A synthesis method of a chemical intermediate 2-fluoro-3-aminobenzoic acid

Abstract

This invention belongs to the field of organic chemical synthesis technology, specifically relating to a method for synthesizing 2-fluoro-3-aminobenzoic acid, an important chemical intermediate. Specifically, o-nitroaniline is condensed with hydrated trichloroacetaldehyde and hydroxylamine hydrochloride to obtain 2-(hydroxyimino)-N-(2-nitrophenyl)acetamide; the resulting product undergoes an intramolecular Beckmann rearrangement to generate 7-nitroindigo; 7-nitroindigo undergoes Bayer-Villedge oxidation to generate 2-amino-3-nitrobenzoic acid; 2-amino-3-nitrobenzoic acid undergoes diazotization and halogenation reactions to generate 2-fluoro-3-nitrobenzoic acid or 2-chloro-3-nitrobenzoic acid; 2-fluoro-3-nitrobenzoic acid can be further reduced by nitro to obtain 2-fluoro-3-aminobenzoic acid; or, 2-chloro-3-nitrobenzoic acid can be esterified to obtain 2-chloro-3-nitrobenzoic acid ester, which can then be fluorinated, saponified, and reduced to obtain 2-fluoro-3-aminobenzoic acid. The raw materials of this invention are low in cost and readily available, and the entire reaction route has specific regioselectivity, making it suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis technology, specifically relating to a method for synthesizing 2-fluoro-3-aminobenzoic acid, an important chemical intermediate. Background Technology

[0002] 2-Fluoro-3-aminobenzoic acid is an important organic synthesis intermediate and a key intermediate for pesticides such as bromofenozide. Researching its industrial synthesis methods is of great significance.

[0003] Currently, there are roughly five methods for synthesizing 2-fluoro-3-aminobenzoic acid.

[0004] Method 1:

[0005]

[0006] Method 1 uses 2-fluoro-3-chloroaniline as a starting material, which reacts with sodium cyanide to produce 2-fluoro-3-cyanoaniline, which is then hydrolyzed under alkaline conditions to obtain 2-fluoro-3-aminobenzoic acid (Reference: US200614761 / WO202170124). Because it uses highly toxic sodium cyanide, it generates a large amount of cyanide-containing wastewater, and the source of the starting material is limited, making this method unsuitable for industrial production.

[0007] Method 2:

[0008]

[0009] Method 2 uses methyl 2-fluoro-3-carboxybenzoate as a starting material. A first-step Curious rearrangement yields methyl 2-fluoro-3-(tert-butoxycarbonylamino)benzoate, which is then demethylated and deoxygenated to produce 2-fluoro-3-aminobenzoic acid. (Reference: US2008188450). This method uses DPPA and tert-butanol, which are difficult to recover, generates a large amount of waste, and trifluoroacetic acid causes significant environmental pollution, making it unsuitable for industrial production.

[0010] Method 3:

[0011]

[0012] Method 3 uses o-fluorotoluene as the starting material, first undergoing nitration, then oxidation with potassium permanganate, and finally reduction with palladium on carbon (reference: WO2009137391). In this method, the nitration reaction has poor selectivity, and the potassium permanganate wastewater is difficult to treat.

[0013] Method 4:

[0014]

[0015] Method 4 uses 2,6-dichlorobenzoic acid as the starting material, first undergoing nitration, then fluorination, and finally dechlorination by hydrogen-palladium-carbon reduction (reference: CN111320548A). Although the nitration reaction of this method has relatively ideal selectivity, the subsequent selective fluorination reaction is difficult to achieve, and separation is challenging, resulting in high costs.

[0016] Method 5:

[0017]

[0018] Method 5 uses 2,5-dihalobenzoic acid as the starting material, first undergoing nitration, then fluorination, and finally dehalogenation by palladium-carbon reduction with hydrogen (reference: CN114920661A). In this method, both the nitration and fluorination reactions have considerable selectivity, but the raw material cost is too high, which greatly limits its practical production.

[0019] As can be seen from the above literature, the most significant problem encountered in the synthesis of 2-fluoro-3-aminobenzoic acid is reaction selectivity, which results in either low product yield and difficulty in separation and purification, or the need to introduce other groups for site occupancy, leading to a longer reaction process and additional waste. Therefore, we hope to design a new synthetic route with high selectivity to solve the above problems. As is well known, the two carbons in the benzo[a] ring structure are located in two ring structures, and the selectivity of the reaction can be determined by the two rings. The literature (J.Org.Chem.,2013,78(17),8217) introduces the generation of 7-nitroindigo from o-nitroaniline as a starting material through one-step condensation and one-step Beckmann rearrangement, and the further Bayer-Villedge oxidation of 7-nitroindigo to generate o-aminobenzoic acid. Based on the above research, we designed the following synthetic route: using inexpensive o-nitroaniline as the starting material, condensation and Beckmann rearrangement are performed to generate 7-nitroindigo. Then, 7-nitroindigo undergoes Bayer-Villedge oxidation to generate the key trisubstituted intermediate 2-amino-3-nitrobenzoic acid. The obtained 2-amino-3-nitrobenzoic acid is then subjected to a series of reactions including diazo fluorination and hydrogenation or diazo chlorination, esterification, fluorination, hydrolysis, and hydrogenation to synthesize the target product 2-fluoro-3-aminobenzoic acid. Summary of the Invention

[0020] This invention provides a method for synthesizing 2-fluoro-3-aminobenzoic acid, an important chemical intermediate.

[0021] To achieve the above objectives, the present invention adopts the following technical solution:

[0022] A method for synthesizing the chemical intermediate 2-fluoro-3-aminobenzoic acid, the reaction route is as follows:

[0023]

[0024] R represents a C1-C4 alkyl group; preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. Furthermore, R may preferably be methyl or ethyl.

[0025] (1) o-nitroaniline is condensed with trichloroacetaldehyde hydrate and hydroxylamine hydrochloride to give 2-(hydroxyimino)-N-(2-nitrophenyl)acetamide;

[0026] (2) 2-(hydroxyimino)-N-(2-nitrophenyl)acetamide undergoes an intramolecular Beckmann rearrangement to generate 7-nitroindigo;

[0027] (3) 7-Nitroindigo undergoes Bayer-Villedge oxidation to produce 2-amino-3-nitrobenzoic acid;

[0028] (4) 2-Amino-3-nitrobenzoic acid undergoes diazotization and halogenation reactions to produce 2-fluoro-3-nitrobenzoic acid or 2-chloro-3-nitrobenzoic acid;

[0029] (5) 2-Fluoro-3-nitrobenzoic acid can be further reduced by nitro to obtain 2-fluoro-3-aminobenzoic acid;

[0030] Alternatively, 2-chloro-3-nitrobenzoic acid can be esterified to obtain 2-chloro-3-nitrobenzoate, and then fluorinated, saponified, and reduced to obtain 2-fluoro-3-aminobenzoic acid.

[0031] In step (1), o-nitroaniline, hydrated trichloroacetaldehyde, hydroxylamine hydrochloride and hydrochloric acid are mixed with water and reacted at a reaction temperature of 25-100℃ for 1-10h; the molar ratio of o-nitroaniline, hydrated trichloroacetaldehyde and hydroxylamine hydrochloride is 1:(0.9-5):(2-10); the concentration of hydrochloric acid in the reaction system is 0.5-12M, and the mass ratio of water to o-nitroaniline is (1-50):1.

[0032] Step (2) 2-(hydroxyimino)-N-(2-nitrophenyl)acetamide undergoes intramolecular Beckmann rearrangement under heating in an acidic environment to generate 7-nitroindigo; wherein the mass ratio of 2-(hydroxyimino)-N-(2-nitrophenyl)acetamide to acid is 1:(2-20).

[0033] The acid is one or more of sulfuric acid, phosphoric acid, or polyphosphoric acid, and the reaction temperature is 30-150℃.

[0034] Step (3) Mix 7-nitroindigo with alkali, add oxidant and carry out oxidation reaction under low temperature alkaline conditions of -40-25℃, wherein the molar ratio of indigo, alkali and oxidant is 1:(1-10):(1-10).

[0035] The alkali is an alkali metal hydroxide; the oxidant is hydrogen peroxide or peracetic acid.

[0036] Step (4) 2-amino-3-nitrobenzoic acid is subjected to diazotization and halogenation reactions. When the reagent used in the halogenation reaction is a fluorinating reagent, 2-fluoro-3-nitrobenzoic acid is obtained. When the reagent used in the halogenation reaction is a chlorinating reagent, 2-chloro-3-nitrobenzoic acid is obtained.

[0037] Furthermore, in step (4), sodium nitrite and a halogenating agent are added to an aqueous solution of 2-amino-3-nitrobenzoic acid, and the reaction is carried out at -10-100℃ (preferably -10-70℃) for 1-24 hours.

[0038] The fluorinating agent is hydrofluoric acid, sodium fluoride, potassium fluoride, tetrafluoroborate, or silver tetrafluoroborate; the molar ratio of 2-amino-3-nitrobenzoic acid, sodium nitrite, and the fluorinating agent in the system is 1:(0.9-5):(2-20); the chlorinating agent is hydrochloric acid, copper chloride, or cuprous chloride; the molar ratio of 2-amino-3-nitrobenzoic acid, sodium nitrite, and the chlorinating agent in the system is 1:(0.9-5):(2-20).

[0039] The 2-fluoro-3-nitrobenzoic acid can be further reduced to 2-fluoro-3-aminobenzoic acid; the reduction reaction employs metal or metal compound reduction or catalytic hydrogenation reduction; the metal or metal compound reduction involves dissolving 2-fluoro-3-nitrobenzoic acid in a solvent and reacting it with a metal or metal compound under acidic conditions at 0-150°C for 1-24 hours; the metal or metal compound includes magnesium powder, zinc powder, iron powder, and tin dichloride; the solvent includes one or more of water, methanol, ethanol, toluene, dichloromethane, 1,4-dioxane, tetrahydrofuran, DMF, DMSO, and ethyl acetate; the acid includes one or more of sulfuric acid, hydrochloric acid, acetic acid, and ammonium chloride; the 2-fluoro-3-nitrobenzoic acid, acid, and metal... Alternatively, the molar ratio of the metal compound is 1:(0.1-20):(0.1-20); the mass ratio of 2-fluoro-3-nitrobenzoic acid to the solvent is 1:(1-50); the catalytic hydrogenation reduction involves dissolving 2-fluoro-3-nitrobenzoic acid in a solvent, adding a catalyst, and hydrogenating for 1-24 hours at a reaction pressure of 0.1-5 MPa and a reaction temperature of 25-150°C; the solvent includes one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, diethyl ether, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, methyl acetate, ethyl acetate, and n-butyl acetate; the catalyst includes 1-10% by mass of Pd / C and Raney Ni; the mass ratio of 2-fluoro-3-nitrobenzoic acid, solvent, and catalyst is 1:(1-50):(0.1-10).

[0040] The esterification reaction involves 2-chloro-3-nitrobenzoic acid reacting with an alcohol having 1-4 carbon atoms at 50-150°C for 1-24 hours under the catalysis of a suitable acid to produce 2-chloro-3-nitrobenzoic acid ester. The acid catalyst is concentrated sulfuric acid, methanesulfonic acid, or p-toluenesulfonic acid, and the alcohol is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, or tert-butanol. The mass ratio of 2-chloro-3-nitrobenzoic acid to alcohol is specified. The ratio is 1:(0.01-10):(0.5-50); or 2-chloro-3-nitrobenzoic acid is first acylated with an acylation reagent at -20-50℃, and then reacted with an alcohol at 25-150℃; the acylation reagent is thionyl chloride, phosphorus oxychloride, triphosgene or oxalyl chloride; the mass ratio of 2-chloro-3-nitrobenzoic acid, acylation reagent and alcohol is 1:(0.01-10):(0.5-50).

[0041] 2-Chloro-3-nitrobenzene ester is dissolved in a solvent, a fluorinating agent and a catalyst are added, and the mixture is reacted at 50-200°C for 1-72 hours to generate 2-fluoro-3-nitrobenzene ester. The fluorinating agent is sodium fluoride, potassium fluoride, hydrofluoric acid or TBAF. The solvent includes one or more of DMF, DMSO, DMAc, sulfolane or NMP. The catalyst includes quaternary ammonium salts such as tetrabutylammonium bromide, tetrabutylammonium chloride, hexadecyltrimethylammonium chloride, benzyltriethylammonium bromide or crown ethers such as 18-crown-6, 15-crown-5. The mass ratio of the catalyst to the solvent in the 2-chloro-3-nitrobenzene ester is 1:(0.1-10):(1-50). The molar ratio of the 2-chloro-3-nitrobenzene ester to the fluorinating agent is 1:(0.5-10).

[0042] 2-Fluoro-3-nitrobenzoate undergoes a saponification reaction under alkaline conditions to produce 2-fluoro-3-nitrobenzoic acid; the reaction solvent includes one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, and water; the base includes alkali metal compounds such as sodium hydroxide and potassium hydroxide.

[0043] Advantages of this invention:

[0044] Compared with the previous patent reports, the raw materials of this solution are lower in cost and more readily available, and the entire reaction route has specific regional selectivity, producing a single product, which is suitable for industrial production. Detailed Implementation

[0045] The following describes in detail the specific embodiments of the technical solution of the present invention, but the present invention is not limited to the following description.

[0046] The present invention will now be described in conjunction with specific embodiments:

[0047] Example 1

[0048] 1) Synthesis of 2-(hydroxyimino)-N-(2-nitrophenyl)acetamide

[0049]

[0050] Under mechanical stirring, 30 g of o-nitroaniline was mixed with 600 g of water and 30 mL of hydrochloric acid (2 M). Then, 43 g of trichloroacetaldehyde hydrate and 91 g of hydroxylamine hydrochloride were added. The mixture was heated to 65 °C and stirred for 8 hours. Liquid chromatography analysis showed the reaction was complete. The reaction solution was brought to room temperature, filtered, and the precipitate was washed with copious amounts of water until the pH of the eluent was >5. The precipitate was then dried under an infrared lamp for at least 8 hours to obtain 46 g of the yellow solid 2-(hydroxyimino)-N-(2-nitrophenyl)acetamide, with a yield of 95% and a purity of 94%. ESI-MS: 210 (M+H).

[0051] 2) Synthesis of 7-nitroindigo

[0052]

[0053] 46 g of 2-(hydroxyimino)-N-(2-nitrophenyl)acetamide was slowly added to 150 mL of concentrated sulfuric acid at 65 °C. The reaction was carried out at 65 °C for 4 hours, and the reaction was confirmed to be complete by liquid chromatography. The reaction solution was brought to room temperature and then poured into 1 L of ice water with stirring, resulting in the precipitation of a precipitate. The precipitate was filtered off and washed with water until the pH of the eluent was >5. The precipitate was then dried to give 33 g of the orange-red solid 7-nitroindigo, with a yield of 85% and a purity of 93%. ESI-MS: 193 (M+H).

[0054] 3) Synthesis of 2-amino-3-nitrobenzoic acid

[0055]

[0056] 13g of 7-nitroindigo was mixed with 75mL of 30% alkali solution and stirred at room temperature, resulting in the formation of a large precipitate. After liquid chromatography showed no reaction material, the mixture was cooled to 0℃, and 8mL of 49% hydrogen peroxide was added dropwise. Numerous bubbles were generated; the temperature was carefully controlled below 5℃. As the solution was added, the precipitate gradually disappeared, and liquid chromatography confirmed the reaction was complete. The pH of the reaction solution was adjusted to 4–5 using 37% hydrochloric acid, resulting in the precipitation of a new precipitate. The precipitate was filtered, washed with water, and dried. 7g of the product, a yellow solid 2-amino-3-nitrobenzoic acid, was obtained, with a yield of 55% and a purity of 96%. ESI-MS: 183 (M+H).

[0057] 4) Synthesis of 2-chloro-3-nitrobenzoic acid

[0058]

[0059] 7 g of 2-amino-3-nitrobenzoic acid was mixed with 40 g of water, and 5 g of hydrochloric acid (37%) was added. A 25% sodium nitrite aqueous solution (1.3 eq) was then added dropwise below 0 °C, and the mixture was stirred below 0 °C for 1 hour after the addition was complete. The reaction solution was then added dropwise to a mixed solution of copper chloride and hydrochloric acid preheated to 50 °C until no more bubbles were produced, at which point a sample was taken for analysis. The reaction solution was filtered and dried to obtain 6.1 g of the yellow solid 2-chloro-3-nitrobenzoic acid, with a yield of 72% and a purity of 92%.

[0060] 5) Synthesis of methyl 2-chloro-3-nitrobenzene

[0061]

[0062] 10 g of 2-chloro-3-nitrobenzoic acid was dissolved in 70 mL of methanol, and 2 mL of concentrated sulfuric acid was added dropwise. The mixture was refluxed for 3 hours. The reaction solution was desolvated, dissolved in dichloromethane, washed with water, and the organic phase was desolvated to give 9.7 g of methyl 2-chloro-3-nitrobenzoate, with a yield of 98% and a purity of 91%.

[0063] 6) Synthesis of methyl 2-fluoro-3-nitrobenzoate

[0064]

[0065] 5 g of methyl 2-chloro-3-nitrobenzoate, KF (1.5 eq), TBAB (0.1 eq), and anhydrous DMF were reacted at 140 °C for 7 hours. The reaction solution was filtered, and the filtrate was dissolved in toluene, washed with water, and the organic phase was further dissolved to obtain the product methyl 2-fluoro-3-nitrobenzoate, with a yield of 80% and a purity of 95%.

[0066] 7) Synthesis of 2-fluoro-3-nitrobenzoic acid

[0067]

[0068] 10 g of methyl 2-fluoro-3-nitrobenzoate was dissolved in 30 mL of methanol and 30 mL of 30% alkali solution and stirred at room temperature for 2 hours. Methanol was removed from the reaction solution, and the pH was adjusted to 2-3 with 2M hydrochloric acid, resulting in the precipitation of a precipitate. The reaction solution was filtered, and the precipitate was washed with water to obtain 8.6 g of the yellow solid 2-fluoro-3-nitrobenzoic acid, with a yield of 95% and a purity of 98%.

[0069] 8) Synthesis of 2-fluoro-3-aminobenzoic acid

[0070]

[0071] 20 g of 2-fluoro-3-nitrobenzoic acid was dissolved in 200 mL of methanol and placed in an autoclave. 0.2 g of palladium on carbon (10% wt) was added, and H2 was introduced at 4 MPa. The mixture was stirred at room temperature for 3 hours. The reaction solution was filtered through diatomaceous earth to remove the solvent, yielding 16 g of the product 2-fluoro-3-aminobenzoic acid, with a yield of 98% and a purity of 96%.

[0072] Example 2

[0073] The synthesis was carried out according to steps 1)-4) and 6)-8) of Example 1 above. The difference from Example 1 is:

[0074] 5) Synthesis of methyl 2-chloro-3-nitrobenzene

[0075]

[0076] 10 g of 2-chloro-3-nitrobenzoic acid was dissolved in 50 mL of dichloromethane. 5 g of oxaloyl chloride was slowly added under ice bath conditions, and the mixture was kept at this temperature for 3 hours. The reaction solution was then desolvated, and 50 g of methanol was added. The mixture was stirred at 30 °C for 6 hours. The reaction solution was then desolvated again to give 10.1 g of methyl 2-chloro-3-nitrobenzoate, with a yield of 92% and a purity of 97%.

[0077] Example 3

[0078] The synthesis was carried out according to steps 1)-3) of Example 1 above. The difference from Example 1 is: 4) the synthesis of 2-fluoro-3-nitrobenzoic acid.

[0079]

[0080] 7g of the product 2-amino-3-nitrobenzoic acid obtained in step 3 of Example 1 was mixed with 1.5 eq of hydrofluoric acid. A 33% sodium nitrite aqueous solution (1.3 eq) was added dropwise below 0°C. After the addition was complete, the mixture was stirred below 0°C for 1 hour. The reaction solution was allowed to naturally rise to room temperature until no more bubbles were generated, and then stirring was continued for 3 hours. The reaction solution was filtered and dried to obtain 4.5g of the product 2-fluoro-3-nitrobenzoic acid, with a yield of 56% and a purity of 87%.

[0081] 5) Synthesis of 2-fluoro-3-aminobenzoic acid

[0082]

[0083] 20 g of 2-fluoro-3-nitrobenzoic acid was dissolved in 100 mL of methanol and 100 mL of water. 3 eq of iron powder and 3 eq of acetic acid were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was filtered to remove methanol, and extracted with ethyl acetate to obtain 16 g of the product 2-fluoro-3-aminobenzoic acid, with a yield of 96% and a purity of 98%.

Claims

1. A method for synthesizing the chemical intermediate 2-fluoro-3-aminobenzoic acid, characterized in that: The reaction route is R represents a C1 to C4 alkyl group; (1) o-nitroaniline is condensed with trichloroacetaldehyde hydrate and hydroxylamine hydrochloride to give 2-(hydroxyimino)-N-(2-nitrophenyl)acetamide; (2) 2-(hydroxyimino)-N-(2-nitrophenyl)acetamide undergoes an intramolecular Beckmann rearrangement to generate 7-nitroindigo; (3) 7-Nitroindigo undergoes Bayer-Villedge oxidation to produce 2-amino-3-nitrobenzoic acid; (4) 2-Amino-3-nitrobenzoic acid undergoes diazotization and halogenation reactions to produce 2-fluoro-3-nitrobenzoic acid or 2-chloro-3-nitrobenzoic acid; (5) 2-Fluoro-3-nitrobenzoic acid can be further reduced by nitro to obtain 2-fluoro-3-aminobenzoic acid; Alternatively, 2-chloro-3-nitrobenzoic acid can be esterified to obtain 2-chloro-3-nitrobenzoate, and then fluorinated, saponified, and reduced to obtain 2-fluoro-3-aminobenzoic acid.

2. The method for synthesizing the chemical intermediate 2-fluoro-3-aminobenzoic acid according to claim 1, characterized in that: In step (1), o-nitroaniline, hydrated trichloroacetaldehyde, hydroxylamine hydrochloride and hydrochloric acid are mixed with water and reacted at a reaction temperature of 25-100℃ for 1-10h; the molar ratio of o-nitroaniline, hydrated trichloroacetaldehyde and hydroxylamine hydrochloride is 1:(0.9-5):(2-10); the concentration of hydrochloric acid in the reaction system is 0.5-12M, and the mass ratio of water to o-nitroaniline is (1-50):

1.

3. The method for synthesizing the chemical intermediate 2-fluoro-3-aminobenzoic acid according to claim 1, characterized in that: Step (2) 2-(hydroxyimino)-N-(2-nitrophenyl)acetamide undergoes intramolecular Beckmann rearrangement under heating in an acidic environment to generate 7-nitroindigo; wherein the mass ratio of 2-(hydroxyimino)-N-(2-nitrophenyl)acetamide to acid is 1:(2-20).

4. The method for synthesizing the chemical intermediate 2-fluoro-3-aminobenzoic acid according to claim 3, characterized in that: The acid is one or more of sulfuric acid, phosphoric acid, or polyphosphoric acid, and the reaction temperature is 30-150℃.

5. The method for synthesizing the chemical intermediate 2-fluoro-3-aminobenzoic acid according to claim 1, characterized in that: Step (3) Mix 7-nitroindigo with alkali, add oxidant and carry out oxidation reaction under low temperature alkaline conditions of -40-25℃, wherein the molar ratio of indigo, alkali and oxidant is 1:(1-10):(1-10).

6. The method for synthesizing the chemical intermediate 2-fluoro-3-aminobenzoic acid according to claim 1, characterized in that: Step (4) 2-amino-3-nitrobenzoic acid is subjected to diazotization and halogenation reactions. When the reagent used in the halogenation reaction is a fluorinating reagent, 2-fluoro-3-nitrobenzoic acid is obtained. When the reagent used in the halogenation reaction is a chlorinating reagent, 2-chloro-3-nitrobenzoic acid is obtained.

7. The method for synthesizing the chemical intermediate 2-fluoro-3-aminobenzoic acid according to claim 6, characterized in that: The fluorinating agent is hydrofluoric acid, sodium fluoride, potassium fluoride, tetrafluoroborate, or silver tetrafluoroborate; the molar ratio of 2-amino-3-nitrobenzoic acid, sodium nitrite, and the fluorinating agent in the system is 1:(0.9-5):(2-20); the chlorinating agent is hydrochloric acid, copper chloride, or cuprous chloride; the molar ratio of 2-amino-3-nitrobenzoic acid, sodium nitrite, and the chlorinating agent in the system is 1:(0.9-5):(2-20).

8. The method for synthesizing the chemical intermediate 2-fluoro-3-aminobenzoic acid according to claim 1, characterized in that: Step (5) involves further nitro reduction of 2-fluoro-3-nitrobenzoic acid by metal or metal compound reduction or catalytic hydrogenation reduction to obtain 2-fluoro-3-aminobenzoic acid; the metal or metal compound is one or more of magnesium powder, zinc powder, iron powder, and tin dichloride; the catalyst includes Pd / C and Raney Ni with a mass fraction of 1-10%.

9. The method for synthesizing the chemical intermediate 2-fluoro-3-aminobenzoic acid according to claim 1, characterized in that: Step (5) is the esterification reaction in which 2-chloro-3-nitrobenzoic acid reacts with an alcohol having 1-4 carbon atoms at 50-150°C for 1-24 hours under the catalysis of the corresponding acid to generate 2-chloro-3-nitrobenzoic acid ester. The 2-chloro-3-nitrobenzoate obtained above is dissolved in a solvent, a fluorinating agent and a catalyst are added, and the reaction is carried out at 50-200℃ for 1-72 hours to generate 2-fluoro-3-nitrobenzoate. The 2-fluoro-3-nitrobenzoate obtained above is then saponified under alkaline conditions to generate 2-fluoro-3-nitrobenzoic acid.

Images