Synthesis method of 2-chloro-3-methyl-4-methylthio benzoic acid

Abstract

The invention relates to the technical field of compound synthesis, in particular to a synthesis method of 2-chloro-3-methyl-4-methylthiobenzoic acid, which comprises the following steps: reacting raw materials such as trichloroacetyl chloride, 3-chloro-2-methylphenyl dimethyl sulfide and the like to produce 2, 2, 2-trichloro-1-(2-chloro-3-methyl-4-methylsulfuryl phenyl)-ethanone, then carrying out haloform reaction on the 2, 2, 2-trichloro-1-(2-chloro-3-methyl-4-methylsulfuryl phenyl)-ethanone and liquid caustic soda to obtain 2, 2, 2-trichloro-1-(2-chloro-3-methyl-4-methylthiobenzoic acid. And after the reaction is finished, neutralizing to obtain the 2-chloro-3-methyl-4-methylthio benzoic acid. The method solves the problems of large equipment investment, high cost, high three-waste content and high safety risk in the prior art, reduces reaction steps, improves the total yield, reduces the reaction cost, is easy to operate, improves the process safety and environmental protection property, and produces few three wastes.

Description

Technical Field

[0001] This invention relates to the field of compound synthesis technology, and specifically to a method for synthesizing 2-chloro-3-methyl-4-methylthiobenzoic acid. Background Technology

[0002] p-Hydroxyphenylpyruvate dioxygenase, also known as HPPD, is one of the most important targets for herbicides. This inhibitory class of herbicides holds a significant position among the 18 classes of herbicides globally, accounting for 5.8% of the global herbicide market. These herbicides are known for their broad spectrum, high efficacy, and slow resistance development. Cyclosulfonyl and furazolidone are triketone herbicides in the HPPD series. Cyclosulfonyl has higher activity than mesosulfonyl and is safer for crops, primarily used for weed control in corn fields, offering a broad spectrum of weed control. Furazolidone, on the other hand, is mainly used for weed control in rice paddies.

[0003] 2-Chloro-3-methyl-4-methanesulfonylbenzoic acid is a key intermediate in the synthesis of cyclosulfonone and furazolidone. In existing technologies, 2-chloro-3-methyl-4-methanesulfonylbenzoic acid is generally prepared using the haloform reaction mechanism, but this requires the use of large amounts of sodium hypochlorite and liquid alkali. On average, about 15 tons of acidic wastewater are generated per ton of product, with an inorganic salt content of up to 2 tons. The resulting wastewater and solid waste volume is large, which contradicts the currently advocated green chemistry.

[0004] CN118619857A discloses a method for preparing 2-chloro-3-methyl-4-methanesulfonylbenzoic acid. The method involves dissolving 2-chloro-3-methyl-4-methanesulfonylacetophenone in an organic solvent, then introducing chlorine gas to induce a chlorination reaction, followed by hydrolysis and acidification to obtain 2-chloro-3-methyl-4-methanesulfonylbenzoic acid. This method requires the introduction of chlorine gas, which is time-consuming, causes significant equipment corrosion, and has low production efficiency.

[0005] CN112194603A discloses a method for preparing 2-chloro-3-methyl-4-methanesulfonylbenzoic acid, in which 2-chloro-3-methyl-4-methanesulfonylacetophenone and an oxidant react under the catalysis of a metal catalyst to obtain the 2-chloro-3-methyl-4-methanesulfonylbenzoic acid. This method requires high-pressure reaction conditions, places high demands on equipment, and the oxidation reaction under high temperature and pressure is prone to runaway, posing a high risk to production.

[0006] Through production practice, 2-chloro-3-methyl-4-methylthiobenzoic acid can be obtained by hydrogen peroxide oxidation. However, since 2-chloro-3-methyl-4-methylthiobenzoic acid is not suitable for industrial production, the synthesis of 2-chloro-3-methyl-4-methylthiobenzoic acid still faces problems such as large equipment investment, high cost, high levels of waste, and high safety risks. Summary of the Invention

[0007] The purpose of this invention is to provide a method for synthesizing 2-chloro-3-methyl-4-methanesulfonylbenzoic acid, an intermediate suitable for industrial production, which solves the problems of high equipment investment, high cost, high levels of waste, and high safety risks in existing technologies. This method reduces reaction steps, increases the overall yield, lowers reaction costs, is easy to operate, improves process safety and environmental protection, and produces less waste.

[0008] The technical solution of this invention is:

[0009] A method for synthesizing 2-chloro-3-methyl-4-methylthiobenzoic acid, the key technical points of which include the following steps:

[0010] Step 1: First, add the solvent and Lewis acid to the reactor, start stirring, control the reaction temperature within the set range, then add 3-chloro-2-methylphenyl methyl sulfide to the reactor, and then add a mixture of trichloroacetyl chloride and solvent dropwise. After the dropwise addition is complete, continue to keep the reaction at the set temperature for a set time, take a sample for testing until the reaction is complete, then quench the system with water and separate the organic phase for later use.

[0011] Step 2: Add 15% liquid alkali to another reactor, add the organic phase separated in Step 1 dropwise to the reactor, continue to keep the reaction at the set temperature for a set time, take a sample for testing until the reaction is complete, and separate the organic phase.

[0012] Step 3: Add 15% acid to the organic phase separated in Step 2, adjust the pH to the set value, separate the liquid and add anhydrous sodium sulfate to dehydrate and obtain the organic phase;

[0013] Step 4: Add activated carbon to the organic phase of step 3, stir for a set time at a set temperature to decolorize, stir and keep warm for a set time, filter, desolvent, and dry to obtain the target product 2-chloro-3-methyl-4-methylthiobenzoic acid.

[0014] In the above-mentioned method for synthesizing 2-chloro-3-methyl-4-methylthiobenzoic acid, in step 1, the solvent is one of dichloromethane, dichloroethane, and tetrahydrofuran.

[0015] In the above-mentioned method for synthesizing 2-chloro-3-methyl-4-methylthiobenzoic acid, the reaction temperature in step 1 is 0–15 °C.

[0016] In the above-described method for synthesizing 2-chloro-3-methyl-4-methylthiobenzoic acid, in step 1, the molar ratio of 3-chloro-2-methylphenyl methyl sulfide to trichloroacetyl chloride is 1:1.5 to 1:1.

[0017] In the above-described method for synthesizing 2-chloro-3-methyl-4-methylthiobenzoic acid, in step 1, the Lewis acid is aluminum trichloride.

[0018] In the above-described method for synthesizing 2-chloro-3-methyl-4-methylthiobenzoic acid, in step 1, the molar ratio of the Lewis acid to 3-chloro-2-methylphenyl methyl sulfide is 1:1 to 1.5:1.

[0019] In the above-mentioned method for synthesizing 2-chloro-3-methyl-4-methylthiobenzoic acid, the reaction temperature in step 2 is 15℃~30℃.

[0020] In the above-described method for synthesizing 2-chloro-3-methyl-4-methylthiobenzoic acid, the liquid alkali is a sodium hydroxide solution, and the acid is either hydrochloric acid or sulfuric acid.

[0021] The beneficial effects of this invention are:

[0022] 1. This synthetic method uses trichloroacetyl chloride and 3-chloro-2-methylphenyl methyl sulfide as raw materials to produce 2,2,2-trichloro-1-(2-chloro-3-methyl-4-methylthiophenyl)-ethyl ketone, which then undergoes a haloform reaction with liquid alkali. After the reaction is complete, neutralization yields 2-chloro-3-methyl-4-methylthiobenzoic acid. The use of trichloroacetyl chloride instead of acetyl chloride and sodium hypochlorite eliminates the need for an oxidizing agent, reducing reaction steps, increasing the overall yield, and offering advantages in cost control. Furthermore, the reaction conditions are relatively simple, reducing reaction costs.

[0023] 2. This synthesis method uses a haloform reaction instead of an oxidation reaction to prepare formic acid, which is easy to operate, improves process safety and environmental protection, and produces less waste.

[0024] Based on the above, this invention proposes a new synthetic process route suitable for industrial production, which can achieve high selectivity, high yield, safe and environmentally friendly process, high quality and low cost production of 2-chloro-3-methyl-4-methylthiobenzoic acid pharmaceutical intermediate, suitable for industrial promotion and application. Detailed Implementation

[0025] The technical solution of the present invention will be described below through specific embodiments.

[0026] The synthetic method for 2-chloro-3-methyl-4-methylthiobenzoic acid is as follows:

[0027]

[0028] The specific synthesis steps are as follows:

[0029] Step 1: First, add the solvent and Lewis acid to the reactor, start stirring, control the reaction temperature within the set range, then add 3-chloro-2-methylphenyl methyl sulfide to the reactor, and then add a mixture of trichloroacetyl chloride and solvent dropwise. After the addition is complete, continue to keep the reaction at the set temperature for the set time, take a sample for testing until the reaction is complete, then quench the system with water and separate the organic phase for later use.

[0030] The solvent is one of dichloromethane, dichloroethane, and tetrahydrofuran; the reaction temperature is 0–15°C, preferably 0–5°C; the molar ratio of 3-chloro-2-methylphenyl methyl sulfide to trichloroacetyl chloride is 1:1.5–1:1, preferably 1:1.5–1:1.15; the Lewis acid is aluminum trichloride; the molar ratio of the Lewis acid to 3-chloro-2-methylphenyl methyl sulfide is 1:1–1.5:1, preferably 1.3:1–1.5:1.

[0031] Step 2: Add 15% liquid alkali to another reactor, and add the organic phase separated in Step 1 dropwise to the reactor. After the addition is complete, continue the reaction at the set temperature for a set time, then take a sample for testing until the reaction is complete and the organic phase is separated. The reaction temperature is 15℃~30℃, preferably 25℃~30℃. The liquid alkali is a sodium hydroxide solution.

[0032] Step 3: Add 15% acid to the organic phase from Step 2, adjust the pH to the specified value, separate the layers, and add anhydrous sodium sulfate to dehydrate and obtain the organic phase. The acid is either hydrochloric acid or sulfuric acid.

[0033] Step 4: Add activated carbon to the organic phase of step 3, stir at 50°C for 0.5 h for decolorization, keep stirring and heat for a set time, filter, remove solvent, dry, and obtain the target product 2-chloro-3-methyl-4-methylthiobenzoic acid.

[0034] Example 1.

[0035] Step 1: Add 150g of dichloroethane and 34.7g of aluminum trichloride to a 500mL reactor. Start stirring and control the reaction temperature at 0-5℃. Add 34.4g of 3-chloro-2-methylphenyl methyl sulfide to the reactor, and then add a mixture of 38.2g of trichloroacetyl chloride and 50g of dichloroethane dropwise. After the addition is complete, continue the reaction at this temperature for 2 hours. Take a sample for testing until the reaction is complete. Quench the system with water, separate the organic phase, wash it once more with water, and separate the organic phase for later use. The molar ratio of 3-chloro-2-methylphenyl methyl sulfide to trichloroacetyl chloride is 1:1.05; the molar ratio of aluminum trichloride to 3-chloro-2-methylphenyl methyl sulfide is 1.3:1.

[0036] Step 2: Add 160g of 15% liquid alkali to another 500mL reactor, turn on the stirrer, and add the organic phase separated in Step 1 dropwise into the reactor. After the addition is complete, maintain the temperature at 25-30℃ for 6 hours. Take a sample for testing until the reaction is complete, let it stand and separate the liquid to retain the organic phase, and wash the organic phase once with water.

[0037] Step 3: Add 15% acid to the organic phase from Step 2, adjust the pH to 2-3, separate the liquids, add anhydrous sodium sulfate to dehydrate and obtain the organic phase.

[0038] Step 4: Add activated carbon to the organic phase of step 3 for decolorization. Stir at 50°C for 0.5 h for decolorization. Stir and keep warm for a set time. After filtration, remove solvent and dry to obtain 40.6 g of the target product 2-chloro-3-methyl-4-methylthiobenzoic acid with a purity of 99.1% and a total yield of 94.0%.

[0039] Example 2.

[0040] Step 1: Add 150g of dichloroethane and 34.7g of aluminum trichloride to a 500mL reactor. Start stirring and control the reaction temperature at 5-10℃. Add 34.4g of 3-chloro-2-methylphenyl methyl sulfide to the reactor, and then add a mixture of 43.6g of trichloroacetyl chloride and 50g of dichloroethane dropwise. After the addition is complete, continue the reaction at this temperature for 2 hours. Take a sample for testing until the reaction is complete. Quench the system with water, separate the organic phase, wash it once with water, and separate the organic phase for later use. The molar ratio of 3-chloro-2-methylphenyl methyl sulfide to trichloroacetyl chloride is 1:1.2; the molar ratio of Lewis acid to 3-chloro-2-methylphenyl methyl sulfide is 1.3:1.

[0041] Step 2: Add 160g of 15% liquid alkali to another 500mL reactor and start stirring. Add the organic phase separated in Step 1 dropwise to the reactor. After the addition is complete, maintain the temperature at 25-30℃ and react for 6 hours. Take a sample for testing until the reaction is complete. Allow the mixture to stand, separate the liquids, and retain the organic phase. Wash the organic phase once with water.

[0042] Step 3: Add 15% acid to the organic phase from Step 2, adjust the pH to 2-3, separate the liquids, add anhydrous sodium sulfate to dehydrate and obtain the organic phase; after decolorization with activated carbon, remove solvent and dry to obtain 41.5g of the target product 2-chloro-3-methyl-4-methylthiobenzoic acid, with a purity of 99.0% and an overall yield of 96.0%.

[0043] Example 3.

[0044] Step 1: Add 150g of dichloroethane and 34.7g of aluminum trichloride to a 500mL reactor. Start stirring and control the reaction temperature at 5-10℃. Add 34.4g of 3-chloro-2-methylphenyl methyl sulfide to the reactor, and dropwise add a mixture of 50.9g of trichloroacetyl chloride and 50g of dichloroethane. After the addition is complete, continue the reaction at this temperature for 2 hours. Take a sample for testing until the reaction is complete. Quench the system with water, separate the organic phase, wash it once with water, and separate the organic phase for later use. The molar ratio of 3-chloro-2-methylphenyl methyl sulfide to trichloroacetyl chloride is 1:1.4; the molar ratio of Lewis acid to 3-chloro-2-methylphenyl methyl sulfide is 1.3:1.

[0045] Step 2: Add 160g of 15% liquid alkali to another 500mL reactor and start stirring. Add the organic phase separated in Step 1 dropwise to the reactor. After the addition is complete, maintain the temperature at 25-30℃ and react for 6 hours. Take a sample for testing until the reaction is complete. Allow the mixture to stand, separate the liquids, and retain the organic phase. Wash the organic phase once with water.

[0046] Step 3: Add 15% acid to the organic phase from Step 2, adjust the pH to 2-3, separate the liquids, add anhydrous sodium sulfate to dehydrate and obtain the organic phase; after decolorization with activated carbon, remove solvent and dry to obtain 39.5g of the target product 2-chloro-3-methyl-4-methylthiobenzoic acid, with a purity of 98.9% and an overall yield of 91.4%.

[0047] Example 4.

[0048] Step 1: Add 150g of dichloroethane and 29.4g of aluminum trichloride to a 500mL reactor. Start stirring and control the reaction temperature at 5-10℃. Add 34.4g of 3-chloro-2-methylphenyl methyl sulfide to the reactor, and then add a mixture of 43.6g of trichloroacetyl chloride and 50g of dichloroethane dropwise. After the addition is complete, continue the reaction at this temperature for 2 hours. Take a sample for analysis until the reaction is complete. Quench the system with water, separate the organic phase, wash it once more with water, and separate the organic phase for later use. The molar ratio of 3-chloro-2-methylphenyl methyl sulfide to trichloroacetyl chloride is 1:1.2; the molar ratio of Lewis acid to 3-chloro-2-methylphenyl methyl sulfide is 1.1:1.

[0049] Step 2: Add 160g of 15% liquid alkali to another 500mL reactor and start stirring. Add the organic phase separated in Step 1 dropwise to the reactor. After the addition is complete, maintain the temperature at 25-30℃ and react for 6 hours. Take a sample for testing until the reaction is complete. Allow the mixture to stand, separate the liquids, and retain the organic phase. Wash the organic phase once with water.

[0050] Step 3: Add 15% acid to the organic phase from Step 2, adjust the pH to 2-3, separate the liquids, add anhydrous sodium sulfate to dehydrate and obtain the organic phase; after decolorization with activated carbon, remove solvent and dry to obtain 37.1g of the target product 2-chloro-3-methyl-4-methylthiobenzoic acid, with a purity of 99.0% and an overall yield of 85.8%.

[0051] Example 5.

[0052] Step 1: Add 150g of dichloroethane and 37.3g of aluminum trichloride to a 500mL reactor. Start stirring and control the reaction temperature at 5-10℃. Add 34.4g of 3-chloro-2-methylphenyl methyl sulfide to the reactor, and then add a mixture of 43.6g of trichloroacetyl chloride and 50g of dichloroethane dropwise. After the addition is complete, continue the reaction at this temperature for 2 hours. Take a sample for analysis until the reaction is complete. Quench the system with water, separate the organic phase, wash it once more with water, and separate the organic phase for later use. The molar ratio of 3-chloro-2-methylphenyl methyl sulfide to trichloroacetyl chloride is 1:1.2; the molar ratio of Lewis acid to 3-chloro-2-methylphenyl methyl sulfide is 1.4:1.

[0053] Step 2: Add 160g of 15% liquid alkali to another 500mL reactor and start stirring. Add the organic phase separated in Step 1 dropwise to the reactor. After the addition is complete, maintain the temperature at 25-30℃ and react for 6 hours. Take a sample for testing until the reaction is complete. Allow the mixture to stand, separate the liquids, and retain the organic phase. Wash the organic phase once with water.

[0054] Step 3: Add 15% acid to the organic phase from Step 2, adjust the pH to 2-3, separate the liquids, add anhydrous sodium sulfate to dehydrate and obtain the organic phase; after decolorization with activated carbon, remove solvent and dry to obtain 40.5g of the target product 2-chloro-3-methyl-4-methylthiobenzoic acid, with a purity of 99.0% and an overall yield of 93.9%.

[0055] Example 6.

[0056] Step 1: Add 150g of dichloroethane and 40.0g of aluminum trichloride to a 500mL reactor. Start stirring and control the reaction temperature at 5-10℃. Add 34.4g of 3-chloro-2-methylphenyl methyl sulfide to the reactor, and dropwise add a mixture of 43.6g of trichloroacetyl chloride and 50g of dichloroethane. After the addition is complete, continue the reaction at this temperature for 2 hours. Take a sample for testing until the reaction is complete. Quench the system with water, separate the organic phase, wash once with water, and separate the organic phase for later use. The molar ratio of 3-chloro-2-methylphenyl methyl sulfide to trichloroacetyl chloride is 1:1.2; the molar ratio of Lewis acid to 3-chloro-2-methylphenyl methyl sulfide is 1.5:1.

[0057] Step 2: Add 160g of 15% liquid alkali to another 500mL reactor and start stirring. Add the organic phase separated in Step 1 dropwise to the reactor. After the addition is complete, maintain the temperature at 25-30℃ and react for 6 hours. Take a sample for testing until the reaction is complete. Allow the mixture to stand, separate the liquids, and retain the organic phase. Wash the organic phase once with water.

[0058] Step 3: Add 15% acid to the organic phase from Step 2, adjust the pH to 2-3, separate the liquids, add anhydrous sodium sulfate to dehydrate and obtain the organic phase; after decolorization with activated carbon, remove solvent, dry, and obtain 38.1g of the target product 2-chloro-3-methyl-4-methylthiobenzoic acid with a purity of 99.0% and an overall yield of 88.0%.

[0059] The embodiments of the present invention have been described in detail above, but the content described is only a preferred embodiment of the present invention and should not be considered as limiting the scope of the present invention. All equivalent changes and improvements made within the scope of the present invention should still fall within the scope of the present invention.

Claims

1. A method for synthesizing 2-chloro-3-methyl-4-methylthiobenzoic acid, characterized in that, Includes the following steps: Step 1: First, add the solvent and Lewis acid to the reactor, start stirring, control the reaction temperature within the set range, then add 3-chloro-2-methylphenyl methyl sulfide to the reactor, and then add a mixture of trichloroacetyl chloride and solvent dropwise. After the dropwise addition is complete, continue to keep the reaction at the set temperature for a set time, take a sample for testing until the reaction is complete, then quench the system with water and separate the organic phase for later use. Step 2: Add 15% liquid alkali to another reactor, add the organic phase separated in Step 1 dropwise to the reactor, continue to keep the reaction at the set temperature for a set time, take a sample for testing until the reaction is complete, and separate the organic phase. Step 3: Add 15% acid to the organic phase separated in Step 2, adjust the pH to the set value, separate the liquid and add anhydrous sodium sulfate to dehydrate and obtain the organic phase; Step 4: Add activated carbon to the organic phase of step 3, stir for a set time at a set temperature to decolorize, stir and keep warm for a set time, filter, desolvent, and dry to obtain the target product 2-chloro-3-methyl-4-methylthiobenzoic acid.

2. The method for synthesizing 2-chloro-3-methyl-4-methylthiobenzoic acid according to claim 1, characterized in that: In step 1, the solvent is one of dichloromethane, dichloroethane, and tetrahydrofuran.

3. The method for synthesizing 2-chloro-3-methyl-4-methylthiobenzoic acid according to claim 1, characterized in that: In step 1, the reaction temperature is 0–15°C.

4. The method for synthesizing 2-chloro-3-methyl-4-methylthiobenzoic acid according to claim 1, characterized in that: In step 1, the molar ratio of 3-chloro-2-methylphenyl methyl sulfide to trichloroacetyl chloride is 1:1.5 to 1:

1.

5. The method for synthesizing 2-chloro-3-methyl-4-methylthiobenzoic acid according to claim 1, characterized in that: In step 1, the Lewis acid is aluminum trichloride.

6. The method for synthesizing 2-chloro-3-methyl-4-methylthiobenzoic acid according to claim 1, characterized in that: In step 1, the molar ratio of the Lewis acid to 3-chloro-2-methylphenyl methyl sulfide is 1:1 to 1.5:

1.

7. The method for synthesizing 2-chloro-3-methyl-4-methylthiobenzoic acid according to claim 1, characterized in that: In step 2, the reaction temperature is 15℃~30℃.

8. The method for synthesizing 2-chloro-3-methyl-4-methylthiobenzoic acid according to claim 1, characterized in that: The liquid alkali is a sodium hydroxide solution, and the acid is either hydrochloric acid or sulfuric acid.

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