A method for synthesizing 4-methylsulfonyl toluene

Abstract

The application belongs to the technical field of chemical synthesis, and particularly relates to a synthesis method of 4-methylsulfonyl toluene. Specifically, 4-methylsulfonamide chloride is used as raw material, and under the action of a catalyst, the raw material is reacted with chloromethane Grignard solution at normal pressure, and high-yield and high-purity 4-methylsulfonyl toluene is obtained after purification. The method has the advantages of simple steps, high yield, almost no other impurities, high atomic utilization rate, easy industrialization, and good application value.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for synthesizing 4-methylsulfonyl toluene. Background Technology

[0002] 4-Methylsulfonyltoluene is an important pharmaceutical and pesticide intermediate, used in herbicides such as nifedipine, antibiotics such as methotrexate, and veterinary antibacterial drugs such as fluprofen, and has significant value. Current reaction routes can be divided into three types: 1) As in patents CN105566181A and CN107089935A: using 4-toluenesulfonyl chloride as a raw material, it is reduced with sodium sulfite to obtain sodium 4-methylbenzenesulfinate, which is then methylated via chloromethane / dimethyl sulfate to obtain 4-methylsulfonyltoluene, with a yield of 78-82%. Although this method uses inexpensive and readily available raw materials, it involves many steps and requires pressurized reaction; 2) using 4-methylthiotoluene as a raw material, hydrogen peroxide as an oxidant, and oxidation under a catalyst to obtain 4-methylsulfonyltoluene, as reported in the literature (Mater. Chem. Phys., 2017, 201, 323-330) using acidic graphene oxide as a catalyst. This method has a short procedure and high yield, but the raw materials and catalysts are expensive, resulting in high costs. 3) Using toluene as a raw material, the methanesulfonation reaction is carried out directly under the action of a catalyst. The literature (Org. Biomol. Chem. 2004, 2, 3150-3154) uses zeolite as a catalyst and methanesulfonic anhydride as a sulfonating agent to synthesize 4-methylsulfonyl toluene, with a selectivity of over 90%, but a conversion rate of less than 60%. Boroujeni's team (Bull. Korean Chem. Soc. 2010, 31, 1887-1890) uses aluminum trifluoromethanesulfonate as a catalyst and methanesulfonic acid as a sulfonating agent to synthesize 4-methylsulfonyl toluene, with a final yield of up to 81%, but the catalyst is expensive. Patent CN108440350A uses toluene as raw material and phosphorus pentoxide as reactant. Methanesulfonic acid, methanesulfonic anhydride, or methanesulfonyl chloride are used as sulfonating agents. The reaction requires a certain pressure, 0.1–5.0 MPa. The para-selectivity is only 86–92%, and the yield is 84%–90%. Separation is difficult, and a large amount of phosphorus-containing wastewater is generated, which is difficult to treat.

[0003] Among the aforementioned existing technologies, the synthesis of 4-methylsulfonyl toluene still faces challenges such as difficulties in treating waste, high raw material prices, or complex synthesis processes, requiring further improvement in modern clean industrial production. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to address the shortcomings of the prior art by providing a method for one-step synthesis of 4-methylsulfonyl toluene from 4-toluenesulfonyl chloride.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] A method for synthesizing 4-methylsulfonyl toluene involves using 4-toluenesulfonyl chloride as a raw material, reacting it with chloromethane Grignard liquid at atmospheric pressure under the action of a catalyst, and then purifying the product to obtain 4-methylsulfonyl toluene in high yield and high purity.

[0007] The process involves adding 4-toluenesulfonyl chloride to a solvent, followed by the addition of a catalyst. Chloromethane Grignard solution is then added dropwise at a temperature of -20°C to 50°C. After the addition is complete, the reaction is maintained at this temperature until the reaction reaches the acceptable level. The resulting synthetic solution is then added dropwise to acidic water for hydrolysis. Following hydrolysis, the solution is washed with alkali and water, and then desolventized to obtain 4-methylsulfonyl toluene. The chemical reaction formula is shown below:

[0008]

[0009] Reaction mechanism

[0010]

[0011] The solvent is one or more of toluene, xylene, THF, methyltetrahydrofuran, and diethyl ether; preferably, the solvent is one or more of THF, methyltetrahydrofuran, toluene, and diethyl ether; the amount of solvent used is 1-5 times the reaction equivalent mass of the chloromethane Grignard solution. Preferably, the amount of solvent used is 2-4 times the reaction equivalent mass of the chloromethane Grignard solution.

[0012] In the above technical solution, the palladium catalyst is preferably bis(triphenylphosphine) palladium chloride and its derivatives, or palladium acetate; the platinum catalyst is preferably platinum chloride; the ruthenium catalyst is preferably ruthenium chloride or ruthenium acetate; the nickel catalyst is preferably nickel chloride or nickel acetate; the triphenylphosphine catalyst is preferably p-methyltriphenylphosphine and its derivatives; the type of catalyst can be any one or two; wherein, the mass amount of the catalyst is 0.5‰-3% of the mass of 4-toluenesulfonyl chloride, preferably 1‰-2%.

[0013] The molar amount of the chloromethane Grignard solution is 0.8-1.5 times, preferably 0.95-1.2 times, of the molar amount of 4-toluenesulfonyl chloride; the chloromethane Grignard solution is added dropwise over 4-10 hours (preferably 6-10 hours).

[0014] The reaction temperature is controlled at -20℃ to 50℃, preferably -15℃ to -5℃; the heat preservation reaction time is 4-40h, preferably 4-10h.

[0015] The synthesized liquid after the reaction is added dropwise to acidic water and hydrolyzed at 20-40℃. After hydrolysis, it is washed with alkali and water in sequence. After washing, the temperature is raised to the boiling point of the above solvent for desolvation until the solvent content in the oil layer is ≤0.5%, thus obtaining 4-methylsulfonyl toluene with high yield and high purity.

[0016] The acid solution is hydrochloric acid with a concentration of about 5%; the alkaline washing is carried out using liquid sodium hydroxide with a concentration of about 1%.

[0017] The advantages of the technical solution of this invention are:

[0018] This invention discloses a one-step method for synthesizing 4-methylsulfonyl toluene from 4-toluenesulfonyl chloride. This method is simple, yields high output, produces almost no other impurities, has high atom utilization, is easily industrialized, and has good application value. Detailed Implementation

[0019] 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:

[0020] The present invention will now be described in conjunction with specific embodiments:

[0021] Example 1:

[0022] Synthesis method of 4-methylsulfonyl toluene: In a 1000L stirred reactor, add 200kg THF, 200kg toluene, 100kg 4-toluenesulfonyl chloride, 0.1kg ruthenium chloride, and 1kg triphenylphosphine. Cool to -5℃, and add 195.5kg of 20% chloromethane Grignard solution dropwise over 8 hours. After the addition is complete, maintain the temperature for 10 hours, then take a sample for monitoring. The 4-toluenesulfonyl chloride content should be ≤0.2%. After the reaction is deemed satisfactory, [the following steps are taken]. The reaction solution was added dropwise to 400 kg of 5% dilute hydrochloric acid and hydrolyzed at 40 °C for 2 h. After hydrolysis, the mixture was allowed to stand and separate into layers. The oil layer was collected and 50 kg of 1% liquid alkali solution was added for alkali washing. The oil layer after alkali washing was then washed with water. After washing, the solution was removed by heating to 120 °C under normal pressure. After the removal treatment, the solution was removed by further removal at -0.08 to -0.095 MPa negative pressure and 100 °C to obtain 85.4 kg of 4-methylsulfonyl toluene, with a yield of 95% and a content of ≥99.2%.

[0023] Example 2:

[0024] Synthesis of 4-methylsulfonyl toluene: In a 1000L stirred reactor, add 500kg of methyltetrahydrofuran, 100kg of 4-toluenesulfonyl chloride, 0.2kg of palladium chloride from bis(triphenylphosphine)phosphide, and 1kg of triphenylphosphine. Cool to -15℃, and add 215.1kg of 20% (w / w) chloromethane Grignard solution dropwise over a period of 6 hours. After the addition is complete, maintain the temperature for 4 hours, then take a sample for monitoring. Control the 4-toluenesulfonyl chloride... ≤0.2%, after the reaction is qualified, the reaction solution is added dropwise to 450kg of 5% dilute hydrochloric acid and hydrolyzed at 40℃ for 2h. After hydrolysis, it is allowed to stand and separate into layers. The oil layer is collected and 60kg of 1% liquid alkali solution is added to it for alkali washing. The oil layer after alkali washing is then washed with water. After water washing, the temperature is raised to 85℃ under normal pressure for solvent removal treatment. After treatment, it is further subjected to solvent removal treatment at -0.08~-0.095MPa negative pressure and 100℃ to obtain 85.0kg of 4-methylsulfonyl toluene, with a yield of 94.1% and a content of ≥99.2%.

[0025] Example 3:

[0026] Synthesis of 4-methylsulfonyl toluene: In a 1000L stirred reactor, add 200kg of methyltetrahydrofuran, 200kg of toluene, 100kg of 4-toluenesulfonyl chloride, 0.1kg of ruthenium acetate, and 1kg of p-methyltriphenylphosphine. Cool to -10℃, and add 205.3kg of 20% (w / w) chloromethane Grignard solution dropwise over a period of 10 hours. After the addition is complete, maintain the temperature for 4 hours, then take a sample for monitoring the 4-methylsulfonyl toluene content. After the sulfonyl chloride concentration is ≤0.2% and the reaction is qualified, the reaction solution is added dropwise to 430 kg of 5% dilute hydrochloric acid and hydrolyzed at 40℃ for 2 hours. After hydrolysis, the mixture is allowed to stand and separate into layers. The oil layer is collected and 60 kg of 1% liquid alkali solution is added for alkali washing. The oil layer after alkali washing is then washed with water. After water washing, the temperature is raised to 120℃ under normal pressure for solvent removal. After treatment, solvent removal is carried out again at -0.08 to -0.095 MPa negative pressure and 100℃ to obtain 85.2 kg of 4-methylsulfonyl toluene, with a yield of 94.8% and a content of ≥99.3%.

[0027] Example 4:

[0028] Synthesis of 4-methylsulfonyl toluene: In a 1000L stirred reactor, add 200kg THF, 200kg toluene, 100kg 4-toluenesulfonyl chloride, 1kg nickel chloride, and 1kg triphenylphosphine. Cool to -10℃, and add 195.5kg of 20% chloromethane Grignard solution dropwise over 8 hours. After the addition is complete, maintain the temperature for 4 hours, then take a sample for monitoring. The concentration of 4-toluenesulfonyl chloride should be ≤0. After the reaction was qualified, the reaction solution was added dropwise to 400 kg of 5% dilute hydrochloric acid and hydrolyzed at 40℃ for 2 hours. After hydrolysis, the mixture was allowed to stand and separate into layers. The oil layer was collected and 50 kg of 1% liquid alkali solution was added for alkali washing. The oil layer after alkali washing was then washed with water. After water washing, the temperature was raised to 120℃ under normal pressure for solvent removal. After treatment, solvent removal was carried out again at -0.08 to -0.095 MPa negative pressure and 100℃ to obtain 85.7 kg of 4-methylsulfonyl toluene, with a yield of 95.2% and a content of ≥99.1%.

[0029] The above examples are merely illustrative of the technical concept and features of the present invention and should not be construed as limiting the scope of protection of the present invention. All equivalent transformations or modifications made in accordance with the essence of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for synthesizing 4-methylsulfonyltoluene, characterized in that, 4-Toluenesulfonyl chloride was used as a raw material and reacted with chloromethane Grignard liquid at atmospheric pressure in the presence of a catalyst. After the reaction, 4-methylsulfonyl toluene was obtained by purification. The catalyst is a palladium-based catalyst and a triphenylphosphine-based catalyst, or a platinum-based catalyst and a triphenylphosphine-based catalyst, or a ruthenium-based catalyst and a triphenylphosphine-based catalyst, or a nickel-based catalyst and a triphenylphosphine-based catalyst; The palladium-based catalyst is bis(triphenylphosphine) palladium chloride or palladium acetate; the platinum-based catalyst is platinum chloride; the ruthenium-based catalyst is ruthenium chloride or ruthenium acetate; the nickel-based catalyst is nickel chloride or nickel acetate; and the triphenylphosphine-based catalyst is triphenylphosphine or p-methyltriphenylphosphine.

2. The method for synthesizing 4-methylsulfonyl toluene according to claim 1, characterized in that, 4-Toluenesulfonyl chloride was added to a solvent, followed by a catalyst. Chloromethane Grignard solution was then added dropwise at a temperature of -20°C to 50°C. After the addition was complete, the reaction was maintained at this temperature until the reaction was deemed acceptable. The resulting solution was then added dropwise to acidic water for hydrolysis. Following hydrolysis, the solution was washed with alkali and water, and then dissolved to obtain 4-methylsulfonyltoluene. The chemical reaction formula is shown below: 。 3. The method for synthesizing 4-methylsulfonyl toluene according to claim 2, characterized in that, The solvent is one or more of toluene, xylene, THF, methyltetrahydrofuran, and diethyl ether; the amount of solvent used is 1-5 times the equivalent mass of the chloromethane Grignard liquid reaction.

4. The method for synthesizing 4-methylsulfonyl toluene according to claim 2, characterized in that, The mass of the catalyst used is 0.5‰-3% of the mass of 4-toluenesulfonyl chloride.

5. The method for synthesizing 4-methylsulfonyl toluene according to claim 2, characterized in that, The molar amount of the chloromethane Grignard solution is 0.8-1.5 times the molar amount of 4-toluenesulfonyl chloride; the chloromethane Grignard solution is added dropwise over 4-10 hours.

6. The method for synthesizing 4-methylsulfonyl toluene according to claim 2, characterized in that, The heat preservation reaction time is 4-40 hours.

7. The method for synthesizing 4-methylsulfonyl toluene according to claim 2, characterized in that, After the reaction, the synthesized liquid is added dropwise to acidic water and hydrolyzed at 20-40℃. After hydrolysis, it is washed with alkali and water in sequence. After washing, the temperature is raised to the boiling point of the solvent for desolvation until the solvent content in the oil layer is ≤0.5%, thus obtaining 4-methylsulfonyl toluene.

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