A process for the preparation of 3-chloro-5-fluoro-2-methylbenzoic acid

Abstract

The application discloses a preparation method of 3-chloro-5-fluoro-2-methylbenzoic acid, relates to the technical field of 3-chloro-5-fluoro-2-methylbenzoic acid production, and the method is characterized in that: 2-methyl-5-nitrobenzoic acid is used as a starting raw material, selective chlorination is carried out on the starting raw material in preheated high-temperature concentrated sulfuric acid and dichloro hydantoin, then esterification is completed by a one-pot method, catalytic hydrogenation reduction is carried out under low-pressure and low-temperature conditions by the synergistic action of a Raney nickel catalyst and a platinum-carbon catalyst, a high-purity amino intermediate is obtained, smooth thermal decomposition fluorination is carried out in a diglycol dimethyl ether solvent, alkaline hydrolysis and refinement are carried out, and finally the end product is obtained; the product has high purity and high yield.

Description

Technical Field

[0001] This invention relates to the field of 3-chloro-5-fluoro-2-methylbenzoic acid production technology, specifically to a method for preparing 3-chloro-5-fluoro-2-methylbenzoic acid. Background Technology

[0002] 3-Chloro-5-fluoro-2-methylbenzoic acid is an important benzoic acid compound containing fluorine and chlorine substituents. The halogen atoms and carboxyl groups in its molecular structure make it a key intermediate in the synthesis of fine chemicals such as pharmaceuticals, pesticides, and liquid crystal materials. Particularly in the design of novel drug molecules, this type of multi-substituted aromatic ring structure is often used to regulate the polarity, metabolic stability, and biological activity of the molecule. Therefore, developing efficient and highly selective synthetic routes has significant application value. Currently, the synthesis of this class of polyhalogenated benzoic acid derivatives suffers from low yields and purity, as well as high costs. Summary of the Invention

[0003] The technical problem to be solved by the present invention is to provide a method for preparing 3-chloro-5-fluoro-2-methylbenzoic acid, which has high purity and yield, in order to address the shortcomings of the existing technology.

[0004] To solve the above-mentioned technical problems, the technical solution of the present invention is as follows:

[0005] A method for preparing 3-chloro-5-fluoro-2-methylbenzoic acid includes the following steps:

[0006] A: 2-Methyl-5-nitrobenzoic acid and dichlorohydantoin were added to concentrated sulfuric acid I and reacted. After the reaction was completed, the temperature was lowered to room temperature, and ethanol and concentrated sulfuric acid II were added to continue the reaction. The reaction solution was poured into ice water, stirred, filtered, and the filter cake was washed with water to obtain crude ethyl 2-methyl-3-chloro-5-nitrobenzoate.

[0007] B: Crude ethyl 2-methyl-3-chloro-5-nitrobenzoate was dissolved in ethanol, Raney nickel and platinum carbon were added, hydrogen gas was introduced, and after the reaction was completed, the mixture was filtered and concentrated to obtain ethyl 2-methyl-3-chloro-5-aminobenzoate.

[0008] C: Ethyl 2-methyl-3-chloro-5-aminobenzoate is added to purified water or 36-38%wt concentrated hydrochloric acid, and 20-30%wt sodium nitrite aqueous solution is added dropwise at 0-5℃ for 1-2 hours. After the addition is complete, the temperature is maintained at 0-5℃ for 0.5-1 hours. Then, 40-50%wt fluoroboric acid aqueous solution is added, and the mixture is stirred at 0-5℃ for another 0.5-1 hours. The mixture is then filtered and dried to obtain ethyl 2-methyl-3-chloro-5-diazofluoroboronic acid benzoate powder.

[0009] D: 2-Methyl-3-chloro-5-diazofluoroborate ethyl benzoate powder was mixed with diethylene glycol dimethyl ether and heated to 100-130℃. After the nitrogen gas was completely released, the reaction solution was cooled to room temperature. Then, ethyl acetate was added to the reaction solution. The organic phase was dried over anhydrous sodium sulfate, concentrated under vacuum, and the solvent was recovered to obtain 2-methyl-3-chloro-5-fluorobenzoate ethyl ester.

[0010] E: Ethyl 2-methyl-3-chloro-5-fluorobenzoate is added to an ethanol-water mixed solvent, and sodium hydroxide is added to react. After the reaction is completed, the product is acidified, filtered, washed, and dried to obtain 3-chloro-5-fluoro-2-methylbenzoic acid.

[0011] Preferably, in step A, the molar ratio of 2-methyl-5-nitrobenzoic acid to dichlorohydantoin is 1:0.55-0.65, the ratio of 2-methyl-5-nitrobenzoic acid to concentrated sulfuric acid I is 1:4-5 w / v, the ratio of 2-methyl-5-nitrobenzoic acid to ethanol is 1:6-7 w / v, and the ratio of 2-methyl-5-nitrobenzoic acid to concentrated sulfuric acid II is 1:0.13-0.16 w / v.

[0012] Preferably, in step A, concentrated sulfuric acid I is preheated to 55-65°C, and then 2-methyl-5-nitrobenzoic acid and dichlorohydantoin are added in 2-3 portions. After the addition is complete, the reaction is carried out at 78-82°C for 18-22 hours.

[0013] After adding ethanol and concentrated sulfuric acid II, the mixture is refluxed at 75-80℃ for 7-9 hours.

[0014] Preferably, the crude ethyl 2-methyl-3-chloro-5-nitrobenzoate from step A is added to ethanol, heated to dissolve, then cooled to 0-5°C to crystallize, filtered, and the collected pure ethyl 2-methyl-3-chloro-5-nitrobenzoate is used in the reaction in step B, wherein the ratio of crude ethyl 2-methyl-3-chloro-5-nitrobenzoate to ethanol is 1:5-8 w / v.

[0015] Preferably, in step B, hydrogen gas is introduced to a pressure of 0.3-0.5 MPa during the reaction process, and the reaction is carried out at 40-45°C. The reaction endpoint is considered to be when the hydrogen pressure no longer decreases and is maintained for 1-2 hours.

[0016] Preferably, in step B, the molar ratio of pure ethyl 2-methyl-3-chloro-5-nitrobenzoate to Raney nickel and platinum carbon is 1:0.08-0.12:0.02-0.04, and the ratio of pure ethyl 2-methyl-3-chloro-5-nitrobenzoate to ethanol is 1:8.0-12.0 w / v.

[0017] Preferably, in step C, the volume ratio of ethyl 2-methyl-3-chloro-5-aminobenzoate to purified water is 1:2-4, and the volume ratio of ethyl 2-methyl-3-chloro-5-aminobenzoate to concentrated hydrochloric acid is 1:2-3.

[0018] The molar ratio of ethyl 2-methyl-3-chloro-5-aminobenzoate to sodium nitrite and fluoroboric acid is 1:1-1.05:1.0-1.2.

[0019] Preferably, in step D, the mass ratio of ethyl 2-methyl-3-chloro-5-diazofluoroborate benzoate powder to diethylene glycol dimethyl ether is 1:1-2.

[0020] The organic phase is washed with water 1-2 times before being dried with anhydrous sodium sulfate.

[0021] Preferably, the 3-chloro-5-fluoro-2-methylbenzoic acid product in step E is dissolved in hot water, activated carbon is added for decolorization, and after hot filtration, the filtrate is cooled to 0-5℃ for crystallization. The filter cake is filtered and dried to obtain pure 3-chloro-5-fluoro-2-methylbenzoic acid.

[0022] Preferably, the reaction temperature in step E is 80-85℃ and the reaction time is 6-8h;

[0023] The molar ratio of ethyl 2-methyl-3-chloro-5-fluorobenzoate to sodium hydroxide is 1:2.5-3.5, the ratio of ethyl 2-methyl-3-fluoro-5-aminobenzoate to the ethanol-water mixed solvent is 1:5-10, the volume ratio of ethanol to water in the ethanol-water mixed solvent is 1:1, and the acidification process involves adding concentrated hydrochloric acid until the pH of the system is 1-2.

[0024] Due to the adoption of the above technical solution, the beneficial effects of the present invention are:

[0025] 1. In the chlorination reaction, high-temperature concentrated sulfuric acid enhances the solubility of solid raw materials, preventing local aggregation of 2-methyl-5-nitrobenzoic acid due to its low solubility. This ensures uniform contact between 2-methyl-5-nitrobenzoic acid and dichlorohydantoin, fundamentally solving the problems of "undissolved materials and incomplete local reactions" in existing technologies. The batch feeding of 2-methyl-5-nitrobenzoic acid and dichlorohydantoin, combined with a reaction temperature of 78-82℃, allows for precise control of the chlorination reaction rate, reducing polychlorinated byproducts caused by excessively high local concentrations. This significantly improves the selectivity of ethyl 2-methyl-3-chloro-5-nitrobenzoate, laying the foundation for high purity in subsequent steps.

[0026] 2. Raney nickel acts as the main catalyst, efficiently activating hydrogen and catalyzing nitro reduction. Platinum-carbon, as a co-catalyst, effectively targets difficult-to-reduc sites, preventing intermediate product accumulation or catalyst poisoning, lowering the activation energy, and accelerating the conversion of nitro to amino groups. This allows the reaction to proceed under mild conditions of 0.3-0.5 MPa and 40-45°C, avoiding side reactions such as ester hydrolysis or aromatic ring hydrogenation caused by high temperature and pressure. Simultaneously, the dual-catalyst system significantly shortens the reaction time to the endpoint, and greatly reduces the residual nitro impurity content in the reduced product, ethyl 2-methyl-3-chloro-5-aminobenzoate, significantly improving intermediate purity and reducing interference from subsequent diazotization steps. The synergistic effect between the two catalysts makes the nitro reduction reaction more thorough and rapid, with a clear endpoint (determined by the cessation of hydrogen pressure drop), effectively avoiding side reactions such as over-reduction or dehalogenation.

[0027] 3. From the simplified one-pot chlorination-esterification process in step A, to the low-temperature diazotization and stable precipitation of fluoroborate in step C, to the efficient and stable thermal decomposition fluorination using diethylene glycol dimethyl ether as a solvent in step D, and the refining process of mild alkaline hydrolysis combined with activated carbon decolorization and recrystallization in step E, each step contributes to achieving a high-purity final product. In particular, the high-purity chlorinated intermediate in step A, the high-purity amino intermediate in step B, and the successful introduction of fluorine atoms in step D are interconnected and work synergistically to greatly reduce the generation and accumulation of by-products. This results in excellent chemical purity and overall process yield of the final product, 3-chloro-5-fluoro-2-methylbenzoic acid, fully meeting the high-quality requirements for pharmaceutical and pesticide intermediates. Attached Figure Description

[0028] Figure 1 This is a liquid chromatogram of the 3-chloro-5-fluoro-2-methylbenzoic acid product in Example 2 of the present invention. Detailed Implementation

[0029] The present invention will be further illustrated below with reference to the embodiments.

[0030] Example 1

[0031] A method for preparing 3-chloro-5-fluoro-2-methylbenzoic acid includes the following steps:

[0032] A: Concentrated sulfuric acid I was heated to 55℃, and then 100 kg of 2-methyl-5-nitrobenzoic acid and dichlorohydantoin were added to concentrated sulfuric acid I in two portions. After the addition was complete, the reaction was carried out at 78℃ for 18 h. After the reaction was completed, the temperature was lowered to room temperature, and ethanol and concentrated sulfuric acid II were added. The mixture was then refluxed at 75℃ for 7 h. The reaction solution was poured into ice water, stirred, filtered, and the filter cake was washed with water to obtain 113 kg of crude ethyl 2-methyl-3-chloro-5-nitrobenzoate. The molar ratio of 2-methyl-5-nitrobenzoic acid to dichlorohydantoin was 1:0.55, the ratio of 2-methyl-5-nitrobenzoic acid to concentrated sulfuric acid I was 1:4 w / v, the ratio of 2-methyl-5-nitrobenzoic acid to ethanol was 1:6 w / v, and the ratio of 2-methyl-5-nitrobenzoic acid to concentrated sulfuric acid II was 1:0.13 w / v.

[0033] Crude ethyl 2-methyl-3-chloro-5-nitrobenzoate was added to ethanol, heated to dissolve, then cooled to 0℃ to crystallize, filtered, and 106.5 kg of pure ethyl 2-methyl-3-chloro-5-nitrobenzoate was collected. The ratio of crude ethyl 2-methyl-3-chloro-5-nitrobenzoate to ethanol was 1:5 w / v.

[0034] B: Pure ethyl 2-methyl-3-chloro-5-nitrobenzoate was dissolved in ethanol, Raney nickel and platinum carbon were added, and hydrogen gas was introduced to a pressure of 0.3 MPa. The reaction was carried out at 40°C. The reaction endpoint was considered to be when the hydrogen pressure no longer decreased and was maintained for 1 hour. After the reaction was completed, the mixture was filtered and concentrated to obtain 101.5 kg of ethyl 2-methyl-3-chloro-5-aminobenzoate. In step B, the molar ratio of pure ethyl 2-methyl-3-chloro-5-nitrobenzoate to Raney nickel and platinum carbon was 1:0.08:0.02, and the ratio of the amount of pure ethyl 2-methyl-3-chloro-5-nitrobenzoate to ethanol added was 1:8.0 w / v.

[0035] C: Ethyl 2-methyl-3-chloro-5-aminobenzoate was added to purified water, and 20% wt sodium nitrite aqueous solution was added dropwise at 0℃ for 1 hour. After the addition was completed, the solution was kept at 0℃ for 0.5 hours. Then, 40% wt fluoroboric acid aqueous solution was added, and the mixture was stirred at 0℃ for another 0.5 hours. The mixture was filtered and dried to obtain 139.5 kg of ethyl 2-methyl-3-chloro-5-diazofluoroboronic acid benzoate powder. The volume ratio of ethyl 2-methyl-3-chloro-5-aminobenzoate to purified water was 1:2, the volume ratio of ethyl 2-methyl-3-chloro-5-aminobenzoate to concentrated hydrochloric acid was 1:2, and the molar ratio of ethyl 2-methyl-3-chloro-5-aminobenzoate to sodium nitrite and fluoroboric acid was 1:1:1.0.

[0036] D: 2-Methyl-3-chloro-5-diazofluoroborate ethyl benzoate powder was mixed with diethylene glycol dimethyl ether and heated to 100°C. After the nitrogen gas was completely released, the reaction solution was cooled to room temperature. Then, ethyl acetate was added to the reaction solution. The organic phase was washed once with water and dried with anhydrous sodium sulfate. The solution was then concentrated under vacuum, and the solvent was recovered to obtain 79.5 kg of 2-methyl-3-chloro-5-fluorobenzoate ethyl ester. The mass ratio of 2-methyl-3-chloro-5-diazofluoroborate ethyl benzoate powder to diethylene glycol dimethyl ether was 1:1.

[0037] E: Ethyl 2-methyl-3-chloro-5-fluorobenzoate was added to an ethanol-water mixed solvent, sodium hydroxide was added, and the reaction was carried out at 80°C for 6 hours. After the reaction was completed, the product was acidified, filtered, washed, and dried to obtain 3-chloro-5-fluoro-2-methylbenzoic acid. The molar ratio of ethyl 2-methyl-3-chloro-5-fluorobenzoate to sodium hydroxide was 1:2.5, the ratio of ethyl 2-methyl-3-fluoro-5-aminobenzoate to the ethanol-water mixed solvent was 1:5, the volume ratio of ethanol to water in the ethanol-water mixed solvent was 1:1, and the acidification process involved adding concentrated hydrochloric acid until the pH of the system reached 1.

[0038] The 3-chloro-5-fluoro-2-methylbenzoic acid product was dissolved in hot water, and activated carbon was added for decolorization. After hot filtration, the filtrate was cooled to 0°C to crystallize. The filter cake was filtered and dried to obtain 69.5 kg of pure 3-chloro-5-fluoro-2-methylbenzoic acid with a purity of 98.09%.

[0039] Example 2

[0040] A method for preparing 3-chloro-5-fluoro-2-methylbenzoic acid includes the following steps:

[0041] A: Concentrated sulfuric acid I was heated to 60°C, and then 100 kg of 2-methyl-5-nitrobenzoic acid and dichlorohydantoin were added to concentrated sulfuric acid I in three portions. After the addition was complete, the reaction was carried out at 80°C for 20 h. After the reaction was completed, the temperature was lowered to room temperature, and ethanol and concentrated sulfuric acid II were added. The mixture was then refluxed at 78°C for 8 h. The reaction solution was poured into ice water, stirred, filtered, and the filter cake was washed with water to obtain 2-methyl-3-chloro-5-nitrobenzoic acid. 114.5 kg of crude ethyl acetate was produced; the molar ratio of 2-methyl-5-nitrobenzoic acid to dichlorohydantoin was 1:0.60, the ratio of 2-methyl-5-nitrobenzoic acid to concentrated sulfuric acid I was 1:4.5 w / v, the ratio of 2-methyl-5-nitrobenzoic acid to ethanol was 1:6.5 w / v, and the ratio of 2-methyl-5-nitrobenzoic acid to concentrated sulfuric acid II was 1:0.15 w / v.

[0042] Crude ethyl 2-methyl-3-chloro-5-nitrobenzoate was added to ethanol, heated to dissolve, then cooled to 2°C to crystallize, filtered, and 108.5 kg of pure ethyl 2-methyl-3-chloro-5-nitrobenzoate was collected. The ratio of crude ethyl 2-methyl-3-chloro-5-nitrobenzoate to ethanol was 1:7 w / v.

[0043] B: Pure ethyl 2-methyl-3-chloro-5-nitrobenzoate was dissolved in ethanol, Raney nickel and platinum carbon were added, and hydrogen gas was introduced to a pressure of 0.4 MPa. The reaction was carried out at 42°C. The reaction endpoint was considered to be when the hydrogen pressure no longer decreased and was maintained for 1.5 h. After the reaction was completed, the mixture was filtered and concentrated to obtain 103.8 kg of ethyl 2-methyl-3-chloro-5-aminobenzoate. In step B, the molar ratio of pure ethyl 2-methyl-3-chloro-5-nitrobenzoate to Raney nickel and platinum carbon was 1:0.10:0.03, and the ratio of pure ethyl 2-methyl-3-chloro-5-nitrobenzoate to ethanol was 1:10 w / v.

[0044] C: Ethyl 2-methyl-3-chloro-5-aminobenzoate was added to 37% wt concentrated hydrochloric acid, and 25% wt sodium nitrite aqueous solution was added dropwise at 2℃ over 1.5 h. After the addition was complete, the solution was kept at 2℃ for 0.8 h, and then 45% wt fluoroboric acid aqueous solution was added. The mixture was stirred at 3℃ for another 0.8 h. After filtration and drying, 142.5 kg of ethyl 2-methyl-3-chloro-5-diazofluoroboronic acid benzoate powder was obtained. The volume ratio of ethyl 2-methyl-3-chloro-5-aminobenzoate to purified water was 1:3, the volume ratio of ethyl 2-methyl-3-chloro-5-aminobenzoate to concentrated hydrochloric acid was 1:2.5, and the molar ratio of ethyl 2-methyl-3-chloro-5-aminobenzoate to sodium nitrite and fluoroboric acid was 1:1.02:1.1.

[0045] D: 2-Methyl-3-chloro-5-diazofluoroborate ethyl benzoate powder was mixed with diethylene glycol dimethyl ether and heated to 120°C. After the nitrogen gas was completely released, the reaction solution was cooled to room temperature. Then, ethyl acetate was added to the reaction solution. The organic phase was washed twice with water and dried with anhydrous sodium sulfate. The solution was then concentrated under vacuum, and the solvent was recovered to obtain 81.8 kg of 2-methyl-3-chloro-5-fluorobenzoate ethyl ester. The mass ratio of 2-methyl-3-chloro-5-diazofluoroborate ethyl benzoate powder to diethylene glycol dimethyl ether was 1:1.5.

[0046] E: Ethyl 2-methyl-3-chloro-5-fluorobenzoate was added to an ethanol-water mixed solvent, sodium hydroxide was added, and the reaction was carried out at 82°C for 7 hours. After the reaction was completed, the product was acidified, filtered, washed, and dried to obtain 3-chloro-5-fluoro-2-methylbenzoic acid. The molar ratio of ethyl 2-methyl-3-chloro-5-fluorobenzoate to sodium hydroxide was 1:3.0, the ratio of ethyl 2-methyl-3-fluoro-5-aminobenzoate to the ethanol-water mixed solvent was 1:8, the volume ratio of ethanol to water in the ethanol-water mixed solvent was 1:1, and the acidification process involved adding concentrated hydrochloric acid until the pH of the system reached 2.

[0047] The 3-chloro-5-fluoro-2-methylbenzoic acid product was dissolved in hot water, and activated carbon was added for decolorization. After hot filtration, the filtrate was cooled to 3°C to crystallize. The filter cake was filtered and dried to obtain 71.5 kg of pure 3-chloro-5-fluoro-2-methylbenzoic acid with a purity of 98.70%.

[0048] Example 3

[0049] A method for preparing 3-chloro-5-fluoro-2-methylbenzoic acid includes the following steps:

[0050] A: Concentrated sulfuric acid I was heated to 65℃, and then 100 kg of 2-methyl-5-nitrobenzoic acid and dichlorohydantoin were added to concentrated sulfuric acid I in three portions. After the addition was complete, the reaction was carried out at 82℃ for 22 h. After the reaction was completed, the temperature was lowered to room temperature, and ethanol and concentrated sulfuric acid II were added. The mixture was then refluxed at 80℃ for 9 h. The reaction solution was poured into ice water, stirred, filtered, and the filter cake was washed with water to obtain 113.8 kg of crude ethyl 2-methyl-3-chloro-5-nitrobenzoate. The molar ratio of 2-methyl-5-nitrobenzoic acid to dichlorohydantoin was 1:0.65, the ratio of 2-methyl-5-nitrobenzoic acid to concentrated sulfuric acid I was 1:5 w / v, the ratio of 2-methyl-5-nitrobenzoic acid to ethanol was 1:7 w / v, and the ratio of 2-methyl-5-nitrobenzoic acid to concentrated sulfuric acid II was 1:0.16 w / v.

[0051] Crude ethyl 2-methyl-3-chloro-5-nitrobenzoate was added to ethanol, heated to dissolve, then cooled to 5°C to crystallize, filtered, and 107.5 kg of pure ethyl 2-methyl-3-chloro-5-nitrobenzoate was collected. The ratio of crude ethyl 2-methyl-3-chloro-5-nitrobenzoate to ethanol was 1:8 w / v.

[0052] B: Pure ethyl 2-methyl-3-chloro-5-nitrobenzoate was dissolved in ethanol, Raney nickel and platinum carbon were added, hydrogen gas was introduced to a pressure of 0.5 MPa, and the reaction was carried out at 45°C. The reaction endpoint was considered to be when the hydrogen pressure no longer decreased and was maintained for 2 hours. After the reaction was completed, the mixture was filtered and concentrated to obtain 102.5 kg of ethyl 2-methyl-3-chloro-5-aminobenzoate. In step B, the molar ratio of pure ethyl 2-methyl-3-chloro-5-nitrobenzoate to Raney nickel and platinum carbon was 1:0.12:0.04, and the ratio of pure ethyl 2-methyl-3-chloro-5-nitrobenzoate to ethanol was 1:12.0 w / v.

[0053] C: Ethyl 2-methyl-3-chloro-5-aminobenzoate was added to 38% wt concentrated hydrochloric acid, and 30% wt sodium nitrite aqueous solution was added dropwise at 5°C over 2 hours. After the addition was complete, the solution was kept at 5°C for 1 hour. Then, 50% wt fluoroboric acid aqueous solution was added, and the mixture was stirred at 5°C for another hour. The mixture was filtered and dried to obtain 141.0 kg of ethyl 2-methyl-3-chloro-5-diazofluoroboronic acid benzoate powder. The volume ratio of ethyl 2-methyl-3-chloro-5-aminobenzoate to purified water was 1:4, the volume ratio of ethyl 2-methyl-3-chloro-5-aminobenzoate to concentrated hydrochloric acid was 1:3, and the molar ratio of ethyl 2-methyl-3-chloro-5-aminobenzoate to sodium nitrite and fluoroboric acid was 1:1.05:1.2.

[0054] D: 2-Methyl-3-chloro-5-diazofluoroborate ethyl benzoate powder was mixed with diethylene glycol dimethyl ether and heated to 130°C. After the nitrogen gas was completely released, the reaction solution was cooled to room temperature. Then, ethyl acetate was added to the reaction solution. The organic phase was washed twice with water and dried with anhydrous sodium sulfate. The solution was then concentrated under vacuum, and the solvent was recovered to obtain 80.2 kg of 2-methyl-3-chloro-5-fluorobenzoate ethyl ester. The mass ratio of 2-methyl-3-chloro-5-diazofluoroborate ethyl benzoate powder to diethylene glycol dimethyl ether was 1:2.

[0055] E: Ethyl 2-methyl-3-chloro-5-fluorobenzoate was added to an ethanol-water mixed solvent, sodium hydroxide was added, and the reaction was carried out at 85°C for 8 hours. After the reaction was completed, the product was acidified, filtered, washed, and dried to obtain 3-chloro-5-fluoro-2-methylbenzoic acid. The molar ratio of ethyl 2-methyl-3-chloro-5-fluorobenzoate to sodium hydroxide was 1:3.5, the ratio of ethyl 2-methyl-3-fluoro-5-aminobenzoate to the ethanol-water mixed solvent was 1:10, the volume ratio of ethanol to water in the ethanol-water mixed solvent was 1:1, and the acidification process involved adding concentrated hydrochloric acid until the pH of the system reached 2.

[0056] The 3-chloro-5-fluoro-2-methylbenzoic acid product was dissolved in hot water, and activated carbon was added for decolorization. After hot filtration, the filtrate was cooled to 5°C to crystallize. The filter cake was filtered and dried to obtain 70.3 kg of pure 3-chloro-5-fluoro-2-methylbenzoic acid with a purity of 98.19%.

[0057] Comparative Example 1

[0058] After heating concentrated sulfuric acid I to 55°C, all of the 2-methyl-5-nitrobenzoic acid and dichlorohydantoin were added at once. The remaining steps and control parameters were exactly the same as those in Example 2, yielding 65.0 kg of pure 3-chloro-5-fluoro-2-methylbenzoic acid with a purity of 95.2%.

[0059] Comparative Example 2

[0060] In step B, only Raney nickel was used as the catalyst, and its molar feed amount was the same as the total amount of the original dual catalysts. The remaining steps and control parameters were exactly the same as those in Example 2, yielding 67.5 kg of pure 3-chloro-5-fluoro-2-methylbenzoic acid with a purity of 96.5%.

[0061] Comparative Example 3

[0062] In step D, an equal amount of ethylene glycol dimethyl ether was used instead of diethylene glycol dimethyl ether as the thermal decomposition solvent. The remaining steps and control parameters were exactly the same as in Example 2, yielding 62.0 kg of pure 3-chloro-5-fluoro-2-methylbenzoic acid with a purity of 96.1%.

[0063] Comparative Example 4

[0064] In step A, concentrated sulfuric acid I is not preheated. At room temperature (about 25°C), 2-methyl-5-nitrobenzoic acid and dichlorohydantoin are added directly in 2-3 portions. The remaining steps and control parameters are exactly the same as in Example 2, yielding 60.0 kg of pure 3-chloro-5-fluoro-2-methylbenzoic acid with a purity of 94.7%.

[0065] It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing 3-chloro-5-fluoro-2-methylbenzoic acid, characterized in that... Includes the following steps: A: 2-Methyl-5-nitrobenzoic acid and dichlorohydantoin were added in 2-3 portions to concentrated sulfuric acid I preheated to 55-65℃ and reacted at 78-82℃ for 18-22 hours. After the reaction was completed, the mixture was cooled to room temperature, and ethanol and concentrated sulfuric acid II were added. The mixture was then refluxed at 75-80℃ for 7-9 hours. The reaction solution was poured into ice water, stirred, filtered, and the filter cake was washed with water to obtain crude ethyl 2-methyl-3-chloro-5-nitrobenzoate. The crude ethyl 2-methyl-3-chloro-5-nitrobenzoate was added to ethanol, heated to dissolve, and then cooled to 0-5℃ to crystallize. The crystals were filtered, and the obtained 2-methyl... The pure product is ethyl 3-chloro-5-nitrobenzoate, wherein the molar ratio of 2-methyl-5-nitrobenzoic acid to dichlorohydantoin is 1:0.55-0.65, the ratio of 2-methyl-5-nitrobenzoic acid to concentrated sulfuric acid I is 1:4-5 w / v, the ratio of 2-methyl-5-nitrobenzoic acid to ethanol is 1:6-7 w / v, the ratio of 2-methyl-5-nitrobenzoic acid to concentrated sulfuric acid II is 1:0.13-0.16 w / v, and the ratio of crude ethyl 2-methyl-3-chloro-5-nitrobenzoate to ethanol is 1:5-8 w / v. B: Pure ethyl 2-methyl-3-chloro-5-nitrobenzoate was dissolved in ethanol, Raney nickel and platinum carbon were added, and hydrogen gas was introduced. After the reaction was completed, the mixture was filtered and concentrated to obtain ethyl 2-methyl-3-chloro-5-aminobenzoate. During the reaction, hydrogen gas was introduced to a pressure of 0.3-0.5 MPa and the reaction was carried out at 40-45℃. The reaction endpoint was considered to be when the hydrogen pressure no longer decreased and was maintained for 1-2 hours. The molar ratio of pure ethyl 2-methyl-3-chloro-5-nitrobenzoate to Raney nickel and platinum carbon is 1:0.08-0.12:0.02-0.04, and the ratio of pure ethyl 2-methyl-3-chloro-5-nitrobenzoate to ethanol is 1:8.0-12.0 w / v. C: Ethyl 2-methyl-3-chloro-5-aminobenzoate was added to purified water or concentrated hydrochloric acid, sodium nitrite aqueous solution was added dropwise, and then fluoroboric acid aqueous solution was added. The mixture was stirred at 0-5℃ for 0.5-1h, filtered and dried to obtain ethyl 2-methyl-3-chloro-5-diazofluoroboronic acid benzoate powder. The volume ratio of ethyl 2-methyl-3-chloro-5-aminobenzoate to purified water is 1:2-4, and the volume ratio of ethyl 2-methyl-3-chloro-5-aminobenzoate to concentrated hydrochloric acid is 1:2-3. The molar ratio of ethyl 2-methyl-3-chloro-5-aminobenzoate to sodium nitrite and fluoroboric acid is 1:1-1.05:1.0-1.

2. D: 2-Methyl-3-chloro-5-diazofluoroborate ethyl benzoate powder is mixed with diethylene glycol dimethyl ether and heated to 100-130℃. After the nitrogen gas is completely released, the reaction solution is cooled to room temperature. Then, ethyl acetate is added to the reaction solution. The organic phase is dried over anhydrous sodium sulfate, concentrated under vacuum, and the solvent is recovered to obtain 2-methyl-3-chloro-5-fluorobenzoate ethyl ester. The mass ratio of ethyl benzoate powder of 2-methyl-3-chloro-5-diazofluoroborate to diethylene glycol dimethyl ether is 1:1-2. The organic phase is washed with water 1-2 times before drying with anhydrous sodium sulfate. E: Ethyl 2-methyl-3-chloro-5-fluorobenzoate was added to an ethanol-water mixed solvent, and sodium hydroxide was added to react. After the reaction was completed, the product was acidified, filtered, washed, and dried to obtain 3-chloro-5-fluoro-2-methylbenzoic acid. The 3-chloro-5-fluoro-2-methylbenzoic acid product was dissolved in hot water, and activated carbon was added for decolorization. After hot filtration, the filtrate was cooled to 0-5℃ to crystallize. The filter cake was filtered and dried to obtain pure 3-chloro-5-fluoro-2-methylbenzoic acid. The reaction temperature is 80-85℃, and the reaction time is 6-8h. The molar ratio of ethyl 2-methyl-3-chloro-5-fluorobenzoate to sodium hydroxide is 1:2.5-3.5, the ratio of ethyl 2-methyl-3-fluoro-5-aminobenzoate to the ethanol-water mixed solvent is 1:5-10, the volume ratio of ethanol to water in the ethanol-water mixed solvent is 1:1, and the acidification process involves adding concentrated hydrochloric acid until the pH of the system is 1-2.

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