Preparation method of m-amino benzoic acid bisamide compound

Abstract

The invention discloses a preparation method of m-aminobenzoic acid bisamide compounds, which is characterized in that N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl) phenyl)-2-fluoro-3-(hydroxylamino) benzamide and 2-fluoropyridine-5-formyl chloride are used as raw materials, and the m-aminobenzoic acid bisamide compounds are prepared through condensation reaction. And the 2-fluoropyridine-5-formyl chloride is prepared from 6-fluoronicotinic acid and phosgene. According to the preparation method disclosed by the invention, the 2-fluoropyridine-5-formyl chloride with high yield and high purity is taken as a raw material, so that a purification step can be omitted, a synthetic route can be shortened, the preparation efficiency can be improved, the reaction selectivity can be improved, the yield of the product can be improved while impurities are reduced, and the product with high yield and high purity can be efficiently prepared; the method has the advantages of simple process, convenience in operation, low cost, mild reaction conditions, 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 invention belongs to the technical field of pesticide synthesis, and relates to a method for preparing a 3-aminobenzoic acid diamide compound, and in particular to a method for preparing a broflanilide analogue 3-diamide compound. Background Art

[0002] Broflanilide is a representative of diamide compounds with good insecticidal / acaricidal activity. At the same time, with the large-scale use of broflanilide, resistance has increased, and the development of new compounds is of great significance.

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

[0004]

[0005] However, in the preparation method of the above-mentioned inter-aminobenzoic acid diamide compounds, there is room for further improvement in terms of product yield and purity. Meanwhile, in the preparation method of each intermediate (such as nitroamide, bromo-benzamide, substituted hydroxylamine) adopted by it, product yield and purity are still on the low side, which is also not conducive to improving the yield and purity of the inter-aminobenzoic acid diamide compounds product. For example, in the bromination step, the method of bromination by NBS is adopted, which is difficult to accurately bromine, and the yield is low; in the nitro reduction step, zinc powder is adopted for reduction, which involves dangerous reactions, low reaction efficiency, poor selectivity, and cannot be industrialized; meanwhile, in order to enable each intermediate to meet the preparation needs, it is usually necessary to increase the purification step, which also increases the complexity and preparation cost of the preparation process. Therefore, obtaining a preparation method of the inter-aminobenzoic acid diamide compounds with simple process, convenient operation, low cost, high yield and high purity is of great significance for promoting the industrial application of inter-aminobenzoic acid diamide compounds. Summary of the invention

[0006] The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a method for preparing an aminobenzoic acid bisamide compound with simple process, convenient operation, low cost, high yield and high purity.

[0007] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0008] A method for preparing a meta-aminobenzoic acid bisamide compound, 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, and preparing the meta-aminobenzoic acid bisamide compound through a condensation reaction, the reaction formula is as follows:

[0009]

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

[0011]

[0012] The above preparation method is further improved, and the preparation conditions of the said meta-aminobenzoic acid bisamide compound meet at least one of the 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-(hydroxyamino)benzamide to the 2-fluoropyridine-5-carbonyl chloride is 1:1 to 1.3;

[0014] 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;

[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 to the condensation reaction system is 1:1-8;

[0016] Condition (1.4): The condensation reaction is carried out at a temperature of 0°C to 50°C;

[0017] Condition (1.5): The condensation reaction time is 1 h to 8 h;

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

[0019] Condition (1.7): After the condensation reaction is completed, the following treatment is also included: the crude product obtained after the condensation reaction is completed is recrystallized using an organic solvent to obtain an 3-aminobenzoic acid diamide compound; 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, wherein 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 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 chlorination reaction is carried out under stirring; the stirring speed is 50r / min to 220r / min;

[0032] Condition (2.8): During the acyl chlorination reaction, nitrogen is continuously introduced into the system;

[0033] Condition (2.9): the nitrogen 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 into 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 chlorination reaction, the following treatment is also included: introducing nitrogen gas to remove the chlorinated acylating agent in the system and using reduced pressure treatment to remove the solvent in the system.

[0036] The above preparation method is further improved, wherein the N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxyamino)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 reggie nickel, palladium carbon, and platinum carbon.

[0039] The above preparation method is further improved, wherein the preparation conditions of 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 of the effective substance in the hydrogenation catalytic reaction catalyst is 2% to 8%;

[0042] 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;

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

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

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

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

[0047] The above preparation method is further improved, wherein 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, and the reaction formula is as follows:

[0048]

[0049] The above preparation method is further improved, wherein the preparation conditions of 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 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;

[0051] 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%;

[0052] 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;

[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 to the bromination reaction system is 1:1 to 8;

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

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

[0056] The above preparation method is further improved, wherein the 2-fluoro-3-nitro-N-(4-(perfluoropropane-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:

[0057]

[0058] The above preparation method is further improved, wherein the 2-fluoro-3-nitrobenzoyl chloride is prepared by acyl chlorination reaction of 2-fluoro-3-nitrobenzoic acid and an acyl chlorination reagent;

[0059] The preparation conditions of the 2-fluoro-3-nitrobenzoyl chloride satisfy 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 chloride reagent is 1:0.5-3.0;

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

[0062] Condition (5.3): the reaction solvent added to the system of the acyl chlorination reaction 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 to the acyl chlorination reaction system is 1:1-8;

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

[0065] Condition (5.6): The acyl chlorination reaction time is 2.5h to 8h;

[0066] Condition (5.7): During the acyl chlorination reaction, the process further includes: adding a catalyst into the system; the catalyst is N,N-dimethylformamide; 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 advantages of the present invention are:

[0068] (1) In view of the shortcomings of the existing preparation methods, such as complex process, difficult operation, high cost, low yield and low purity, the present invention creatively proposes a preparation method of m-aminobenzoic acid bisamide compounds, 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, wherein 2-fluoropyridine-5-carbonyl chloride is made from 6-fluoronicotinic acid as raw material and phosgene as chlorination reagent, through chlorination reaction The preparation method has the advantages of high yield and high purity. Therefore, when the 2-fluoropyridine-5-carbonyl chloride is used as a raw material for preparing the inter-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, and the yield of the product can be improved while reducing the generation of impurities, so that the inter-aminobenzoic acid bisamide compounds with high yield and high purity can be efficiently prepared, and the purity of the obtained inter-aminobenzoic acid bisamide compounds product is ≥97%, and the yield is ≥96%. In addition, the preparation method of the inter-aminobenzoic acid bisamide compounds of the present invention has the advantages of simple process, convenient operation, low cost, mild reaction conditions, high preparation efficiency, high yield, high purity, environmental friendliness, etc., and the inter-aminobenzoic acid bisamide compounds can be prepared on a large scale, which is convenient for realizing the industrial application of the inter-aminobenzoic acid bisamide compounds.

[0069] (2) In the present invention, 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)benzamide is used as a raw material, and a catalytic hydrogenation reaction is performed under the action of a hydrogenation catalytic catalyst such as reggie nickel, palladium carbon, platinum carbon, etc. to prepare N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxyamino)benzamide with high yield and high purity. Further, the When N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxylamino)benzamide is used as a raw material for preparing inter-aminobenzoic acid bisamide compounds, not only can the purification step 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, and the yield of the product can be increased while reducing the generation of impurities, thereby efficiently preparing inter-aminobenzoic acid bisamide compounds with high yield and high purity. At the same time, under the action of hydrogenation catalytic reaction catalysts such as reggie nickel, palladium carbon, and platinum carbon, by optimizing conditions such as hydrogen pressure and reaction temperature, the catalytic efficiency and the selectivity of the reaction can be improved, and at the same time, excessive hydrogenation to form amino by-products can be prevented, thereby ensuring that the prepared N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxylamino)benzamide has the advantages of high yield and high purity.

[0070] (3) In the present invention, 2-fluoro-3-nitro-N-(4-(perfluoropropane-2-yl)-2-(trifluoromethyl)phenyl)benzamide is used as a raw material, and under the action of sodium bromide and sodium hypochlorite, bromination can be accurately performed 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 atoms in the present invention has simple and mild conditions and is suitable for industrial production.

[0071] (4) In the present invention, by optimizing the preparation steps of various intermediates, the yield and purity of these intermediates can be improved, and no purification is required. The next step can be directly carried out to synthesize the target raw drug. Therefore, with their cooperation, the synthesis route can be shortened, and higher quality inter-aminobenzoic acid bisamide compound products can be obtained, which is convenient for the industrial application of inter-aminobenzoic acid bisamide compound products. DETAILED DESCRIPTION

[0072] In view of the shortcomings of the existing preparation methods, such as complex process, difficult operation, high cost, low yield and low purity, the present invention creatively proposes a preparation method of an aminobenzoic acid bisamide compound, wherein N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxyamino)benzamide and 2-fluoropyridine-5-carbonyl chloride are used as raw materials, wherein 2-fluoropyridine-5-carbonyl chloride is prepared by using 6-fluoronicotinic acid as raw material and phosgene as chlorination reagent through chlorination reaction. The method has the advantages of high yield and high purity. Therefore, when the 2-fluoropyridine-5-carbonyl chloride is used as a raw material for preparing the inter-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, and the yield of the product can be improved while reducing the generation of impurities, so that the inter-aminobenzoic acid bisamide compounds with high yield and high purity can be efficiently prepared, and the purity of the obtained inter-aminobenzoic acid bisamide compounds product is ≥97%, and the yield is ≥96%. In addition, the preparation method of the inter-aminobenzoic acid bisamide compounds of the present invention has the advantages of simple process, convenient operation, low cost, mild reaction conditions, high preparation efficiency, high yield, high purity, environmental friendliness, etc., and can prepare the inter-aminobenzoic acid bisamide compounds on a large scale, which is convenient for realizing the industrial application of the inter-aminobenzoic acid bisamide compounds.

[0073] In this embodiment, the preparation method of the inter-aminobenzoic acid bisamide compound is to use N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxyamino)benzamide and 2-fluoropyridine-5-carbonyl chloride as raw materials to prepare the inter-aminobenzoic acid bisamide compound by condensation reaction, and the reaction formula is as follows:

[0074]

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

[0076]

[0077] In this embodiment, the preparation conditions of the m-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-(hydroxyamino)benzamide to 2-fluoropyridine-5-carbonyl chloride is 1:1 to 1.3; further preferably, the molar ratio of N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxyamino)benzamide to 2-fluoropyridine-5-carbonyl chloride is 1:1.

[0079] 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; more preferably, the reaction solvent is tetrahydrofuran or 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 to the condensation reaction system is 1:1-8; more 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°C to 50°C; more preferably, the condensation reaction is carried out at a temperature of 0°C to 25°C.

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

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

[0084] Condition (1.7): After the condensation reaction is completed, the following treatment is also included: the crude product obtained after the condensation reaction is completed is recrystallized using an organic solvent to obtain an 3-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 2-fluoropyridine-5-carbonyl chloride adopted comprises the following steps:

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

[0087] Step S2, introducing phosgene into the mixed solution obtained in step S1 to carry out acyl chlorination reaction to obtain a reaction product liquid;

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

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

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

[0091] Condition (2.2): The rate of introduction of phosgene is 120 g / h to 200 g / h, for example, the rate of introduction 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, 200 g / h; more preferably, the rate of introduction of phosgene is 120 g / h to 180 g / h.

[0092] Condition (2.3): The solvent is at least one of benzene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene, and dichlorobenzene; more 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 chlorination reaction is 25°C to 100°C, for example, the temperature is 25°C, 40°C, 50°C, 80°C, 100°C; more preferably, the temperature of the chlorination reaction is 25°C to 80°C.

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

[0096] Condition (2.7): The acyl chloride reaction is carried out under stirring conditions; 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 was continuously introduced into the system during the acyl chlorination reaction.

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

[0099] Condition (2.10): The process of the acyl chlorination reaction also 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 completion of the acyl chlorination reaction, the following treatment is also included: introducing nitrogen gas to remove the chlorinated acylating agent 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-(hydroxyamino)benzamide used 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:

[0102]

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

[0104] In this embodiment, the preparation conditions of 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)benzamide used 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-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)benzamide to the hydrogenation catalytic reaction catalyst is 1:0.001-0.02. For example, the mass ratio of the two 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. More preferably, the mass ratio of the two is 1:0.005-0.02.

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

[0107] 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.

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

[0109] Condition (3.5): The hydrogen pressure of the catalytic hydrogenation reaction is 0.5 MPa to 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 to 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 2.5 h to 10 h. For example, the time is 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, preferably, the time is 2.5-5 h.

[0112] In this embodiment, the 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)benzamide used 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:

[0113]

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

[0115] Condition (4.1): The bromination reaction also includes 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; more 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 of the sodium hypochlorite solution is 10% to 12%.

[0117] 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.

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

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

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

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

[0122]

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

[0124] In this embodiment, the preparation conditions of 2-fluoro-3-nitrobenzoyl chloride used 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 chloride reagent is 1:0.5-3.0.

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

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

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

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

[0130] Condition (5.6): The reaction time of the acyl chloride is 2.5 h to 8 h, for example, 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 6 h, 7 h, 8 h, preferably, 2.5-5 h.

[0131] Condition (5.7): During the acyl chlorination reaction, the process also includes: adding a catalyst into the system; the catalyst is N,N-dimethylformamide; the mass ratio of 2-fluoro-3-nitrobenzoic acid to the catalyst is 100:0.5-3.

[0132] The present invention is further described below in conjunction with specific preferred embodiments, but the protection scope of the present invention is not limited thereby.

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

[0134] Embodiment 1:

[0135] A method for preparing a meta-aminobenzoic acid diamide compound, wherein the reaction formula is as follows:

[0136]

[0137] The following steps are involved:

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

[0139] In 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, and 30 g of phosgene was introduced at 60°C. The reaction was kept warm for 3 hours, and the reaction liquid became clear. After the reaction was complete, the excess phosgene was removed by keeping warm and reducing pressure, and the reaction was cooled and the solvent was removed by reducing pressure to obtain 2-fluoro-3-nitrobenzoyl chloride, which was directly reacted 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] 151 g (0.46 mol) of 2-trifluoromethyl-4-(heptafluoroisopropyl)aniline and 300 mL of toluene were added to a three-necked flask with a drying tube and a condenser. 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.) for 30 min. The temperature was slowly raised to reflux for reaction for 4.5 h. The mixture was cooled to precipitate a solid to obtain 221 g of a solid, i.e., 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] 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-(perfluoropropane-2-yl)-2-(trifluoromethyl)phenyl)benzamide (Intermediate 1) prepared in the previous step, 26 g (0.25 mol) of sodium bromide, and 800 g of 1,2-dichloroethane and 180g water were stirred and heated. 400g of sodium hypochlorite aqueous solution with a mass concentration of 10% was slowly added dropwise at a reaction temperature of 60°C. After the addition was completed, the mixture was kept warm for 1h, and the organic phase was dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 112g of a light yellow solid target, namely 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)benzamide (intermediate 2), with a purity of 97% and a yield of 95%. It was directly used for the next experiment.

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

[0145] Take 100g (0.17mol) of 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)benzamide (intermediate 2), 1g of platinum-carbon catalyst (the mass percentage of platinum in the catalyst is 3%) and 400mL of ethanol, add them into a 1L high temperature reactor, first replace the air with nitrogen, then replace the nitrogen with hydrogen, react for 2h at a hydrogen pressure of 2MPa and room temperature (25°C), take samples and analyze, the conversion rate is 99%, remove ethanol, and obtain 97g of solid, i.e. N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxyamino)benzamide (intermediate 3), the purity is 93%, the yield is 92.5%, and it can be directly used in the next step reaction.

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

[0147] 400.0 g (2.84 mol) of 6-fluoronicotinic acid, 2500 mL of toluene, and 5.0 g of DMF were added to a four-necked flask with a thermometer and a condenser, and mechanically stirred and mixed to obtain a mixed solution. Under the conditions of a rotation speed of 150 r / min and a temperature of 25° C., according to the introduction rate of phosgene of 170 g / h and the molar ratio of 6-fluoronicotinic acid to phosgene of 1:1.5, phosgene was introduced into the mixed solution for acyl chloride reaction, and nitrogen was continuously introduced under the reaction liquid surface at a flow rate of 0.2 L / min. The reaction time was 5 h. After the reaction was complete, 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%, which was directly used for the next step reaction.

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

[0149] 50.6 g (0.084 mol) of N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxyamino)benzamide (intermediate 3) and 100 mL of THF were added to a three-necked flask with a drying tube and a condenser. Under nitrogen protection, 14.63 g (0.092 mol) of 2-fluoropyridine-5-carbonyl chloride prepared in step (5) was added dropwise under stirring in an ice bath for 20 min. The reaction was allowed to proceed at room temperature (25° C.) for 1.5 h. After LC tracking, the reaction was completed. The solvent was spin-dried to obtain a crude product. The crude product was recrystallized from acetonitrile to obtain 56.2 g of an aminobenzoic acid bisamide compound with a purity of 98.5% and a yield of 96.5%.

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

[0151] Embodiment 2:

[0152] A method for preparing a meta-aminobenzoic acid diamide compound comprises the following steps:

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

[0154] In a four-necked flask equipped 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, and 0.22 mol of thionyl chloride was added dropwise. The mixture was refluxed at room temperature (25°C) for 3 h. After the reaction was complete, the solvent was removed under reduced pressure to obtain 2-fluoro-3-nitrobenzoyl chloride with a purity of 97 and a yield of 97%, which was directly used for the next step.

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

[0156] 151 g (0.46 mol) of 2-trifluoromethyl-4-(heptafluoroisopropyl)aniline and 300 mL of toluene were added to a three-necked flask with a drying tube and a condenser. 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 addition was completed over 30 min. The temperature was slowly raised to reflux for reaction for 4 h. The mixture was cooled to precipitate a solid to obtain 218.6 g of a solid, i.e., 2-fluoro-3-nitro-N-(4-(perfluoropropane-2-yl)-2-(trifluoromethyl)phenyl)benzamide (intermediate 1). The purity was 96% and the yield was 92%.

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

[0158] 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-(perfluoropropane-2-yl)-2-(trifluoromethyl)phenyl)benzamide (Intermediate 1) prepared in the previous step, 26 g (0.25 mol) of sodium bromide, and 800 g of 1,2-dichloroethane and 180g of water were stirred and heated. 400g of a 10% sodium hypochlorite aqueous solution was slowly added dropwise at a reaction temperature of 60°C. After the addition was completed, the mixture was kept warm for 1h. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain 112g of a light yellow solid target product, namely 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-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 experiment.

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

[0160] Take 100g (0.17mol) of 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)benzamide (intermediate 2), 1g of platinum-carbon catalyst (the mass percentage of platinum in the catalyst is 2%) and 400mL of ethanol, add them into a 1L high temperature reactor, first replace the air with nitrogen, then replace the nitrogen with hydrogen, react for 2h at a hydrogen pressure of 2.5MPa and room temperature (25°C), take samples and analyze, the conversion rate is 99%, remove ethanol, and obtain 97g of solid, i.e. N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxyamino)benzamide (intermediate 3), the purity is 93%, the yield is 92.0%, and it can be directly used in the next step reaction.

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

[0162] 400.0 g (2.84 mol) of 6-fluoronicotinic acid, 2500 mL of toluene, and 5.0 g of DMF were added to a four-necked flask with a thermometer and a condenser, and mechanically stirred and mixed to obtain a mixed solution. Under the conditions of a rotation speed of 150 r / min and a temperature of 25° C., according to the introduction rate of phosgene of 170 g / h and the molar ratio of 6-fluoronicotinic acid to phosgene of 1:1.5, phosgene was introduced into the mixed solution for acyl chloride reaction, and nitrogen was continuously introduced under the reaction liquid surface at a flow rate of 0.2 L / min. The reaction time was 5 h. After the reaction was complete, 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%, which was directly used for the next step reaction.

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

[0164] In a three-necked flask with a drying tube and a condenser, 46.80 g (0.084 mol) of N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxyamino)benzamide (intermediate 3) and 100 mL of THF were added. Under nitrogen protection, 14.63 g (0.092 mol) of 2-fluoropyridine-5-carbonyl chloride was added dropwise under stirring in an ice bath for 20 min. The reaction was carried out at room temperature (25° C.) for 1.5 h. After LC tracking, the reaction was completed, and the solvent was spin-dried to obtain a crude product. The crude product was recrystallized from acetonitrile to obtain 56.0 g of m-aminobenzoic acid bisamide compounds 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] Embodiment 3:

[0167] A method for preparing a meta-aminobenzoic acid diamide compound comprises the following steps:

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

[0169] In a four-necked flask equipped 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 dropwise, and 30.2 g (0.24 mol) of oxalyl chloride was added dropwise. The mixture was refluxed at room temperature (25°C) for 3 h. After the reaction was complete, 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 for the next step.

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

[0171] 151 g (0.46 mol) of 2-trifluoromethyl-4-(heptafluoroisopropyl)aniline and 300 mL of toluene were added to a three-necked flask with a drying tube and a condenser. 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.) for 30 min. The temperature was slowly raised to reflux for reaction for 5 h. The mixture was cooled to precipitate a solid. The solid was washed twice with ethanol and dried to obtain 226 g of a solid, i.e., 2-fluoro-3-nitro-N-(4-(perfluoropropane-2-yl)-2-(trifluoromethyl)phenyl)benzamide (intermediate 1), with a content of 95% and a yield of 94%.

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

[0173] 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-(perfluoropropane-2-yl)-2-(trifluoromethyl)phenyl)benzamide (Intermediate 1) prepared in the previous step, 26 g (0.25 mol) of sodium bromide, and 800 g of 1,2-dichloroethane and 180g of water were stirred and heated. 400g of a 10% sodium hypochlorite aqueous solution was slowly added dropwise at a reaction temperature of 60°C. After the addition was completed, the mixture was kept warm for 1h. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain 112g of a light yellow solid target product, namely 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-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 experiment.

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

[0175] Take 100g (0.17mol) of 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)benzamide (intermediate 2), 1g of platinum-carbon catalyst (the mass percentage of platinum in the catalyst is 2%) and 400mL of toluene, add them into a 1L high temperature reactor, first replace the air with nitrogen, then replace the nitrogen with hydrogen, react for 5h at a hydrogen pressure of 3MPa and room temperature (25°C), take samples and analyze, the conversion rate is 99%, remove ethanol, and obtain 97g of solid, i.e. N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxyamino)benzamide (intermediate 3), the target product content is 90%, the yield is 92.0%, and it can be directly used in the next step reaction.

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

[0177] 400.0 g (2.84 mol) of 6-fluoronicotinic acid, 2500 mL of toluene, and 5.0 g of DMF were added to a four-necked flask with a thermometer and a condenser, and mechanically stirred and mixed to obtain a mixed solution. Under the conditions of a rotation speed of 150 r / min and a temperature of 25° C., according to the introduction rate of phosgene of 170 g / h and the molar ratio of 6-fluoronicotinic acid to phosgene of 1:1.5, phosgene was introduced into the mixed solution for acyl chloride reaction, and nitrogen was continuously introduced under the reaction liquid surface at a flow rate of 0.2 L / min. The reaction time was 2.5 h. After the reaction was complete, the solvent was removed under reduced pressure to obtain 2-fluoropyridine-5-carbonyl chloride with a purity of 98% and a yield of 97%, which was directly used for the next step reaction.

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

[0179] In a three-necked flask with a drying tube and a condenser, 46.80 g (0.084 mol) of N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxyamino)benzamide (intermediate 3) and 100 mL of THF were added. Under nitrogen protection, 14.63 g (0.092 mol) of 2-fluoropyridine-5-carbonyl chloride was added dropwise under stirring in an ice bath for 20 min. The reaction was carried out at room temperature (25° C.) for 1.5 h. After LC tracking, the reaction was completed, and 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 compounds with a purity of 97.9% and a yield of 96.5%.

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

[0181] Embodiment 4:

[0182] A method for preparing a meta-aminobenzoic acid diamide compound comprises the following steps:

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

[0184] In a four-necked flask equipped 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 dropwise at room temperature (25°C), and 52.4 g (0.44 mol) of thionyl chloride was added dropwise. After the addition was complete, the mixture was refluxed for 4 hours and the reaction was complete under GC tracking. The solvent was removed under reduced pressure to obtain 2-fluoro-3-nitrobenzoyl chloride with a purity of 97.4% and a yield of 99.5%, which was directly used for the next step of reaction.

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

[0186] 165 g (0.5 mol) of 2-trifluoromethyl-4-(heptafluoroisopropyl)aniline and 400 mL of toluene were added to a three-necked flask with a drying tube and a condenser, and 111 g (0.55 mol) of 2-fluoro-3-nitrobenzoyl chloride was added dropwise under stirring at room temperature (25°C). The addition was completed within 30 min, and the temperature was slowly raised to reflux for reaction for 5 h. The mixture was cooled to precipitate a solid, which was washed twice with ethanol and dried to obtain 245 g of a solid, i.e., 2-fluoro-3-nitro-N-(4-(perfluoropropane-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-(perfluoropropane-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-(perfluoropropane-2-yl)-2-(trifluoromethyl)phenyl)benzamide (Intermediate 1) prepared in the previous step, 26 g (0.25 mol) of sodium bromide, and 800 g of 1,2-dichloroethane and 180g of water were stirred and heated. 400g of a 10% sodium hypochlorite aqueous solution was slowly added dropwise at a reaction temperature of 60°C. After the addition was completed, the mixture was kept warm for 1h. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain 113.6g of a light yellow solid target, namely 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-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 experiment.

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

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

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

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

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

[0194] In a three-necked flask with a drying tube and a condenser, 46.80 g (0.084 mol) of N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(hydroxyamino)benzamide (intermediate 3) and 100 mL of THF were added. Under nitrogen protection, 14.63 g (0.092 mol) of 2-fluoropyridine-5-carbonyl chloride was added dropwise under stirring in an ice bath. The addition was completed within 20 min. The reaction was kept warm for 1.5 h. After LC tracking, the reaction was completed. The solvent was spin-dried to obtain a crude product. The crude product was recrystallized from acetonitrile to obtain 57.9 g of m-aminobenzoic acid bisamide compounds 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] As can be seen from the above results, compared with the conventional method, in the present invention, 6-fluoronicotinic acid is used as a raw material, phosgene is used as an acyl chloride reagent, and 2-fluoropyridine-5-carbonyl chloride with high yield and high purity is prepared by acyl chloride reaction, and when it is used as a raw material for preparing inter-aminobenzoic acid bisamide compounds, not only can the purification step be omitted, the synthetic route is shortened, and the preparation efficiency is improved, but also the selectivity of the reaction can be improved, while reducing the generation of impurities, the yield of the product can also be improved, so that the inter-aminobenzoic acid bisamide compounds with high yield and high purity can be efficiently prepared, and the purity of the obtained inter-aminobenzoic acid bisamide compounds product is ≥97%, and the yield is ≥96%. In addition, the preparation method of the inter-aminobenzoic acid bisamide compounds of the present invention has the advantages of simple process, convenient operation, low cost, mild reaction conditions, high preparation efficiency, high yield, high purity, environmental friendliness, etc., and can prepare inter-aminobenzoic acid bisamide compounds on a large scale, which is convenient for realizing the industrial application of inter-aminobenzoic acid bisamide compounds.

[0197] The above embodiments are only preferred implementations of the present invention, and the protection scope of the present invention is not limited to the above embodiments. All technical solutions under the concept of the present invention belong to the protection scope of the present invention. It should be pointed out that for ordinary technicians in this technical field, improvements and modifications without departing from the principle of the present invention should also be regarded as the protection scope of the present invention.

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 are prepared by condensation reaction. The reaction formula is as follows: The 2-fluoropyridine-5-carbonyl chloride is prepared by 6-fluoronicotinic acid and phosgene through an acyl chlorination reaction, and the reaction formula is as follows:

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 1:1-8; 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 also included: the crude product obtained after the condensation reaction is completed is recrystallized using an organic solvent to obtain an 3-aminobenzoic acid diamide 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 method of the 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 acyl chlorination reaction to obtain a reaction product liquid; Step S3, removing phosgene and solvent from the reaction product liquid obtained in step S2 to obtain 2-fluoropyridine-5-carbonyl chloride.

4. The preparation method according to claim 3, characterized in that: The preparation conditions of the 2-fluoropyridine-5-carbonyl chloride satisfy at least one of conditions (2.1) to (2.11): Condition (2.1): the molar ratio of 6-fluoronicotinic acid to phosgene is 1:1.2-5.0; Condition (2.2): the phosgene introduction rate is 120 g / h to 200 g / h; 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 2.5h to 8h; Condition (2.7): The acyl chlorination reaction is carried out under stirring; the stirring speed is 50r / min to 220r / min; Condition (2.8): During the acyl chlorination reaction, nitrogen is continuously introduced into the system; Condition (2.9): the nitrogen introduction rate is 0.1 L / min to 0.3 L / min; Condition (2.10): The acyl chlorination reaction further comprises adding a catalyst into 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 treatment is also included: introducing nitrogen gas to remove the chlorinated acylating agent in the system and using reduced pressure treatment to remove the solvent in the system.

5. The preparation method according to any one of claims 1 to 4, characterized in that: 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: The hydrogenation catalytic reaction catalyst is at least one of reggie nickel, palladium carbon, and platinum carbon.

6. The preparation method according to claim 5, characterized in that: The preparation conditions of the 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)benzamide satisfy 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 catalytic reaction 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 time of the catalytic hydrogenation reaction is 2.5h to 10h.

7. The preparation method according to claim 5, 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:

8. The preparation method according to claim 7, characterized in that: The preparation conditions of the 2-fluoro-3-nitro-N-(2-bromo-4-(perfluoropropane-2-yl)-6-(trifluoromethyl)phenyl)benzamide satisfy 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.

9. The preparation method according to claim 7, characterized in that: The 2-fluoro-3-nitro-N-(4-(perfluoropropane-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. The reaction formula is as follows:

10. The preparation method according to claim 9, characterized in that: The 2-fluoro-3-nitrobenzoyl chloride is prepared by acyl chlorination reaction of 2-fluoro-3-nitrobenzoic acid and an acyl chlorination agent; The preparation conditions of the 2-fluoro-3-nitrobenzoyl chloride satisfy 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 system of the acyl chlorination reaction 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 2.5h to 8h; Condition (5.7): The process of the acyl chlorination reaction further comprises: adding a catalyst to the system; The catalyst is N,N-dimethylformamide; the mass ratio of the 2-fluoro-3-nitrobenzoic acid to the catalyst is 100:0.5-3.

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