A method for preparing a meta-aminobenzoic acid bisamide compound

Abstract

The application discloses a preparation method of a meta-aminobenzoic acid bisamide compound. The method is prepared by condensation reaction with N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxyl amido)benzamide and 2-fluoropyridine-5-formyl chloride as raw materials. The 2-fluoropyridine-5-formyl chloride is prepared from 6-fluoronicotinic acid and phosgene. The preparation method takes the 2-fluoropyridine-5-formyl chloride with high yield and high purity as raw material, can omit the purification step, shorten the synthesis route, improve the preparation efficiency, improve the selectivity of the reaction, reduce the generation of impurities, improve the yield of the product, efficiently prepare the product with high yield and high purity, has the advantages of simple process, convenient operation, low cost, mild reaction condition, high preparation efficiency, high yield, high purity, environmental friendliness and the like, is suitable for large-scale preparation, and is convenient for industrial application.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pesticide insecticide synthesis, and relates to a preparation method of a meta-aminobenzoic acid bisamide compound, in particular to a preparation method of a meta-bisamide compound of a Broflanilide analogue. BACKGROUND

[0002] The meta-bisamide compound represented by Broflanilide has good insecticidal / miticidal activity. Meanwhile, with the large-area use of Broflanilide, the resistance increases, and it is of great significance to develop new compounds.

[0003] Patent CN202311327561.8 discloses a meta-aminobenzoic acid bisamide compound, numbered as compound II-56, which has the characteristics of good insecticidal effect and high activity and has very high application value. The compound II-56 is prepared by condensation reaction from N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxyl amido)benzamide and 6-fluoronicotinyl chloride, and the structural formula of the compound II-56 is as follows:

[0004]

[0005] However, the preparation method of the meta-aminobenzoic acid bisamide compound has room for improvement in product yield and purity, and at the same time, the preparation method of each intermediate (such as nitroamide, bromo-benzamide and substituted hydroxylamine) used by the method has a low product yield and purity, which is not conducive to improving the product yield and purity of the meta-aminobenzoic acid bisamide compound. For example, in the bromination step, the NBS bromination method is difficult to accurately brominate, and the yield is low; in the nitro reduction step, the zinc powder reduction involves a dangerous reaction, has low reaction efficiency and poor selectivity, and cannot be industrialized; at the same time, in order to meet the preparation needs of each intermediate, a purification step is usually needed, which also increases the complexity of the preparation process and the preparation cost. Therefore, it is of great significance to obtain a preparation method of a meta-aminobenzoic acid bisamide compound with simple process, convenient operation, low cost, high yield and high purity, for promoting the industrial application of the meta-aminobenzoic acid bisamide compound. SUMMARY

[0006] The technical problem to be solved by the present application is to overcome the shortcomings of the prior art and provide a preparation method of a meta-aminobenzoic acid bisamide compound with simple process, convenient operation, low cost, high yield and high purity.

[0007] To solve the above technical problems, the present application adopts the following technical solutions:

[0008] A preparation method of a meta-aminobenzoic acid bisamide compound, which comprises the following steps: taking N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxylamino)benzamide and 2-fluoropyridine-5-formyl chloride as raw materials, and preparing the meta-aminobenzoic acid bisamide compound through a condensation reaction, and the reaction formula is as follows:

[0009]

[0010] The 2-fluoropyridine-5-formyl chloride is prepared through an acyl chloride reaction of 6-fluoronicotinic acid and phosgene, and the reaction formula is as follows:

[0011]

[0012] The preparation method is further improved, and the preparation conditions of the meta-aminobenzoic acid bisamide compound meet at least one of conditions (1.1) to (1.7).

[0013] Condition (1.1): the molar ratio of the N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxylamino)benzamide to the 2-fluoropyridine-5-formyl chloride is 1:1-1.3.

[0014] Condition (1.2): at least one of tetrahydrofuran, benzene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene and dichlorobenzene is added as a reaction solvent in the condensation reaction system.

[0015] Condition (1.3): the mass ratio of the 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)benzamide to the reaction solvent added in the condensation reaction system is 1:1-8.

[0016] Condition (1.4): the condensation reaction is carried out at a temperature of 0-50°C.

[0017] Condition (1.5): the condensation reaction is carried out for 1-8 hours.

[0018] Condition (1.6): the condensation reaction is carried out under nitrogen protection.

[0019] Condition (1.7): after the completion of the condensation reaction, the following treatment is further included: recrystallization of the crude product obtained after the completion of the condensation reaction is carried out by using an organic solvent to obtain the meta-aminobenzoic acid bisamide compound; and the organic solvent is at least one of dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, ethanol, isopropanol, ethyl acetate and acetonitrile.

[0020] The above preparation method is further improved, and the preparation method of 2-fluoropyridine-5-carbonyl chloride comprises the following steps:

[0021] Step S1, mixing 6-fluoronicotinic acid with a solvent to obtain a mixed solution;

[0022] Step S2, introducing phosgene into the mixed solution obtained in step S1 to carry out an acyl chlorination reaction to obtain a reaction product liquid;

[0023] Step S3: removing phosgene and solvent from the reaction product liquid obtained in step S2 to obtain 2-fluoropyridine-5-carbonyl chloride.

[0024] The above preparation method is further improved, wherein the preparation conditions of the 2-fluoropyridine-5-carbonyl chloride meet at least one of conditions (2.1) to (2.11):

[0025] Condition (2.1): the molar ratio of 6-fluoronicotinic acid to phosgene is 1:1.2-5.0;

[0026] Condition (2.2): the phosgene introduction rate is 120 g / h to 200 g / h;

[0027] Condition (2.3): The solvent is at least one of benzene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene, and dichlorobenzene;

[0028] Condition (2.4): the mass ratio of the 6-fluoronicotinic acid to the solvent is 1:1 to 8;

[0029] Condition (2.5): The temperature of the acyl chlorination reaction is 25°C to 100°C;

[0030] Condition (2.6): The acyl chlorination reaction time is 2.5h to 8h;

[0031] Condition (2.7): The acyl chloride reaction is carried out under stirring; the stirring speed is 50 rpm to 220 rpm;

[0032] Condition (2.8): Nitrogen is continuously introduced into the system during the acyl chlorination reaction;

[0033] Condition (2.9): The nitrogen gas introduction rate is 0.1 L / min to 0.3 L / min;

[0034] Condition (2.10): The acyl chlorination reaction further comprises adding a catalyst to the system; the catalyst is N,N-dimethylformamide; the mass ratio of the 6-fluoronicotinic acid to the catalyst is 100:0.5-3;

[0035] Condition (2.11): after the completion of the acyl chloride reaction, the following treatment is further included: nitrogen is introduced to remove the chloroacylating reagent in the system, and a reduced pressure treatment is used to remove the solvent in the system.

[0036] The preparation method is further improved, and the N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxylamino)benzamide is prepared by catalytic hydrogenation reaction under the action of a hydrogenation catalytic reaction catalyst, using 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)benzamide as a raw material, and the reaction formula is as follows:

[0037]

[0038] The hydrogenation catalytic reaction catalyst is at least one of Raney nickel, palladium on carbon, and platinum on carbon.

[0039] The preparation method is further improved, and the preparation conditions of the 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)benzamide meet at least one of conditions (3.1) to (3.7):

[0040] Condition (3.1): the mass ratio of the 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)benzamide to the hydrogenation catalytic reaction catalyst is 1:0.001-0.02;

[0041] Condition (3.2): the mass percentage content of the effective substance in the hydrogenation catalytic reaction catalyst is 2%-8%;

[0042] Condition (3.3): the reaction solvent added in the catalytic hydrogenation reaction system is at least one of ethanol, methanol, ethyl acetate, benzene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene, and dichlorobenzene;

[0043] Condition (3.4): the reducing agent added in the catalytic hydrogenation reaction system is hydrogen;

[0044] Condition (3.5): the hydrogen pressure of the catalytic hydrogenation reaction is 0.5 MPa-5.0 MPa;

[0045] Condition (3.6): the temperature of the catalytic hydrogenation reaction is 25°C-125°C;

[0046] Condition (3.7): the time of the catalytic hydrogenation reaction is 2.5 h-10 h.

[0047] The preparation method is further improved, and the 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl) phenyl) benzamide is prepared from 2-fluoro-3-nitro-N-(4-(perfluoropropane-2-yl)-2-(trifluoromethyl) phenyl) benzamide as a raw material, sodium bromide as a bromine source, through a bromination reaction, and the reaction formula is as follows:

[0048]

[0049] The preparation method is further improved, and the preparation conditions of the 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl) phenyl) benzamide meet at least one of conditions (4.1) to (4.6):

[0050] Condition (4.1): The bromination reaction further includes adding sodium hypochlorite; and the molar ratio of the 2-fluoro-3-nitro-N-(4-(perfluoropropane-2-yl)-2-(trifluoromethyl) phenyl) benzamide to sodium bromide and sodium hypochlorite is 1:1-2:1-3.

[0051] Condition (4.2): In the process of the bromination reaction, the sodium hypochlorite is added in the form of a sodium hypochlorite solution; and the mass percentage content of the sodium hypochlorite solution is 10%-12%.

[0052] Condition (4.3): The reaction solvent added in the bromination reaction system is at least one of benzene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene, and dichlorobenzene.

[0053] Condition (4.4): The mass ratio of the 2-fluoro-3-nitro-N-(4-(perfluoropropane-2-yl)-2-(trifluoromethyl) phenyl) benzamide to the reaction solvent added in the bromination reaction system is 1:1-8.

[0054] Condition (4.5): The temperature of the bromination reaction is 50°C-100°C.

[0055] Condition (4.6): The time of the bromination reaction is 1h-5h.

[0056] The preparation method is further improved, and the 2-fluoro-3-nitro-N-(4-(perfluoropropane-2-yl)-2-(trifluoromethyl) phenyl) benzamide is prepared from 2-fluoro-3-nitro-N-(4-(perfluoropropane-2-yl)-2-(trifluoromethyl) phenyl) benzamide as a raw material, sodium bromide as a bromine source, through a bromination reaction, and the reaction formula is as follows:

[0057]

[0058] The preparation method is further improved, and the 2-fluoro-3-nitrobenzoyl chloride is prepared from 2-fluoro-3-nitrobenzoic acid and an acyl chlorination reagent through an acyl chlorination reaction.

[0059] The preparation conditions of the 2-fluoro-3-nitrobenzoyl chloride meet at least one of conditions (5.1) to (5.7):

[0060] Condition (5.1): the molar ratio of the 2-fluoro-3-nitrobenzoic acid to the acyl chlorination reagent is 1:0.5-3.0;

[0061] Condition (5.2): the acyl chlorination reagent is any one of thionyl chloride, oxalyl chloride and phosgene;

[0062] Condition (5.3): the reaction solvent added in the acyl chlorination reaction system is at least one of benzene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene and dichlorobenzene;

[0063] Condition (5.4): the mass ratio of the 2-fluoro-3-nitrobenzoic acid to the reaction solvent added in the acyl chlorination reaction system is 1:1-8;

[0064] Condition (5.5): the temperature of the acyl chlorination reaction is 25-150°C;

[0065] Condition (5.6): the time of the acyl chlorination reaction is 2.5-8h;

[0066] Condition (5.7): in the process of the acyl chlorination reaction, a catalyst is further added into the system; the catalyst is N,N-dimethylformamide; and the mass ratio of the 2-fluoro-3-nitrobenzoic acid to the catalyst is 100:0.5-3.

[0067] Compared with the prior art, the present application has the following advantages:

[0068] (1) In view of the deficiencies of complex process, difficult operation, high cost, low yield and low purity in the existing preparation method, the application creatively proposes a preparation method of m-aminobenzoic acid bisamide compounds, which takes N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxyl amido) benzamide and 2-fluoropyridine-5-formyl chloride as raw materials. The 2-fluoropyridine-5-formyl chloride is prepared by acylchlorination reaction with 6-fluoronicotinic acid as raw material and phosgene as acylchlorination reagent, which has the advantages of high yield and high purity. Therefore, when the 2-fluoropyridine-5-formyl chloride is used as raw material to prepare m-aminobenzoic acid bisamide compounds, not only the purification step can be omitted, the synthesis route can be shortened, and the preparation efficiency can be improved, but also the selectivity of the reaction can be improved, the generation of impurities can be reduced, and the yield of the product can be improved, so that the m-aminobenzoic acid bisamide compounds with high yield and high purity can be efficiently prepared. The purity of the obtained m-aminobenzoic acid bisamide compound product is ≥97%, and the yield is ≥96%. In addition, the preparation method of the m-aminobenzoic acid bisamide compound has the advantages of simple process, convenient operation, low cost, mild reaction conditions, high preparation efficiency, high yield, high purity and environmental friendliness, and can be used to prepare m-aminobenzoic acid bisamide compounds on a large scale, which is convenient for the industrial application of m-aminobenzoic acid bisamide compounds.

[0069] (2) In the application, N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxyl amido) benzamide is used as raw material, and N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxyl amido) benzamide with high yield and high purity can be prepared by catalytic hydrogenation reaction under the action of hydrogenation catalysts such as regen nickel, palladium carbon and platinum carbon. Further, when N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxyl amido) benzamide is used as raw material to prepare m-aminobenzoic acid bisamide compounds, not only the purification step can be omitted, the synthesis route can be shortened, and the preparation efficiency can be improved, but also the selectivity of the reaction can be improved, the generation of impurities can be reduced, and the yield of the product can be improved, so that the m-aminobenzoic acid bisamide compounds with high yield and high purity can be efficiently prepared. At the same time, under the action of hydrogenation catalysts such as regen nickel, palladium carbon and platinum carbon, by optimizing the conditions of hydrogen pressure and reaction temperature, the catalytic efficiency can be improved, the selectivity of the reaction can be improved, and the generation of amino by-product due to excessive hydrogenation can be prevented, so that the prepared N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxyl amido) benzamide has the advantages of high yield and high purity.

[0070] (3) In the present application, 2-fluoro-3-nitro-N-(4-(perfluoropropane-2-yl)-2-(trifluoromethyl)phenyl)benzamide is used as the raw material, and under the action of sodium bromide and sodium hypochlorite, precise bromination can be achieved without other side reactions, so that 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)benzamide with high yield and high purity can be prepared by bromination reaction, which is also conducive to shortening the synthesis route and obtaining high-quality meta-aminobenzoic acid bisamide compound products. At the same time, the method of introducing bromine atom in the present application has simple and mild conditions, which is suitable for industrial production.

[0071] (4) In the present application, by optimizing the preparation steps of each intermediate, the yield and purity of these intermediates can be improved, and purification is not required, so that the next step can be directly performed until the target original drug is synthesized, thereby shortening the synthesis route and obtaining higher-quality meta-aminobenzoic acid bisamide compound products, which facilitates the industrial application of meta-aminobenzoic acid bisamide compound products. DETAILED DESCRIPTION

[0072] In view of the deficiencies of the existing preparation method, such as complex process, difficult operation, high cost, low yield and low purity, the present application creatively proposes a preparation method of meta-aminobenzoic acid bisamide compound, which uses N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxyl amido)benzamide and 2-fluoropyridine-5-formyl chloride as raw materials. The 2-fluoropyridine-5-formyl chloride is prepared by chloroformylation reaction using 6-fluoronicotinic acid as raw material and phosgene as chloroformylation reagent, which has the advantages of high yield and high purity. Therefore, when using the 2-fluoropyridine-5-formyl chloride as raw material to prepare meta-aminobenzoic acid bisamide compound, not only the purification step can be omitted, the synthesis route can be shortened, and the preparation efficiency can be improved, but also the selectivity of the reaction can be improved, the generation of impurities can be reduced, and the yield of the product can be improved, so that meta-aminobenzoic acid bisamide compound with high yield and high purity can be efficiently prepared. The purity of the obtained meta-aminobenzoic acid bisamide compound product is ≥97%, and the yield is ≥96%. In addition, the preparation method of meta-aminobenzoic acid bisamide compound in the present application has the advantages of simple process, convenient operation, low cost, mild reaction conditions, high preparation efficiency, high yield, high purity and environmental friendliness, and can be used to prepare meta-aminobenzoic acid bisamide compound on a large scale, which facilitates the industrial application of meta-aminobenzoic acid bisamide compound.

[0073] In this embodiment, the preparation method of the meta-aminobenzoic acid bisamide compound is as follows: taking N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxylamino)benzamide and 2-fluoropyridine-5-formyl chloride as raw materials, a meta-aminobenzoic acid bisamide compound is prepared through a condensation reaction, and the reaction formula is as follows:

[0074]

[0075] In this embodiment, the 2-fluoropyridine-5-formyl chloride is prepared through an acyl chloride reaction of 6-fluoronicotinic acid and phosgene, and the reaction formula is as follows:

[0076]

[0077] In this embodiment, the preparation conditions of the meta-aminobenzoic acid bisamide compound meet at least one of conditions (1.1) to (1.7):

[0078] Condition (1.1): the molar ratio of N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxylamino)benzamide to 2-fluoropyridine-5-formyl chloride is 1:1-1.3; further preferably, the molar ratio of N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxylamino)benzamide to 2-fluoropyridine-5-formyl chloride is 1:1.

[0079] Condition (1.2): the reaction solvent added in the condensation reaction system is at least one of tetrahydrofuran, benzene, dimethylbenzene, dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene, and dichlorobenzene; further preferably, the reaction solvent is tetrahydrofuran and benzene.

[0080] Condition (1.3): the mass ratio of 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)benzamide to the reaction solvent added in the condensation reaction system is 1:1-8; further preferably, the mass ratio of the two is 1:2-5.

[0081] Condition (1.4): the condensation reaction is carried out at a temperature of 0-50°C; further preferably, the condensation reaction is carried out at a temperature of 0-25°C.

[0082] Condition (1.5): the condensation reaction time is 1-8h; further preferably, the condensation reaction time is 1-5h.

[0083] Condition (1.6): the condensation reaction is carried out under nitrogen protection.

[0084] The condition (1.7) further comprises the following treatment after the completion of the condensation reaction: recrystallizing the crude product obtained after the completion of the condensation reaction with an organic solvent to obtain the meta-aminobenzoic acid bisamide compound, wherein the organic solvent is at least one of dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, ethanol, isopropanol, ethyl acetate, and acetonitrile.

[0085] In this embodiment, the preparation method of the 2-fluoropyridine-5-formyl chloride comprises the following steps:

[0086] Step S1, mixing 6-fluoronicotinic acid with a solvent to obtain a mixed solution;

[0087] Step S2, passing phosgene into the mixed solution obtained in step S1 to perform an acyl chloride reaction to obtain a reaction product liquid;

[0088] Step S3, removing phosgene and the solvent from the reaction product liquid obtained in step S2 to obtain 2-fluoropyridine-5-formyl chloride.

[0089] In this embodiment, the preparation conditions of the 2-fluoropyridine-5-formyl chloride meet at least one of the conditions (2.1) to (2.11):

[0090] Condition (2.1): the molar ratio of 6-fluoronicotinic acid to phosgene is 1:1.2-5.0; further preferably, the molar ratio of 6-fluoronicotinic acid to phosgene is 1:1.2-3.0.

[0091] Condition (2.2): the passing speed of phosgene is 120 g / h-200 g / h, for example, the passing speed of phosgene is 120 g / h, 130 g / h, 140 g / h, 150 g / h, 160 g / h, 170 g / h, 180 g / h, 190 g / h, or 200 g / h; further preferably, the passing speed of phosgene is 120 g / h-180 g / h.

[0092] Condition (2.3): the solvent is at least one of benzene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene, and dichlorobenzene; further preferably, the solvent is one of benzene and xylene.

[0093] Condition (2.4): the mass ratio of 6-fluoronicotinic acid to the solvent is 1:1-8.

[0094] Condition (2.5): the temperature of the acyl chloride reaction is 25°C-100°C, for example, the temperature is 25°C, 40°C, 50°C, 80°C, or 100°C; further preferably, the temperature of the acyl chloride reaction is 25°C-80°C.

[0095] Condition (2.6): the time of the acyl chloride reaction is 2.5h-8h; for example, the time is 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 6h, 7h, 8h, preferably, the time of the acyl chloride reaction is 2.5-5h.

[0096] Condition (2.7): the acyl chloride reaction is carried out under stirring; the stirring speed is 50r / min-220r / min, for example, the stirring speed is 50r / min, 80r / min, 100r / min, 120r / min, 130r / min, 150r / min, 180r / min, 200r / min, 220r / min; further preferably, the stirring speed is 50r / min-180r / min.

[0097] Condition (2.8): nitrogen is continuously introduced into the system during the acyl chloride reaction.

[0098] Condition (2.9): the introduction rate of nitrogen is 0.1L / min-0.3L / min, for example, the introduction rate of nitrogen is 0.1L / min, 0.15L / min, 0.18L / min, 0.2L / min, 0.21L / min, 0.24L / min, 0.25L / min, 0.26L / min, 0.27L / min, 0.28L / min, 0.3L / min; further preferably, the introduction rate of nitrogen is 0.15L / min-0.3L / min.

[0099] Condition (2.10): the acyl chloride reaction further includes adding a catalyst into the system; the catalyst is N,N-dimethylformamide; the mass ratio of 6-fluoronicotinic acid to the catalyst is 100:0.5-3.

[0100] Condition (2.11): after the acyl chloride reaction is completed, the following treatment is further included: introducing nitrogen to remove the acyl chloride reagent in the system and using reduced pressure treatment to remove the solvent in the system.

[0101] In this embodiment, the N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxylamino)benzamide is prepared by catalytic hydrogenation reaction using 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)benzamide as the raw material and under the action of a hydrogenation catalyst, and the reaction formula is as follows:

[0102]

[0103] In this embodiment, the hydrogenation catalytic reaction catalyst is at least one of Raney nickel, palladium on carbon, and platinum on carbon. Further preferably, the hydrogenation catalytic reaction catalyst is one of palladium on carbon and platinum on carbon.

[0104] In this embodiment, the preparation conditions of 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)benzamide meet at least one of conditions (3.1) to (3.7):

[0105] Condition (3.1): The mass ratio of 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)benzamide to the hydrogenation catalytic reaction catalyst is 1:0.001-0.02. For example, the mass ratio is 1:0.001, 1:0.002, 1:0.005, 1:0.008, 1:0.01, 1:0.012, 1:0.015, 1:0.018, 1:0.02. Further preferably, the mass ratio is 1:0.005-0.02.

[0106] Condition (3.2): The mass percentage of the effective substance in the hydrogenation catalytic reaction catalyst is 2%-8%. For example, when the hydrogenation catalytic reaction catalyst is platinum on carbon catalyst, the mass percentage of platinum in the catalyst is 2%-8%. It can also be expressed as "2%-8% of the hydrogenation catalytic reaction catalyst".

[0107] Condition (3.3): The reaction solvent added in the catalytic hydrogenation reaction system is at least one of ethanol, methanol, ethyl acetate, benzene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene, and dichlorobenzene.

[0108] Condition (3.4): The reducing agent added in the catalytic hydrogenation reaction system is hydrogen.

[0109] Condition (3.5): The hydrogen pressure in the catalytic hydrogenation reaction is 0.5 MPa-5.0 MPa. For example, the hydrogen pressure is 0.5 MPa, 0.8 MPa, 1.0 MPa, 1.5 MPa, 1.8 MPa, 2.0 MPa, 2.5 MPa, 3.0 MPa, 3.5 MPa, 4.0 MPa, 4.5 MPa, 5.0 MPa. Preferably, the hydrogen pressure is 1.0-4.0 MPa.

[0110] Condition (3.6): The temperature of the catalytic hydrogenation reaction is 25°C-125°C. For example, the temperature is 25°C, 40°C, 50°C, 80°C, 100°C, 120°C, 125°C. Preferably, the temperature is 25-80°C.

[0111] Condition (3.7): the time of the catalytic hydrogenation reaction is 2.5h-10h. For example, the time is 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 6h, 7h, 8h, 9h, 10h, preferably, the time is 2.5-5h.

[0112] In this embodiment, the 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6- (trifluoromethyl) phenyl) benzamide used is prepared from 2-fluoro-3-nitro-N-(4-(perfluoropropane-2-yl)-2-(trifluoromethyl) phenyl) benzamide as a raw material, and sodium bromide as a bromine source, through a bromination reaction, and the reaction formula is as follows:

[0113]

[0114] In this embodiment, the preparation conditions of the 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl) phenyl) benzamide meet at least one of conditions (4.1) to (4.6):

[0115] Condition (4.1): during the bromination reaction, sodium hypochlorite is also added; the molar ratio of 2-fluoro-3-nitro-N-(4-(perfluoropropane-2-yl)-2-(trifluoromethyl) phenyl) benzamide to sodium bromide and sodium hypochlorite is 1:1-2:1-3; further preferably, the molar ratio of the three is 1:1-1.2:1.5-2.5.

[0116] Condition (4.2): during the bromination reaction, sodium hypochlorite is added in the form of a sodium hypochlorite solution; the mass percentage content of the sodium hypochlorite solution is 10%-12%.

[0117] Condition (4.3): the reaction solvent added in the bromination reaction system is at least one of benzene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene, and dichlorobenzene.

[0118] Condition (4.4): the mass ratio of 2-fluoro-3-nitro-N-(4-(perfluoropropane-2-yl)-2-(trifluoromethyl) phenyl) benzamide to the reaction solvent added in the bromination reaction system is 1:1-8.

[0119] Condition (4.5): the temperature of the bromination reaction is 50°C-100°C; preferably, the temperature is 70-80°C.

[0120] Condition (4.6): the time of the bromination reaction is 1h-5h; preferably, the time is 2h.

[0121] In the embodiment, the 2-fluoro-3-nitro-N-(4-(perfluoropropan-2-yl)-2- (trifluoromethyl)phenyl)benzamide is prepared by condensation reaction using 2-fluoro-3-nitrobenzoyl chloride and 2-trifluoromethyl-4-(heptafluoroisopropyl)aniline as raw materials, and the reaction formula is as follows:

[0122]

[0123] In the embodiment, the 2-fluoro-3-nitrobenzoyl chloride is prepared by acyl chlorination reaction using 2-fluoro-3-nitrobenzoic acid and an acyl chlorination reagent.

[0124] In the embodiment, the preparation conditions of the 2-fluoro-3-nitrobenzoyl chloride meet at least one of conditions (5.1) to (5.7):

[0125] Condition (5.1): the molar ratio of 2-fluoro-3-nitrobenzoic acid to the acyl chlorination reagent is 1:0.5-3.0.

[0126] Condition (5.2): the acyl chlorination reagent is any one of thionyl chloride, oxalyl chloride and phosgene.

[0127] Condition (5.3): the reaction solvent added in the acyl chlorination reaction system is at least one of benzene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene and dichlorobenzene.

[0128] Condition (5.4): the mass ratio of 2-fluoro-3-nitrobenzoic acid to the reaction solvent added in the acyl chlorination reaction system is 1:1-8.

[0129] Condition (5.5): the temperature of the acyl chlorination reaction is 25-150°C. For example, the temperature is 25°C, 40°C, 50°C, 80°C, 100°C, 120°C or 150°C, and preferably, the temperature is 50-80°C.

[0130] Condition (5.6): the time of the acyl chlorination reaction is 2.5-8h. For example, the time is 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 6h, 7h or 8h, and preferably, the time is 2.5-5h.

[0131] Condition (5.7): during the acyl chlorination reaction, a catalyst is further added into the system, the catalyst is N,N-dimethylformamide, and the mass ratio of 2-fluoro-3-nitrobenzoic acid to the catalyst is 100:0.5-3.

[0132] The application is further described below in combination with specific preferred embodiments, but the protection scope of the application is not limited by the embodiments.

[0133] In the following examples of the present application, the materials and instruments used are commercially available unless otherwise specified, the equipment used is conventional equipment, and the data obtained are the average values of more than three repeated experiments.

[0134] Example 1:

[0135] A preparation method of a meta-aminobenzoic acid bisamide compound, the reaction formula of which is as follows:

[0136]

[0137] comprising the following steps:

[0138] (1) Synthesis of 2-fluoro-3-nitrobenzoyl chloride, specifically prepared by acyl chlorination reaction from 2-fluoro-3-nitrobenzoic acid and an acyl chlorination reagent, comprising the following steps:

[0139] Into a four-necked flask with a thermometer and a condenser, 37.0 g (0.2 mol) of 2-fluoro-3-nitrobenzoic acid, 150 mL of toluene, and 0.74 g of DMF were added, 30 g of phosgene was introduced at 60°C, and the reaction was kept for 3 h. The reaction liquid became clear, and GC tracking was performed. After the reaction was completed, the excess phosgene was removed by vacuum extraction, the reaction liquid was cooled, and the solvent was removed by vacuum distillation. 2-Fluoro-3-nitrobenzoyl chloride was obtained, which was directly used in the next step. In this step, the purity was 99%, and the yield was 98%.

[0140] (2) Synthesis of 2-fluoro-3-nitro-N-(4-(perfluoropropane-2-yl)-2-(trifluoromethyl) phenyl) benzamide (intermediate 1), specifically prepared by condensation reaction using 2-fluoro-3-nitrobenzoyl chloride and 2-trifluoromethyl-4-(heptafluoroisopropyl) aniline as raw materials, comprising the following steps:

[0141] Into a three-necked flask with a drying tube and a condenser, 151 g (0.46 mol) of 2-trifluoromethyl-4-(heptafluoroisopropyl) aniline, 300 mL of toluene were added, and 103 g (0.51 mol) of 2-fluoro-3-nitrobenzoyl chloride prepared in step (1) was added dropwise under stirring at room temperature (25°C). The dropwise addition was completed in 30 min, and the temperature was slowly increased to reflux. The reaction was kept for 4.5 h, and the reaction liquid was cooled. Solid was precipitated, and 221 g of solid was obtained, which was 2-fluoro-3-nitro-N-(4-(perfluoropropane-2-yl)-2-(trifluoromethyl) phenyl) benzamide (intermediate 1). The purity was 98%, and the yield was 95%.

[0142] (3) Synthesis of 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl) phenyl) benzamide (intermediate 2):

[0143] Into a 2000 mL three-necked round bottom flask, equipped with a magnetic stirrer, thermometer, reflux condenser, was added 100 g (0.2 mol) of 2-fluoro-3-nitro-N-(4-(perfluoropropan-2-yl)-2- (trifluoromethyl) phenyl) benzamide (Intermediate 1) prepared in the previous step, 26 g (0.25 mol) of sodium bromide, 800 g of 1,2-dichloroethane and 180 g of water, stirred, heated to temperature, slowly added 400 g of 10% sodium hypochlorite aqueous solution at 60 °C, after the addition, the reaction was maintained for 1 h, separated, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 112 g of the target product, 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropan-2-yl)-6- (trifluoromethyl) phenyl) benzamide (Intermediate 2), with a purity of 97% and a yield of 95%. It was directly used in the next step.

[0144] (4) Synthesis of N-(2-bromo-4-(perfluoropropan-2-yl)-6- (trifluoromethyl) phenyl)-2-fluoro-3-(hydroxylamino) benzamide (Intermediate 3):

[0145] Into a 1 L autoclave, 100 g (0.17 mol) of 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropan-2-yl)-6- (trifluoromethyl) phenyl) benzamide (Intermediate 2), 1 g of platinum-carbon catalyst (3% platinum by mass) and 400 mL of ethanol were added. The autoclave was first replaced with nitrogen and then with hydrogen. The reaction was carried out at room temperature (25 °C) under a hydrogen pressure of 2 MPa for 2 h. The conversion rate was 99% as determined by sampling analysis. The ethanol was removed to obtain 97 g of a solid, which was N-(2-bromo-4-(perfluoropropan-2-yl)-6- (trifluoromethyl) phenyl)-2-fluoro-3-(hydroxylamino) benzamide (Intermediate 3), with a purity of 93% and a yield of 92.5%. It was directly used in the next step.

[0146] (5) Synthesis of 2-fluoropyridine-5-carbonyl chloride:

[0147] Into a four-necked flask equipped with a thermometer and a condenser, 400.0 g (2.84 mol) of 6-fluoronicotinic acid, 2500 mL of toluene and 5.0 g of DMF were added, and the mixture was stirred to obtain a homogeneous solution. The reaction was carried out by bubbling phosgene into the solution at a rate of 170 g / h, with a molar ratio of 6-fluoronicotinic acid to phosgene of 1:1.5, at a rotation speed of 150 r / min and a temperature of 25 °C. At the same time, nitrogen was continuously bubbled into the reaction solution at a flow rate of 0.2 L / min. The reaction was carried out for 5 h. After the reaction was completed, the solvent was removed under reduced pressure to obtain 2-fluoropyridine-5-carbonyl chloride, with a purity of 98.6% and a yield of 97.5%. It was directly used in the next step.

[0148] (6) Synthesis of m-aminobenzoic acid bisamide compound:

[0149] Into a three-necked flask with drying tube and condenser, was placed 50.6 g (0.084 mol) of N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3- (hydroxylamino)benzamide (Intermediate 3), 100 mL of THF, and 14.63 g (0.092 mol) of 2-fluoropyridine-5-carbonyl chloride prepared in step (5) was added dropwise under stirring with ice-bath cooling. The dropwise addition was completed in 20 min, and the reaction was carried out at room temperature (25 °C) for 1.5 h. The reaction was completed as monitored by LC. The solvent was removed by rotary evaporation to give a crude product, which was recrystallized from acetonitrile to give 56.2 g of m-aminobenzoic acid bisamide compound with a purity of 98.5% and a yield of 96.5%.

[0150] In this example, the total yield based on 2-trifluoromethyl-4-(heptafluoroisopropyl)aniline was 80.5%.

[0151] Example 2:

[0152] A method for preparing a m-aminobenzoic acid bisamide compound, comprising the following steps:

[0153] (1) Synthesis of 2-fluoro-3-nitrobenzoyl chloride:

[0154] Into a four-necked flask with thermometer and condenser, was placed 37.0 g (0.2 mol) of 2-fluoro-3-nitrobenzoic acid, 150 mL of toluene, and 0.74 g of DMF. 0.22 mol of thionyl chloride was added dropwise. The reaction was carried out at room temperature (25 °C) for 3 h under reflux. After the reaction was completed, the solvent was removed under reduced pressure to give 2-fluoro-3-nitrobenzoyl chloride with a purity of 97% and a yield of 97%, which was directly used in the next step.

[0155] (2) Synthesis of 2-fluoro-3-nitro-N-(4-(perfluoropropan-2-yl)-2- (trifluoromethyl)phenyl)benzamide (Intermediate 1):

[0156] Into a three-necked flask with drying tube and condenser, was placed 151 g (0.46 mol) of 2-trifluoromethyl-4-(heptafluoroisopropyl)aniline, 300 mL of toluene, and 103 g (0.51 mol) of 2-fluoro-3-nitrobenzoyl chloride prepared in step (1) was added dropwise under stirring at room temperature (25 °C). The dropwise addition was completed in 30 min, and the reaction was carried out at reflux for 4 h with slow warming. After cooling, a solid was precipitated to give 218.6 g of a solid, which was 2-fluoro-3-nitro-N-(4-(perfluoropropan-2-yl)-2- (trifluoromethyl)phenyl)benzamide (Intermediate 1) with a purity of 96% and a yield of 92%.

[0157] (3) Synthesis of 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropan-2-yl)-6- (trifluoromethyl)phenyl)benzamide (Intermediate 2):

[0158] Into a 2000 mL three-necked round-bottom flask, equipped with a magnetic stirrer, thermometer, reflux condenser, was added 100 g (0.2 mol) of 2-fluoro-3-nitro-N-(4- (perfluoropropan-2-yl)-2-(trifluoromethyl)phenyl)benzamide (Intermediate 1) prepared in the previous step, 26 g (0.25 mol) of sodium bromide, 800 g of 1,2-dichloroethane and 180 g of water, stirred, heated to temperature, slowly added 400 g of 10% sodium hypochlorite aqueous solution at 60 °C, after the addition was completed, the reaction was kept for 1 h, separated, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 112 g of the target product, 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropan-2-yl)-6- (trifluoromethyl)phenyl)benzamide (Intermediate 2), with a purity of 96% and a yield of 95%, which was directly used in the next step.

[0159] (4) Synthesis of N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-2- fluoro-3-(hydroxylamino)benzamide (Intermediate 3):

[0160] Into a 2000 mL three-necked round-bottom flask, equipped with a magnetic stirrer, thermometer, reflux condenser, was added 100 g (0.2 mol) of 2-fluoro-3-nitro-N-(4- (perfluoropropan-2-yl)-2-(trifluoromethyl)phenyl)benzamide (Intermediate 1) prepared in the previous step, 26 g (0.25 mol) of sodium bromide, 800 g of 1,2-dichloroethane and 180 g of water, stirred, heated to temperature, slowly added 400 g of 10% sodium hypochlorite aqueous solution at 60 °C, after the addition was completed, the reaction was kept for 1 h, separated, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 112 g of the target product, 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropan-2-yl)-6- (trifluoromethyl)phenyl)benzamide (Intermediate 2), with a purity of 96% and a yield of 95%, which was directly used in the next step.

[0161] (5) Synthesis of 2-fluoropyridine-5-carboxylic chloride:

[0162] Into a four-necked flask with thermometer and condenser, 37.0 g (0.2 mol) of 2-fluoro-3-nitrobenzoic acid, 150 mL of toluene, 0.74 g of DMF were added, and 30.2 g (0.24 mol) of oxalyl chloride was added dropwise. The reaction was carried out at room temperature (25 °C) under reflux for 3 h. After the reaction was completed, the solvent was removed under reduced pressure to obtain 2-fluoro-3-nitrobenzoyl chloride with a purity of 95% and a yield of 97%, which was directly used in the next step.

[0163] (6) Synthesis of m-aminobenzoic acid bisamide compound:

[0164] Into a three-necked flask with drying tube and condenser, 46.80 g (0.084 mol) of N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3- (hydroxylamino)benzamide (Intermediate 3), 100 mL of THF were added, and 14.63 g (0.092 mol) of 2-fluoropyridine-5-carbonyl chloride was added dropwise under ice-bath stirring under nitrogen protection. The addition was completed in 20 min, and the reaction was carried out at room temperature (25 °C) for 1.5 h. LC tracking showed that the reaction was completed. The solvent was dried to obtain a crude product, which was recrystallized from acetonitrile to obtain 56.0 g of m-aminobenzoic acid bisamide compound with a purity of 98.2% and a yield of 96.0%.

[0165] In this example, the total yield based on 2-trifluoromethyl-4-(heptafluoroisopropyl)aniline was 77.0%.

[0166] Example 3:

[0167] A method for preparing an m-aminobenzoic acid bisamide compound comprises the following steps:

[0168] (1) Synthesis of 2-fluoro-3-nitrobenzoyl chloride:

[0169] Into a four-necked flask with thermometer and condenser, 37.0 g (0.2 mol) of 2-fluoro-3-nitrobenzoic acid, 150 mL of toluene, 0.74 g of DMF were added, and 30.2 g (0.24 mol) of oxalyl chloride was added dropwise. The reaction was carried out at room temperature (25 °C) under reflux for 3 h. After the reaction was completed, the solvent was removed under reduced pressure to obtain 2-fluoro-3-nitrobenzoyl chloride with a purity of 95% and a yield of 97%, which was directly used in the next step.

[0170] (2) Synthesis of 2-fluoro-3-nitro-N-(4-(perfluoropropane-2-yl)-2- (trifluoromethyl)phenyl)benzamide (Intermediate 1):

[0171] A three-necked flask with drying tube and condenser was charged with 151 g (0.46 mol) of 2-trifluoromethyl-4-(heptafluoroisopropyl)aniline, 300 mL of toluene, and 103 g (0.51 mol) of 2-fluoro-3-nitrobenzoyl chloride prepared in step (1) was added dropwise with stirring at room temperature (25 °C), and the dropwise addition was completed in 30 min. The reaction was slowly warmed to reflux for 5 h, and the reaction was cooled. A solid was precipitated, which was washed twice with ethanol and dried to give 226 g of a solid, which was 2-fluoro-3-nitro-N-(4-(perfluoropropan-2-yl)-2- (trifluoromethyl)phenyl)benzamide (Intermediate 1) with a purity of 95% and a yield of 94%.

[0172] (3) Synthesis of 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropan-2-yl)-6- (trifluoromethyl)phenyl)benzamide (Intermediate 2):

[0173] A 2000 mL three-necked round-bottom flask equipped with a magnetic stirrer, thermometer, and reflux condenser was charged with 100 g (0.2 mol) of 2-fluoro-3-nitro-N-(4-(perfluoropropan-2-yl)-2- (trifluoromethyl)phenyl)benzamide (Intermediate 1) prepared in the previous step, 26 g (0.25 mol) of sodium bromide, 800 g of 1,2-dichloroethane, and 180 g of water, and the mixture was stirred and heated. A 400 g aqueous solution of sodium hypochlorite with a mass concentration of 10% was slowly added dropwise at a reaction temperature of 60 °C. After the dropwise addition was completed, the reaction was maintained for 1 h. The organic phase was separated and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 112 g of a light yellow solid, which was 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropan-2-yl)-6- (trifluoromethyl)phenyl)benzamide (Intermediate 2) with a purity of 96% and a yield of 95%. The product was used directly in the next step.

[0174] (4) Synthesis of N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-2- fluoro-3-(hydroxylamino)benzamide (Intermediate 3):

[0175] Into a 1 L autoclave, 100 g (0.17 mol) of 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)benzamide (Intermediate 2), 1 g of platinum-carbon catalyst (2% by mass of platinum in the catalyst), and 400 mL of toluene were placed, the air was first replaced with nitrogen, and then the nitrogen was replaced with hydrogen. The reaction was carried out under a hydrogen pressure of 3 MPa at room temperature (25°C) for 5 h. The conversion rate was 99% as determined by sampling and analysis. The ethanol was removed, and 97 g of solid was obtained, which was N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxylamino)benzamide (Intermediate 3). The content of the target product was 90%, and the yield was 92.0%. The product was directly used in the next step.

[0176] (5) Synthesis of 2-fluoropyridine-5-carbonyl chloride:

[0177] Into a four-necked flask equipped with a thermometer and a condenser, 400.0 g (2.84 mol) of 6-fluoronicotinic acid, 2500 mL of toluene, and 5.0 g of DMF were placed, and the mixture was stirred mechanically to obtain a mixed solution. The reaction was carried out by passing phosgene into the mixed solution at a rate of 170 g / h at a rotation speed of 150 r / min and a temperature of 25°C, while continuously passing nitrogen gas at a flow rate of 0.2 L / min to the surface of the reaction solution. The reaction was carried out for 2.5 h. After the reaction was completed, the solvent was removed under reduced pressure to obtain 2-fluoropyridine-5-carbonyl chloride. The purity was 98%, and the yield was 97%. The product was directly used in the next step.

[0178] (6) Synthesis of m-aminobenzoic acid bisamide compound:

[0179] Into a three-necked flask equipped with a drying tube and a condenser, 46.80 g (0.084 mol) of N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxylamino)benzamide (Intermediate 3), and 100 mL of THF were placed, and 14.63 g (0.092 mol) of 2-fluoropyridine-5-carbonyl chloride was added dropwise under ice-bath stirring with nitrogen protection. The dropwise addition was completed in 20 min, and the reaction was carried out at room temperature (25°C) for 1.5 h. The reaction was completed as determined by LC tracking. The solvent was dried to obtain a crude product. The crude product was recrystallized from acetonitrile to obtain 56.5 g of m-aminobenzoic acid bisamide compound. The purity was 97.9%, and the yield was 96.5%.

[0180] In this example, the total yield based on 2-trifluoromethyl-4-(heptafluoroisopropyl)aniline was 77.5%.

[0181] Example 4:

[0182] A preparation method of a meta-aminobenzoic acid bisamide compound, comprising the following steps:

[0183] (1) Synthesis of 2-fluoro-3-nitrobenzoyl chloride:

[0184] In a four-necked flask with a thermometer and a condenser, 74.0 g (0.4 mol) of 2-fluoro-3-nitrobenzoic acid, 400 mL of toluene, and 1.5 g of DMF were added, 52.4 g (0.44 mol) of thionyl chloride was added dropwise at room temperature (25 °C), and the reaction was carried out at reflux for 4 h. The reaction was tracked by GC, and the reaction was complete. The product, 2-fluoro-3-nitrobenzoyl chloride, was obtained by solvent removal under reduced pressure, with a purity of 97.4% and a yield of 99.5%, and was directly used in the next step.

[0185] (2) Synthesis of 2-fluoro-3-nitro-N-(4-(perfluoropropan-2-yl)-2-(trifluoromethyl)phenyl)benzamide (intermediate 1):

[0186] In a three-necked flask with a drying tube and a condenser, 165 g (0.5 mol) of 2-trifluoromethyl-4-(heptafluoroisopropyl)aniline, 400 mL of toluene, and 111 g (0.55 mol) of 2-fluoro-3-nitrobenzoyl chloride were added and stirred at room temperature (25 °C). The addition was completed in 30 min, and the reaction was carried out at reflux for 5 h. The solid was precipitated after cooling, and was washed twice with ethanol and dried to obtain 245 g of a solid, which was 2-fluoro-3-nitro-N-(4-(perfluoropropan-2-yl)-2-(trifluoromethyl)phenyl)benzamide (intermediate 1), with a purity of 96% and a yield of 95%.

[0187] (3) Synthesis of 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)benzamide (intermediate 2):

[0188] In a 2000 mL three-necked round-bottom flask equipped with a magnetic stirrer, a thermometer, and a reflux condenser, 100 g (0.2 mol) of 2-fluoro-3-nitro-N-(4-(perfluoropropan-2-yl)-2-(trifluoromethyl)phenyl)benzamide (intermediate 1) prepared in the previous step, 26 g (0.25 mol) of sodium bromide, 800 g of 1,2-dichloroethane, and 180 g of water were added and stirred. The reaction was carried out at 60 °C by slowly adding 400 g of a 10% sodium hypochlorite aqueous solution. After the addition was completed, the reaction was carried out for 1 h. The organic phase was dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 113.6 g of a light yellow solid, which was the target product, 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)benzamide (intermediate 2), with a purity of 96% and a yield of 95%. It was directly used in the next step.

[0189] (4) Synthesis of N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxylamino)benzamide (Intermediate 3):

[0190] Take 150 g (0.26 mol) of 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)benzamide (Intermediate 2), 1.5 g of palladium-carbon catalyst (the mass percentage of palladium in the catalyst is 5%), and 400 mL of toluene, add them to a 1 L high-temperature reaction kettle, first replace the air with nitrogen, then replace the nitrogen with hydrogen, react at room temperature (25°C) under a hydrogen pressure of 3.5 MPa for 5 h, sample analysis shows that the conversion rate is 95%, and the toluene is removed under reduced pressure to obtain 145 g of solid, which is N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxylamino)benzamide (Intermediate 3), the purity of the target product is 85%, and the yield is 85%, which can be directly used in the next step reaction.

[0191] (5) Synthesis of 2-fluoropyridine-5-carboxylic chloride:

[0192] A four-necked flask with a thermometer and a condenser is charged with 400.0 g (2.84 mol) of 6-fluoronicotinic acid, 2500 mL of toluene, 5.0 g of DMF, and mechanically stirred to obtain a mixed solution. Under the conditions of a rotation speed of 150 r / min and a temperature of 25°C, the phosgene is introduced into the mixed solution at a rate of 170 g / h, and the molar ratio of 6-fluoronicotinic acid to phosgene is 1:1.5. The phosgene is introduced into the mixed solution for acyl chloride reaction, and nitrogen is continuously introduced into the reaction liquid surface at a flow rate of 0.2 L / min at the same time. The reaction time is 2.5 h, and after the reaction is completed, the solvent is removed under reduced pressure to obtain 2-fluoropyridine-5-carboxylic chloride with a purity of 98% and a yield of 97%, which is directly used in the next step reaction.

[0193] (6) Synthesis of m-aminobenzoic acid bisamide compound:

[0194] A three-necked flask with a drying tube and a condenser is charged with 46.80 g (0.084 mol) of N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxylamino)benzamide (Intermediate 3), 100 mL of THF, and nitrogen protection. 14.63 g (0.092 mol) of 2-fluoropyridine-5-carboxylic chloride is added dropwise under ice bath stirring, and the addition is completed in 20 min. The reaction is incubated for 1.5 h, and LC tracking shows that the reaction is complete. The solvent is dried to obtain a crude product, which is recrystallized with acetonitrile to obtain 57.9 g of m-aminobenzoic acid bisamide compound with a purity of 96.5% and a yield of 97.4%.

[0195] In this embodiment, the total yield based on 2-trifluoromethyl-4-(heptafluoroisopropyl) aniline is 74.7%.

[0196] From the above results, compared with the conventional method, in the present application, 6-fluoronicotinic acid is used as the raw material, and phosgene is used as the acyl chloride reagent, 2-fluoropyridine-5-carbonyl chloride with high yield and high purity is prepared by acyl chloride reaction, and it is used as a raw material for preparing m-aminobenzoic acid bisamide compounds. Not only can the purification step be omitted, the synthesis route can be shortened, the preparation efficiency can be improved, but also the selectivity of the reaction can be improved, the generation of impurities can be reduced, and the yield of the product can be improved, so that the m-aminobenzoic acid bisamide compound with high yield and high purity can be efficiently prepared. The purity of the obtained m-aminobenzoic acid bisamide compound product is ≥97%, and the yield is ≥96%. In addition, the preparation method of the m-aminobenzoic acid bisamide compound of the present application has the advantages of simple process, convenient operation, low cost, mild reaction condition, high preparation efficiency, high yield, high purity, environmental friendliness and the like. The m-aminobenzoic acid bisamide compound can be prepared on a large scale, and the industrialized application of the m-aminobenzoic acid bisamide compound is convenient.

[0197] The above embodiments are only preferred embodiments of the present application, and the protection scope of the present application is not limited to the above embodiments. Any technical solutions falling within the concept of the present application shall fall within the protection scope of the present application. It should be pointed out that, for ordinary skilled persons in the art, improvements and refinements without departing from the principles of the present application shall also be considered as the protection scope of the present application.

Claims

1. A method for preparing a meta-aminobenzoic acid bisamide compound, characterized in that: Using N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxyamino)benzamide and 2-fluoropyridine-5-carbonyl chloride as raw materials, m-aminobenzoic acid bisamide compounds were prepared by condensation reaction. The reaction formula is as follows: ； The 2-fluoropyridine-5-carbonyl chloride is prepared by chlorination reaction of 6-fluoronicotinic acid and phosgene, and the reaction formula is as follows: The preparation method of 2-fluoropyridine-5-carbonyl chloride comprises the following steps: Step S1, mixing 6-fluoronicotinic acid with a solvent to obtain a mixed solution; Step S2, introducing phosgene into the mixed solution obtained in step S1 to carry out an acyl chlorination reaction to obtain a reaction product liquid; the phosgene introduction rate is 120 g / h to 200 g / h; nitrogen is continuously introduced into the system during the acyl chlorination reaction; the nitrogen introduction rate is 0.1 L / min to 0.3 L / min; Step S3: removing phosgene and solvent from the reaction product liquid obtained in step S2 to obtain 2-fluoropyridine-5-carbonyl chloride.

2. The preparation method according to claim 1, characterized in that The preparation conditions of the meta-aminobenzoic acid bisamide compound meet at least one of conditions (1.1) to (1.7): Condition (1.1): The molar ratio of the N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxyamino)benzamide to the 2-fluoropyridine-5-carbonyl chloride is 1:1 to 1.3; Condition (1.2): The reaction solvent added to the condensation reaction system is at least one of tetrahydrofuran, benzene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene, and dichlorobenzene; Condition (1.3): The mass ratio of the 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)benzamide to the reaction solvent added to the condensation reaction system is 1:1 to 8; Condition (1.4): The condensation reaction is carried out at a temperature of 0°C to 50°C; Condition (1.5): The condensation reaction time is 1 h to 8 h; Condition (1.6): The condensation reaction is carried out under nitrogen protection; Condition (1.7): After the condensation reaction is completed, the following treatment is further included: recrystallizing the crude product obtained after the condensation reaction using an organic solvent to obtain a meta-aminobenzoic acid bisamide compound; the organic solvent is at least one of dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, ethanol, isopropanol, ethyl acetate, and acetonitrile.

3. The preparation method according to claim 2, characterized in that The preparation conditions of the 2-fluoropyridine-5-carbonyl chloride meet at least one of conditions (2.1), conditions (2.3) to conditions (2.7), and conditions (2.10) to conditions (2.11): Condition (2.1): the molar ratio of 6-fluoronicotinic acid to phosgene is 1:1.2-5.0; Condition (2.3): The solvent is at least one of benzene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene, and dichlorobenzene; Condition (2.4): the mass ratio of the 6-fluoronicotinic acid to the solvent is 1:1 to 8; Condition (2.5): The temperature of the acyl chlorination reaction is 25°C to 100°C; Condition (2.6): The acyl chlorination reaction time is 2.5 h to 8 h; Condition (2.7): The acyl chloride reaction is carried out under stirring; the stirring speed is 50 r / min to 220 r / min; Condition (2.10): The acyl chlorination reaction further comprises adding a catalyst to the system; the catalyst is N,N-dimethylformamide; the mass ratio of the 6-fluoronicotinic acid to the catalyst is 100:0.5-3; Condition (2.11): After the completion of the acyl chlorination reaction, the following treatments are further included: nitrogen is introduced to remove the chlorinated acylating agent in the system and reduced pressure treatment is used to remove the solvent in the system.

4. The preparation method according to any one of claims 1 to 3, characterized in that The N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxyamino)benzamide is prepared by catalytic hydrogenation reaction using 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)benzamide as a raw material. The reaction formula is as follows: ； The hydrogenation catalytic reaction catalyst is at least one of palladium carbon and platinum carbon.

5. The preparation method according to claim 4, characterized in that The preparation conditions of the 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)benzamide meet at least one of conditions (3.1) to (3.7): Condition (3.1): The mass ratio of the 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)benzamide to the hydrogenation catalyst is 1:0.001-0.02; Condition (3.2): The mass percentage of the effective substance in the hydrogenation catalytic reaction catalyst is 2% to 8%; Condition (3.3): The reaction solvent added to the catalytic hydrogenation reaction system is at least one of ethanol, methanol, ethyl acetate, benzene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene, and dichlorobenzene; Condition (3.4): The reducing agent added to the catalytic hydrogenation reaction system is hydrogen; Condition (3.5): The hydrogen pressure of the catalytic hydrogenation reaction is 0.5 MPa to 5.0 MPa; Condition (3.6): The temperature of the catalytic hydrogenation reaction is 25°C to 125°C; Condition (3.7): The catalytic hydrogenation reaction time is 2.5 h to 10 h.

6. The preparation method according to claim 4, characterized in that The 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)benzamide is prepared by bromination reaction using 2-fluoro-3-nitro-N-(4-(perfluoropropane-2-yl)-2-(trifluoromethyl)phenyl)benzamide as a raw material and sodium bromide as a bromine source. The reaction formula is as follows: 。 7. The preparation method according to claim 6, characterized in that The preparation conditions of the 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)benzamide meet at least one of conditions (4.1) to (4.6): Condition (4.1): The bromination reaction further comprises adding sodium hypochlorite; the molar ratio of 2-fluoro-3-nitro-N-(4-(perfluoropropane-2-yl)-2-(trifluoromethyl)phenyl)benzamide to sodium bromide and sodium hypochlorite is 1:1-2:1-3; Condition (4.2): During the bromination reaction, the sodium hypochlorite is added in the form of a sodium hypochlorite solution; the mass percentage of the sodium hypochlorite solution is 10% to 12%; Condition (4.3): The reaction solvent added to the bromination reaction system is at least one of benzene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene, and dichlorobenzene; Condition (4.4): The mass ratio of the 2-fluoro-3-nitro-N-(4-(perfluoropropane-2-yl)-2-(trifluoromethyl)phenyl)benzamide to the reaction solvent added to the bromination reaction system is 1:1 to 8; Condition (4.5): The temperature of the bromination reaction is 50°C to 100°C; Condition (4.6): The bromination reaction time is 1 h to 5 h.

8. The preparation method according to claim 6, characterized in that The 2-fluoro-3-nitro-N-(4-(perfluoropropane-2-yl)-2-(trifluoromethyl)phenyl)benzamide is prepared by a condensation reaction using 2-fluoro-3-nitrobenzoyl chloride and 2-trifluoromethyl-4-(heptafluoroisopropyl)aniline as raw materials. The reaction formula is as follows: 。 9. The preparation method according to claim 8, characterized in that The 2-fluoro-3-nitrobenzoyl chloride is prepared by reacting 2-fluoro-3-nitrobenzoic acid with an acyl chloride reagent through an acyl chloride reaction; The preparation conditions of the 2-fluoro-3-nitrobenzoyl chloride meet at least one of conditions (5.1) to (5.7): Condition (5.1): The molar ratio of the 2-fluoro-3-nitrobenzoic acid to the acyl chloride reagent is 1:0.5-3.0; Condition (5.2): The acyl chloride reagent is any one of thionyl chloride, oxalyl chloride, and phosgene; Condition (5.3): The reaction solvent added to the acyl chlorination reaction system is at least one of benzene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene, and dichlorobenzene; Condition (5.4): The mass ratio of the 2-fluoro-3-nitrobenzoic acid to the reaction solvent added to the acyl chlorination reaction system is 1:1-8; Condition (5.5): The temperature of the acyl chlorination reaction is 25°C to 150°C; Condition (5.6): The acyl chlorination reaction time is 2.5 h to 8 h; Condition (5.7): The acyl chlorination reaction further comprises: adding a catalyst to the system; the catalyst is N,N-dimethylformamide; and the mass ratio of the 2-fluoro-3-nitrobenzoic acid to the catalyst is 100:0.5-3.

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