Synthesis method of 2-fluoro-3-nitrobenzoic acid

Abstract

The invention relates to the technical field of chemical synthesis, and particularly discloses a synthesis method of 2-fluoro-3-nitrobenzoic acid. The preparation method comprises the following steps: by taking 2-methyl-6-nitroaniline as an initial raw material, firstly preparing aromatic diazonium salt through diazotization reaction, and then carrying out Balz-Schiemann reaction on the aromatic diazonium salt and fluoboric acid under the condition of a specific catalyst, so as to prepare the 2-fluoro-3-nitrotoluene. And finally, under the condition of a specific catalyst, carrying out oxidation reaction on the 2-fluoro-3-nitrotoluene to prepare the 2-fluoro-3-nitrobenzoic acid. The white 2-fluoro-3-nitrobenzoic acid with the total yield being 85% or above and the purity being 99% or above is finally prepared, the method has the advantages of being low in production cost, high in process safety and the like, large-scale production of the 2-fluoro-3-nitrobenzoic acid is easily achieved, and the method has very important significance for widening the application range of the 2-fluoro-3-nitrobenzoic acid.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for synthesizing 2-fluoro-3-nitrobenzoic acid. Background Art

[0002] 2-Fluoro-3-nitrobenzoic acid can be used as an intermediate for the preparation of bromofenac, and is also widely used in the synthesis of benzenesulfonamide thiazole drugs, quinolone derivatives, active biological enzymes and other substances. In addition, 2-Fluoro-3-nitrobenzoic acid is also an important pharmaceutical intermediate, and it is one of the main synthetic raw materials for the BRAF inhibitor Dabrafenib.

[0003] There are three methods for synthesizing 2-fluoro-3-nitrobenzoic acid reported in the literature: ① Using 2-methyl-6-nitroaniline as a raw material, diazotization and chlorination reactions are performed to generate 2-chloro-3-nitrotoluene, and then 2-fluoro-3-nitrotoluene is obtained through a chlorine-fluorine exchange reaction, and finally 2-fluoro-3-nitrobenzoic acid is prepared through an oxidation reaction. ② Using o-methylphenol as a raw material, nitration is performed under the action of nitrate and p-toluenesulfonic acid to prepare 2-methyl-6-nitrophenol, and then chlorination is performed to obtain 2-chloro-3-nitrotoluene, and then 2-chloro-3-nitrotoluene is subjected to a halogen exchange reaction under the action of cesium fluoride to obtain 2-fluoro-3-nitrotoluene, and finally 2-fluoro-3-nitrobenzoic acid is prepared through an oxidation reaction. ③ Using 2-fluoronitrobenzene as the raw material, using lithium diisopropylamide or tert-butyl lithium under low temperature conditions, 2-fluoronitrobenzene is lithiolated at the ortho-fluorine position, and then reacts with dry ice to undergo carbonyl insertion reaction, and finally undergoes acidic hydrolysis to obtain 2-fluoro-3-nitrobenzoic acid. Among the above three routes, the first two routes require halogen exchange reactions, which are not easy to occur and require higher temperatures to be carried out. Although the third route has relatively fewer reaction steps, the reaction needs to be carried out at -30℃ to -50℃, the conditions are harsh, and lithium diisopropylamide or tert-butyl lithium needs to be used, which poses a great safety hazard. Therefore, it is necessary to develop a new synthesis process for 2-fluoro-3-nitrobenzoic acid with mild reaction conditions and high safety. Summary of the invention

[0004] In view of the problems of harsh reaction conditions and poor safety in the process of preparing 2-fluoro-3-nitrobenzoic acid in the prior art, the present invention provides a method for synthesizing 2-fluoro-3-nitrobenzoic acid. The method effectively avoids the need for a halogen exchange reaction with high reaction conditions required in the production process of 2-fluoro-3-nitrobenzoic acid, and also avoids a carbonyl insertion reaction with harsh conditions and great safety hazards, which is conducive to the industrial production of 2-fluoro-3-nitrobenzoic acid and has high application value.

[0005] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0006] A synthetic method for 2-fluoro-3-nitrobenzoic acid comprises the steps:

[0007] S1, diazotizing 2-methyl-6-nitroaniline to obtain an aromatic diazonium salt;

[0008] S2, under the condition of catalyst a, the aromatic diazonium salt and fluoroboric acid are subjected to Balz-Schiemann reaction to obtain 2-fluoro-3-nitrotoluene; the catalyst a is one or more of the simple substances or oxides corresponding to Fe, Cu, and Mn;

[0009] S3, under the conditions of catalyst b and oxidant, 2-fluoro-3-nitrotoluene is oxidized to obtain 2-fluoro-3-nitrobenzoic acid; the catalyst b is one or more of tetrabutylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium iodide.

[0010] Compared with the prior art, the present invention provides a novel synthesis method of 2-fluoro-3-nitrobenzoic acid by designing a new synthesis route. The method uses 2-methyl-6-nitroaniline as a starting material, firstly prepares an aromatic diazonium salt by a diazotization reaction, then, under specific catalyst conditions, the aromatic diazonium salt and fluoroboric acid undergo a Balz-Schiemann reaction to prepare 2-fluoro-3-nitrotoluene; finally, under specific catalyst conditions, 2-fluoro-3-nitrotoluene undergoes an oxidation reaction to prepare 2-fluoro-3-nitrobenzoic acid.

[0011] The preparation method of 2-fluoro-3-nitrobenzoic acid provided by the present invention avoids the halogen exchange reaction with high requirements on reaction conditions, adopts the Balz-Schiemann reaction with mild reaction conditions to replace the halogen exchange reaction, and at the same time, adds a specific catalyst in the oxidation step, effectively improves the reaction rate and conversion rate of the oxidation reaction, and finally prepares white 2-fluoro-3-nitrobenzoic acid with a total yield of more than 85% and a purity of more than 99%. The present invention has the advantages of reasonable process design, high product yield and purity, low production cost, high process safety, etc., is conducive to realizing the large-scale production of 2-fluoro-3-nitrobenzoic acid, and is of great significance for expanding the application range of 2-fluoro-3-nitrobenzoic acid.

[0012] As a specific embodiment of the present invention, the synthesis method of 2-fluoro-3-nitrobenzoic acid specifically comprises the following steps:

[0013] S1, performing a diazotization reaction on 2-methyl-6-nitroaniline and sodium nitrite in a hydrochloric acid solution, and after the reaction is completed, adding urea to the reaction solution to remove excess sodium nitrite, thereby obtaining an aromatic diazonium salt reaction solution;

[0014] S2, adding a fluoroboric acid aqueous solution to the aromatic diazonium salt reaction solution, mixing evenly, freezing, and performing solid-liquid separation to obtain a fluoroboric acid diazonium salt; adding the fluoroboric acid diazonium salt and catalyst a to an organic solvent, performing a Balz-Schiemann reaction, and obtaining 2-fluoro-3-nitrotoluene;

[0015] S3, 2-fluoro-3-nitrotoluene, an oxidant and a catalyst b are subjected to an oxidation reaction in water to obtain 2-fluoro-3-nitrobenzoic acid.

[0016] The reaction equation of the above preparation process is as follows:

[0017]

[0018] As a specific implementation of the present invention, S1 specifically includes the following steps:

[0019] Add 2-methyl-6-nitroaniline to hydrochloric acid solution, mix well, add sodium nitrite aqueous solution, monitor by TLC, add urea after the reaction is completed, monitor by starch potassium iodide test paper, and when the starch potassium iodide test paper does not turn blue, the aromatic diazonium salt reaction solution is obtained.

[0020] Preferably, in S1, the molar ratio of 2-methyl-6-nitroaniline, HCl in the hydrochloric acid solution and sodium nitrite is 1:(1-2.5):(1-2.5).

[0021] Preferably, in S1, the temperature for adding 2-methyl-6-nitroaniline is 45°C to 65°C.

[0022] Specifically, in S1, the sodium nitrite aqueous solution is added dropwise for 20 min to 40 min, and the temperature of the reaction system when the sodium nitrite aqueous solution is added is -10°C to 0°C.

[0023] Specifically, in S1, the diazotization reaction time is 0.5 h to 1.5 h.

[0024] Specifically, in S1, the hydrochloric acid solution is prepared by mixing concentrated hydrochloric acid and water in a volume ratio of 1:1 to 1:4.

[0025] The preferred reaction conditions of S1 can promote the full progress of the diazotization reaction and increase the reaction rate of the diazotization reaction.

[0026] As a specific implementation of the present invention, S2 specifically includes the following steps:

[0027] Add the fluoroboric acid aqueous solution to the aromatic diazonium salt reaction solution, stir for 0.5h~1h, then freeze for 0.5h~1h, separate the solid and liquid, rinse the obtained filter cake (fluoroboric acid diazonium salt) with water, anhydrous ethanol and isopropyl ether in turn, and dry; add the fluoroboric acid diazonium salt and catalyst a to an organic solvent, heat to reflux, monitor by TLC until the reaction is completed, separate the solid and liquid, and decompress the obtained filtrate to obtain 2-fluoro-3-nitrotoluene.

[0028] Preferably, in S2, the molar ratio of HBF4 to 2-methyl-6-nitroaniline in the fluoroboric acid aqueous solution is (1-3):1.

[0029] Specifically, the mass concentration of the fluoroboric acid aqueous solution is 45% to 55%.

[0030] Preferably, in S2, the organic solvent is acetone, and the amount added is 2 to 4 times the mass of the diazonium fluoroborate salt.

[0031] Preferably, in S2, the temperature of the Balz-Schiemann reaction is 45° C. to 60° C., and the reaction time is 0.5 h to 3 h.

[0032] Preferably, in S2, the added amount of the catalyst a is 0.1% to 2% of the mass of the diazonium fluoroborate salt.

[0033] Further preferably, in S2, the catalyst a is iron powder or copper powder.

[0034] Specifically, in S2, the freezing temperature is -5°C to 0°C.

[0035] The preferred reaction conditions in S2 can promote the full reaction of 2-methyl-6-nitroaniline and fluoroboric acid, and at the same time, are also beneficial to improving the reaction rate of the Balz-Schiemann reaction.

[0036] As a specific implementation of the present invention, S3 specifically includes the following steps:

[0037] The prepared 2-fluoro-3-nitrotoluene and catalyst b are added to water, mixed evenly, heated, and an oxidant is added. The temperature is kept to carry out an oxidation reaction, and the reaction is monitored by TLC until the reaction is completed to obtain 2-fluoro-3-nitrobenzoic acid.

[0038] Preferably, in S3, the molar ratio of the 2-fluoro-3-nitrotoluene to the oxidant is 1:(1-3).

[0039] Preferably, in S3, the added amount of the catalyst b is 0.5% to 2% of the mass of 2-fluoro-3-nitrotoluene.

[0040] Preferably, in S3, the oxidant is potassium permanganate or chromium trioxide.

[0041] Preferably, in S3, the temperature of the oxidation reaction is 80°C to 100°C, and the reaction time is 1h to 4h.

[0042] It should be noted that after the S3 reaction is completed, a post-treatment process is also included: filtering the reaction solution while hot, rinsing the filter cake with hot water, allowing the filtrate to stand and cool to room temperature, adjusting the pH to 2-4 with hydrochloric acid, cooling and crystallizing, solid-liquid separation, rinsing the filter cake with cold water, and drying to obtain a crude 2-fluoro-3-nitrobenzoic acid product; adding petroleum ether to the crude 2-fluoro-3-nitrobenzoic acid product for slurrying, solid-liquid separation, and drying to obtain a 2-fluoro-3-nitrobenzoic acid product.

[0043] Specifically, in S3, the temperature of the cooling and crystallization is -5°C to 0°C, and the time of the cooling and crystallization is 0.5h to 1h.

[0044] The synthesis method of 2-fluoro-3-nitrobenzoic acid provided by the present invention does not need to carry out a chlorine-fluorine exchange reaction, avoids high temperature conditions, is more energy-saving and environmentally friendly, and does not need to undergo a carbonyl insertion reaction with harsh conditions and great safety hazards, is safer and more reliable, and has higher process controllability. At the same time, the yield and purity of the product are high, the total yield can reach more than 85%, and the purity can reach more than 99%, thereby providing a new process route for preparing 2-fluoro-3-nitrobenzoic acid. The development of the method provides strong support for the wide application of 2-fluoro-3-nitrobenzoic acid, and has high promotion and application value. DETAILED DESCRIPTION

[0045] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0046] Example 1

[0047] This embodiment provides a method for synthesizing 2-fluoro-3-nitrobenzoic acid, comprising the following steps:

[0048] Step 1: Synthesis of aromatic diazonium salts

[0049]

[0050] Take a 500mL three-necked flask, add 60mL concentrated hydrochloric acid and 120mL water, turn on stirring and add 50.0g (0.329mol) of 2-methyl-6-nitroaniline in batches, heat and control the temperature to 50℃, add after 0..5h, then keep stirring and cool to 0℃, add 23.8g (0.345mol) NaNO2 to 100mL water at room temperature to dissolve, add it dropwise to the reaction system at a uniform speed, react after 0.5h, monitor the reaction endpoint by TLC, add urea in small amounts and multiple times to consume excess NaNO2, monitor the process with starch potassium iodide test paper, stop adding urea when the test paper does not turn blue and go directly to the next step;

[0051] Step 2: Synthesis of 2-fluoro-3-nitrotoluene

[0052]

[0053] Add 86.6g of 50wt.% fluoroboric acid aqueous solution (fluoroboric acid content 0.493mol) to the reaction system in the previous step, stir for 0.5h to precipitate crystals, freeze at -3℃ for 0.5h, filter with suction, rinse the filter cake with water, anhydrous ethanol, and isopropyl ether in turn, and dry. Take acetone 3 times the mass of the filter cake, add it to a 500mL three-necked flask and heat it to 58℃ for reflux, add 1% of the mass of the filter cake, add the dried filter cake several times, absorb the tail gas with cold water, monitor the reaction end point by TLC, filter with suction, decompress the filtrate and desolventize to obtain a light yellow liquid, i.e. 47.2g of 2-fluoro-3-nitrotoluene, with a yield of 92.6% and a chromatographic purity of 98.6%.

[0054] 1 H NMR (400MHz, CDCl3): δ7.85 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.0 Hz, 1H), 7.18 (t, J = 7.9 Hz, 1H), 2.38 (d, J = 2.2 Hz, 3H).

[0055] Step 3: Synthesis of 2-fluoro-3-nitrobenzoic acid

[0056]

[0057] 47.2 g (0.304 mol) of 2-fluoro-3-nitrotoluene was put into a reaction flask, 0.47 g of tetrabutylammonium bromide and 150 mL of water were added, the temperature was raised to 95°C, 96.1 g (0.608 mol) of potassium permanganate was dissolved in hot water, and the mixture was uniformly added to the reaction system. The reaction was kept at 95°C for reaction, and the reaction end point was monitored by TLC. After the reaction was completed, the mixture was filtered while hot, and the filter cake was rinsed with hot water. After the filtrate was allowed to stand and cooled to room temperature, the pH value was adjusted to 3 with hydrochloric acid, the temperature was lowered to -3°C, the mixture was kept for crystallization for 1 h, filtered, the filter cake was rinsed with cold water, and dried to obtain a crude product of 2-fluoro-3-nitrobenzoic acid. 60 mL of petroleum ether was added to the crude product for pulping, filtered, and the filter cake was dried to obtain 52.8 g of 2-fluoro-3-nitrobenzoic acid as a white solid, with a yield of 93.8%, a chromatographic purity of 99.0%, and a total yield of 86.9%.

[0058] 1 H NMR (600MHz, DMSO): δ13.88(s,1H),8.35(t,J=6.9Hz,1H),8.23(t,J=6.8Hz,1H),7.54(t,J=8.0Hz,1H). 13 C NMR (101MHz, DMSO) δ164.12, 155.61, 152.89, 138.78, 137.75, 130.44, 125.33, 122.57.

[0059] Example 2

[0060] This embodiment provides a method for synthesizing 2-fluoro-3-nitrobenzoic acid, comprising the following steps:

[0061] Step 1: Synthesis of aromatic diazonium salts

[0062] Take a 500mL three-necked flask, add 30mL concentrated hydrochloric acid and 120mL water, turn on the stirring and add 2-methyl-6-nitroaniline 50.0g (0.329mol) in batches, heat and control the temperature at 45℃, add 0.5h, then keep stirring and cool to -5℃, add 36.7g (0.532mol) NaNO2 to 100mL water at room temperature to dissolve, add it dropwise to the reaction system at a uniform speed, react for 0.5h after addition, monitor the reaction end point by TLC, add urea in small amounts and multiple times to consume excess NaNO2, monitor the process with starch potassium iodide test paper, stop adding urea when the test paper does not turn blue and go directly to the next step;

[0063] Step 2: Synthesis of 2-fluoro-3-nitrotoluene

[0064] Add 57.8 g of 50 wt.% fluoroboric acid aqueous solution (fluoroboric acid content 0.329 mol) to the reaction system in the previous step, stir for 0.5 h to precipitate crystals, freeze at -5 ° C for 0.5 h, filter with suction, rinse the filter cake with water, anhydrous ethanol, and isopropyl ether in turn, and dry. Take acetone twice the mass of the filter cake and add it to a 500 mL three-necked flask and heat it to 60 ° C for reflux, add 0.1% copper powder of the mass of the filter cake, add the dried filter cake several times, absorb the tail gas with cold water, monitor the reaction end point by TLC, filter with suction, and desolventize the filtrate to obtain a light yellow liquid, i.e. 46.8 g of 2-fluoro-3-nitrotoluene, with a yield of 91.8% and a chromatographic purity of 98.8%.

[0065] 1 H NMR (400MHz, CDCl3): δ7.85 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.0 Hz, 1H), 7.18 (t, J = 7.9 Hz, 1H), 2.38 (d, J = 2.2 Hz, 3H).

[0066] Step 3: Synthesis of 2-fluoro-3-nitrobenzoic acid

[0067] 46.8 g (0.302 mol) of 2-fluoro-3-nitrotoluene was put into a reaction flask, 0.23 g of tetrabutylammonium chloride and 150 mL of water were added, the temperature was raised to 100° C., 30.5 g (0.305 mol) of chromium trioxide was dissolved in hot water, and the mixture was uniformly added to the reaction system. The reaction was kept at 80° C. and the reaction end point was monitored by TLC. After the reaction was completed, the mixture was filtered while hot, and the filter cake was rinsed with hot water. After the filtrate was allowed to stand and cooled to room temperature, the pH value was adjusted to 3.5 with hydrochloric acid, the temperature was lowered to -5° C., the mixture was kept for crystallization for 0.5 h, filtered, the filter cake was rinsed with cold water, and dried to obtain a crude product of 2-fluoro-3-nitrobenzoic acid. 60 mL of petroleum ether was added to the crude product for pulping, filtered, and the filter cake was dried to obtain 52.7 g of 2-fluoro-3-nitrobenzoic acid as a white solid, with a yield of 94.3%, a chromatographic purity of 99.2%, and a total yield of 86.6%.

[0068] 1 H NMR (600MHz, DMSO): δ13.88(s,1H),8.35(t,J=6.9Hz,1H),8.23(t,J=6.8Hz,1H),7.54(t,J=8.0Hz,1H). 13 C NMR (101MHz, DMSO) δ164.12, 155.61, 152.89, 138.78, 137.75, 130.44, 125.33, 122.57.

[0069] Example 3

[0070] This embodiment provides a method for synthesizing 2-fluoro-3-nitrobenzoic acid, comprising the following steps:

[0071] Step 1: Synthesis of aromatic diazonium salts

[0072] Take a 500mL three-necked flask, add 68mL concentrated hydrochloric acid and 80mL water, turn on stirring and add 50.0g (0.329mol) of 2-methyl-6-nitroaniline in batches, heat and control the temperature to 65℃, add after 0.5h, then keep stirring and cool to -10℃, add 56.0g (0.812mol) NaNO2 to 100mL water at room temperature to dissolve, add it dropwise to the reaction system at a uniform speed, react after 0.5h, monitor the reaction end point by TLC, add urea in small amounts and multiple times to consume excess NaNO2, monitor the process with starch potassium iodide test paper, stop adding urea when the test paper does not turn blue and go directly to the next step;

[0073] Step 2: Synthesis of 2-fluoro-3-nitrotoluene

[0074] Add 173.2 g of 50 wt.% fluoroboric acid aqueous solution (fluoroboric acid content 0.986 mol) to the reaction system in the previous step, stir for 1 hour to precipitate crystals, freeze at -5°C for 1 hour, filter with suction, rinse the filter cake with water, anhydrous ethanol, and isopropyl ether in turn, and dry. Take acetone 4 times the mass of the filter cake, add it to a 500 mL three-necked flask and heat it to 45°C for reflux, add 2% of the mass of the filter cake with iron oxide, add the dried filter cake several times, absorb the tail gas with cold water, monitor the reaction end point with TLC, filter with suction, decompress the filtrate to obtain a light yellow liquid, i.e. 47.4 g of 2-fluoro-3-nitrotoluene, with a yield of 93.0% and a chromatographic purity of 98.5%.

[0075] 1 H NMR (400MHz, CDCl3): δ7.85 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.0 Hz, 1H), 7.18 (t, J = 7.9 Hz, 1H), 2.38 (d, J = 2.2 Hz, 3H).

[0076] Step 3: Synthesis of 2-fluoro-3-nitrobenzoic acid

[0077] 47.4 g (0.306 mol) of 2-fluoro-3-nitrotoluene was put into a reaction flask, 0.95 g of tetrabutylammonium iodide and 150 mL of water were added, the temperature was raised to 95°C, 144.1 g (0.912 mol) of potassium permanganate was dissolved in hot water, and the mixture was uniformly added to the reaction system. The reaction was kept at 95°C for reaction, and the reaction end point was monitored by TLC. After the reaction was completed, the mixture was filtered while hot, and the filter cake was rinsed with hot water. After the filtrate was allowed to stand and cooled to room temperature, the pH value was adjusted to 3 with hydrochloric acid, the temperature was lowered to -5°C, the mixture was kept for crystallization for 0.5 h, filtered, the filter cake was rinsed with cold water, and dried to obtain a crude product of 2-fluoro-3-nitrobenzoic acid. 60 mL of petroleum ether was added to the crude product for pulping, filtered, and the filter cake was dried to obtain 53.0 g of 2-fluoro-3-nitrobenzoic acid as a white solid, with a yield of 93.7%, a chromatographic purity of 99.4%, and a total yield of 87.1%.

[0078] 1 H NMR (600MHz, DMSO): δ13.88(s,1H),8.35(t,J=6.9Hz,1H),8.23(t,J=6.8Hz,1H),7.54(t,J=8.0Hz,1H). 13 C NMR (101MHz, DMSO) δ164.12, 155.61, 152.89, 138.78, 137.75, 130.44, 125.33, 122.57.

[0079] Comparative Example 1

[0080] This comparative example provides a method for synthesizing 2-fluoro-3-nitrobenzoic acid, which differs from Example 1 only in that no catalyst is added in step 2, and the remaining steps are identical. Finally, 29.7 g of white solid 2-fluoro-3-nitrobenzoic acid is prepared, with a chromatographic purity of 99.1% and a total yield of 48.8%.

[0081] Comparative Example 2

[0082] This comparative example provides a method for synthesizing 2-fluoro-3-nitrobenzoic acid, which is different from Example 1 only in that the catalyst iron powder in step 2 is replaced with an equal amount of nickel powder, and the remaining steps are exactly the same. Finally, 36.6 g of white solid 2-fluoro-3-nitrobenzoic acid is prepared, with a chromatographic purity of 99.0% and a total yield of 60.2%.

[0083] Comparative Example 3

[0084] This comparative example provides a method for synthesizing 2-fluoro-3-nitrobenzoic acid, which differs from Example 1 only in that no catalyst is added in step 3, and the remaining steps are exactly the same. Finally, 29.1 g of white solid 2-fluoro-3-nitrobenzoic acid is prepared, with a chromatographic purity of 99.2% and a total yield of 47.8%.

[0085] Comparative Example 4

[0086] This comparative example provides a method for synthesizing 2-fluoro-3-nitrobenzoic acid, which specifically comprises the following steps:

[0087] 45.0g (0.296mol) of 2-methyl-6-nitroaniline was dissolved in a mixed solution consisting of 100mL of water and 100mL of concentrated hydrochloric acid, cooled to 0°C, and 100mL of 25% sodium nitrite aqueous solution was added dropwise for 0.5h, and the reaction system was stirred. Cuprous chloride (50.0g, 0.505mol) was added to 130mL of concentrated hydrochloric acid to obtain a concentrated hydrochloric acid solution of cuprous chloride, and added to the previous solution system for stirring reaction, the reaction temperature was 35°C, TLC was used to monitor the reaction end point, and a crude product was obtained by steam distillation. After vacuum distillation, 40.2g of light yellow oily 2-chloro-3-nitrotoluene was collected, with a yield of 79.2% and a chromatographic purity of 97.8%.

[0088] 40.2 g (0.234 mol) of 2-chloro-3-nitrotoluene was dissolved in 500 mL of dimethyl sulfoxide, and 25.0 g (0.430 mol) of potassium fluoride, 6.0 g (15 mmol) of butyltriphenylphosphonium bromide and 18-crown ether-6 (4.0 g, 15 mmol) were added. The temperature was raised to 130°C for reaction, and the reaction endpoint was monitored by TLC. The temperature was lowered to room temperature, water was added with stirring, and 9.0 g of 2-fluoro-3-nitrotoluene was obtained by steam distillation with a yield of 24.8% and a chromatographic purity of 98.4%.

[0089] 9.0 g (0.058 mol) of 2-fluoro-3-nitrotoluene was dissolved in a mixed solution of 400 mL of ethanol and 200 mL of water, and 18.3 g (0.116 mol) of potassium permanganate was added. The reaction mixture was reacted at 30°C for 1 h, filtered, and the filtrate was evaporated to remove the organic solvent under reduced pressure. Water was added to the residue with stirring, and the temperature was raised to dissolve. The temperature was lowered to below 0°C for recrystallization to obtain 5.8 g of 2-fluoro-3-nitrobenzoic acid with a yield of 53.6%, a chromatographic purity of 98.7%, and a total yield of 10.5%.

[0090] Examples 1 to 3 may also use other catalysts a defined in the present invention. As long as they are within the scope defined in the present invention, they can achieve technical effects that are substantially equivalent to those of Examples 1 to 3.

[0091] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing 2-fluoro-3-nitrobenzoic acid, characterized in that: The steps include: S1, diazotizing 2-methyl-6-nitroaniline to obtain an aromatic diazonium salt; S2, under the condition of catalyst a, the aromatic diazonium salt and fluoroboric acid are subjected to Balz-Schiemann reaction to obtain 2-fluoro-3-nitrotoluene; the catalyst a is one or more of the simple substances or oxides corresponding to Fe, Cu, and Mn; S3, under the conditions of catalyst b and oxidant, 2-fluoro-3-nitrotoluene is oxidized to obtain 2-fluoro-3-nitrobenzoic acid; the catalyst b is one or more of tetrabutylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium iodide.

2. The method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 1, wherein The specific steps include: S1, performing a diazotization reaction on 2-methyl-6-nitroaniline and sodium nitrite in a hydrochloric acid solution, and after the reaction is completed, adding urea to the reaction solution to remove excess sodium nitrite, thereby obtaining an aromatic diazonium salt reaction solution; S2, adding a fluoroboric acid aqueous solution to the aromatic diazonium salt reaction solution, mixing evenly, freezing, and performing solid-liquid separation to obtain a fluoroboric acid diazonium salt; adding the fluoroboric acid diazonium salt and catalyst a to an organic solvent, performing a Balz-Schiemann reaction, and obtaining 2-fluoro-3-nitrotoluene; S3, 2-fluoro-3-nitrotoluene, an oxidant and a catalyst b are subjected to an oxidation reaction in water to obtain 2-fluoro-3-nitrobenzoic acid.

3. The method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 2, characterized in that: In S1, the molar ratio of the 2-methyl-6-nitroaniline, HCl in the hydrochloric acid solution and sodium nitrite is 1:(1-2.5):(1-2.5).

4. The method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 2, characterized in that: In S2, the molar ratio of HBF4 to 2-methyl-6-nitroaniline in the fluoroboric acid aqueous solution is (1-3):

1.

5. The method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 2, characterized in that: In S2, the organic solvent is acetone, and the amount added is 2 to 4 times the mass of the diazonium fluoroborate salt.

6. The method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 2, characterized in that: In S2, the temperature of the Balz-Schiemann reaction is 45°C to 60°C, and the reaction time is 0.5h to 3h.

7. The method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 2, characterized in that: In S2, the added amount of the catalyst a is 0.1% to 2% of the mass of diazonium fluoroborate.

8. The method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 2, characterized in that: In S3, the molar ratio of the 2-fluoro-3-nitrotoluene to the oxidant is 1:(1-3).

9. The method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 2, characterized in that: In S3, the added amount of the catalyst b is 0.5% to 2% of the mass of 2-fluoro-3-nitrotoluene.

10. The method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 2, characterized in that: In S3, the oxidant is potassium permanganate or chromium trioxide; and / or In S3, the temperature of the oxidation reaction is 80°C to 100°C, and the reaction time is 1h to 4h.

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