group, preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, and particularly preferably a methyl group or an ethyl group, and is prepared by an esterification reaction of the corresponding alcohols.
  • the catalyst for the esterification reaction is concentrated sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid.
  • Concentrated sulfuric acid is preferred, with a preferred mass concentration of 80-100%, and an amount of 0.5%-20% of the weight of the 2-fluoro-3-nitrobenzoic acid raw material, preferably 1-5%.
  • Alcohols are generally selected from C1-C5 alcohols, preferably methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and particularly preferably methanol or ethanol; the amount is 2-10 times the weight of the 2-fluoro-3-nitrobenzoic acid raw material, preferably 3-5 times; the reaction temperature is generally 50-200°C, preferably the boiling reflux reaction temperature of the corresponding alcohol; the reaction time is generally 5-48 hours, preferably 5-24 hours.
  • 2-fluoro-3-nitrobenzoic acid is an important intermediate for medicine and pesticides.
  • synthetic routes can generally be purchased from the market or synthesized. The content is generally more than 95% of the industrial grade. Generally, it is obtained through market purchase, and those skilled in the art can also achieve it through the following classic synthesis reaction route:
  • the reaction solvent generally uses alcohols, such as methanol, ethanol, n-propanol, isopropanol, tert-butanol; ethers, such as tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, etc., preferably alcohols, such as methanol, ethanol, isopropanol, tert-butanol.
  • the amount of solvent used is 2-20 times the weight of 2-fluoro-3-nitrobenzoate, preferably 2-10 times.
  • the catalyst generally uses a mass concentration of
  • the catalyst is used in an amount of 0.1%-10% by weight of 2-fluoro-3-nitrobenzoate on a dry basis, preferably 1%-5%, and can be recycled 5-10 times for economic considerations.
  • Hydrogen is more than 99% of industrial grade, the reaction pressure is 0-2Mpa, preferably 0-0.5Mpa, and particularly preferably close to normal pressure reaction.
  • the reaction temperature is 0-100° C., preferably 5-50° C.
  • the reaction time is generally 2-24 hours until the catalyst stops absorbing hydrogen.
  • R1 substituents are independently selected from H, fluorine, trifluoromethyl, cyano or nitro; R3 is as defined above.
  • the benzoyl chloride series raw materials used in the amidation reaction are generally prepared by chlorinating the corresponding benzoic acid series raw materials and thionyl chloride in an inert solvent followed by desolventizing, and the amount used is generally 1.0-1.2 times the molar amount of 2-fluoro-3-aminobenzoate, preferably 1.0-1.05 times.
  • the acidifying agent commonly used in the amidation reaction is triethylamine, pyridine, N,N-diisopropylethylamine, N,N-dimethylaniline, tetramethylethylenediamine, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium methoxide, sodium tert-butoxide or potassium tert-butoxide, etc., preferably triethylamine or pyridine, the molar amount is 0.1-5.0 times of the benzoyl chloride series raw materials, and the preferred economic amount is 0.1-2.0 times;
  • the solvent used in the amidation reaction is dichloromethane, chloroform, dichloroethane, tetrahydrofuran, dioxane, dimethyl sulfoxide, acetonitrile, toluene, xylene, N,N-dimethylformamide, N,N-dimethyl
  • the obtained product can be used to implement the preparation method of the intermediate compound of the present invention, and the process flow of the method is shown in formula (1):
  • R 3 is selected from C1-C5 alkyl
  • the solvent in the N-alkylation reaction is selected from: one or more mixtures of N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dichloroethane, cyclohexane, methylcyclohexane, toluene, ethylbenzene, and xylene; the preferred solvent is: one or more mixtures of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, cyclohexane, methylcyclohexane, and toluene.
  • the amount of one or more mixtures is 2-10 times, preferably 2-5 times, the weight of the 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 used is 1-3 times the molar amount of the amide or 2-fluoro-3-aminobenzoate raw material, preferably 1-2 times.
  • the bromoalkane in the N-alkylation reaction is selected from: 2-methoxybromoethane, 2-ethoxybromoethane, 3-methoxypropane bromide, 3-ethoxypropane bromide, 2-n-propoxybromoethane, 2-isopropoxybromoethane, 2-n-butoxybromoethane, bromomethylcyclopropane, methyl bromide or ethyl bromide; it can usually be obtained from the market or synthesized.
  • the present invention does not specifically state that it generally refers to obtaining from the market.
  • the dosage is 1-3 times the molar amount of the amide or 2-fluoro-3-aminobenzoate raw material, preferably 1-2 times.
  • the present invention uses bromoalkane and avoids the use of iodoalkane. This is because iodoalkane has high activity, but it causes high industrialization cost and is not conducive to industrialization. Bromoalkane is usually less active, poor selectivity, and low yield. It is necessary to use a catalyst in the presence of and under optimized process conditions to achieve better results.
  • the catalyst in the N-alkylation reaction is selected from one or more mixtures of hexadecyltrimethylammonium chloride, benzyltriethylammonium chloride, polyethylene glycol 400-800, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, 15-crown-5-ether, 18-crown-6-ether or 4-dimethylaminopyridine (DMAP).
  • DMAP 4-dimethylaminopyridine
  • the catalyst can also be an iodide salt, such as potassium iodide, sodium iodide, etc., but the catalytic effect is not as good as that of a phase transfer catalyst or 4-dimethylaminopyridine (DMAP).
  • a phase transfer catalyst or 4-dimethylaminopyridine (DMAP).
  • DMAP 4-dimethylaminopyridine
  • tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, 18-crown-6-ether or 4-dimethylaminopyridine (DMAP) is used.
  • the amount of the catalyst is 1-10% of the weight of the amide or 2-fluoro-3-aminobenzoic acid ester raw material, preferably 1-5%.
  • the use of the catalyst in the present invention can reduce the reaction temperature, improve the reaction selectivity and product yield.
  • the present invention also provides another method for preparing the above intermediate compound, the process of which is shown in formula (2):
  • R 3 is selected from a C1-C5 alkyl group
  • the solvent in the N-alkylation reaction is selected from: one or more mixtures of N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dichloroethane, cyclohexane, methylcyclohexane, toluene, ethylbenzene, and xylene;
  • the preferred solvent is: one or more mixtures of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, cyclohexane, methylcyclohexane, and toluene, and the amount used is 2-10 times the weight of the amide or 2-fluoro-3-aminobenzoic acid ester raw material, preferably 2-5 times.
  • the base in the N-alkylation reaction is selected from potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, preferably potassium carbonate, sodium carbonate or sodium hydride, and the amount used is 1-3 times the molar amount of the amide or 2-fluoro-3-aminobenzoate raw material, preferably 1-2 times.
  • the bromoalkane in the N-alkylation reaction is selected from: 2-methoxybromoethane, 2-ethoxybromoethane, 3-methoxypropane bromide, 3-ethoxypropane bromide, 2-n-propoxybromoethane, 2-isopropoxybromoethane, 2-n-butoxybromoethane, bromomethylcyclopropane, methyl bromide or ethyl bromide; it can usually be obtained from the market or synthesized.
  • the present invention does not specifically state that it generally refers to obtaining from the market.
  • the dosage is 1-3 times the molar amount of the amide or 2-fluoro-3-aminobenzoate raw material, preferably 1-2 times.
  • the present invention uses bromoalkane and avoids the use of iodoalkane. This is because iodoalkane has high activity, but it causes high industrialization cost and is not conducive to industrialization. Bromoalkane is usually less active, poor selectivity, and low yield. It is necessary to use a catalyst in the presence of and under optimized process conditions to achieve better results.
  • the catalyst in the N-alkylation reaction is selected from one or more mixtures of hexadecyltrimethylammonium chloride, benzyltriethylammonium chloride, polyethylene glycol 400-800, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, 15-crown-5-ether, 18-crown-6-ether or 4-dimethylaminopyridine (DMAP).
  • DMAP 4-dimethylaminopyridine
  • the catalyst may also be an iodide salt, such as potassium iodide, sodium iodide, etc., but the catalytic effect is not as good as that of a phase transfer catalyst or 4-dimethylaminopyridine (DMAP).
  • a phase transfer catalyst or 4-dimethylaminopyridine (DMAP).
  • DMAP 4-dimethylaminopyridine
  • tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, 15-crown-5-ether, 18-crown-6-ether or 4-dimethylaminopyridine (DMAP) is used.
  • the amount of the catalyst is 1-10% of the weight of the amide or 2-fluoro-3-aminobenzoic acid ester raw material, preferably 1-5%.
  • the 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: one or more mixtures of N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, ethyl acetate, dichloromethane, dichloroethane, cyclohexane, methylcyclohexane, toluene, ethylbenzene, and xylene.
  • the preferred solvent is: one or more mixtures of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, tetrahydrofuran, ethyl acetate, dichloromethane, dichloroethane, and toluene.
  • the amount used is 2-10 times the weight of the benzoic acid series acyl chloride raw material, preferably 2-5 times.
  • the amidation reaction can be carried out by adding DMAP catalyst, the amount of which is 1-10% by weight of the benzoic acid series acyl chloride raw material, preferably 1-5%.
  • DMAP catalyst the amount of which is 1-10% by weight of the benzoic acid series acyl chloride raw material, preferably 1-5%.
  • the reaction yield and reaction time under the process conditions of the present invention are acceptable, so the present invention does not necessarily have to use it; in the preparation method of the intermediate compound of the present invention, the amidation reaction does not need to use an acid agent, and under the process conditions of the present invention, the conversion yield and reaction time are acceptable.
  • the amidation reaction temperature is 0-200°C, preferably 0-150°C
  • the hydrolysis reaction conditions are generally normal conditions, generally using alcohols Solvents such as methanol, ethanol, isopropanol, etc., or ether solvents such as 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, etc., preferably methanol and ethanol, are generally used in an amount of 2-10 times the weight of the corresponding ester, preferably 2-5 times; the base generally uses sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, preferably sodium hydroxide, and the concentration generally uses a mass concentration of 1-35%, and the molar amount is 1.1-3.0 times the corresponding ester.
  • the reaction temperature is generally 5-50°C, preferably 20-30°C.
  • the reaction time is generally 1-5 hours, preferably 1-2 hours.
  • the N-alkylation reaction temperature is 50-200°C, preferably 50-150°C.
  • the reaction temperature is preferably the azeotropic temperature, and the water produced by the reaction can be removed by azeotropy, which can shorten the reaction time.
  • the reaction pressure is generally normal pressure reaction.
  • the bromoalkane is methyl bromide or ethyl bromide, due to the low boiling point of the bromoalkane, volatilization is avoided, and preferably a closed reaction is performed, and the pressure is 0-0.2MPa.
  • the N-alkylation reaction time is usually 2-12 hours, preferably 2-8 hours.
  • the present invention also provides a heptafluoroisopropyl-containing bisamide compound, the structure of which is shown in general formula (II):
  • R1 substituents are independently selected from H, fluorine, trifluoromethyl, cyano or nitro;
  • R2 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 compound, and the process flow of the method is shown in formula (3):
  • the usual method of the acyl chloride reaction is that the raw material of the general formula (I) reacts with thionyl chloride in an inert solvent, and then undergoes a desolventizing treatment to enter the next step of the reaction.
  • the solvent used in the acyl chloride reaction is dichloromethane, chloroform, dichloroethane, toluene or xylene, etc., preferably dichloroethane or toluene, etc.;
  • the acyl chloride reaction temperature is generally 20-150°C, preferably 40-100°C;
  • the acyl chloride reaction time is generally 1-5 hours, preferably 2-3 hours.
  • the solvent in the amidation reaction is selected from one or more mixtures of dichloromethane, dichloroethane, cyclohexane, methylcyclohexane, toluene, ethylbenzene, xylene, ethyl acetate, tetrahydrofuran or acetonitrile; preferably, the solvent is dichloroethane, cyclohexane, methylcyclohexane, toluene, ethyl acetate or acetonitrile, and the amount used is generally 2-10 times, preferably 3-8 times, the weight of the raw material corresponding to the general formula (I).
  • the amidation can also use a catalyst 4-dimethylaminopyridine (DMAP) to shorten the reaction time, but under the preferred conditions of the present invention, the amidation does not require the use of a catalyst and a succinic acid agent, and the reaction yield and reaction time are acceptable, so the present invention does not necessarily have to use it.
  • Another raw material for the amidation reaction 4-heptafluoroisopropyl-2-trifluoromethylaniline, can be obtained by synthesis or market purchase.
  • the synthesis method is prepared by alkylation reaction of o-trifluoromethylaniline raw material and 2-bromoheptafluoropropane or 2-iodoheptafluoropropane in the presence of hydrosulfite.
  • the synthesis is detailed in the disclosure of Chinese invention patent CN 102119173B.
  • the amount of the raw material 4-heptafluoroisopropyl-2-trifluoromethylaniline used is 1.0-1.3 times the molar amount of the raw material of the general formula (I), and the preferred amount is 1.0-1.05 times.
  • the bromination reaction uses liquid bromine as a brominating agent, which is cheap, the raw material is easily available, and the byproduct bromide salt is easy to recycle. Compared with N-bromosuccinimide, the brominating agent has low cost and is environmentally friendly.
  • the amount used is 1-2 times the molar amount of the raw material of the general formula (I), and the preferred amount is 1-1.5 times.
  • the preferred method of use is dropwise reaction, and the dropwise reaction can also be carried out under ultraviolet light conditions. Preferably, the reaction can be carried out without light.
  • the bromination reaction can also be carried out to reduce the amount of bromine used.
  • An oxidant is added shortly after the reaction so that the generated bromide salt is oxidized into elemental bromine and is used again in the bromination reaction. This can reduce the amount of bromine used, but it will lead to complex operation of the reaction system and related side reaction impurities, which is not necessarily required in the present invention.
  • 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.
  • the solvent is a mixture of one or more mixtures of dichloroethane, methanol, ethanol, isopropanol, and tert-butanol.
  • the amount used is generally 2-10 times, preferably 3-8 times, the weight of the raw material of the general formula (I).
  • the base in the bromination reaction is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or any concentration of aqueous solution thereof, or any concentration of sodium methoxide methanol solution, sodium ethoxide ethanol solution, sodium isopropanol isopropanol solution, sodium tert-butoxide tert-butanol solution, preferably solid sodium hydroxide, potassium hydroxide, potassium carbonate; the amount used is generally 1-2 times the molar amount of the raw material of general formula (I), preferably 1-1.5 times.
  • the bromination reaction temperature is 0-100°C, preferably 20-80°C.
  • R1 substituents are independently selected from H or fluorine;
  • R2 substituents are independently selected from 2-methoxyethyl, 2-ethoxyethyl, 2-n-propoxyethyl, 2-isopropoxyethyl, 2-n-butoxyethyl, cyclopropylmethyl, methyl or ethyl;
  • R3 is methyl.
  • the present invention also provides a bisamide compound crystal containing a heptafluoroisopropyl group, when R 1 is H and R 2 is 2-methoxyethyl, the crystal has a characteristic peak at the following position in X-ray powder diffraction:
  • the crystals are obtained by crystallization with 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 dimethyl ether, ethylene glycol dimethyl ether, A mixture of one or more of diethyl ether and methyl tert-butyl ether.
  • the solvent is selected from methanol, ethanol, isopropanol, tetrahydrofuran, isopropyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol dimethyl ether, ethylene glycol dimethyl ether, A mixture of one or more of diethyl ether and methyl tert-butyl ether.
  • the heptafluoroisopropyl-containing bisamide compounds obtained by the invention have excellent insecticidal activity, and the chemical reaction conditions are mild, environmentally friendly, high in total yield, high in final product content, low in cost, easy in industrial production, and have high application prospects.
  • FIG1 is an X-ray powder crystal diffraction analysis result of a compound sample of Synthesis Example 17;
  • FIG2 is an X-ray powder crystal diffraction analysis result of the compound sample of Synthesis Example 18;
  • FIG3 is the result of X-ray powder crystal diffraction analysis of the compound sample of Synthesis Example 20.
  • the raw materials described in the synthesis examples of the present invention are generally purchased from the market unless otherwise specified, and the content specification is usually ⁇ 95%, and the content is not accurately calibrated.
  • the percentage concentration described in the synthesis examples generally refers to the weight percentage concentration unless otherwise specified.
  • the HPLC content data is the area-normalized content and is not accurately calibrated.
  • the yield refers to the molar yield, and the yield data is not accurately calibrated.
  • the filtrate was decompressed and desolventized to obtain 46g of oily liquid, which was 2-fluoro-3-aminobenzoic acid ethyl ester, with an HPLC normalized content of 96% and a yield of 96.3%, which was used for the synthesis reaction.
  • the solvent layer was separated and transferred to a 500ml rotary evaporator, and the solvent was removed under reduced pressure to 80°C to obtain 53g of methyl 2-fluoro-3-[(phenylcarbonyl)amino]benzoate as an off-white solid with a HPLC normalized content of 94% (yield 91.2%).
  • the solid was used for standby use without further treatment and directly used in the synthesis reaction.
  • the synthesis preparation example 5 was followed except that 25 g (0.20 mol) of benzoic acid was replaced by 28 g (0.20 mol) of p-fluorobenzoic acid. Other operations were the same to obtain 56 g of off-white solid methyl 2-fluoro-3-[(4-fluorophenylcarbonyl)amino]benzoate with a HPLC normalized content of 94% (yield 90.2%) for standby use and used directly in the synthesis reaction without further treatment.
  • the H-NMR spectra were measured using a Bruker AV-400 spectrometer (400 MHz), TMS was used as the internal standard, and the solvent was CDCl 3 or DMSO-d 6 (unless otherwise specified, the same below); the high-resolution mass spectra were measured using a UHR-TOF maXis (ESI) mass spectrometer (unless otherwise specified, the same below).
  • ESI UHR-TOF maXis
  • Synthesis Example 8 The operation of Synthesis Example 8 was followed, except that 1 g of 4-dimethylaminopyridine (DMAP) was added during the second step of amidation, and other materials and operations remained unchanged, and similar results were obtained.
  • DMAP 4-dimethylaminopyridine
  • the catalyst tetrabutylammonium bromide 1g was not added, and the other materials and operations were all the same, and finally 24g of off-white solid was obtained, the target product 2-fluoro-3-[(2-methoxyethyl)(phenylcarbonyl)amino]benzoic acid
  • the HPLC normalized content was about 55%, the yield was 48.3%, and the rest was mainly 2-fluoro-3-[(phenylcarbonyl)amino]benzoic acid.
  • Synthesis Example 8 The operation of Synthesis Example 8 was followed, except that 1 g of the catalyst tetrabutylammonium bromide was not added, and other materials and operations were the same. Finally, an oily material with a normalized content of about 45% was obtained, but no solid crystals of the target product were obtained.
  • the H NMR spectra were measured using a Bruker AV-400 spectrometer (400 MHz) with TMS as the internal standard and DMSO-d6 as the solvent (unless otherwise specified).
  • the high-resolution mass spectra were measured using a UHR-TOF maXis (ESI) mass spectrometer (unless otherwise specified).
  • the target compound sample was analyzed by X-ray powder crystal diffraction using a Japanese Rigaku SmartLab diffractometer (the same below unless otherwise specified).
  • the sample obtained in this synthesis example was recrystallized with 3 times the weight of isopropyl ether.
  • the X-ray powder crystal diffraction analysis of the finally obtained sample showed that the characteristic peaks of the crystals were exactly the same as above.
  • the sample obtained in this synthesis example was recrystallized with 3 times the weight of ethylene glycol monomethyl ether.
  • the X-ray powder crystal diffraction analysis of the finally obtained sample showed that the characteristic peaks of the crystals were exactly the same as above.
  • the mixture was cooled to about 25°C, 150g of new dichloroethane was added to dissolve the mixture, and the mixture was transferred to a reaction bottle.
  • 27.8g (0.08mol) of 4-(1,1,1,2,3,3,3-heptafluoropropane-2-yl)-2-(trifluoromethyl)aniline raw material was added, and the mixture was heated and refluxed for 5-10 hours.
  • the mixture was cooled to room temperature, 5g of sodium hydroxide was added, and 13.5g of liquid bromine was added dropwise at 35-55°C for about 2 hours to react.
  • the mixture was heated for 2 hours, 50 ml of water was added, the water layer was separated and separated, and the solvent layer was decompressed and desolventized to obtain the residual material, 120 g of ethylene glycol monomethyl ether was added, the temperature was raised and refluxed for 1 hour, the temperature was lowered and crystallized, and the crystallization was carried out at 0-5°C for 1 hour.
  • the white crystalline powder solid of 44 g was obtained by filtration and drying, which was the target compound, with a melting point of 152.4-153.2°C, a HPLC normalized content of about 98%, and a total yield of 83.7% in three steps.
  • the reaction formula is as follows:
  • the sample obtained in this synthesis example was recrystallized with 3 times the weight of ethanol.
  • the X-ray powder crystal diffraction analysis of the finally obtained sample showed that the characteristic peaks of the crystals were exactly the same as above.
  • the sample obtained in this synthesis example was recrystallized with 3 times the weight of isopropyl ether.
  • the X-ray powder crystal diffraction analysis of the finally obtained sample showed that the characteristic peaks of the crystals were exactly the same as above.
  • the sample obtained in this synthesis example was recrystallized with 3 times the weight of ethanol.
  • the X-ray powder crystal diffraction analysis of the finally obtained sample showed that the characteristic peaks of the crystals were exactly the same as above.
  • the sample obtained in this synthesis example was recrystallized with 3 times the weight of ethylene glycol monomethyl ether.
  • the X-ray powder crystal diffraction analysis of the finally obtained sample showed that the characteristic peaks of the crystals were exactly the same as above.
  • the sample obtained in this synthesis example was recrystallized with 3 times the weight of ethylene glycol dimethyl ether.
  • the sample finally obtained was analyzed by X-ray powder crystal diffraction, and the characteristic peaks of the crystals were exactly the same as above.
  • the sample obtained in this synthesis example was recrystallized with 3 times the weight of methanol, isopropanol, tetrahydrofuran, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, and methyl tert-butyl ether, respectively.
  • the X-ray powder crystal diffraction analysis of the finally obtained sample showed that the characteristic peaks of the crystals were exactly the same as above.
  • the crystals obtained by crystallizing the compound in solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, isopropyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, methyl tert-butyl ether, etc., are of consistent crystal type, are easy to obtain and have good stability.
  • the reference synthesis preparation example 5 was operated, wherein 25 g (0.20 mol) of benzoic acid was replaced by 29.5 g (0.20 mol) of p-cyanobenzoic acid, and the other operations were the same to synthesize 2-fluoro-3-[(4-cyanophenylcarbonyl)amino]methyl benzoate, and 27.2 g (0.086 mol) of 2-fluoro-3-[(4-fluorophenylcarbonyl)amino]methyl benzoate as the raw material in Synthesis Example 13 was replaced by 26.7 g (0.086 mol), and 16.8 g (0.11 mol) of 1-bromo-2-ethoxyethane was used to replace the synthesis.
  • the synthesis of the target compound was carried out according to the similar operation as in Synthesis Example 20, wherein the raw material 2-fluoro-3-[(2-ethoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid 26g (0.071mol) was replaced by 2-fluoro-3-[(2-n-propoxyethyl)(4-fluorophenylcarbonyl)amino]benzoic acid 27g (0.071mol) obtained above, and other operations were similar to obtain the target compound: 2-fluoro-3-[(4-fluorophenylcarbonyl)(2-n-propoxyethyl)amino]-N-[2-bromo-4-(1,1,1,2,3,3,3-heptafluoropropane-2-yl)-6-(trifluoromethyl)phenyl]benzamide, melting point: 156.5-156.8, and the yield and content results were similar.
  • Compound preparation Weigh a certain mass of the original drug with a balance (0.001 g), prepare it into a 1% mother solution with DMF, and then dilute it with distilled water containing 0.1% Tween-80 to the test concentration for use; if it is a preparation, weigh a certain mass of the preparation sample with a balance (0.001 g) according to the content of the active ingredient in the preparation, and dilute it with distilled water to the test concentration for use.
  • Test Example 1 Indoor biological activity determination of some compounds of general formula (II) against Plutella xylostella
  • the diamondback moth (Plutella xylostella) was sensitive and chlorantraniliprole-resistant, and was reared indoors on radish seedlings;
  • Test method Diamondback moth activity determination: Use the dipping method, take an appropriate amount of radish leaves and soak them in the medicine for 30 seconds, then place them in a plastic petri dish with filter paper to dry naturally in the shade, and inoculate 10 2-year-old diamondback moths in each dish, and place them in an observation room at 22°C and light (16/8h). Observe after 2 days, touch the insect body with a brush, and if there is no reaction, it is considered dead. Repeat 3 times, and set up a blank control without adding the medicine.
  • SYN104, SYN105, SYN106, and SYN107 still showed excellent insecticidal activity against the sensitive population of Plutella xylostella and the population of Plutella xylostella resistant to chlorantraniliprole, all reaching 100%.
  • Test Example 2 Indoor biological activity determination of some compounds of general formula (II) against fall armyworm
  • Determination of fall armyworm activity Use the dipping method, take an appropriate amount of corn leaves and soak them in the drug for 30 seconds, then place them in a plastic petri dish lined with filter paper to dry naturally in the shade, and inoculate 10 2-year-old fall armyworms in each dish, and place them in an observation room at 26°C and light (16/8h). Observe after 2 days, touch the insect body with a brush, and if there is no reaction, it is considered dead. Repeat 3 times, and set up a blank control without adding the drug.
  • the present invention illustrates a method for preparing a heptafluoroisopropyl-containing bisamide compound and its intermediates through the above representative embodiments, but the present invention is not limited to the above embodiments, nor does it mean that the present invention must rely on the above embodiments to be realized.
  • Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

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Abstract

本发明提供一种用于制备含七氟异丙基的双酰胺类化合物的中间体化合物的制备方法，以及所述含七氟异丙基的双酰胺类化合物的制备方法，所述方法流程如式(3)所示。本发明得到的含七氟异丙基的双酰胺类化合物具有优异的杀虫活性，该化学反应条件温和，环境友好，总收率高，最终产品含量高，成本低，易于产业生产，具有很高的应用前景。

Description

一种含七氟异丙基的双酰胺类化合物及其中间体化合物，其制备方法与用途
本发明请求优先权日为2022年10月24日、优先权号为CN 2022113037189、名称为“一种含七氟异丙基的双酰胺类化合物及其中间体化合物，其制备方法与用途”的发明专利申请。
【技术领域】
本发明属于杀虫剂领域，涉及一种含七氟异丙基的双酰胺类化合物及其中间体化合物，还涉及它们的制备方法，还涉及含七氟异丙基的双酰胺类化合物结晶体的x-射线粉末衍射特性，及它们的用途。
【技术背景】
由于杀虫剂的大量频繁的使用，目前在全球大部分地区造成了严重的抗性问题，必须增加剂量才能起到原有的效果，有些病害已无药可治，对农业生产、环境、生态势必造成一定的问题。需要推出活性更好、用量更低、环境更友好的新型杀虫剂。国内外科研机构及企业不断加大对农药创制的投入，出现了多个活性高、用量低、环境友好的新型杀虫剂。
日本三井化学公司与巴斯夫公司共同合作开发的间二酰胺类杀虫剂Broflanilide(结构式：01)，现已经商业化，中文名称:溴虫氟苯双酰胺，主要用于果蔬、豆类、棉花、玉米、谷物、花卉及非作物用途，防治鳞翅目、鞘翅目、白蚁、蚁类、蜚蠊、蝇类等害虫，具有非常好的效果，详见中国专利CN102119173B，酰胺衍生物、含有该酰胺衍生物的有害生物防除剂及其使用方法。但国内多家企业及研究机构在此基础上进行了结构优化及改进，发现了一系列活性更高、用量更低、环境更友好的新型杀虫剂。中国专利CN 109497062 B一种间二酰胺类化合物及其制备方法和应用，代表性结构，环丙氟虫胺(结构式：02)；我们发现一种含七氟异丙基的双酰胺类化合物，结构通式(Ⅱ)具有较高的杀虫活性，代表性结构(结构式：03)；使得在农业及园艺等作物生产中，提供了更多的用药选择与用药方案。
其中，R1取代基独立地选自H、氟、三氟甲基、氰基或硝基；
R2取代基独立地选自2-甲氧基乙基、2-乙氧基乙基、3-甲氧基丙基、3-乙氧基丙基、2-正丙氧基乙基、2-异丙氧基乙基、2-正丁氧基乙基、环丙基甲基、甲基或乙基。
但相关化合物制备工艺存在路线复杂、化学反应条件苛刻、选择性差、环境不友好、总收率偏低、提纯困难或工艺成本过高等缺点，不利于工业化生产与规模化应用。 详细可参阅相关文献或专利，如：柳爱平，等。溴虫氟苯双酰胺(Broflanilide)的合成与生物活性，精细化工中间体期刊，2020年12月，第50卷第6期16-20页。
【发明内容】
针对现有技术的不足，本发明目的在于通过制备工艺流程的优化设计，反应条件的优化改进，提供一种制备工艺流程操作简单、化学反应条件温和、环境友好、总收率高、最终产品含量高、成本低、易于产业化生产的含七氟异丙基的双酰胺类化合物及其制备方法，还涉及用于制备所述含七氟异丙基的双酰胺类化合物的中间体化合物及其制备方法。
为达此目的，本发明提供一种用于制备含七氟异丙基的双酰胺类化合物的中间体化合物的制备方法，所述中间体如下通式(Ⅰ)所示，
其中，R1取代基独立地选自H、氟、三氟甲基、氰基或硝基；
R2取代基独立地选自2-甲氧基乙基、2-乙氧基乙基、3-甲氧基丙基、3-乙氧基丙基、2-正丙氧基乙基、2-异丙氧基乙基、2-正丁氧基乙基、环丙基甲基、甲基或乙基。
其特征在于所述的通式(Ⅰ)所示结构的中间体化合物制备方法的工艺流程如式(1)或式(2)：
其中，R3为C1-C5的烷基；
式(1)或式(2)中所述N-烷基化反应溶剂选自：N,N-二甲基甲酰胺、N,N-二甲基 乙酰胺、N,N-二乙基甲酰胺、N-甲基吡咯烷酮、1,3-二甲基-2-咪唑啉酮、二甲基亚砜、乙腈、四氢呋喃、二氯乙烷、环己烷、甲基环己烷、甲苯、乙苯、二甲苯中的一种或多种混合物；
式(1)或式(2)中所述N-烷基化反应碱选自：碳酸钾、碳酸钠、氢化钠；
式(1)或式(2)中所述N-烷基化反应溴代烷选自：2-甲氧基溴乙烷、2-乙氧基溴乙烷、3-甲氧基溴丙烷、3-乙氧基溴丙烷、2-正丙氧基溴乙烷、2-异丙氧基溴乙烷、2-正丁氧基溴乙烷、溴甲基环丙烷、溴甲烷或溴乙烷；
式(1)或式(2)中所述N-烷基化反应催化剂选自：十六烷基三甲基氯化铵、苄基三乙基氯化铵、聚乙二醇400-800、四丁基氯化铵、四丁基溴化铵、四丁基硫酸氢铵、15-冠-5-醚、18-冠-6-醚或4-二甲氨基吡啶(DMAP)中的一种或多种混合物；
式(2)中所述酰胺化反应溶剂选自：N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺、N-甲基吡咯烷酮、1,3-二甲基-2-咪唑啉酮、二甲基亚砜、乙腈、四氢呋喃、乙酸乙酯、二氯甲烷、二氯乙烷、环己烷、甲基环己烷、甲苯、乙苯、二甲苯中的一种或多种混合物。
对于上述中间体化合物的制备方法，为达此目的，本发明采用以下技术方案。
首先，使用2-氟-3-硝基苯甲酸原料和相应的醇类，在催化剂存在下进行酯化反应，得到相应的2-氟-3-硝基苯甲酸酯，反应式如下：
其中，R3为C1-C5的烷基，优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基，特别优选为甲基或乙基，由相对应的醇类通过酯化反应而制备。
酯化反应催化剂为浓硫酸、对甲苯磺酸、甲基磺酸、三氟甲基磺酸。优选为浓硫酸，优选质量浓度为80-100％，用量为2-氟-3-硝基苯甲酸原料重量的0.5％-20％，优选为1-5％。醇类，一般选用C1-C5的醇，优选为甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇，特别优选为甲醇或乙醇；用量为2-氟-3-硝基苯甲酸原料重量的2-10倍，优选为3-5倍；反应温度，一般为50-200℃，优选为相应醇的沸点回流反应温度；反应时间，一般为5-48小时，优选反应时间5-24小时。
其中，2-氟-3-硝基苯甲酸是医药、农药重要中间体，有多种合成路线实现，一般可通过市场采购或合成获得，含量一般为工业级95％以上。本发明如果没有特别说明，一 般是指通过市场采购获得，本领域技术人员也可通过下列经典合成反应路线实现：
然后，将所得到的2-氟-3-硝基苯甲酸酯，在溶剂中、在钯炭或雷尼镍催化剂存在下，进行加氢还原反应，将硝基还原为相应的氨基，得到相应的2-氟-3-氨基苯甲酸酯。反应式如下：
其中，反应溶剂一般采用，醇类，如：甲醇、乙醇、正丙醇、异丙醇、叔丁醇；醚类，如：四氢呋喃、甲基叔丁基醚、异丙醚、1,4-二氧六环，乙二醇单甲醚、乙二醇单乙醚、乙二醇二甲醚、乙二醇二乙醚等，优选使用醇类，如：甲醇、乙醇、异丙醇、叔丁醇。溶剂使用量为2-氟-3-硝基苯甲酸酯重量的2-20倍，优选使用2-10倍。催化剂一般采用质量浓度
1-5％的钯炭或雷尼镍，优选使用5％的钯炭催化剂，催化剂折干基使用量为2-氟-3-硝基苯甲酸酯重量的0.1％-10％，优选使用1％-5％，从经济考虑，可循环套用5-10次。氢气为工业级99％以上，反应压力为0-2Mpa，优选压力0-0.5Mpa，特优选接近常压反应。
反应温度为0-100℃，优选反应温度为5-50℃。反应时间一般为反应至催化剂不吸氢，一般为2-24小时。
接着，将所得到的2-氟-3-氨基苯甲酸酯(或可以通过市场直接购买获取)，在溶剂存在下和系列苯甲酰氯反应得到酰胺中间体。反应式如下：
其中，R1取代基独立地选自H、氟、三氟甲基、氰基或硝基；R3定义同前。
此处，酰胺化反应所采用的苯甲酰氯系列原料一般由对应苯甲酸系列原料和氯化亚砜在惰性溶剂中通过酰氯化反应后脱溶制备得到，使用量一般为2-氟-3-氨基苯甲酸酯摩尔量的1.0-1.2倍，优选1.0-1.05倍。
酰胺化反应通常采用的傅酸剂为三乙胺、吡啶、N,N-二异丙基乙胺、N,N-二甲基苯胺、四甲基乙二胺、碳酸氢钠、碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、氢氧化锂、甲醇钠、甲醇钾、叔丁醇钠或叔丁醇钾等，优选采用三乙胺或吡啶，摩尔用量为苯甲酰氯系列原料的0.1-5.0倍，优选的经济用量为0.1-2.0倍；酰胺化反应采用的溶剂为二氯甲烷、氯仿、二氯乙烷、四氢呋喃、二氧六环、二甲基亚砜、乙腈、甲苯、二甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺、N-甲基吡咯烷酮或1,3-二甲基-2-咪唑啉酮等，优选溶剂为二氯乙烷、甲苯、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或1,3-二甲基-2-咪唑啉酮等，用量为苯甲酰氯系列原料重量的1-20倍，优选的经济用量为2-5倍；酰胺化反应温度一般为-5-150℃，优选反应温度0-130℃；反应时间一般为1-5小时，优选1-2小时。
所得产物可用于实现本发明的中间体化合物的制备方法，所述方法流程如式(1)所示：
其中，R3选自C1-C5的烷基；
N-烷基化反应中的溶剂选自：N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺、N-甲基吡咯烷酮、1,3-二甲基-2-咪唑啉酮、二甲基亚砜、乙腈、四氢呋喃、二氯乙烷、环己烷、甲基环己烷、甲苯、乙苯、二甲苯中的一种或多种混合物；优选溶剂为：N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙腈、环己烷、甲基环己烷、甲苯中的一 种或多种混合物，用量为酰胺或2-氟-3-氨基苯甲酸酯原料重量的2-10倍，优选为2-5倍。
N-烷基化反应中的碱选自碳酸钾、碳酸钠、氢氧化钠、氢氧化钾、氢化钠，优选为：碳酸钾、碳酸钠、氢化钠，用量为酰胺或2-氟-3-氨基苯甲酸酯原料摩尔量的1-3倍，优选为1-2倍。
N-烷基化反应中的溴代烷选自：2-甲氧基溴乙烷、2-乙氧基溴乙烷、3-甲氧基溴丙烷、3-乙氧基溴丙烷、2-正丙氧基溴乙烷、2-异丙氧基溴乙烷、2-正丁氧基溴乙烷、溴甲基环丙烷、溴甲烷或溴乙烷；通常可以通过市场获取或合成获得，本发明没有特别说明，一般是指通过市场获取。用量为酰胺或2-氟-3-氨基苯甲酸酯原料摩尔量的1-3倍，优选为1-2倍。本发明采用溴代烷，避免使用碘代烷，这是由于碘代烷活性高，但造成工业化成本高，不利于产业化，而溴代烷通常活性较低，选择性差，收率较低，需要在催化剂存在及优化工艺条件下，才能达到较好的效果。
N-烷基化反应中的催化剂选自：十六烷基三甲基氯化铵、苄基三乙基氯化铵、聚乙二醇400-800、四丁基氯化铵、四丁基溴化铵、四丁基硫酸氢铵、15-冠-5-醚、18-冠-6-醚或4-二甲氨基吡啶(DMAP)中的一种或多种混合物。此外，催化剂也可采用碘化物盐，如：碘化钾、碘化钠等，但催化效果不及相转移催化剂或4-二甲氨基吡啶(DMAP)，优选使用为四丁基氯化铵、四丁基溴化铵、四丁基硫酸氢铵、18-冠-6-醚或4-二甲氨基吡啶(DMAP)，催化剂用量为酰胺或2-氟-3-氨基苯甲酸酯原料重量的1-10％，优选为1-5％，本发明使用催化剂，可降低反应温度，提高反应选择性及产品收率。
本发明还提供上述中间体化合物的另一种制备方法，所述方法流程如式(2)所示：
与第一种制备方法类似，R3选自C1-C5的烷基；
N-烷基化反应中的溶剂选自：N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺、N-甲基吡咯烷酮、1,3-二甲基-2-咪唑啉酮、二甲基亚砜、乙腈、四氢呋喃、二氯乙烷、环己烷、甲基环己烷、甲苯、乙苯、二甲苯中的一种或多种混合物；优选溶剂为：N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙腈、环己烷、甲基环己烷、甲苯中的一种或多种混合物，用量为酰胺或2-氟-3-氨基苯甲酸酯原料重量的2-10倍，优选为2-5 倍。
N-烷基化反应中的碱选自碳酸钾、碳酸钠、氢氧化钠、氢氧化钾、氢化钠，优选为碳酸钾、碳酸钠或氢化钠，用量为酰胺或2-氟-3-氨基苯甲酸酯原料摩尔量的1-3倍，优选为1-2倍。
N-烷基化反应中的溴代烷选自：2-甲氧基溴乙烷、2-乙氧基溴乙烷、3-甲氧基溴丙烷、3-乙氧基溴丙烷、2-正丙氧基溴乙烷、2-异丙氧基溴乙烷、2-正丁氧基溴乙烷、溴甲基环丙烷、溴甲烷或溴乙烷；通常可以通过市场获取或合成获得，本发明没有特别说明，一般是指通过市场获取。用量为酰胺或2-氟-3-氨基苯甲酸酯原料摩尔量的1-3倍，优选为1-2倍。本发明采用溴代烷，避免使用碘代烷，这是由于碘代烷活性高，但造成工业化成本高，不利于产业化，而溴代烷通常活性较低，选择性差，收率较低，需要在催化剂存在及优化工艺条件下，才能达到较好的效果。
N-烷基化反应中的催化剂选自：十六烷基三甲基氯化铵、苄基三乙基氯化铵、聚乙二醇400-800、四丁基氯化铵、四丁基溴化铵、四丁基硫酸氢铵、15-冠-5-醚、18-冠-6-醚或4-二甲氨基吡啶(DMAP)中的一种或多种混合物。此外，催化剂也可采用碘化物盐，如：碘化钾、碘化钠等，但催化效果不及相转移催化剂或4-二甲氨基吡啶(DMAP)，优选使用为四丁基氯化铵、四丁基溴化铵、四丁基硫酸氢铵、15-冠-5-醚、18-冠-6-醚或4-二甲氨基吡啶(DMAP)，催化剂用量为酰胺或2-氟-3-氨基苯甲酸酯原料重量的1-10％，优选为1-5％，本发明使用催化剂，可降低反应温度，提高反应选择性及产品收率。
酰胺化反应溶剂选自：N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺、N-甲基吡咯烷酮、1,3-二甲基-2-咪唑啉酮、二甲基亚砜、乙腈、四氢呋喃、乙酸乙酯、二氯甲烷、二氯乙烷、环己烷、甲基环己烷、甲苯、乙苯、二甲苯中的一种或多种混合物。优选溶剂为：N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙腈、四氢呋喃、乙酸乙酯、二氯甲烷、二氯乙烷、甲苯中的一种或多种混合物。用量为苯甲酸系列酰氯原料重量的2-10倍，优选为2-5倍。
其中，酰胺化反应可采用加入DMAP催化剂，用量为苯甲酸系列酰氯原料重量的1-10％，优选为1-5％，在不加入催化剂时，本发明工艺条件下反应收率及反应时间都可接受，所以本发明不一定必须使用；本发明的中间体化合物的制备方法中，酰胺化反应无需要采用傅酸剂，在本发明工艺条件下，转化收率及反应时间都可以接受。其中，酰胺化反应温度为0-200℃，优选为0-150℃
前述两种中间体化合物的制备方法中水解反应条件一般为通常条件，一般采用醇类 溶剂如甲醇、乙醇、异丙醇等，或醚类溶剂如1,4-二氧六环、甲基叔丁基醚、乙二醇二甲醚、乙二醇二乙醚等，优选甲醇、乙醇，使用量一般为对应酯重量的2-10倍，优选2-5倍；碱一般采用氢氧化钠、氢氧化钾、碳酸钠、碳酸钾，优选氢氧化钠，浓度一般采用质量浓度1-35％，摩尔用量为对应酯的1.1-3.0倍。反应温度，一般为5-50℃，优选温度为20-30℃。反应时间一般为1-5小时，优选为1-2小时。
在上述两种中间体化合物的制备方法中，N-烷基化反应温度为50-200℃，优选温度为50-150℃，当溶剂为与水能产生共沸溶剂时，反应温度优选为共沸温度，并可通过共沸脱出反应产生的水，可缩短反应时间；反应压力一般为常压反应，当溴代烷为溴甲烷或溴乙烷时，由于溴代烷沸点低，避免挥发，优选为密闭反应，压力为0-0.2MPa。而N-烷基化反应时间通常为2-12小时，优选2-8小时。
进一步地，本发明还提供一种含七氟异丙基的双酰胺类化合物，所述化合物的结构如通式(II)所示，
其中，R1取代基独立地选自H、氟、三氟甲基、氰基或硝基；
R2取代基独立地选自2-甲氧基乙基、2-乙氧基乙基、3-甲氧基丙基、3-乙氧基丙基、2-正丙氧基乙基、2-异丙氧基乙基、2-正丁氧基乙基、环丙基甲基、甲基或乙基。
本发明还提供上述含七氟异丙基的双酰胺类化合物的制备方法，所述方法流程如式(3)所示：

其中，酰氯化反应的通常方法为通式(Ⅰ)原料在惰性溶剂中和氯化亚砜反应，脱溶处理进入下一步反应。酰氯化反应所采用的溶剂为二氯甲烷、氯仿、二氯乙烷、甲苯或二甲苯等，优选溶剂为二氯乙烷或甲苯等；酰氯化反应温度一般为20-150℃，优选反应温度40-100℃；酰氯化反应时间一般为1-5小时，优选2-3小时。
酰胺化反应中的溶剂选自二氯甲烷、二氯乙烷、环己烷、甲基环己烷、甲苯、乙苯、二甲苯、乙酸乙酯、四氢呋喃或乙腈中的一种或多种混合物；优选使用溶剂为二氯乙烷、环己烷、甲基环己烷、甲苯、乙酸乙酯或乙腈，使用量一般为对应通式(Ⅰ)原料重量的2-10倍，优选3-8倍。酰胺化也可以使用催化剂4-二甲氨基吡啶(DMAP)，可缩短反应时间，但在本发明优选条件下，酰胺化无需使用催化剂及傅酸剂，反应收率及反应时间都可接受，所以本发明不一定必须使用。酰胺化反应另一原料4-七氟异丙基-2-三氟甲基苯胺可以通过合成或市场购买获取，合成方法是由邻三氟甲基苯胺原料和2-溴七氟丙烷或2-碘七氟丙烷在保险粉存在下，烷基化反应制备而得，合成详见中国发明专利CN 102119173B公开的内容。原料4-七氟异丙基-2-三氟甲基苯胺的使用量为通式(Ⅰ)原料摩尔量的1.0-1.3倍，优选使用量为1.0-1.05倍。溴化反应使用液溴为溴化剂，价格便宜，原料易得，副产物溴化盐易于回收利用，相比N-溴代琥珀酰亚胺溴化剂成本低，又利于环保，使用量为通式(Ⅰ)原料摩尔量的1-2倍，优选使用量为1-1.5倍，优选使用方式为滴入反应，也可采用紫外光照条件下滴入反应，优选不需要光照，就能进行反应。
溴化反应也可为降低溴的使用量，在反应后不久加入氧化剂，使得生成的溴化盐被氧化成单质溴再次被用于溴代反应，可以降低溴的使用量，但会带来反应体系的操作复杂及相关的副反应杂质，本发明不一定必须采用。
溴化反应中的溶剂选自二氯甲烷、二氯乙烷、甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇中的一种或多种混合物，优选使用溶剂为二氯乙烷、甲醇、乙醇、异丙醇、叔丁醇一种或多种混合物。使用量一般为对应通式(Ⅰ)原料重量的2-10倍，优选3-8倍。
溴化反应中的碱选自氢氧化钠、氢氧化钾、碳酸钾、碳酸钠或它们的任意浓度水溶液，或者使用任意浓度甲醇钠甲醇溶液、乙醇钠乙醇溶液、异丙醇钠异丙醇溶液、叔丁醇钠叔丁醇溶液，优选使用固体氢氧化钠、氢氧化钾、碳酸钾；使用量一般为通式(Ⅰ)原料摩尔量的1-2倍，优选使用量为1-1.5倍。溴化反应温度为0-100℃，优选使用温度为20-80℃。
在本发明中，优选地，R1取代基独立地选自H或氟；R2取代基独立地选自2-甲氧基乙基、2-乙氧基乙基、2-正丙氧基乙基、2-异丙氧基乙基、2-正丁氧基乙基、环丙基甲基、甲基或乙基；R3为甲基。
本发明还提供含七氟异丙基的双酰胺类化合物结晶体，当R1为H且R2为2-甲氧基乙基，所述结晶体x-射线粉末衍射在如下位置具有特征峰：
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°。
当R1为氟且R2为2-甲氧基乙基，所述结晶体x-射线粉末衍射在如下位置具有特征峰：
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°。
当R1为氟且R2为2-乙氧基乙基，结晶体x-射线粉末衍射在如下位置具有特征峰：
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°。
在本发明中，所述结晶体是通过结晶溶剂结晶得到的，所述溶剂选自甲醇、乙醇、异丙醇、四氢呋喃、异丙醚、乙二醇单甲醚、乙二醇单乙醚、乙二醇二甲醚、乙二醇二 乙醚、甲基叔丁基醚中的一种或多种混合物。
本发明得到的含七氟异丙基的双酰胺类化合物具有优异的杀虫活性，该化学反应条件温和，环境友好，总收率高，最终产品含量高，成本低，易于产业生产，具有很高的应用前景。
在本发明中，制备方法操作中涉及的蒸馏、减压蒸馏、过滤、干燥、萃取、分层、结晶、重结晶等操作为常规操作，再次不再详述。
【附图说明】
图1为合成实施例17的化合物样品经X-射线粉末晶体衍射分析结果；
图2为合成实施例18的化合物样品经X-射线粉末晶体衍射分析结果；
图3为合成实施例20的化合物样品经X-射线粉末晶体衍射分析结果。
【具体实施方式】
以下实施例用于非限制性地解释本发明的技术方案，不应视为对本发明的具体限制。
本发明合成实施例中所述的原料，除特别说明外，一般为通过市场购买获取的，通常含量规格≥95％，含量没有精确校正，合成实施例中所述的百分比浓度除特别说明外，一般指重量百分比浓度，所述的HPLC含量数据为面积归一含量，没有精确校正，收率是指摩尔收率，收率数据也没有精确校正。
合成准备实施例1
在250ml的四口玻璃反应瓶中，投入甲醇100g，2-氟-3-硝基苯甲酸50g，98％硫酸2.5g，升温回流反应24小时，降温至0-5℃左右结晶，过滤，50℃烘干得到2-氟-3-硝基苯甲酸甲酯51g固体，HPLC含量98％，收率94.8％，用于合成反应。
合成准备实施例2
在250ml的四口玻璃反应瓶中，投入乙醇100g，2-氟-3-硝基苯甲酸50g，98％硫酸2.5g，升温回流反应24小时，降温至0-5℃左右结晶，过滤，50℃烘干得到2-氟-3-硝基苯甲酸乙酯54.5g固体，HPLC含量98％，收率94.6％，用于合成反应。
合成准备实施例3
在500ml加氢反应釜中，投入甲醇250g，5％钯炭折干2g(含水量50％)，投入合成准备实施例1得到的2-氟-3-硝基苯甲酸甲酯51g固体，密闭反应釜，氮气置换空气后，在用氢气置换两次氮气，在5-15℃维持压力0-0.05MPa通入氢气反应12小时，HPLC检测反应完成，取出，过滤掉催化剂(可回收套用)，滤液减压脱溶，得到油状液体43g，为2-氟-3-氨基苯甲酸甲酯，HPLC含量97％，收率98.3％，用于合成反应。
合成准备实施例4
在500ml加氢反应釜中，投入甲醇250g，5％钯炭折干2g(含水量50％)，投入合成准备实施例2得到的2-氟-3-硝基苯甲酸乙酯54.5g固体，密闭反应釜，氮气置换空气后，在用氢气置换两次氮气，在5-15℃维持压力0-0.05MPa通入氢气反应12小时，HPLC检测反应完成，取出，过滤掉催化剂(可回收套用)，滤液减压脱溶，得到油状液体46g，为2-氟-3-氨基苯甲酸乙酯，HPLC归一含量96％，收率96.3％，用于合成反应。
合成准备实施例5
苯甲酸25g(0.20mol)，氯化亚砜72g(0.60mol)，升温回流反应2-5小时，降温至室温，反应液旋转蒸发，减压脱溶至80℃，得到苯甲酰氯油状液体，降温至25℃左右，加入新的二氯乙烷25g溶解备用。
另一250ml的四口玻璃反应瓶中，投入二氯乙烷100g，3-氨基-2-氟苯甲酸甲酯35g(0.20mol)，吡啶24g(0.30mol)，冰浴降温至5-25℃，1小时内滴入上面苯甲酰氯备用液，5-25℃反应1-2小时，反应完成，加入水50ml，搅拌0.5小时，分层得到溶剂层，转移至500ml旋转蒸发器中，减压脱溶至80℃，得到2-氟-3-[(苯基羰基)氨基]苯甲酸甲酯米白色固体53g，HPLC归一含量94％(收率91.2％)备用，不做进一步处理直接用于合成反应。
合成准备实施例6
按照合成准备实施例5相似操作，其中3-氨基-2-氟苯甲酸甲酯35g(0.20mol)原料用合成准备实施例4所得3-氨基-2-氟苯甲酸乙酯38g(0.20mol)代替，其他不变，最后得到2-氟-3-[(苯基羰基)氨基]苯甲酸乙酯米白色固体55g，HPLC归一含量94％(收率90％)备用，不做进一步处理直接用于合成反应。
合成准备实施例7
按照合成准备实施例5操作，苯甲酸25g(0.20mol)用对氟苯甲酸28g(0.20mol)代替，其他操作相同，最后得到2-氟-3-[(4-氟苯基羰基)氨基]苯甲酸甲酯米白色固体56g，HPLC归一含量94％(收率90.2％)备用，不做进一步处理直接用于合成反应。
合成实施例1
2-氟-3-[(2-甲氧乙基)(苯基羰基)氨基]苯甲酸的合成。
在250ml的四口玻璃反应瓶中，投入溶剂N,N-二甲基甲酰胺200g，碱碳酸钾15g(0.10mol)，再投入合成准备实施例5合成得到的2-氟-3-[(苯基羰基)氨基]苯甲酸甲酯物料25g(0.086mol)，催化剂四丁基溴化铵1g，升温至55-65℃，1小时内滴入1-溴- 2-甲氧基乙烷15.8g(0.11mol)，保温反应2小时左右，水降温至室温，过滤，滤液减压脱溶，得到残余物料，加入甲醇50g，10％液碱60g(0.15mol)，升温25-35℃，保温反应2小时左右，加入水150g，30％盐酸调节pH为1-2，10-25℃左右结晶，过滤、水洗，烘干得到26.5g米白色固体，熔点：155.8-157.9℃，HPLC归一含量95％左右，收率92.3％，为2-氟-3-[(2-甲氧乙基)(苯基羰基)氨基]苯甲酸。反应式如下：
合成实施例2-4
按照合成实施例1的操作，催化剂四丁基溴化铵1g，分别用四丁基氯化铵1g、四丁基硫酸氢铵1g、18-冠-6-醚1g代替，其他投料及操作不变，得到的结果相近。
合成实施例5
在250ml的四口玻璃反应瓶中，投入溶剂甲苯100g，投入碱碳酸钾15g(0.10mol)，投入合成准备实施例5合成得到的2-氟-3-[(苯基羰基)氨基]苯甲酸甲酯物料25g(0.086mol)，催化剂四丁基溴化铵1g，加入1-溴-2-甲氧基乙烷15.8g(0.11mol)，装上回流分水器，升温至回流反应，脱出反应生成水，回流反应约2小时左右，至无水生成，水降温至室温，过滤，滤液减压脱溶，得到残余料，加入甲醇50g，10％液碱60g(0.15mol)，升温25-35℃，保温反应2小时左右，加入水150g，30％盐酸调节pH为1-2，10-25℃左右结晶，过滤、水洗，烘干得到27g米白色固体，HPLC归一含量95％左右，收率94％，为2-氟-3-[(2-甲氧乙基)(苯基羰基)氨基]苯甲酸。
合成实施例6-7
按照合成实施例5的操作，溶剂甲苯100g，分别用甲基环己烷100g、二甲苯100g代替，其他投料及操作不变，得到的结果相近。
合成实施例8
2-氟-3-[(2-乙氧乙基)(4-氟苯基羰基)氨基]苯甲酸的合成。
在一250ml的四口玻璃反应瓶中，投入溶剂二氯乙烷100g，4-氟苯甲酸12.5g(0.088mol)，氯化亚砜25g(0.20mol)，升温回流反应2-5小时，减压脱溶得到油状液体为4-氟苯甲酰氯，待用。
在另一250ml的四口玻璃反应瓶中，投入溶剂N,N-二甲基甲酰胺200g，氮气保护，投入碱60％氢化钠3.5g(0.091mol)，再投入合成准备实施例3合成得到的2-氟-3- 氨基苯甲酸甲酯15g(0.086mol)，催化剂四丁基溴化铵1g，加入1-溴-2-乙氧基乙烷16.8g(0.11mol)，升温至110-120℃，保温反应8小时左右，水降温至室温，过滤后，滤液减压脱溶，残余物料加入二氯乙烷100ml萃取、水洗涤(产物核磁氢谱、质谱数据附后)，溶剂层用无水硫酸镁干燥过滤得到的滤液在25-35℃，加入上面合成得到的4-氟苯甲酰氯，升温至回流反应2-5小时，减压脱溶，得到残余油状物料(产物核磁氢谱、质谱数据附后)，加入甲醇50g，10％液碱60g(0.15mol)，升温25-35℃，保温反应2小时左右，加入水150g，30％盐酸调节pH为1-2，10-25℃左右结晶，过滤、水洗，烘干得到29.4g米黄色固体，熔点：77.3-79.2℃，HPLC归一含量92％左右，收率90.1％，为2-氟-3-[(2-乙氧乙基)(苯基羰基)氨基]苯甲酸(产物的核磁氢谱、质谱数据附后)。反应式如下：
核磁氢谱使用Bruker AV-400spectrometer(400MHz)，TMS作为内标，溶剂使用CDCl3or DMSO-d6(如无特别说明，下同)；高分辨率质谱使用UHR-TOF maXis(ESI)质谱仪测定(如无特别说明，下同)。
2-氟-3-[(2-乙氧乙基)氨基]苯甲酸甲酯的核磁氢谱、质谱数据如下：
1H-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 C12H16FNNaO3[(M+Na)+]:264.1012；Found:264.0988。
2-氟-3-(4-氟-N-(2-乙氧乙基)苯甲酰氨基)苯甲酸甲酯的核磁氢谱、质谱数据如下：
1H-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 C19H19F2NNaO4[(M+Na)+]:386.1180；Found:386.1173。
2-氟-3-[(2-乙氧乙基)(苯基羰基)氨基]苯甲酸的核磁氢谱、质谱数据如下：
1H-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 C18H17F2NNaO4[(M+Na)+]:372.1023；Found:372.1024。
合成实施例9
按照合成实施例8的操作，第二步酰胺化时加入4-二甲氨基吡啶(DMAP)1g，其他投料及操作不变，得到的结果相近。
合成实施例10
2-氟-3-[(2-甲氧乙基)(4-氟苯基羰基)氨基]苯甲酸的合成。
在一250ml的四口玻璃反应瓶中，投入溶剂二氯乙烷100g，对氟苯甲酸12.5g(0.088mol)，氯化亚砜25g(0.20mol)，升温回流反应2-5小时，减压脱溶得到油状液体为对氟苯甲酰氯，待用。
在另一250ml的四口玻璃反应瓶中，投入溶剂甲苯100g，投入碱碳酸钾15g(0.10mol)，投入合成准备实施例3合成得到的2-氟-3-氨基苯甲酸甲酯15g(0.086mol)，催化剂四丁基溴化铵1g，加入1-溴-2-甲氧基乙烷15.8g(0.11mol)，升温至100-120℃，回流脱水反应，约5小时左右，水降温至室温，过滤，水洗、减压脱溶得到物料(产物核磁氢谱、质谱数据附后)加入二氯乙烷100g溶解，在25-35℃，加入上面合成得到的对氟苯甲酰氯，升温回流反应2-5小时。降温加水100ml，分层、洗涤，减压脱溶，得到残余油状物料(产物核磁氢谱、质谱数据附后)，加入甲醇50g，10％液碱60g(0.15mol)，升温25-35℃，保温反应2小时左右，加入水150g，30％盐酸调节pH为1-2，10-25℃左右结晶，过滤、水洗，烘干得到28g米黄色固体，熔点：120.5-122.5℃，HPLC归一含量93％左右，收率90.3％，为2-氟-3-[(2-甲氧乙基)(4-氟苯基羰基)氨基]苯甲酸(产物核磁氢谱、质谱数据附后)。反应式如下：
2-氟-3-[(2-甲氧乙基)氨基]苯甲酸甲酯的核磁氢谱、质谱数据如下：
1H-NMR(400MHz,CDCl3)δ(ppm):7.00-6.91(m,3H,ArH),5.50(s,1H,NH),3.80(s,3H,OCH3),4.45(t,J＝3.9Hz,2H,OCH2),3.25-7.24(m,5H,NCH2and OCH3)。
HRMS(ESI)calcd.for C11H14FNNaO3[(M+Na)+]:250.0855；Found:250.0836。
2-氟-3-(4-氟-N-(2-甲氧乙基)苯甲酰氨基)苯甲酸甲酯的核磁氢谱、质谱数据如下：
1H-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 C18H17F2NNaO4[(M+Na)+]:372.1023；Found:372.1024。
2-氟-3-[(2-甲氧乙基)(4-氟苯基羰基)氨基]苯甲酸的核磁氢谱、质谱数据如下：
1H-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 C17H15F2NNaO4[(M+Na)+]:358.0867；Found:358.0858。
合成实施例11
2-氟-3-[(甲基)(苯基羰基)氨基]苯甲酸的合成。
在500ml的压力反应釜中，投入溶剂N,N-二甲基甲酰胺200g，投入碱碳酸钾15g(0.10mol)，投入合成准备实施例5合成得到的2-氟-3-[(苯基羰基)氨基]苯甲酸甲酯物料25g(0.086mol)，催化剂四丁基溴化铵1g，室温通入溴甲烷20g(0.21mol)，密闭反应釜，升温至55-65℃，保温反应2小时左右，降温至室温，过滤，滤液减压脱溶得油状液体，加入甲醇50g，10％液碱60g(0.15mol)，升温25-35℃，保温反应2小时左右，加入水150g，30％盐酸调节pH为1-2，10-25℃左右结晶，过滤、水洗，烘干得到23g米白色固体，HPLC归一含量95％左右，收率93％，为2-氟-3-[(甲基)(苯基羰基)氨基]苯甲酸。反应式如下：
合成实施例12
按照合成实施例11操作，溴甲烷20g(0.21mol)用溴乙烷22g(0.20mol)代替，加入压力釜，其他操作相似，最后得到24g米白色固体，HPLC归一含量95％左右，收率92.3％，为2-氟-3-[(乙基)(苯基羰基)氨基]苯甲酸。反应式如下：
合成实施例13
在250ml的四口玻璃反应瓶中，投入溶剂甲苯100g，投入碱碳酸钾15g (0.10mol)，投入合成准备实施例7合成得到的2-氟-3-[(4-氟苯基羰基)氨基]苯甲酸甲酯物料26.7g(0.086mol)，催化剂四丁基溴化铵1g，加入1-溴-2-甲氧基乙烷15.8g(0.11mol)，装上回流分水器，升温至回流反应，脱出反应生成水，回流反应约2小时左右，至无水生成，水降温至室温，过滤，减压脱溶，得到残余料，加入甲醇50g，10％液碱60g(0.15mol)，升温25-35℃，保温反应2小时左右，加入水150g，30％盐酸调节pH为1-2，10-25℃左右结晶，过滤、水洗，烘干得到28.5g米黄色固体，熔点：122.5-123.4℃，HPLC归一含量95％左右，收率93.9％，为2-氟-3-[(2-甲氧乙基)(4-氟苯基羰基)氨基]苯甲酸。反应式及产物的核磁氢谱、质谱数据如下：
1H-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 C17H15F2NNaO4[(M+Na)+]:358.0867；Found:358.0858。
合成实施例14
按照合成实施例13操作，1-溴-2-甲氧基乙烷15.8g(0.11mol)用溴甲基环丙烷16.5g(0.12mol)代替，其他操作相同，最后得到28g米白色固体，HPLC归一含量95％左右，收率93.3％，为2-氟-3-[(环丙基甲基)(4-氟苯基羰基)氨基]苯甲酸。
合成实施例15-16
分别按照合成实施例1及合成实施例5操作，2-氟-3-[(苯基羰基)氨基]苯甲酸甲酯物料25g(0.086mol)用合成准备实施例6所得2-氟-3-[(苯基羰基)氨基]苯甲酸乙酯26.3g(0.086mol)代替，其他操作相同，得到的结果相近。
合成对比实施例1
按照合成实施例1，其中催化剂四丁基溴化铵1g不加，其他的投料及操作全部相同，最后得到24g米白色固体，目标产物2-氟-3-[(2-甲氧乙基)(苯基羰基)氨基]苯甲酸 HPLC归一含量55％左右，收率48.3％，其他主要为2-氟-3-[(苯基羰基)氨基]苯甲酸。
合成对比实施例2
按照合成实施例5，其中催化剂四丁基溴化铵1g不加，其他的投料及操作全部相同，最后得到21g米白色固体，目标产物2-氟-3-[(2-甲氧乙基)(苯基羰基)氨基]苯甲酸HPLC归一含量5％左右，收率3.8％，其他主要为2-氟-3-[(苯基羰基)氨基]苯甲酸。
合成对比实施例3
按照合成实施例8的操作，其中催化剂四丁基溴化铵1g不加，其他的投料及操作全部相同，最后得到油状物料归一含量45％左右，没有得到目标产物固体结晶。
合成实施例17
2-氟-3-[(苯基羰基)(2-甲氧乙基)氨基]-N-[2-溴-4-(1,1,1,2,3,3,3-七氟丙烷-2-基)-6-(三氟甲基)苯基]苯甲酰胺的合成制备。
250ml的四口玻璃反应瓶中，投入二氯乙烷200g，合成实施例1得到的2-氟-3-[(2-甲氧乙基)(苯基羰基)氨基]苯甲酸23.7g(0.071mol)，氯化亚砜24g(0.20mol)，升温回流反应3-5小时，降温至室温，反应液转移至500ml旋转蒸发器中，减压脱溶至80℃，得到酰氯油状液体，降温至25℃左右，加入乙腈150g溶解，转移至反应瓶中，并加入4-(1,1,1,2,3,3,3-七氟丙烷-2-基)-2-(三氟甲基)苯胺原料27.8g(0.08mol)，升温回流反应5-10小时。
降温至室温，加入粉状碳酸钾20g，在25-45℃，2小时左右滴入液溴13.5g反应，保温2小时，过滤，滤去无机盐，滤液减压脱溶，得到残余料，加入乙醇120g，升温回流1小时，降温结晶，在0-5℃结晶1小时，过滤干燥得到白色结晶粉末固体42g，为目标化合物，熔点：179.5-180.5℃，HPLC归一含量98％左右，三步总收率81.9％。反应式如下：
核磁氢谱、质谱数据如下：
核磁氢谱使用Bruker AV-400spectrometer(400MHz)，TMS作为内标，溶剂使用DMSO-d6(如无特别说明，下同)；高分辨率质谱使用UHR-TOF maXis(ESI)质谱仪测定(如无特别说明，下同)。
1H-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 C27H18BrF11N2NaO3[(M+Na)+]:729.0223[(M+Na)+],731.0202[(M+2+Na)+]；Found:729.0213[(M+Na)+],731.0196[(M+2+Na)+]。
目标化合物样品经X-射线粉末晶体衍射分析，仪器使用日本理学SmartLab衍射仪分析(如无特别说明，下同),结晶体在如下位置有特征峰，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°，详见附图1。
将本次合成实施例所得样品用3倍重量异丙醚重结晶，最后得到的样品，经X-射线粉末晶体衍射分析，结晶体特征峰和上面完全一致。
将本次合成实施例所得样品用3倍重量乙二醇单甲醚重结晶，最后得到的样品，经X-射线粉末晶体衍射分析，结晶体特征峰和上面完全一致。
以上结果说明，所得化合物分别在乙醇、异丙醚、乙二醇单甲醚溶剂中结晶所得结晶体，晶体类型一致，易得且稳定性好。
合成实施例18
2-氟-3-[(4-氟苯基羰基)(2-甲氧乙基)氨基]-N-[2-溴-4-(1,1,1,2,3,3,3-七氟丙烷-2-基)-6-(三氟甲基)苯基]苯甲酰胺的合成制备。
250ml的四口玻璃反应瓶中，投入二氯乙烷200g，合成实施例13得到的2-氟-3-[(2-甲氧乙基)(4-氟苯基羰基)氨基]苯甲酸25g(0.071mol)，氯化亚砜24g(0.20mol)，升温回流反应3-5小时，降温至室温，反应液转移至500ml旋转蒸发器中，减压脱溶至80℃，得到酰氯油状液体，降温至25℃左右，加入新的二氯乙烷150g溶解，转移至反应瓶中，并加入4-(1,1,1,2,3,3,3-七氟丙烷-2-基)-2-(三氟甲基)苯胺原料27.8g(0.08mol)，升温回流反应5-10小时。降温至室温，加入氢氧化钠5g，在35-55℃，2小时左右滴入液溴13.5g反 应，保温2小时，加入水50ml，分层分去水层，得到溶剂层减压脱溶，得到残余料，加入乙二醇单甲醚120g，升温回流1小时，降温结晶，在0-5℃结晶1小时，过滤干燥得到白色结晶粉末固体44g，为目标化合物，熔点：152.4-153.2℃，HPLC归一含量98％左右，三步总收率83.7％。反应式如下：
核磁氢谱、质谱数据如下：
1H-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 C27H17BrF12N2NaO3[(M+Na)+]:747.0129[(M+Na)+],749.0108[(M+2+Na)+]；Found:747.0111[(M+Na)+],749.0094[(M+2+Na)+]。
目标化合物样品经X-射线粉末晶体衍射分析，结晶体在如下位置有特征峰，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°，详见附图2。
将本次合成实施例所得样品用3倍重量乙醇重结晶，最后得到的样品，经X-射线粉末晶体衍射分析，结晶体特征峰和上面完全一致。
将本次合成实施例所得样品用3倍重量异丙醚重结晶，最后得到的样品，经X-射线粉末晶体衍射分析，结晶体特征峰和上面完全一致。
以上结果说明，所得化合物分别在乙醇、异丙醚、乙二醇单甲醚溶剂中结晶所得结晶体，晶体类型一致，易得且稳定性好。
合成实施例19
2-氟-3-[(4-氟苯基羰基)(2-甲氧乙基)氨基]-N-[2-溴-4-(1,1,1,2,3,3,3-七氟丙烷-2-基)-6-(三氟甲基)苯基]苯甲酰胺的合成制备。
按照合成实施例18的操作，其中2-氟-3-[(2-甲氧乙基)(4-氟苯基羰基)氨基]苯甲酸25g(0.071mol)用合成实施例10所得到的2-氟-3-[(2-甲氧乙基)(4-氟苯基羰基)氨基]苯甲酸25.6g(0.071mol)代替，最后得到白色结晶粉末固体42g，为目标化合物，熔点：152.4-153.2℃，HPLC归一含量98％左右，三步总收率79.9％。样品经核磁、质谱、X-射线粉末晶体衍射分析，结果完全一致。
合成实施例20
2-氟-3-[(4-氟苯基羰基)(2-乙氧乙基)氨基]-N-[2-溴-4-(1,1,1,2,3,3,3-七氟丙烷-2-基)-6-(三氟甲基)苯基]苯甲酰胺的合成制备。
250ml的四口玻璃反应瓶中，投入二氯乙烷200g，合成实施例8得到的2-氟-3-[(2-乙氧乙基)(4-氟苯基羰基)氨基]苯甲酸26g(0.071mol)，氯化亚砜24g(0.20mol)，升温回流反应3-5小时，降温至室温，反应液转移至500ml旋转蒸发器中，减压脱溶至80℃，得到酰氯油状液体，降温至25℃左右，加入甲苯150g溶解，转移至反应瓶中，并加入4-(1,1,1,2,3,3,3-七氟丙烷-2-基)-2-(三氟甲基)苯胺原料27.8g(0.08mol)，升温回流反应5-10小时，减压脱溶得到残余料，加入甲醇120g，降温至室温，加入氢氧化钠5g，在35-55℃，2小时左右滴入液溴13.5g反应，保温2小时，加入水50ml，分层分去水层，得到溶剂层减压脱溶，得到残余料，加入异丙醚120g，升温回流1小时，降温结晶，在0-5℃结晶1小时，过滤干燥得到白色结晶粉末固体44.5g，为目标化合物，熔点：168.2-169.2℃，HPLC归一含量98％左右，三步总收率83.1％。反应式如下：

核磁氢谱、质谱数据如下：
1H-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 C28H19BrF12N2NaO3[(M+Na)+]:761.0285[(M+Na)+],763.0265[(M+2+Na)+]；Found:761.0263[(M+Na)+],763.0248[(M+2+Na)+]。
目标化合物样品经X-射线粉末晶体衍射分析，结晶体在如下位置有特征峰，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°，详见附图3。
将本次合成实施例所得样品用3倍重量乙醇重结晶，最后得到的样品，经X-射线粉末晶体衍射分析，结晶体特征峰和上面完全一致。
将本次合成实施例所得样品用3倍重量乙二醇单甲醚重结晶，最后得到的样品，经X-射线粉末晶体衍射分析，结晶体特征峰和上面完全一致。
将本次合成实施例所得样品用3倍重量乙二醇二甲醚重结晶，最后得到的样品，经X-射线粉末晶体衍射分析,结晶体特征峰和上面完全一致。
说明，化合物分别在乙醇、异丙醚、乙二醇单甲醚、乙二醇二甲醚溶剂中结晶所得结晶体，晶体类型一致，易得且稳定性好。
将本次合成实施例所得样品分别用3倍重量的甲醇、异丙醇、四氢呋喃、乙二醇单乙醚、乙二醇二乙醚、甲基叔丁基醚重结晶，最后得到的样品，经X-射线粉末晶体衍射分析，结晶体特征峰和上面完全一致。
说明，化合物分别在甲醇、乙醇、异丙醇、四氢呋喃、异丙醚、乙二醇单甲醚、乙二醇单乙醚、乙二醇二甲醚、乙二醇二乙醚、甲基叔丁基醚等溶剂中结晶所得结晶体，晶体类型一致，易得且稳定性好。
合成实施例21
2-氟-3-[(苯基羰基)(甲基)氨基]-N-[2-溴-4-(1,1,1,2,3,3,3-七氟丙烷-2-基)-6-(三氟甲基)苯基]苯甲酰胺的合成制备。
按照合成实施例18的操作，其中原料2-氟-3-[(2-甲氧乙基)(4-氟苯基羰基)氨基]苯甲酸25g(0.071mol)用合成实施例11所得2-氟-3-[(甲基)(苯基羰基)氨基]苯甲酸20.4g(0.071mol)代替。其他操作相同，最后得到白色结晶粉末固体40.1g，为目标化合物，熔点：155.1-156.4℃，HPLC归一含量98％左右，三步总收率83.4％。反应式如下：
核磁氢谱、质谱数据如下：
1H-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 C25H14BrF11N2NaO2[(M+Na)+]:684.9961[(M+Na)+],686.9940[(M+2+Na)+]；Found:684.9956[(M+Na)+],686.9940[(M+2+Na)+]。
合成实施例22
2-氟-3-[(苯基羰基)(乙基)氨基]-N-[2-溴-4-(1,1,1,2,3,3,3-七氟丙烷-2-基)-6-(三氟甲基)苯基]苯甲酰胺的合成制备。
按照合成实施例18的操作，其中原料2-氟-3-[(2-甲氧乙基)(4-氟苯基羰基)氨基]苯甲酸25g(0.071mol)用合成实施例12所得2-氟-3-[(乙基)(苯基羰基)氨基]苯甲酸21.4g(0.071mol)代替。其他操作相同，最后得到白色结晶粉末固体40g，为目标化合物，熔点：166.1-167.8℃，HPLC归一含量98％左右，三步总收率81.5％。反应式如 下：
合成实施例23
2-氟-3-[(4-氟苯基羰基)(环丙基甲基)氨基]-N-[2-溴-4-(1,1,1,2,3,3,3-七氟丙烷-2-基)-6-(三氟甲基)苯基]苯甲酰胺的合成制备。
按照合成实施例18的操作，其中原料2-氟-3-[(2-甲氧乙基)(4-氟苯基羰基)氨基]苯甲酸25g(0.071mol)用合成实施例14所得2-氟-3-[(环丙基甲基)(4-氟苯基羰基)氨基]苯甲酸23.4g(0.071mol)代替。其他操作相同，最后得到白色结晶粉末固体43g，为目标化合物，熔点：152.5-153.3℃，HPLC归一含量98％左右，三步总收率82.3％。反应式如下：
合成实施例24
2-氟-3-[(4-氰基苯基羰基)(2-乙氧乙基)氨基]-N-[2-溴-4-(1,1,1,2,3,3,3-七氟丙烷-2-基)-6-(三氟甲基)苯基]苯甲酰胺的合成制备。
按照参考合成准备实施例5操作，其中苯甲酸25g(0.20mol)用对氰基苯甲酸29.5g(0.20mol)代替，其他操作相同，合成得到2-氟-3-[(4-氰基苯基羰基)氨基]苯甲酸甲酯，并取27.2g(0.086mol)代替合成实施例13中原料2-氟-3-[(4-氟苯基羰基)氨基]苯甲酸甲酯物料26.7g(0.086mol)，同时用1-溴-2-乙氧基乙烷16.8g(0.11mol)代替合 成实施例13中原料1-溴-2-甲氧基乙烷15.8g(0.11mol)，其他操作相同，合成得到的2-氟-3-[(2-乙氧乙基)(4-氰基苯基羰基)氨基]苯甲酸，并取26.6g(0.071mol)代替合成实施例18中原料2-氟-3-[(2-甲氧乙基)(4-氟苯基羰基)氨基]苯甲酸25g(0.071mol)，其他操作相同，最后得到米白色结晶粉末固体43.4g，为目标化合物，熔点：150.1-152.2℃，HPLC归一含量98％左右，后三步总收率80.3％。反应式如下：
核磁氢谱、质谱数据如下：
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 C29H19BrF11N3NaO3[(M+Na)+]:768.0332[(M+Na)+],770.0311[(M+2+Na)+]；Found:768.0310[(M+Na)+],770.0293[(M+2+Na)+]。
合成实施例25
按照合成实施例13的操作，其中1-溴-2-甲氧基乙烷15.8g(0.11mol)用1-溴-2-正丙氧基乙烷18.7g(0.11mol)代替，其他投料及操作相同，得到的中间体2-氟-3-[(2-正丙氧乙基)(4-氟苯基羰基)氨基]苯甲酸收率及含量结果相似。目标化合物合成按照合成实施例20相似的操作，其中原料2-氟-3-[(2-乙氧乙基)(4-氟苯基羰基)氨基]苯甲酸26g(0.071mol)用上面得到的2-氟-3-[(2-正丙氧乙基)(4-氟苯基羰基)氨基]苯甲酸27g(0.071mol)代替，其他操作相似，最后得到目标化合物：2-氟-3-[(4-氟苯基羰基)(2-正丙氧乙基)氨基]-N-[2-溴-4-(1,1,1,2,3,3,3-七氟丙烷-2-基)-6-(三氟甲基)苯基]苯甲酰胺，熔点：156.5-156.8，收率及含量结果相似。
本发明的其他通式(Ⅰ)或(Ⅱ)化合物可以参考上述实施例方法合成。
生物活性测试实施例
用本发明获得的部分通式(Ⅱ)化合物对多种害虫进行了试验。
化合物配制：用天平(0.001g)称取一定质量的原药，用DMF配制成1％母液，然后用含0.1％吐温-80的蒸馏水稀释成试验浓度备用；如果是制剂的，按照制剂活性成分含量，用天平(0.001g)称取一定质量的制剂样品，用蒸馏水稀释成试验浓度备用。
表1：部分通式(Ⅱ)化合物
测试实施例1部分通式(Ⅱ)化合物对小菜蛾室内生物活性测定
小菜蛾(Plutella xylostella)敏感种群及抗氯虫酰胺种群，室内以萝卜苗饲养；
试验方法：小菜蛾活性测定：采用浸渍法，取适量萝卜叶浸药30s后，置于垫有滤纸的塑料培养皿中自然阴干，每皿接2龄小菜蛾10头，置于22℃、光照(16/8h)观察室内。2天后观察，以毛笔轻触虫体，无反应视为死虫，重复3次，另设不加药剂的空白对照。
试验结果:部分通式(Ⅱ)化合物SYN101等对小菜蛾的活性测定结果如表二所示：
结果表明：在所试验浓度0.2mg/L，0.1mg/L，0.05mg/L时，化合物SYN101、SYN102、SYN103、SYN104、SYN105、SYN106、SYN107对小菜蛾敏感种群的活性及小菜蛾抗氯虫酰胺种群活性均表现出优异的杀虫活性，均大于80％，在低浓度0.05mg/L时，SYN104、SYN105、SYN106、SYN107对小菜蛾敏感种群的活性及小菜蛾抗氯虫酰胺种群活性仍表现出优异的杀虫活性，均达100％。
表2：部分通式(Ⅱ)化合物对小菜蛾的活性测定结果

测试实施例2部分通式(Ⅱ)化合物对草地贪夜蛾的室内生物活性测定
草地贪夜蛾活性测定：采用浸渍法，取适量玉米叶浸药30s后，置于垫有滤纸的塑料培养皿中自然阴干，每皿接2龄草地贪夜蛾10头，置于26℃、光照(16/8h)观察室内。2天后观察，以毛笔轻触虫体，无反应视为死虫，重复3次，另设不加药剂的空白对照。
试验结果：部分通式(Ⅱ)化合物SYN101等对草地贪夜蛾的室内生物活性测定试验结果见表3所示：
结果表明：化合物SYN101、SYN102、SYN103在供试浓度0.2mg/L时均有较好的活性，达100％，在供试浓度0.1mg/L时，活性稍差，但均大于80％，在供试浓度0.05mg/L时，活性较差。在供试浓度0.2mg/L时，0.1mg/L，0.05mg/L时，化合物SYN104、SYN105、SYN106、SYN107，均表现出优异的杀虫活性，均达100％。
表3：部分通式(Ⅱ)化合物对草地贪夜蛾的活性测定结果

本申请人声明，本发明通过上述代表性的实施例来说明一种含七氟异丙基的双酰胺类化合物及其中间体的制备方法，但本发明并不局限于上述实施例，也不意味着本发明必须依赖上述实施例才能实现。所属技术领域的技术人员应该明了，对本发明的任何改进，对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本发明的保护范围和公开范围之内。

Claims (13)

  1. 一种制备含七氟异丙基的双酰胺类化合物的中间体化合物的制备方法，所述中间体如下通式(Ⅰ)所示，
    其中，R1取代基独立地选自H、氟、三氟甲基、氰基或硝基；
    R2取代基独立地选自2-甲氧基乙基、2-乙氧基乙基、3-甲氧基丙基、3-乙氧基丙基、2-正丙氧基乙基、2-异丙氧基乙基、2-正丁氧基乙基、环丙基甲基、甲基或乙基。
    其特征在于所述的通式(Ⅰ)所示结构的中间体化合物制备方法的工艺流程如式(1)或式(2)：
    其中，R3为C1-C5的烷基；
    所述N-烷基化反应溶剂选自：N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺、N-甲基吡咯烷酮、1,3-二甲基-2-咪唑啉酮、二甲基亚砜、乙腈、四氢呋喃、二氯乙烷、环己烷、甲基环己烷、甲苯、乙苯、二甲苯中的一种或多种混合物；
    所述N-烷基化反应碱选自：碳酸钾、碳酸钠、氢化钠；
    所述N-烷基化反应溴代烷选自：2-甲氧基溴乙烷、2-乙氧基溴乙烷、3-甲氧基溴丙烷、3-乙氧基溴丙烷、2-正丙氧基溴乙烷、2-异丙氧基溴乙烷、2-正丁氧基溴乙烷、溴甲基环丙烷、溴甲烷或溴乙烷；
    所述N-烷基化反应催化剂选自：十六烷基三甲基氯化铵、苄基三乙基氯化铵、聚乙二醇400-800、四丁基氯化铵、四丁基溴化铵、四丁基硫酸氢铵、15-冠-5醚、18-冠-6-醚或4-二甲氨基吡啶(DMAP)中的一种或多种混合物；
    所述酰胺化反应溶剂选自：N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺、N-甲基吡咯烷酮、1,3-二甲基-2-咪唑啉酮、二甲基亚砜、乙腈、四氢呋喃、乙酸乙酯、二氯甲烷、二氯乙烷、环己烷、甲基环己烷、甲苯、乙苯、二甲苯中的一种或多种混合物。
  2. 一种含七氟异丙基的双酰胺类化合物的制备方法，所述化合物如下通式(Ⅱ)所示结构，
    其中，R1取代基独立地选自H、氟、三氟甲基、氰基或硝基；
    R2取代基独立地选自2-甲氧基乙基、2-乙氧基乙基、3-甲氧基丙基、3-乙氧基丙基、2-正丙氧基乙基、2-异丙氧基乙基、2-正丁氧基乙基、环丙基甲基、甲基或乙基。
    其特征在于所述的通式(Ⅱ)所示结构的化合物的制备方法的工艺流程如式(3)：

    其中，R1取代基独立地选自H、氟、三氟甲基、氰基或硝基；
    R2取代基独立地选自2-甲氧基乙基、2-乙氧基乙基、3-甲氧基丙基、3-乙氧基丙基、2-正丙氧基乙基、2-异丙氧基乙基、2-正丁氧基乙基、环丙基甲基、甲基或乙基；
    所述酰胺化反应溶剂选自：二氯甲烷、二氯乙烷、环己烷、甲基环己烷、甲苯、乙苯、二甲苯、乙酸乙酯、四氢呋喃或乙腈中的一种或多种混合物；
    所述溴化反应溶剂选自：二氯甲烷、二氯乙烷、甲醇、乙醇、异丙醇、叔丁醇中的一种或多种混合物；
    所述溴化反应碱选自：氢氧化钠、氢氧化钾、碳酸钾、碳酸钠或它们的水溶液。
  3. 根据权利要求1所述的制备方法，其特征在于R3为甲基或乙基。
  4. 根据权利要求1所述的制备方法，其特征在于R3为甲基。
  5. 根据权利要求1或2所述的制备方法，其特征在于R1取代基独立地选自H或氟；R2取代基独立地选自2-甲氧基乙基、2-乙氧基乙基、2-正丙氧基乙基、2-异丙氧基乙基、2-正丁氧基乙基、环丙基甲基、甲基或乙基。
  6. 根据权利要求1所述的制备方法，其特征在于N-烷基化反应催化剂选自：四丁基氯化铵、四丁基溴化铵、四丁基硫酸氢铵、15-冠-5-醚、18-冠-6-醚或4-二甲氨基吡啶(DMAP)中的一种或多种混合物。
  7. 根据权利要求1所述的制备方法，其特征在于N-烷基化反应温度为50℃-150℃；酰胺化反应温度为0℃-150℃。
  8. 根据权利要求2所述的制备方法，酰胺化反应温度为20℃-180℃；溴化反应温度为0℃-100℃。
  9. 根据权利要求2或8所述的制备方法，其特征在于酰胺化反应溶剂选自：二氯乙烷、环己烷、甲基环己烷、甲苯或乙腈中的一种或多种混合物；溴化反应溶剂选自：二氯乙烷、甲醇、乙醇、异丙醇、叔丁醇中的一种或多种混合物；溴化反应碱选自：氢氧化钠、碳酸钾或它们的水溶液。
  10. 根据权利要求2所述的制备方法制备得到的化合物的结晶体，所述化合物具有如通式(Ⅱ)所示结构，当R1为H且R2为2-甲氧基乙基，其特征在于结晶体x-射线粉末衍射在如下位置具有特征峰，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. 根据权利要求2所述的制备方法制备得到的化合物的结晶体，所述化合物具有如通式(Ⅱ)所示结构，当R1为氟且R2为2-甲氧基乙基，其特征在于结晶体x-射线粉末衍射在如下位置具有特征峰，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. 根据权利要求2所述的制备方法制备得到的化合物的结晶体，所述化合物具有如通式(Ⅱ)所示结构，当R1为氟且R2为2-乙氧基乙基，其特征在于结晶体x-射线粉末衍射在如下位置具有特征峰，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. 根据权利要求10-12中任一项权利要求所述的结晶体，其特征在于结晶溶剂为甲醇、乙醇、异丙醇、四氢呋喃、异丙醚、乙二醇单甲醚、乙二醇单乙醚、乙二醇二甲醚、乙二醇二乙醚、甲基叔丁基醚中的一种或多种混合物。
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