3-amino-2-fluorobenzamide compound and preparation method thereof

Abstract

The invention provides a 3-amino-2-fluorobenzamide compound and a preparation method thereof, and the preparation method comprises the following steps: (1) carrying out a substitution reaction on 5-chloro-2-hydroxy-3-nitrobenzoic acid to obtain 5-chloro-2-fluoro-3-nitrobenzoyl halide with a structure as shown in a formula I; (2) carrying out an amidation reaction on the 5-chloro-2-fluoro-3-nitrobenzoyl halide and an aniline compound with a structure as shown in a formula II to obtain a 3-nitro-2-fluorobenzamide compound with a structure as shown in a formula III; and (3) carrying out a reduction reaction on the 3-nitro-2-fluorobenzamide compound, so as to obtain the 3-amino-2-fluorobenzamide compound with a structure as shown in a formula IV. The preparation method is low in raw material price, almost quantitative in multi-step reaction, few in by-products, high in target product yield and mild in process condition, avoids severe reaction conditions such as deep cooling and high temperature, and is more suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pesticide preparation, and particularly relates to a 3-amino-2-fluorobenzamide compound and a preparation method thereof. Background Art

[0002] The diamide compounds represented by bromofenac and cyfluthrin are one of the most promising insecticides in the industry due to their unique mechanism of action, novel targets and environmental friendliness. They are increasingly becoming a research hotspot for domestic and foreign pesticide companies.

[0003]

[0004] In the currently reported preparation methods of meta-diamide compounds, aminobenzamide compounds ( R1 and R2 are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, etc.) is an important intermediate, and the preparation process of the intermediate will directly affect the large-scale production and application of diamide compounds.

[0005] CN112707836A discloses a method for preparing an aminobenzamide compound using 2-fluoro-3-nitrobenzoic acid as a raw material. The method first uses 2-fluoro-3-nitrobenzoyl chloride (shown in Formula A1) as a raw material to prepare 2-fluoro-3-nitrobenzoyl chloride, and then condenses it with 4-(perfluoropropane-2-yl)-2-(trifluoromethyl)aniline (shown in Formula A2) to obtain 2-fluoro-3-nitro-N-(4-(perfluoropropane-2-yl)-2-(trifluoromethyl)phenyl)benzamide (shown in Formula A3), and then performs a reduction reaction to obtain an aminobenzamide compound. The preparation reaction formula is as follows:

[0006]

[0007] However, the current price of 2-fluoro-3-nitrobenzoic acid is relatively high (5,000 yuan / kg), which is unaffordable compared to the production cost of pesticides, and there are no reports on its industrial production.

[0008] CN105061251A discloses a method for preparing such aminobenzamide compounds using 2-chloro-3-nitrobenzoic acid as a raw material. The method first prepares 2-chloro-3-nitrobenzoyl chloride, then reacts with substituted 4-(perfluoropropane-2-yl)-2-(trifluoromethyl)aniline, and then reacts the obtained amide compound with potassium fluoride for fluorination, and finally reduces to obtain the target compound. The preparation reaction formula is as follows:

[0009]

[0010]

[0011] The raw material 2-chloro-3-nitrobenzoic acid in this method is also relatively expensive (33,000 yuan / kg), and the yield is only 45% when fluorinated with potassium fluoride, which is not conducive to large-scale production.

[0012] In summary, the existing preparation processes of aminobenzamide compounds have the disadvantages of high raw material prices and low yields. Therefore, developing a synthesis process of aminobenzamide compounds with low raw material costs and high product yields is an urgent problem to be solved in the art. Summary of the invention

[0013] In view of the deficiencies in the prior art, the object of the present invention is to provide a 3-amino-2-fluorobenzamide compound and a preparation method thereof. The preparation method uses 5-chloro-2-hydroxy-3-nitrobenzoic acid as a raw material, has low raw material cost, and the multi-step reaction is almost a quantitative reaction. There are few by-products, the yield of the target product is high, and the reaction conditions are mild, which is more suitable for industrial production.

[0014] To achieve this object, the present invention adopts the following technical solutions:

[0015] In a first aspect, the present invention provides a method for preparing a 3-amino-2-fluorobenzamide compound, the preparation method comprising the following steps:

[0016] (1) 5-chloro-2-hydroxy-3-nitrobenzoic acid is subjected to substitution reaction to obtain 5-chloro-2-fluoro-3-nitrobenzoyl halide of the structure shown in formula I, and the reaction formula is as follows:

[0017]

[0018] Wherein, Z is fluorine or chlorine;

[0019] (2) The 5-chloro-2-fluoro-3-nitrobenzoyl halide obtained in step (1) is subjected to an amide reaction with an aniline compound having a structure represented by formula II to obtain a 3-nitro-2-fluorobenzamide compound having a structure represented by formula III. The reaction formula is as follows:

[0020]

[0021] Wherein, Y is selected from any one of unsubstituted or halogenated C1-C6 straight or branched alkyl, and unsubstituted or halogenated C1-C6 alkoxy;

[0022] R is selected from any one of hydrogen, fluorine or methoxy;

[0023] (3) The 3-nitro-2-fluorobenzamide compound obtained in step (2) is subjected to a reduction reaction to obtain the 3-amino-2-fluorobenzamide compound of the structure shown in formula IV. The reaction formula is as follows:

[0024]

[0025] The preparation method provided by the invention uses 5-chloro-2-hydroxy-3-nitrobenzoic acid as a starting raw material, which is low in price (50 yuan / kg) and easy to obtain; the 5-chloro-2-hydroxy-3-nitrobenzoic acid is sequentially subjected to a substitution reaction, an amide reaction with an aniline compound, and a reduction reaction to obtain a target product, a 3-amino-2-fluorobenzamide compound; the multi-step reaction is almost a quantitative reaction, has few by-products, and a high yield; the total yield is as high as 75%-84%, and harsh reaction conditions such as deep cooling and high temperature are avoided, the process conditions are mild, and expensive raw materials (such as 2-fluoro-3-nitrobenzoic acid and 2-chloro-3-nitrobenzoic acid) are no longer used, so the method is more suitable for industrial production.

[0026] In the prior art CN105061251A, an amide compound is first synthesized and then fluorinated. This route has a low yield due to the low reactivity of the amide compound and poor selectivity of the fluorination reaction. The present invention uses 5-chloro-2-hydroxy-3-nitrobenzoic acid as a raw material, designs a process route of first fluorination, then amidation, and finally reduction, thereby overcoming the technical defect of low fluorination yield of the amide compound.

[0027] In the present invention, the C1-C6 straight chain or branched alkyl group can be a straight chain or branched alkyl group of C1, C2, C3, C4, C5, or C6, illustratively including but not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2-methylbutyl, n-pentyl, isopentyl, neopentyl, n-hexyl, neohexyl, and the like.

[0028] In the present invention, the C1-C6 alkoxy group may be a straight chain or branched chain alkoxy group of C1, C2, C3, C4, C5, or C6, that is, a monovalent group obtained by connecting the aforementioned straight chain or branched chain alkyl group with O.

[0029] In the present invention, the halogenated C1-C6 (C1, C2, C3, C4, C5 or C6) straight chain or branched alkyl, halogenated C1-C6 (C1, C2, C3, C4, C5 or C6) alkoxy, that is, a monovalent group obtained by replacing at least one hydrogen in the C1-C6 straight chain or branched alkyl, C1-C6 alkoxy with a halogen; the halogen includes fluorine, chlorine, bromine or iodine.

[0030] Preferably, Z is fluorine, and the substitution reaction in step (1) is also called the "first route", which includes a first chlorination reaction and a fluorination reaction performed in sequence to obtain 5-chloro-2-fluoro-3-nitrobenzoyl fluoride, and the reaction formula is as follows:

[0031]

[0032] In the first route, the 5-chloro-2-hydroxy-3-nitrobenzoic acid undergoes a first chlorination reaction to obtain 2,5-dichloro-3-nitrobenzoyl chloride; and the 2,5-dichloro-3-nitrobenzoyl chloride undergoes a fluorination reaction to obtain 5-chloro-2-fluoro-3-nitrobenzoyl fluoride.

[0033] Preferably, the first chlorination reaction is carried out in the presence of a first chlorination reagent, which includes any one or a combination of at least two of thionyl chloride, triphosgene, oxalyl chloride, phosphorus trichloride, and phosphorus pentachloride, and thionyl chloride and / or triphosgene are further preferred.

[0034] Preferably, the molar ratio of the 5-chloro-2-hydroxy-3-nitrobenzoic acid to the first chlorinating agent is 1:(0.67-3.0), for example, it can be 1:0.7, 1:0.8, 1:1.0, 1:1.5, 1:2.0, 1:2.2, 1:2.5, 1:3.0, etc., and more preferably 1:(0.7-2.4).

[0035] Preferably, the first chlorination reaction is carried out in the presence of a first chlorination catalyst.

[0036] Preferably, the first chlorination catalyst comprises N,N-dimethylformamide.

[0037] Preferably, the molar ratio of the first chlorination catalyst to 5-chloro-2-hydroxy-3-nitrobenzoic acid is (1.0-5.0):1, for example, it can be 1.2:1, 1.5:1, 1.8:1, 2.0:1, 2.2:1, 2.5:1, 2.8:1, 3.0:1, 3.5:1, 4.0:1 or 4.5:1, and more preferably (1.0-3.0):1.

[0038] Preferably, the first chlorination reaction is carried out in the presence of a solvent.

[0039] Preferably, the solvent for the first chlorination reaction includes an aromatic hydrocarbon solvent, and more preferably toluene and / or xylene.

[0040] Preferably, the mass ratio of the 5-chloro-2-hydroxy-3-nitrobenzoic acid to the solvent is 1:(0.5-3.0), such as 1:0.8, 1:1.0, 1:1.5, 1:2.0 or 1:3.0, and more preferably 1:(1.0-2.0).

[0041] Preferably, the temperature of the first chlorination reaction is 40-150°C, for example, 45°C, 50°C, 60°C, 100°C, 130°C or 150°C, and more preferably 50-140°C.

[0042] Preferably, the first chlorination reaction time is 1-8 h, for example, 2 h, 3 h, 5 h, 6 h or 7 h, and more preferably 2-6 h.

[0043] Preferably, the fluorination reaction is carried out in the presence of a fluorination agent, and the fluorination agent includes potassium fluoride and / or cesium fluoride, and potassium fluoride is more preferred.

[0044] Preferably, the molar ratio of the fluorination agent to 2,5-dichloro-3-nitrobenzoyl chloride is (2.0-4.0):1, for example, it can be 2.2:1, 2.8:1, 3.0:1, 3.2:1, 3.5:1 or 4.0:1, and more preferably (3.0-3.5):1.

[0045] Preferably, the fluorination reaction is carried out in the presence of a phase transfer catalyst.

[0046] Preferably, the phase transfer catalyst comprises any one of 18-crown-6, tetramethylammonium chloride, tetramethylammonium bromide, tetrabutylammonium bromide, and hexadecyltrimethylammonium chloride, or a combination of at least two thereof, and 18-crown-6 and / or tetramethylammonium chloride are further preferred.

[0047] Preferably, based on the mass of 2,5-dichloro-3-nitrobenzoyl chloride as 100%, the mass of the phase transfer catalyst is ≤5.0%, preferably 0.1-5.0%, for example, it can be 0.2%, 0.5%, 1.0%, 1.5%, 2.5%, 3.0%, 3.5% or 4.5%, and more preferably 1.0-1.5%.

[0048] Preferably, the fluorination reaction is carried out in the presence of a solvent.

[0049] Preferably, the solvent for the fluorination reaction includes an aromatic hydrocarbon solvent, more preferably toluene and / or xylene.

[0050] Preferably, the mass ratio of the solvent for the fluorination reaction to 2,5-dichloro-3-nitrobenzoyl chloride is (0.5-3.0):1, for example, it can be 0.8:1, 1.0:1, 1.5:1, 2.0:1, 2.2:1, 2.8:1, etc., and more preferably (0.5-1.5):1.

[0051] Preferably, the temperature of the fluorination reaction is 60-150°C, for example, 70°C, 80°C, 100°C, 120°C, 130°C or 150°C, and more preferably 80-130°C.

[0052] Preferably, the fluorination reaction time is 5-30 h, for example, 5 h, 8 h, 10 h, 14 h, 18 h, 20 h or 28 h, and more preferably 5-24 h.

[0053] Preferably, after the fluorination reaction is completed, a post-treatment step is further included, and the post-treatment method is: filtering the reaction solution obtained by the fluorination reaction, and performing desolventizing and reduced pressure distillation on the obtained filtrate to obtain 5-chloro-2-fluoro-3-nitrobenzoyl fluoride.

[0054] Preferably, the desolventizing pressure is 2-5 kPa, for example, 2.5 kPa, 3.5 kPa or 4.5 kPa.

[0055] Preferably, the pressure of the reduced pressure distillation is 20-500 Pa, for example, it may be 50 Pa, 150 Pa, 200 Pa, 300 Pa, 350 Pa or 450 Pa.

[0056] Preferably, the yield of the 5-chloro-2-fluoro-3-nitrobenzoyl fluoride, i.e., the total yield of the first chlorination reaction and the fluorination reaction, is ≥88.7%; and the content of the 5-chloro-2-fluoro-3-nitrobenzoyl fluoride is ≥98.4%.

[0057] Preferably, Z is chlorine, and the substitution reaction in step (1) is also called the "second route", comprising a first chlorination reaction, a fluorination reaction, a hydrolysis reaction, and a second chlorination reaction performed in sequence to obtain 5-chloro-2-fluoro-3-nitrobenzoyl chloride, and the reaction formula is as follows:

[0058]

[0059] In the second route, the 5-chloro-2-hydroxy-3-nitrobenzoic acid undergoes a first chlorination reaction to obtain 2,5-dichloro-3-nitrobenzoyl chloride; the 2,5-dichloro-3-nitrobenzoyl chloride undergoes a fluorination reaction to obtain 5-chloro-2-fluoro-3-nitrobenzoyl fluoride; the 5-chloro-2-fluoro-3-nitrobenzoyl fluoride undergoes a hydrolysis reaction to obtain 5-chloro-2-fluoro-3-nitrobenzoic acid; the 5-chloro-2-fluoro-3-nitrobenzoic acid undergoes a second chlorination reaction to obtain 5-chloro-2-fluoro-3-nitrobenzoyl chloride.

[0060] It should be noted that the first chlorination reaction and the fluorination reaction in the second route have the same raw materials, dosages, process steps and parameters as those in the first route, and for the sake of brevity, they will not be described one by one.

[0061] Preferably, the hydrolysis reaction is carried out in the presence of a basic compound.

[0062] Preferably, the alkaline compound comprises sodium hydroxide and / or potassium hydroxide.

[0063] Preferably, the molar ratio of the basic compound to 5-chloro-2-fluoro-3-nitrobenzoyl fluoride is (1.0-5.0):1, for example, it can be 1.5:1, 2.0:1, 3.0:1, 3.5:1, 4.5:1, etc.

[0064] Preferably, the hydrolysis reaction is carried out in an aqueous medium comprising a combination of water and an alcohol solvent.

[0065] Preferably, the alcohol solvent includes any one of methanol, ethanol, n-propanol, isopropanol, or a combination of at least two of them, and methanol is more preferred.

[0066] Preferably, the hydrolysis reaction method comprises: mixing 5-chloro-2-fluoro-3-nitrobenzoyl fluoride with an alcohol solvent, adding an aqueous solution of an alkaline compound thereto, and performing a hydrolysis reaction to obtain 5-chloro-2-fluoro-3-nitrobenzoic acid.

[0067] Preferably, the hydrolysis reaction time is 0.5-5 h, for example, 1 h, 2 h, 2.5 h, 3 h, 3.5 h or 4.5 h.

[0068] Preferably, the temperature of the hydrolysis reaction is 50-90°C, for example, 50°C, 60°C, 70°C, 80°C or 90°C, etc., more preferably 80°C.

[0069] Preferably, after the hydrolysis reaction is completed, a post-treatment step is further included, and the post-treatment method includes: adjusting the pH value of the reaction solution obtained by the hydrolysis reaction to 3-5 (for example, 3.2, 3.8, 4, 4.2 or 4.8, etc.), and then crystallizing, solid-liquid separation and drying to obtain 5-chloro-2-fluoro-3-nitrobenzoic acid.

[0070] Preferably, the solid-liquid separation method is filtration.

[0071] Preferably, the post-treatment further comprises a recrystallization and / or washing step to purify the product 5-chloro-2-fluoro-3-nitrobenzoic acid.

[0072] Preferably, the second chlorination reaction is carried out in the presence of a second chlorination reagent, which includes any one of thionyl chloride, triphosgene, oxalyl chloride, phosphorus trichloride, and phosphorus pentachloride, or a combination of at least two thereof, and thionyl chloride and / or triphosgene are further preferred.

[0073] Preferably, the molar ratio of the second chlorination reagent to 5-chloro-2-fluoro-3-nitrobenzoic acid is (0.3-3.0):1, for example, it can be 0.5:1, 0.8:1, 1.0:1, 1.5:1, 2.0:1, 2.2:1 or 2.8:1, and more preferably (0.5-2.0):1.

[0074] Preferably, the second chlorination reaction is carried out in the presence of a second chlorination catalyst.

[0075] Preferably, the second chlorination catalyst comprises N,N-dimethylformamide and / or pyridine.

[0076] Preferably, based on 100% of the mass of 5-chloro-2-fluoro-3-nitrobenzoic acid, the mass of the second chlorination catalyst is 0.1-1%, for example, 0.2%, 0.4%, 0.5%, 0.7%, 0.8% or 0.9%.

[0077] Preferably, the second chlorination reaction is carried out in the presence of a solvent.

[0078] Preferably, the solvent for the second chlorination reaction includes an aromatic hydrocarbon solvent, and more preferably toluene and / or xylene.

[0079] Preferably, the mass ratio of the solvent of the second chlorination reaction to 5-chloro-2-fluoro-3-nitrobenzoic acid is (0.5-3.0):1, for example, it can be 0.6:1, 1.0:1, 1.5:1, 2.0:1, 3.0:1, etc., and more preferably (1.0-2.0):1.

[0080] Preferably, the temperature of the second chlorination reaction is 40-150°C, for example, 45°C, 60°C, 80°C, 110°C, 130°C or 150°C, and more preferably 50-140°C.

[0081] Preferably, the second chlorination reaction time is 1-8 h, for example, 2 h, 3 h, 4 h, 5 h, 6 h or 7 h, and more preferably 2-6 h.

[0082] Preferably, the molar ratio of the 5-chloro-2-fluoro-3-nitrobenzoyl halide to the aniline compound is (1.0-1.5):1, for example, it can be 1.1:1, 1.3:1 or 1.4:1, and more preferably (1.1-1.3):1.

[0083] Preferably, the amide reaction is carried out in the presence of a solvent.

[0084] Preferably, the solvent for the amide reaction includes an aromatic hydrocarbon solvent, and more preferably toluene and / or xylene.

[0085] Preferably, the mass ratio of the 5-chloro-2-fluoro-3-nitrobenzoyl halide to the solvent is 1:(2.0-4.5), for example, it can be 1:2.0, 1:2.5, 1:2.8, 1:3.2, 1:3.5, 1:4.0 or 1:4.3, and more preferably 1:(2.0-4.0).

[0086] Preferably, the temperature of the amide reaction is 40-150°C, for example, 50°C, 60°C, 80°C, 100°C, 120°C, 140°C or 150°C, and more preferably 110-140°C.

[0087] Preferably, the amide reaction time is 3-7 h, for example, 3.5 h, 4.5 h, 5 h, 6 h or 7 h, and more preferably 4-6 h.

[0088] Preferably, after the amide reaction is completed, a post-treatment step is further included, and the post-treatment method includes: mixing the product of the amide reaction with an alkali solution, separating the liquids, and retaining the organic phase; crystallizing the organic phase, separating the solid and the liquid, and obtaining the solid as the 3-nitro-2-fluorobenzamide compound.

[0089] Preferably, the alkali solution is an aqueous solution of an alkaline compound, and the alkaline compound includes any one or a combination of at least two of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, and alkaline earth metal bicarbonates, and sodium hydroxide and / or sodium carbonate are further preferred.

[0090] Preferably, the mixing temperature is 60-100°C, for example, 65°C, 75°C, 80°C, 90°C or 95°C.

[0091] Preferably, the mixing time is 10-40 min, for example, 15 min, 18 min, 23 min, 28 min, 30 min or 38 min.

[0092] Preferably, the crystallization temperature is 0-5°C, for example, 0.5°C, 2°C, 4°C or 4.5°C.

[0093] Preferably, the crystallization time is 1-3 h, for example, 1.3 h, 1.5 h, 2 h, 2.3 h or 2.8 h.

[0094] Preferably, the solid-liquid separation method is filtration.

[0095] Preferably, the post-treatment method further comprises washing and / or drying steps.

[0096] Preferably, the yield of the 3-nitro-2-fluorobenzamide compound obtained in step (2) is ≥94.5%; and the content of the 3-nitro-2-fluorobenzamide compound is ≥97.7%.

[0097] Preferably, the reducing agent for the reduction reaction is hydrogen.

[0098] Preferably, the pressure after the hydrogen is introduced into the reduction reaction is 1.5-3.0 MPa, for example, 1.8 MPa, 2.2 MPa, 2.5 MPa or 2.8 MPa, etc., more preferably 2.0-2.5 MPa.

[0099] Preferably, the reduction reaction is carried out in the presence of a reduction catalyst.

[0100] Preferably, the reduction catalyst comprises any one of platinum carbon, palladium carbon, and Raney nickel, or a combination of at least two thereof, and palladium carbon is more preferred.

[0101] Preferably, the mass percentage of the effective ingredient (specifically metal, such as platinum, palladium, nickel) in the reduction catalyst is ≥10%, and more preferably 10% palladium carbon, where 10% represents the mass percentage of palladium in palladium carbon.

[0102] Preferably, the mass ratio of the 3-nitro-2-fluorobenzamide compound to the reduction catalyst is 1:(0.001-0.01), for example, it can be 1:0.002, 1:0.004, 1:0.005, 1:0.006, 1:0.007 or 1:0.009, and more preferably 1:(0.003-0.006).

[0103] Preferably, the reduction reaction is carried out in the presence of an acid binding agent.

[0104] Preferably, the acid binding agent comprises any one of triethylamine, tri-n-propylamine, diisopropylethylamine, tert-butylamine, triethylenediamine, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium bicarbonate, sodium methoxide, potassium methoxide, potassium tert-butoxide, sodium tert-butoxide, and sodium acetate, or a combination of at least two thereof, and triethylamine and / or sodium acetate are further preferred.

[0105] Preferably, the molar ratio of the 3-nitro-2-fluorobenzamide compound to the acid binding agent is 1:(0.8-2.0), for example, it can be 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.4, 1:1.5, 1:1.7, 1:1.8 or 1:1.9, etc.

[0106] Preferably, the reduction reaction is carried out in the presence of a solvent.

[0107] Preferably, the solvent for the reduction reaction includes any one of an alcohol solvent, an alcohol aqueous solution, and an acidic aqueous solution, or a combination of at least two of them.

[0108] Preferably, the alcohol solvent includes methanol.

[0109] Preferably, the alcohol aqueous solution includes methanol aqueous solution. Preferably, the mass percentage of methanol in the methanol aqueous solution is ≥ 60%, for example, it can be 65%, 70%, 75%, 80%, 85%, 90%, 95%, etc., and 80% methanol aqueous solution is more preferred.

[0110] Preferably, the acidic aqueous solution comprises an acetic acid aqueous solution. Preferably, the mass percentage of acetic acid in the acetic acid aqueous solution is ≥ 60%, for example, it can be 65%, 70%, 75%, 80%, 85%, 90%, 95%, etc., and 80% acetic acid aqueous solution is further preferred.

[0111] Preferably, the mass ratio of the 3-nitro-2-fluorobenzamide compound to the solvent is 1:(1.0-5.0), for example, it can be 1:1.2, 1:2.0, 1:2.5, 1:4.0 or 1:4.8.

[0112] Preferably, the temperature of the reduction reaction is 25-120°C, for example, 30°C, 50°C, 80°C, 90°C or 110°C, and more preferably 60-80°C.

[0113] Preferably, the reduction reaction time is 8-16 h, for example, 9 h, 11 h, 12 h, 13 h or 15 h, and more preferably 10-14 h.

[0114] In a preferred technical solution, the process route of the preparation method is as follows:

[0115] Preferably, the method comprises the following steps:

[0116] (1) 5-chloro-2-hydroxy-3-nitrobenzoic acid and a first chlorination reagent are subjected to a first chlorination reaction in the presence of a first chlorination catalyst to obtain 2,5-dichloro-3-nitrobenzoyl chloride; the molar ratio of the first chlorination reagent to 5-chloro-2-hydroxy-3-nitrobenzoic acid is (0.67-3.0):1; the molar ratio of the first chlorination catalyst to 5-chloro-2-hydroxy-3-nitrobenzoic acid is (1.0-5.0):1; the temperature of the first chlorination reaction is 40-150° C., and the time is 1-8 hours;

[0117] The 2,5-dichloro-3-nitrobenzoyl chloride and the fluorinating agent are subjected to a fluorination reaction in the presence of a phase transfer catalyst to obtain 5-chloro-2-fluoro-3-nitrobenzoyl fluoride; the molar ratio of the fluorinating agent to the 2,5-dichloro-3-nitrobenzoyl chloride is (2.0-4.0):1; the mass ratio of the phase transfer catalyst to the 2,5-dichloro-3-nitrobenzoyl chloride is (0.1%-5.0%):100%; the temperature of the fluorination reaction is 60-150° C., and the time is 0.5-30h;

[0118] (2) the 5-chloro-2-fluoro-3-nitrobenzoyl fluoride obtained in step (1) is subjected to an amide reaction with an aniline compound to obtain a 3-nitro-2-fluorobenzamide compound; the molar ratio of the 5-chloro-2-fluoro-3-nitrobenzoyl fluoride to the aniline compound is (1.0-1.5):1; the temperature of the amide reaction is 40-150° C., and the time is 3-7 hours;

[0119] (3) The 3-nitro-2-fluorobenzamide compound obtained in step (2) is subjected to a reduction reaction with hydrogen in the presence of a reduction catalyst and an acid binding agent to obtain the 3-amino-2-fluorobenzamide compound; the mass ratio of the 3-nitro-2-fluorobenzamide compound to the reduction catalyst is 1:(0.001-0.01), and the molar ratio of the 3-nitro-2-fluorobenzamide compound to the acid binding agent is 1:(0.8-2.0); the pressure after the hydrogen is introduced into the reduction reaction is 1.5-3.0 MPa; the temperature of the reduction reaction is 25-120° C., and the time is 8-16 h.

[0120] In another preferred technical solution, the process route of the preparation method is as follows:

[0121] Preferably, the method specifically comprises the following steps:

[0122] (1) 5-chloro-2-hydroxy-3-nitrobenzoic acid and a first chlorination reagent are subjected to a first chlorination reaction in the presence of a first chlorination catalyst to obtain 2,5-dichloro-3-nitrobenzoyl chloride; the molar ratio of the first chlorination reagent to 5-chloro-2-hydroxy-3-nitrobenzoic acid is (0.67-3.0):1; the molar ratio of the first chlorination catalyst to 5-chloro-2-hydroxy-3-nitrobenzoic acid is (1.0-5.0):1; the temperature of the first chlorination reaction is 40-150° C., and the time is 1-8 hours;

[0123] The 2,5-dichloro-3-nitrobenzoyl chloride and the fluorinating agent are subjected to a fluorination reaction in the presence of a phase transfer catalyst to obtain 5-chloro-2-fluoro-3-nitrobenzoyl fluoride; the molar ratio of the fluorinating agent to the 2,5-dichloro-3-nitrobenzoyl chloride is (2.0-4.0):1; the mass ratio of the phase transfer catalyst to the 2,5-dichloro-3-nitrobenzoyl chloride is (0.1%-5.0%):100%; the temperature of the fluorination reaction is 60-150° C., and the time is 0.5-30h;

[0124] The 5-chloro-2-fluoro-3-nitrobenzoyl fluoride is hydrolyzed in the presence of an alkaline compound to obtain 5-chloro-2-fluoro-3-nitrobenzoic acid; the molar ratio of the alkaline compound to 5-chloro-2-fluoro-3-nitrobenzoyl fluoride is (1.0-5.0):1; the hydrolysis reaction time is 0.5-5h;

[0125] The 5-chloro-2-fluoro-3-nitrobenzoic acid and the second chlorinating agent undergo a second chlorination reaction to obtain 5-chloro-2-fluoro-3-nitrobenzoyl chloride; the molar ratio of the 5-chloro-2-fluoro-3-nitrobenzoic acid to the second chlorinating agent is 1:(0.3-3.0); the temperature of the second chlorination reaction is 40-150° C., and the time is 1-8 hours;

[0126] (2) the 5-chloro-2-fluoro-3-nitrobenzoyl chloride obtained in step (1) is subjected to an amide reaction with an aniline compound to obtain a 3-nitro-2-fluorobenzamide compound; the molar ratio of the 5-chloro-2-fluoro-3-nitrobenzoyl chloride to the aniline compound is (1.0-1.5):1; the temperature of the amide reaction is 40-150° C., and the time is 3-7 hours;

[0127] (3) The 3-nitro-2-fluorobenzamide compound obtained in step (2) is subjected to a reduction reaction with hydrogen in the presence of a reduction catalyst and an acid binding agent to obtain the 3-amino-2-fluorobenzamide compound; the mass ratio of the 3-nitro-2-fluorobenzamide compound to the reduction catalyst is 1:(0.001-0.01), and the molar ratio of the 3-nitro-2-fluorobenzamide compound to the acid binding agent is 1:(0.8-2.0); the pressure after the hydrogen is introduced into the reduction reaction is 1.5-3.0 MPa; the temperature of the reduction reaction is 25-120° C., and the time is 8-16 h.

[0128] As a preferred technical solution of the present invention, the yield of the target product 3-amino-2-fluorobenzamide compounds is ≥96.5%; and the content of the 3-amino-2-fluorobenzamide compounds is ≥97.4%.

[0129] In a second aspect, the present invention provides a 3-nitro-2-fluorobenzamide compound, wherein the 3-nitro-2-fluorobenzamide compound has a structure as shown in Formula IV:

[0130]

[0131] In formula IV, Y is selected from any one of unsubstituted or halogenated C1-C6 (C1, C2, C3, C4, C5 or C6) straight or branched alkyl, and unsubstituted or halogenated C1-C6 (C1, C2, C3, C4, C5 or C6) alkoxy.

[0132] In formula IV, R is selected from any one of hydrogen, fluorine or methoxy.

[0133] The 3-nitro-2-fluorobenzamide compound is prepared by the preparation method described in the first aspect.

[0134] Preferably, Y is selected from any one of C1-C6 straight or branched alkyl, C1-C3 haloalkyl, C1-C6 alkoxy, C1-C3 haloalkoxy, further preferably any one of methyl, ethyl, trifluoromethyl, pentafluoroethyl, heptafluoroisopropyl, trifluoromethoxy or difluoromethoxy, further preferably any one of methyl, trifluoromethyl or trifluoromethoxy.

[0135] Preferably, R is hydrogen or fluorine.

[0136] Compared with the prior art, the present invention has the following beneficial effects:

[0137] The preparation method provided by the invention uses 5-chloro-2-hydroxy-3-nitrobenzoic acid as a raw material, and obtains a target product 3-amino-2-fluorobenzamide compound through substitution reaction, amide reaction with an aniline compound, and reduction reaction. The raw material is cheap, the multi-step reaction is almost a quantitative reaction, the by-products are small, the yield of the target product is high, and the total yield is as high as 75%-84%. Moreover, the process conditions are mild, and harsh reaction conditions such as deep cooling and high temperature are avoided, so the method is more suitable for industrial production. DETAILED DESCRIPTION

[0138] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0139] In the following specific embodiments of the present invention, all raw materials involved are purchased from the market; the contents of all intermediates and products are measured by high performance liquid chromatography (HPLC) external standard method, and the yield is molar yield.

[0140] Example 1

[0141] This embodiment provides a 3-amino-2-fluorobenzamide compound ( The preparation method of compound 1 is as follows:

[0142] The specific steps are as follows:

[0143] (1) 88.8 g (purity: 98%, 0.4 mol) of 5-chloro-2-hydroxy-3-nitrobenzoic acid was weighed and added into a 500 mL three-necked round-bottom flask. 89.0 g of toluene, 29.2 g of N,N-dimethylformamide (DMF, purity: 99.5%, 0.4 mol) and 114.2 g of thionyl chloride (purity: 99%, 0.96 mol) were added thereto. The temperature was raised to 100° C. and the reaction was continued for 2 h. The solvent was removed under reduced pressure to obtain 107.8 g of 2,5-dichloro-3-nitrobenzoyl chloride with a content of 94.43%, which was directly used in the next step.

[0144] (2) 81.2 g KF (purity: 99%, 1.4 mol) and 1.62 g 18-crown ether-6 (purity: 99%) were added to a 500 mL three-necked round-bottom flask in sequence to obtain a KF / catalyst system; 107.8 g 2,5-dichloro-3-nitrobenzoyl chloride (content: 94.43%) obtained in step (1) was added to 75 g toluene to dissolve, and then poured into the above KF / catalyst system, stirred and heated to 80° C. for reaction, reacted for 20 h, cooled to room temperature, filtered, and the filter cake was washed twice with 100 g toluene. The filtrate was decompressed and toluene was recovered at 2 kPa. The residue was further decompressed and distilled at 250 Pa to collect the 90° C.-100° C. fraction to obtain 80.0 g 5-chloro-2-fluoro-3-nitrobenzoyl fluoride, with a content of 98.77% and a yield of 89.2% (total yield of two steps). 1 The H NMR (400 MHz, CDCl 3 ) data are as follows (δ [ppm]): 8.59 (s, 1H), 8.33 (s, 1H).

[0145] (3) 78.4 g (content of 98.77%, 0.35 mol, 1.0 eq) of 5-chloro-2-fluoro-3-nitrobenzoyl fluoride obtained in step (2) and methanol (200 mL) were added sequentially to a 500 mL reaction kettle, and a 30% aqueous sodium hydroxide solution (140 g, wherein the sodium hydroxide content was 1.05 mol, 3.0 eq) was added dropwise. After the addition was completed, the mixture was stirred at 80° C. for 2 h, and the reaction was monitored by thin layer chromatography (TLC) until completion. The solvent was removed under reduced pressure, 200 mL of water was added, the temperature was lowered to 5° C., 30% hydrochloric acid was added dropwise until the pH value was 3.2, the mixture was stirred and crystallized for 2 h at the temperature, and filtered by suction. The filter cake was rinsed with water and dried to obtain 72.9 g of white solid 5-chloro-2-fluoro-3-nitrobenzoic acid, with a content of 98.6% and a yield of 93.6%. 1 H NMR (400 MHz, CDCl 3 ) data are as follows (δ [ppm]): 12.75 (s, 1H), 8.55 (d, J = 6.8 Hz, 1H), 8.49 (d, J = 6.8 Hz, 1H).

[0146] (4) Weigh 66.8 g (content of 98.6%, 0.3 mol) of 5-chloro-2-fluoro-3-nitrobenzoic acid obtained in step (3) and add it into a 500 mL three-necked round-bottom flask, add 74.0 g of toluene, 0.2 g of pyridine and 0.2 g of DMF, raise the temperature to 50° C., add a toluene solution of triphosgene (44.6 g of triphosgene, purity of 99%, 0.15 mol, 60 g of toluene) dropwise, and add for 2 h. After the addition, keep the mixture at 50° C. for 6 h, remove the solvent under reduced pressure, and obtain 74.3 g of 5-chloro-2-fluoro-3-nitrobenzoyl chloride with a content of 96.10%, which is directly used in the next step.

[0147] (5) 61.9 g (content of 96.10%, 0.25 mol) of 5-chloro-2-fluoro-3-nitrobenzoyl chloride obtained in step (4), 63.2 g (purity of 98.9%, 0.19 mol) of compound 1A, and 186 g of xylene were added to a 500 mL reactor in sequence, and the mixture was heated to 140° C. for reaction for 6 h. After cooling slightly, 40 g of 10% aqueous sodium hydroxide solution was slowly added, and the mixture was stirred at 80° C. for 30 min. After hot separation, the organic layer was cooled to room temperature, and then placed in an ice machine and stirred at 5° C. for 3 h. After filtration and drying, 98.5 g of yellow solid compound 1B was obtained, with a content of 98.34% and a yield of 96.1%. 1 H NMR (400 MHz, DMSO-d6) data are as follows (δ [ppm]): 10.84 (s, 1H), 8.47-8.49 (m, 1H), 8.16-8.21 (m, 2H), 8.04-8.07 (m, 1H), 7.96 (s, 1H).

[0148] (6) Into a 1 L autoclave, 86.3 g (content of 98.34%, 0.16 mol) of compound 1B obtained in step (5), 13.1 g (purity of 99.9%, 0.16 mol), 0.26 g of 10% palladium carbon catalyst and 259 g of methanol were added in sequence, and hydrogen was introduced until the pressure in the autoclave reached 2.0 MPa. The reaction was carried out at 60° C. for 10 h, filtered, and the filtrate was concentrated to obtain a blue-gray solid. After drying, the target compound 1 (74.8 g, content of 97.6%, yield of 97.9%) was obtained. LC / MS [M+1]: m / z=467.0612; 1 H NMR (400 MHz, DMSO-d6) data are as follows (δ [ppm]): 10.14 (s, 1H), 8.16–8.03 (m, 2H), 7.93 (s, 1H), 7.07–6.92 (m, 2H), 6.86 (t, J=5.8 Hz, 1H), 5.43 (s, 2H).

[0149] Example 2

[0150] This embodiment provides a 3-amino-2-fluorobenzamide compound ( The preparation method of compound 2 is as follows:

[0151] The specific steps are as follows:

[0152] Steps (1) to (4) adopt the same synthetic route as steps (1) to (4) in Example 1, and the only difference from Example 1 is the type, amount and process parameters of some raw materials, see Table 1 for details; the raw materials and process parameters not shown in Table 1 are the same as those in Example 1.

[0153] (5) 62.3 g (content of 95.46%, 0.25 mol) of 5-chloro-2-fluoro-3-nitrobenzoyl chloride obtained in step (4), 58.5 g (purity of 98.76%, 0.21 mol) and 156 g of xylene were added to a 500 mL reactor in sequence, heated to 130° C. for reaction for 4 h, cooled to 110° C. and then slowly added with 40 g of 10% sodium hydroxide aqueous solution, stirred at 80° C. for 30 min, and the organic layer was cooled to room temperature after hot separation, and then placed in an ice machine at 5° C. and stirred for 3 h. After filtration and drying, 95.84 g of yellow solid compound 2B was obtained, with a content of 98.66% and a yield of 94.5%. 1 H NMR (400 MHz, DMSO-d6) data are as follows (δ [ppm]): 10.23 (s, 1H), 7.38 (s, 1H), 7.34–7.31 (m, 2H), 7.25–7.26 (m, 2H), 2.25 (s, 3H).

[0154] (6) Into a 1 L autoclave, 77.3 g (content of 98.66%, 0.16 mol) of the compound 2B obtained in step (5), 16.2 g (purity of 99.5%, 0.16 mol), 0.46 g of a 10% palladium-carbon catalyst, and 232 g of an 80% methanol aqueous solution were added in sequence, and hydrogen was introduced until the pressure in the autoclave reached 2.2 MPa. The reaction was carried out at 65° C. for 14 h, and the mixture was filtered. The filtrate was concentrated to obtain a gray solid, which was dried to obtain the target compound 2 (64.9 g, content of 98.2%, yield of 96.7%), LC / MS [M+1]: m / z=413.0894; 1 H NMR (400 MHz, DMSO-d6) data are as follows (δ [ppm]): 9.89 (s, 1H), 7.60–7.47 (m, 1H), 7.34 (s, 1H), 7.33 (d, J = 6.1 Hz, 1H), 7.23 (d, J = 5.8 Hz, 1H), 7.06-7.03 (m, 2H), 5.32 (s, 2H), 2.16 (s, 3H).

[0155] Example 3

[0156] This embodiment provides a 3-amino-2-fluorobenzamide compound ( The preparation method of compound 3 is as follows:

[0157] The specific steps are as follows:

[0158] Steps (1) to (4) adopt the same synthetic route as steps (1) to (4) in Example 1, and the only difference from Example 1 is the type, amount and process parameters of some raw materials, see Table 1 for details; the raw materials and process parameters not shown in Table 1 are the same as those in Example 1.

[0159] (5) 61.8 g (content of 96.34%, 0.25 mol) of 5-chloro-2-fluoro-3-nitrobenzoyl chloride obtained in step (4), 76.4 g (purity of 98.44%, 0.23 mol) and 124 g of xylene were added to a 500 mL reactor in sequence, heated to 130° C. for reaction for 5 h, cooled to 110° C., slowly added with 40 g of 10% sodium hydroxide aqueous solution, stirred at 80° C. for 30 min, separated while hot, cooled the organic layer to room temperature, then placed in an ice machine and stirred at 5° C. for 3 h, filtered and dried to obtain 118.3 g of yellow solid compound 3B with a content of 97.72% and a yield of 95.1%. 1H NMR (400 MHz, CDCl3) data are as follows (δ [ppm]): 10.23 (s, 1H), 8.44-8.46 (m, 1H), 8.30-8.33 (m, 1H), 7.79 (d, J = 6.4 Hz, 1H), 7.11 (s, 1H), 6.98 (s, 1H), 6.88-6.85 (m, 1H).

[0160] (6) Into a 1 L autoclave, 108.1 g (content of 97.72%, 0.2 mol) of compound 3B obtained in step (5), 20.2 g (purity of 99.5%, 0.2 mol), 0.65 g of 10% palladium carbon catalyst and 215 g of 80% methanol aqueous solution were added in sequence, and hydrogen was introduced until the pressure in the autoclave reached 2.2 MPa. The reaction was carried out at 65° C. for 10 h, filtered, and the filtrate was concentrated to obtain a blue-gray solid. After drying, the target compound 3 (92.9 g, content of 97.4%, yield of 97.5%) was obtained. LC / MS [M+1]: m / z=465.0655; 1 H NMR (400 MHz, DMSO-d6) data are as follows (δ [ppm]): 10.56 (s, 1H), 7.65–7.60 (m, 2H), 7.06–7.03 (m, 2H), 7.11 (s, 1H), 6.98–6.88 (m, 2H), 5.32 (s, 2H).

[0161] Table 1

[0162]

[0163]

[0164]

[0165] Example 4

[0166] This embodiment provides a 3-amino-2-fluorobenzamide compound ( The preparation method of compound 4 is as follows:

[0167] The specific steps are as follows:

[0168] (1) 88.8 g (purity: 98%, 0.4 mol) of 5-chloro-2-hydroxy-3-nitrobenzoic acid was weighed and added into a 500 mL three-necked round-bottom flask. 89.0 g of xylene, 29.2 g of DMF (purity: 99.5%, 0.4 mol) and 99.9 g of thionyl chloride (purity: 99%, 0.84 mol) were added thereto. The temperature was raised to reflux for reaction for 3 h. The solvent was removed under reduced pressure to obtain 105.3 g of 2,5-dichloro-3-nitrobenzoyl chloride with a content of 96.67%, which was directly used in the next step.

[0169] (2) 81.2 g KF (purity: 99%, 1.4 mol) and 1.1 g tetramethylammonium chloride (purity: 99%) were added to a 500 mL three-necked round-bottom flask in order to obtain a KF / catalyst system; 105.3 g (content: 96.67%) of 2,5-dichloro-3-nitrobenzoyl chloride obtained in step (1) was added to 75 g of toluene to dissolve, and then poured into the above KF / catalyst system, stirred and heated to 100° C. for reaction for 10 h, cooled to room temperature, filtered, and the filter cake was washed twice with 100 g of toluene. The filtrate was reduced pressure at 5 kPa to recover toluene, and the residue was further distilled under reduced pressure at 250 Pa, and the 90° C.-100° C. fraction was collected to obtain 80.4 g of product 5-chloro-2-fluoro-3-nitrobenzoyl fluoride, with a content of 98.90% and a yield of 89.7% (total yield of two steps).

[0170] (3) 47.0 g (content of 98.90%, 0.21 mol) of 5-chloro-2-fluoro-3-nitrobenzoyl fluoride obtained in step (2), 46.0 g (purity of 97.80%, 0.175 mol) of compound 4A, and 141 g of xylene were added to a 500 mL reactor in sequence, heated to 130° C. for reaction for 5 h, cooled to 110° C., added with 40 g of 10% aqueous sodium hydroxide solution, stirred at 80° C. for 30 min, separated while hot, cooled the organic layer to room temperature, then placed in an ice machine and stirred at 0° C. for 3 h, filtered and dried to obtain 76.9 g of yellow solid compound 4B, with a content of 98.71% and a yield of 94.6%. 1 H NMR (400 MHz, DMSO-d6) data are as follows (δ [ppm]): 10.49 (s, 1H), 8.96 (m, 1H), 8.81 (m, 1H), 7.85 (d, J = 6.1 Hz, 1H), 7.60 (d, J = 7.0 Hz, 1H), 7.41-7.38 (m, 1H), 6.98 (s, 1H), 2.23 (s, 3H).

[0171] (4) Into a 1 L autoclave, 74.3 g (content: 98.71%, 0.16 mol) of compound 4B obtained in step (3), 0.34 g of 10% palladium-carbon catalyst, 223 g of 80% acetic acid aqueous solution and 13.1 g of sodium acetate (purity: 99.9%, 0.16 mol) were added in sequence, and hydrogen was introduced until the pressure in the autoclave reached 2.5 MPa. The reaction was carried out at 80° C. for 10 h, filtered, and the filtrate was concentrated to obtain a blue-gray solid. After drying, the target compound 4 (62.2 g, content: 97.9%, yield: 96.5%) was obtained. LC / MS [M+1]: m / z=395.0988; 1 H NMR (400 MHz, DMSO-d6) data are as follows (δ [ppm]): 10.64 (s, 1H), 8.63–8.60 (m, 1H), 8.42–8.38 (m, 1H), 7.66-7.63 (m, 1H), 7.33 (d, J = 5.9 Hz, 1H), 7.20 (d, J = 6.4 Hz, 1H), 7.10-7.06 (m, 1H), 6.43 (s, 1H), 5.32 (s, 2H), 2.71 (s, 3H).

[0172] Example 5

[0173] This embodiment provides a 3-amino-2-fluorobenzamide compound ( The preparation method of compound 5 is as follows:

[0174] The specific steps are as follows:

[0175] Steps (1) and (2) adopt the same synthesis route as steps (1) and (2) in Example 4, and the only difference from Example 4 is the type, amount and process parameters of some raw materials, see Table 2 for details; the raw materials and process parameters not shown in Table 2 are the same as those in Example 4.

[0176] (3) 47.3 g (content: 98.32%, 0.21 mol) of 5-chloro-2-fluoro-3-nitrobenzoyl fluoride obtained in step (2), 50.8 g (purity: 97.87%, 0.16 mol) of compound 5A, and 118 g of xylene were added to a 500 mL reactor in sequence, and the mixture was heated to 140° C. for reaction for 3 h. After cooling to 110° C., 40 g of 10% aqueous sodium hydroxide solution was added, and the mixture was stirred at 80° C. for 30 min. After hot separation, the organic layer was cooled to room temperature, and then placed in an ice machine and stirred at 0° C. for 3 h. After filtration and drying, 79.0 g of yellow solid compound 5B was obtained, with a content of 99.21% and a yield of 95.6%. 1H NMR (400 MHz, DMSO-d6) data are as follows (δ [ppm]): 10.48 (s, 1H), 8.96-8.94 (m, 1H), 8.81 (m, 1H), 7.89 (s, 1H), 7.55-7.50 (m, 2H), 6.94-6.92 (s, 1H).

[0177] (4) Into a 1 L autoclave, 77.5 g (content of 99.21%, 0.15 mol) of compound 5B obtained in step (3), 30.3 g (purity of 99.5%, 0.3 mol) of triethylamine, 0.39 g of 10% palladium carbon catalyst and 233 g of methanol were added in sequence, and hydrogen was introduced until the pressure in the autoclave reached 2.0 MPa. The reaction was carried out at 60° C. for 7 h, filtered, and the filtrate was concentrated to obtain a blue-gray solid. After drying, the target compound 5 (65.8 g, content of 98.4%, yield of 96.3%) was obtained. LC / MS [M+1]: m / z=449.0706; 1 H NMR (400 MHz, DMSO-d6) data are as follows (δ [ppm]): 10.25 (s, 1H), 8.44 (s, 1H), 8.33-8.30 (m, 1H), 8.19-8.15 (m, 2H), 7.57-7.53 (m, 2H), 7.16 (s, 1H), 5.66 (s, 2H).

[0178] Example 6

[0179] This embodiment provides a 3-amino-2-fluorobenzamide compound ( The preparation method of compound 6 is as follows:

[0180] The specific steps are as follows:

[0181] Steps (1) and (2) adopt the same synthesis route as steps (1) and (2) in Example 4, and the only difference from Example 4 is the type, amount and process parameters of some raw materials, see Table 2 for details; the raw materials and process parameters not shown in Table 2 are the same as those in Example 4.

[0182] (3) 47.1 g (content of 98.67%, 0.21 mol) of 5-chloro-2-fluoro-3-nitrobenzoyl fluoride obtained in step (2), 66.9 g (purity of 98.04%, 0.19 mol) of compound 6A and 94 g of xylene were added to a 500 mL reactor in sequence, heated to 120° C. for reaction for 5 h, cooled to 110° C., added with 40 g of 10% aqueous sodium carbonate solution, stirred at 80° C. for 30 min, separated while hot, cooled the organic layer to room temperature, then placed in an ice machine and stirred at 0° C. for 3 h, filtered and dried to obtain 101.2 g of yellow solid compound 6B with a content of 98.34% and a yield of 95.9%. 1 H NMR (400 MHz, DMSO-d6) data are as follows (δ [ppm]): 10.28 (s, 1H), 8.96–8.93 (m, 1H), 8.82–8.80 (m, 1H), 7.78 (d, J=6.3 Hz, 1H), 7.14 (s, 1H), 7.12-7.09 (m, 1H).

[0183] (4) Into a 1 L autoclave, 88.9 g (content of 98.34%, 0.16 mol) of compound 6B obtained in step (3), 13.1 g (purity of 99.9%, 0.16 mol), 0.54 g of 10% palladium carbon catalyst and 266 g of 80% acetic acid aqueous solution were added in sequence, and hydrogen was introduced until the pressure in the autoclave reached 2.5 MPa. The reaction was carried out at 75° C. for 10 h, filtered, and the filtrate was concentrated to obtain a blue-gray solid. After drying, the target compound 6 (76.6 g, content of 98.5%, yield of 97.8%) was obtained. LC / MS [M+1]: m / z=483.0561; 1 H NMR (400 MHz, DMSO-d6) data are as follows (δ [ppm]): 10.55 (s, 1H), 8.68 (d, J = 6.2 Hz, 1H), 8.60–8.57 (m, 1H), 8.12–8.10 (m, 2H), 8.06–8.03 (m, 2H), 5.13 (s, 2H).

[0184] Table 2

[0185]

[0186]

[0187] The applicant declares that the present invention illustrates the 3-amino-2-fluorobenzamide compounds and the preparation method thereof through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing 3-amino-2-fluorobenzamide compounds, characterized in that: The preparation method comprises the following steps: (1) 5-chloro-2-hydroxy-3-nitrobenzoic acid is subjected to substitution reaction to obtain 5-chloro-2-fluoro-3-nitrobenzoyl halide of the structure shown in formula I, and the reaction formula is as follows: Wherein, Z is fluorine or chlorine; (2) The 5-chloro-2-fluoro-3-nitrobenzoyl halide obtained in step (1) is subjected to an amide reaction with an aniline compound having a structure represented by formula II to obtain a 3-nitro-2-fluorobenzamide compound having a structure represented by formula III. The reaction formula is as follows: Wherein, Y is selected from any one of unsubstituted or halogenated C1-C6 straight or branched alkyl, and unsubstituted or halogenated C1-C6 alkoxy; R is selected from any one of hydrogen, fluorine or methoxy; (3) The 3-nitro-2-fluorobenzamide compound obtained in step (2) is subjected to a reduction reaction to obtain the 3-amino-2-fluorobenzamide compound of the structure shown in formula IV. The reaction formula is as follows:

2. The preparation method according to claim 1, characterized in that: The Z is fluorine, and the substitution reaction in step (1) comprises a first chlorination reaction and a fluorination reaction performed sequentially to obtain 5-chloro-2-fluoro-3-nitrobenzoyl fluoride, and the reaction formula is as follows: Preferably, the first chlorination reaction is carried out in the presence of a first chlorination reagent, wherein the first chlorination reagent comprises any one of thionyl chloride, triphosgene, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, or a combination of at least two thereof; Preferably, the molar ratio of the 5-chloro-2-hydroxy-3-nitrobenzoic acid to the first chlorination reagent is 1:(0.67-3.0), and more preferably 1:(0.7-2.4); Preferably, the first chlorination reaction is carried out in the presence of a first chlorination catalyst; Preferably, the first chlorination catalyst comprises N,N-dimethylformamide; Preferably, the molar ratio of the first chlorination catalyst to 5-chloro-2-hydroxy-3-nitrobenzoic acid is (1.0-5.0):1, more preferably (1.0-3.0):1; Preferably, the first chlorination reaction is carried out in the presence of a solvent; Preferably, the solvent comprises an aromatic hydrocarbon solvent, more preferably toluene and / or xylene; Preferably, the temperature of the first chlorination reaction is 40-150°C, more preferably 50-140°C; Preferably, the first chlorination reaction time is 1-8 h, more preferably 2-6 h.

3. The preparation method according to claim 2, characterized in that: The fluorination reaction is carried out in the presence of a fluoriding agent, wherein the fluoriding agent comprises potassium fluoride and / or cesium fluoride; Preferably, the molar ratio of the fluorination agent to 2,5-dichloro-3-nitrobenzoyl chloride is (2.0-4.0):1, more preferably (3.0-3.5):1; Preferably, the fluorination reaction is carried out in the presence of a phase transfer catalyst; Preferably, the phase transfer catalyst comprises any one of 18-crown-6, tetramethylammonium chloride, tetramethylammonium bromide, tetrabutylammonium bromide, and hexadecyltrimethylammonium chloride, or a combination of at least two thereof, and 18-crown-6 and / or tetramethylammonium chloride are further preferred; Preferably, based on the mass of 2,5-dichloro-3-nitrobenzoyl chloride being 100%, the mass of the phase transfer catalyst is 0.1-5.0%, and more preferably 1.0-1.5%; Preferably, the fluorination reaction is carried out in the presence of a solvent; Preferably, the solvent comprises an aromatic hydrocarbon solvent, more preferably toluene and / or xylene; Preferably, the temperature of the fluorination reaction is 60-150°C, more preferably 80-130°C; Preferably, the fluorination reaction time is 0.5-30 h, more preferably 5-24 h.

4. The preparation method according to claim 1, characterized in that: Wherein Z is chlorine, and the substitution reaction in step (1) comprises a first chlorination reaction, a fluorination reaction, a hydrolysis reaction, and a second chlorination reaction performed in sequence to obtain 5-chloro-2-fluoro-3-nitrobenzoyl chloride, and the reaction formula is as follows: Preferably, the hydrolysis reaction is carried out in the presence of a basic compound; Preferably, the alkaline compound comprises sodium hydroxide and / or potassium hydroxide; Preferably, the molar ratio of the basic compound to 5-chloro-2-fluoro-3-nitrobenzoyl fluoride is (1.0-5.0):1; Preferably, the hydrolysis reaction time is 0.5-5h.

5. The preparation method according to claim 4, characterized in that: The second chlorination reaction is carried out in the presence of a second chlorination reagent, wherein the second chlorination reagent comprises any one of thionyl chloride, triphosgene, oxalyl chloride, phosphorus trichloride, and phosphorus pentachloride, or a combination of at least two thereof; Preferably, the molar ratio of the second chlorination reagent to 5-chloro-2-fluoro-3-nitrobenzoic acid is (0.3-3.0):1, more preferably (0.5-2.0):1; Preferably, the second chlorination reaction is carried out in the presence of a second chlorination catalyst; Preferably, the second chlorination catalyst comprises N,N-dimethylformamide and / or pyridine; Preferably, based on 100% of the mass of 5-chloro-2-fluoro-3-nitrobenzoic acid, the mass of the second chlorination catalyst is 0.1-1%; Preferably, the second chlorination reaction is carried out in the presence of a solvent; Preferably, the solvent comprises an aromatic hydrocarbon solvent, more preferably toluene and / or xylene; Preferably, the temperature of the second chlorination reaction is 40-150°C, more preferably 50-140°C; Preferably, the second chlorination reaction time is 1-8 h, more preferably 2-6 h.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The molar ratio of the 5-chloro-2-fluoro-3-nitrobenzoyl halide to the aniline compound is (1.0-1.5):1; Preferably, the amide reaction is carried out in the presence of a solvent; Preferably, the solvent comprises an aromatic hydrocarbon solvent, more preferably toluene and / or xylene; Preferably, the temperature of the amide reaction is 40-150°C, more preferably 110-140°C; Preferably, the amide reaction time is 3-7h; Preferably, after the amide reaction is completed, a post-treatment step is further included, and the post-treatment method includes: mixing the product of the amide reaction with an alkali solution, separating the liquids, and retaining the organic phase; crystallizing the organic phase, separating the solid and the liquid, and obtaining the solid as the 3-nitro-2-fluorobenzamide compound; Preferably, the mixing temperature is 60-100°C; Preferably, the mixing time is 10-40 min; Preferably, the crystallization temperature is 0-5°C; Preferably, the crystallization time is 1-3h.

7. The preparation method according to any one of claims 1 to 6, characterized in that: The reducing agent of the reduction reaction is hydrogen; Preferably, the pressure after hydrogen is introduced into the reduction reaction is 1.5-3.0 MPa; Preferably, the reduction reaction is carried out in the presence of a reduction catalyst; Preferably, the reduction catalyst comprises any one of platinum carbon, palladium carbon, and Raney nickel, or a combination of at least two thereof; Preferably, the mass ratio of the 3-nitro-2-fluorobenzamide compound to the reduction catalyst is 1:(0.001-0.01), and more preferably 1:(0.003-0.006); Preferably, the reduction reaction is carried out in the presence of an acid binding agent; Preferably, the acid binding agent comprises any one of triethylamine, tri-n-propylamine, diisopropylethylamine, tert-butylamine, triethylenediamine, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium bicarbonate, sodium methoxide, potassium methoxide, potassium tert-butoxide, sodium tert-butoxide, and sodium acetate, or a combination of at least two thereof, and triethylamine and / or sodium acetate are further preferred; Preferably, the molar ratio of the 3-nitro-2-fluorobenzamide compound to the acid binding agent is 1:(0.8-2.0); Preferably, the reduction reaction is carried out in the presence of a solvent; Preferably, the solvent includes any one of an alcohol solvent, an alcohol aqueous solution, an acidic aqueous solution, or a combination of at least two thereof, and more preferably any one of methanol, a methanol aqueous solution, or an acetic acid aqueous solution, or a combination of at least two thereof; Preferably, the temperature of the reduction reaction is 25-120°C, more preferably 60-80°C; Preferably, the reduction reaction time is 8-16 hours.

8. The preparation method according to any one of claims 1 to 7, characterized in that: The preparation method specifically comprises the following steps: (1) 5-chloro-2-hydroxy-3-nitrobenzoic acid and a first chlorination reagent are subjected to a first chlorination reaction in the presence of a first chlorination catalyst to obtain 2,5-dichloro-3-nitrobenzoyl chloride; the molar ratio of the first chlorination reagent to 5-chloro-2-hydroxy-3-nitrobenzoic acid is (0.67-3.0):1; the molar ratio of the first chlorination catalyst to 5-chloro-2-hydroxy-3-nitrobenzoic acid is (1.0-5.0):1; the temperature of the first chlorination reaction is 40-150° C., and the time is 1-8 hours; The 2,5-dichloro-3-nitrobenzoyl chloride and the fluorinating agent are subjected to a fluorination reaction in the presence of a phase transfer catalyst to obtain 5-chloro-2-fluoro-3-nitrobenzoyl fluoride; the molar ratio of the fluorinating agent to the 2,5-dichloro-3-nitrobenzoyl chloride is (2.0-4.0):1; the mass ratio of the phase transfer catalyst to the 2,5-dichloro-3-nitrobenzoyl chloride is (0.1%-5.0%):100%; the temperature of the fluorination reaction is 60-150° C., and the time is 0.5-30h; (2) the 5-chloro-2-fluoro-3-nitrobenzoyl fluoride obtained in step (1) is subjected to an amide reaction with an aniline compound to obtain a 3-nitro-2-fluorobenzamide compound; the molar ratio of the 5-chloro-2-fluoro-3-nitrobenzoyl fluoride to the aniline compound is (1.0-1.5):1; the temperature of the amide reaction is 40-150° C., and the time is 3-7 hours; (3) The 3-nitro-2-fluorobenzamide compound obtained in step (2) is subjected to a reduction reaction with hydrogen in the presence of a reduction catalyst and an acid binding agent to obtain the 3-amino-2-fluorobenzamide compound; the mass ratio of the 3-nitro-2-fluorobenzamide compound to the reduction catalyst is 1:(0.001-0.01), and the molar ratio of the 3-nitro-2-fluorobenzamide compound to the acid binding agent is 1:(0.8-2.0); the pressure after the hydrogen is introduced into the reduction reaction is 1.5-3.0 MPa; the temperature of the reduction reaction is 25-120° C., and the time is 8-16 h.

9. The preparation method according to any one of claims 1 to 7, characterized in that: The preparation method specifically comprises the following steps: (1) 5-chloro-2-hydroxy-3-nitrobenzoic acid and a first chlorination reagent are subjected to a first chlorination reaction in the presence of a first chlorination catalyst to obtain 2,5-dichloro-3-nitrobenzoyl chloride; the molar ratio of the first chlorination reagent to 5-chloro-2-hydroxy-3-nitrobenzoic acid is (0.67-3.0):1; the molar ratio of the first chlorination catalyst to 5-chloro-2-hydroxy-3-nitrobenzoic acid is (1.0-5.0):1; the temperature of the first chlorination reaction is 40-150° C., and the time is 1-8 hours; The 2,5-dichloro-3-nitrobenzoyl chloride and the fluorinating agent are subjected to a fluorination reaction in the presence of a phase transfer catalyst to obtain 5-chloro-2-fluoro-3-nitrobenzoyl fluoride; the molar ratio of the fluorinating agent to the 2,5-dichloro-3-nitrobenzoyl chloride is (2.0-4.0):1; the mass ratio of the phase transfer catalyst to the 2,5-dichloro-3-nitrobenzoyl chloride is (0.1%-5.0%):100%; the temperature of the fluorination reaction is 60-150° C., and the time is 0.5-30h; The 5-chloro-2-fluoro-3-nitrobenzoyl fluoride is hydrolyzed in the presence of an alkaline compound to obtain 5-chloro-2-fluoro-3-nitrobenzoic acid; the molar ratio of the alkaline compound to 5-chloro-2-fluoro-3-nitrobenzoyl fluoride is (1.0-5.0):1; the hydrolysis reaction time is 0.5-5h; The 5-chloro-2-fluoro-3-nitrobenzoic acid and the second chlorinating agent undergo a second chlorination reaction to obtain 5-chloro-2-fluoro-3-nitrobenzoyl chloride; the molar ratio of the 5-chloro-2-fluoro-3-nitrobenzoic acid to the second chlorinating agent is 1:(0.3-3.0); the temperature of the second chlorination reaction is 40-150° C., and the time is 1-8 hours; (2) the 5-chloro-2-fluoro-3-nitrobenzoyl chloride obtained in step (1) is subjected to an amide reaction with an aniline compound to obtain a 3-nitro-2-fluorobenzamide compound; the molar ratio of the 5-chloro-2-fluoro-3-nitrobenzoyl chloride to the aniline compound is (1.0-1.5):1; the temperature of the amide reaction is 40-150° C., and the time is 3-7 hours; (3) the 3-nitro-2-fluorobenzamide compound obtained in step (2) is subjected to a reduction reaction with hydrogen in the presence of a reduction catalyst and an acid binding agent to obtain the 3-amino-2-fluorobenzamide compound; The mass ratio of the 3-nitro-2-fluorobenzamide compound to the reduction catalyst is 1:(0.001-0.01), and the molar ratio of the 3-nitro-2-fluorobenzamide compound to the acid binding agent is 1:(0.8-2.0); the pressure after hydrogen is introduced into the reduction reaction is 1.5-3.0MPa; the temperature of the reduction reaction is 25-120°C, and the time is 8-16h.

10. A 3-nitro-2-fluorobenzamide compound, characterized in that: The 3-nitro-2-fluorobenzamide compound has a structure as shown in Formula IV: Wherein, Y is selected from any one of unsubstituted or halogenated C1-C6 straight or branched alkyl, and unsubstituted or halogenated C1-C6 alkoxy; R is selected from any one of hydrogen, fluorine or methoxy; The 3-nitro-2-fluorobenzamide compound is prepared by the preparation method according to any one of claims 1 to 9.

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