Synthetic method of p-methylsulfonyl toluene
Through the Fuke acylation reaction promoted by the supported AlCl3 catalyst and the subsequent reaction with chloroacetic acid, the complex and three-waste problems of the methylsulfone toluene synthesis process were successfully solved, and the efficient synthesis of high-purity products was achieved.
Patent Information
- Application Number
- CN202411274245.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-12
- Publication Date
- 2025-02-07
AI Technical Summary
The existing synthesis process of p-methylsulfone toluene has problems such as complex circuits, large amounts of waste, and low equipment utilization and yield.
The supported AlCl3 catalyst is used to react with toluene and sulfur dioxide in a fixed bed reactor, and sodium p-toluene sulfinate is generated by the Fuke acylation reaction, and p-methylsulfone toluene is formed by reaction with chloroacetic acid, which is insoluble in water. The characteristics of purification are achieved.
High purity synthesis of methylsulfone toluene is achieved, with high reaction purity, simple operation and high yield, and the generation of waste salt and waste gas is reduced, and the safety and operability of the process are improved.
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Figure CN119390620A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing p-methylsulfonyltoluene. Background Art
[0002] p-Methylsulfonyltoluene is an important organic pharmaceutical raw material and an important intermediate of the new spectrum antibiotic thiamphenicol and thiamphenicol glycine ester hydrochloride. Because thiamphenicol and its derivative glycine hydrochloride have low toxicity and few side effects; they have long curative effects and good antibacterial effects, and their antibacterial activity is more than 6 times stronger than chloramphenicol. It has been widely allowed to be used as an antibiotic in immunosuppressive states and as a food and feed additive abroad, and the demand is increasing year by year. At present, thiamphenicol uses p-methylsulfonyltoluene to synthesize p-methylsulfonylphenylserine as a raw material route; the raw materials of this route are easy to obtain, the operation is simple, the process route is short, and the equipment utilization rate and yield are higher than other methods. This method has a high production value in terms of labor protection and cost reduction. Therefore, at this stage, the output of the domestic thiamphenicol synthesis method using p-methylsulfonyltoluene as a raw material is increasing, and the domestic production of p-methylsulfonyltoluene cannot meet the market demand.
[0003] At present, the existing process uses p-toluenesulfonic acid as a raw material, chlorinated with thionyl chloride to form p-toluenesulfonyl chloride, then reduced with sodium sulfite to form sodium p-toluenesulfinate, and then reacted with chloromethane to form p-methylsulfonyltoluene. The disadvantages are that a large amount of waste acid is generated during the preparation of p-toluenesulfonic acid, the amount of three wastes is large, and the environmental pollution is serious; the p-toluenesulfonic acid used contains crystal water, and an extra equivalent of thionyl chloride is consumed during the reaction, the molecular utilization rate is poor, and sulfur dioxide and hydrogen chloride waste gas are generated at the same time, which is difficult to handle; the reaction process of synthesizing p-methylsulfonyltoluene using chloromethane requires a pressurized reaction, and the excessive chloromethane is difficult to recover, and the discharge is not easy to handle, which pollutes the environment. Summary of the invention
[0004] In order to solve the problem that the synthesis route of p-methylsulfonyltoluene in the prior art is complicated and a large amount of three wastes are generated in the post-processing, the purpose of the present invention is to provide a method for synthesizing p-methylsulfonyltoluene.
[0005] In order to achieve the above object, the present invention is implemented through the following technical solutions:
[0006] A method for synthesizing p-methylsulfonyltoluene comprises the following steps:
[0007] The supported AlCl3 catalyst is added to a fixed bed reactor and nitrogen is introduced for protection, and toluene and sulfur dioxide gas are introduced into the fixed bed reactor at 70-80°C at the same time. After the reaction is completed, a reaction mixture is obtained, and the reaction mixture enters a gas-liquid separation device, and unreacted sulfur dioxide is gasified and separated to obtain a reaction liquid;
[0008] The mass ratio of the supported AlCl3 catalyst, toluene and sulfur dioxide gas is 1:92-100:6-13;
[0009] The supported AlCl3 catalyst is Al2O3-AlCl3 loaded on the honeycomb ceramic ball or / and SiO2-AlCl3 loaded on the honeycomb ceramic ball;
[0010] ② Add sodium hydroxide aqueous solution to the reaction solution to adjust the pH to 7-8, stir the reaction at 20-35°C for 0.5-1 hour, filter, and obtain an aqueous solution of sodium p-toluenesulfinate;
[0011] ③ Add chloroacetic acid to the aqueous solution of sodium p-toluenesulfinate obtained in step ②, stir and mix, heat to 95-105° C., keep warm for 1-2 hours, and after the reaction is completed, obtain a mixed solution, cool to 20-35° C., filter, and dry the filter cake to obtain p-methylsulfonyltoluene;
[0012] The molar ratio of sodium p-toluenesulfinate to chloroacetic acid in the sodium p-toluenesulfinate aqueous solution obtained in step ② is 1:1-1.2.
[0013] Preferably, the supported AlCl3 catalyst is prepared according to the following steps:
[0014] Mix oxide powder, water and concentrated nitric acid, ball-mill to obtain active oxide slurry, coat the obtained active oxide slurry on honeycomb ceramic balls, dry at 100-140° C. for 3-5 hours, calcine at 800-850° C. for 3-5 hours, cool to 20-35° C., obtain an activated carrier, and set aside;
[0015] The mass ratio of oxide powder, water, concentrated nitric acid and honeycomb ceramic balls is 1-3:1-3:0.05-0.15:3-5;
[0016] The oxide powder is aluminum oxide and / or silicon dioxide;
[0017] Under the protection of inert gas, toluene, anhydrous aluminum chloride and the activated carrier are added into the reactor, stirred for 2 to 4 hours, filtered under the protection of inert gas, and the obtained filter cake is vacuum dried at 60 to 70° C. for 3 to 4 hours to obtain a supported AlCl3 catalyst;
[0018] The mass ratio of toluene, anhydrous aluminum chloride and activated carrier is 10-15:1:4-8.
[0019] Preferably, the feed rate of toluene is 4 to 6 g / min.
[0020] Preferably, the mass concentration of the sodium hydroxide aqueous solution is 3-5%.
[0021] Preferably, the supported AlCl3 catalyst is SiO2-AlCl3 supported on honeycomb ceramic balls.
[0022] Preferably, the inert gas is nitrogen or argon.
[0023] Preferably, the mass ratio of oxide powder, water, concentrated nitric acid and honeycomb ceramic balls is 2-3:1-2:0.05-0.1:4-5.
[0024] Preferably, the mass ratio of toluene, anhydrous aluminum chloride and activated carrier is 10-12:1:5-6.
[0025] The synthetic route of p-methylsulfonyltoluene of the present invention is:
[0026]
[0027] Compared with the prior art, the present invention has the following advantages:
[0028] The method for synthesizing p-methylsulfonyltoluene of the present invention comprises the following steps: using toluene and sulfur dioxide as raw materials to obtain p-methylsulfonyltoluene by Friedel-Crafts acylation reaction under a supported catalyst, and then forming sodium p-methylsulfonyltoluene with sodium hydroxide, and then adding chloroacetic acid to form p-methylsulfonyltoluene. The p-methylsulfonyltoluene is purified by utilizing the characteristics that the p-methylsulfonyltoluene is insoluble in water while other raw materials are soluble in water, thereby obtaining high-purity p-methylsulfonyltoluene. The method has high reaction purity, is simple to operate, and has high yield.
[0029] Firstly, the use of supported aluminum chloride catalyst fundamentally solves the problem of aluminum chloride waste salt in the Friedel-Crafts acylation process, realizes the application of aluminum chloride catalyst, and reduces the generation of waste salt in the reaction process;
[0030] Secondly, chloroacetic acid is used instead of monochloromethane to prepare p-methylsulfonyltoluene, which changes the high-pressure reaction into a normal-pressure reaction, improves the safety and operability of the reaction, and solves the problem of recovering excess monochloromethane.
[0031] Finally, the method for synthesizing p-methylsulfonyltoluene of the present invention can obtain a high-purity p-methylsulfonyltoluene product by precipitation from an aqueous phase without the need for recrystallization and purification, and the product purity is greater than 99.8%. The production process is safe and environmentally friendly, the product quality is excellent, and it has extremely high industrial promotion value. BRIEF DESCRIPTION OF THE DRAWINGS
[0032] Figure 1 This is the liquid phase spectrum of p-methylsulfonyltoluene. DETAILED DESCRIPTION
[0033] The object of the present invention is to provide a method for synthesizing p-methylsulfonyltoluene. The present invention will be further described below in conjunction with specific embodiments.
[0034] Embodiment 1 A method for synthesizing p-methylsulfonyltoluene comprises the following steps:
[0035] ① Prepare supported AlCl3 catalyst according to the following steps:
[0036] 100 g of alumina powder, 100 g of water and 5 g of concentrated nitric acid were mixed and ball-milled to obtain an active oxide slurry. The active oxide slurry was coated on 300 g of honeycomb ceramic balls, dried at 100° C. for 5 hours, calcined at 800° C. for 3 hours, and cooled to 20° C. to obtain an activated carrier for standby use.
[0037] Under the protection of inert gas, 1 kg of toluene, 100 g of anhydrous aluminum chloride and 400 g of the activated carrier were added to the reactor, stirred for 2 hours, and filtered under the protection of inert gas. The filter cake was vacuum dried at 60° C. for 4 hours to obtain a supported AlCl 3 catalyst.
[0038] ② Add 10 g of the supported AlCl3 catalyst obtained in step ① into a fixed bed reactor and introduce nitrogen protection, and simultaneously introduce 920 g of toluene and 60 g of sulfur dioxide gas into the fixed bed reactor at 70° C. After the reaction is completed, a reaction mixture is obtained, and the reaction mixture enters a gas-liquid separation device, and unreacted sulfur dioxide is gasified and separated to obtain a reaction liquid;
[0039] ③ Add 5% sodium hydroxide aqueous solution to the reaction solution to adjust the pH to 7, stir at 20°C for 1 hour, filter, and obtain an aqueous solution of sodium p-toluenesulfinate with a liquid phase purity of 99.5%;
[0040] ④ Take 851g of the sodium p-toluenesulfinate aqueous solution with a mass concentration of 18.6% obtained in step ③, add 94.5g of chloroacetic acid thereto, stir and mix, heat to 95°C, keep warm for 2 hours, and after the reaction is completed, obtain a mixed solution, cool to 20°C, filter, and dry the filter cake to obtain 150.9g of p-methylsulfonyltoluene, with a yield of 94.57% and a liquid phase purity of 99.4%.
[0041] Embodiment 2 A method for synthesizing p-methylsulfonyltoluene comprises the following steps:
[0042] ① Prepare supported AlCl3 catalyst according to the following steps:
[0043] 300 g of silicon dioxide powder, 300 g of water and 15 g of concentrated nitric acid were mixed and ball-milled to obtain an active oxide slurry. The active oxide slurry was coated on 500 g of honeycomb ceramic balls, dried at 140° C. for 3 hours, calcined at 850° C. for 5 hours, and cooled to 35° C. to obtain an activated carrier for standby use.
[0044] Under the protection of inert gas, 1.5 kg of toluene, 100 g of anhydrous aluminum chloride and 800 g of the activated carrier were added to the reactor, stirred for 4 hours, and filtered under the protection of inert gas. The filter cake was vacuum dried at 70° C. for 3 hours to obtain a supported AlCl 3 catalyst.
[0045] ② Add 10 g of the supported AlCl3 catalyst obtained in step ① into a fixed bed reactor and introduce nitrogen protection, and simultaneously introduce 1 kg of toluene and 130 g of sulfur dioxide gas into the fixed bed reactor at 80° C. After the reaction is completed, a reaction mixture is obtained, and the reaction mixture enters a gas-liquid separation device, and unreacted sulfur dioxide is gasified and separated to obtain a reaction liquid;
[0046] ③ Add 3% sodium hydroxide aqueous solution to the reaction solution to adjust the pH to 8, stir and react at 35°C for 0.5 hour, filter and obtain an aqueous solution of sodium p-toluenesulfinate with a liquid phase purity of 99.3%;
[0047] ④ Take 1405g of the 12.1% aqueous solution of sodium p-toluenesulfinate obtained in step ③, add 113.4g of chloroacetic acid thereto, stir and mix, heat to 105°C, keep warm for 1 hour, and after the reaction is completed, obtain a mixed solution, cool to 35°C, filter, and dry the filter cake to obtain 149.8g of p-methylsulfonyltoluene, with a yield of 92.3% and a liquid phase purity of 99.2%.
[0048] Embodiment 3 A method for synthesizing p-methylsulfonyltoluene comprises the following steps:
[0049] ① Prepare supported AlCl3 catalyst according to the following steps:
[0050] 150 g of alumina powder, 150 g of water and 10 g of concentrated nitric acid were mixed and ball-milled to obtain an active oxide slurry, and the obtained active oxide slurry was coated on 400 g of honeycomb ceramic balls, dried at 110° C. for 3.5 hours, calcined at 810° C. for 3.5 hours, and cooled to 25° C. to obtain an activated carrier for standby use;
[0051] Under the protection of inert gas, 1.1 kg of toluene, 100 g of anhydrous aluminum chloride and 500 g of the activated carrier were added to the reactor, stirred for 2.5 hours, and filter-filtered under the protection of inert gas. The filter cake was vacuum dried at 65° C. for 3.5 hours to obtain a supported AlCl 3 catalyst.
[0052] ② 30 g of the supported AlCl3 catalyst obtained in step ① was added to a fixed bed reactor and nitrogen was introduced for protection. 2850 g of toluene and 240 g of sulfur dioxide gas were introduced into the fixed bed reactor at 72° C. After the reaction was completed, a reaction mixture was obtained. The reaction mixture entered a gas-liquid separation device, and unreacted sulfur dioxide was gasified and separated to obtain a reaction liquid. The feeding rate of toluene was 6 g / min.
[0053] ③ Add 4.5% sodium hydroxide aqueous solution to the reaction solution to adjust the pH to 7.5, stir at 25°C for 45 minutes, filter, and obtain an aqueous solution of sodium p-toluenesulfinate with a liquid phase purity of 99.3%;
[0054] ④ Take 2000g of the sodium p-toluenesulfinate aqueous solution with a mass concentration of 15.4% obtained in step ③, add 180g of chloroacetic acid thereto, stir and mix, heat to 100°C, and keep warm for 1.5 hours. After the reaction is completed, a mixed solution is obtained, which is cooled to 25°C and filtered. The filter cake is dried to obtain 274.1g of p-methylsulfonyltoluene, with a yield of 93.2% and a liquid phase purity of 99.7%.
[0055] Embodiment 4 A method for synthesizing p-methylsulfonyltoluene comprises the following steps:
[0056] ① Prepare supported AlCl3 catalyst according to the following steps:
[0057] 100 g of alumina powder, 150 g of silicon dioxide powder, 150 g of water and 8 g of concentrated nitric acid were mixed and ball-milled to obtain an active oxide slurry, and the obtained active oxide slurry was coated on 450 g of honeycomb ceramic balls, dried at 120° C. for 4.5 hours, calcined at 820° C. for 4.5 hours, and cooled to 28° C. to obtain an activated carrier for standby use;
[0058] Under the protection of inert gas, 1.2 kg of toluene, 100 g of anhydrous aluminum chloride and 500 g of the activated carrier were added to the reactor, stirred for 3.5 hours, and filter-filtered under the protection of inert gas. The filter cake was vacuum dried at 68° C. for 3.2 hours to obtain a supported AlCl 3 catalyst.
[0059] ② Add 10 g of the supported AlCl3 catalyst obtained in step ① into a fixed bed reactor and introduce nitrogen protection, and simultaneously introduce 950 g of toluene and 120 g of sulfur dioxide gas into the fixed bed reactor at 75° C. After the reaction is completed, a reaction mixture is obtained, and the reaction mixture enters a gas-liquid separation device, and unreacted sulfur dioxide is gasified and separated to obtain a reaction liquid; the toluene feed rate is 4 g / min;
[0060] ③ Add 4% sodium hydroxide aqueous solution to the reaction solution to adjust the pH to 7.5, stir and react at 28°C for 40 minutes, filter and obtain an aqueous solution of sodium p-toluenesulfinate with a liquid phase purity of 99.6%;
[0061] ④ Take 900g of the sodium p-toluenesulfinate aqueous solution with a mass concentration of 15.2% obtained in step ③, add 77g of chloroacetic acid thereto, stir and mix, heat to 95°C, keep warm for 2 hours, and after the reaction is completed, obtain a mixed solution, cool to 20°C, filter, and dry the filter cake to obtain 122.1g of p-methylsulfonyltoluene, with a yield of 93.4% and a liquid phase purity of 99.3%.
[0062] Embodiment 5 A method for synthesizing p-methylsulfonyltoluene comprises the following steps:
[0063] ① Prepare supported AlCl3 catalyst according to the following steps:
[0064] 100 g of alumina powder, 100 g of silicon dioxide powder, 200 g of water and 10 g of concentrated nitric acid were mixed and ball-milled to obtain an active oxide slurry. The active oxide slurry was coated on 400 g of honeycomb ceramic balls, dried at 130° C. for 4 hours, calcined at 840° C. for 4 hours, and cooled to 25° C. to obtain an activated carrier for standby use.
[0065] Under the protection of inert gas, 1.2 kg of toluene, 100 g of anhydrous aluminum chloride and 600 g of the activated carrier were added to the reactor, stirred for 3 hours, and filtered under the protection of inert gas. The filter cake was vacuum dried at 65° C. for 3.5 hours to obtain a supported AlCl 3 catalyst.
[0066] ② 30 g of the supported AlCl3 catalyst obtained in step ① is added to a fixed bed reactor and nitrogen is introduced for protection. 2880 g of toluene and 300 g of sulfur dioxide gas are introduced into the fixed bed reactor at 75° C. After the reaction is completed, a reaction mixture is obtained. The reaction mixture enters a gas-liquid separation device, and unreacted sulfur dioxide is gasified and separated to obtain a reaction liquid. The toluene feed rate is 5 g / min.
[0067] ③ Add 4% sodium hydroxide aqueous solution to the reaction solution to adjust the pH to 8, stir and react at 28°C for 40 minutes, filter and obtain an aqueous solution of sodium p-toluenesulfinate with a liquid phase purity of 99.6%;
[0068] ④ Take 2000g of the sodium p-toluenesulfinate aqueous solution with a mass concentration of 15.3% obtained in step ③, add 179g of chloroacetic acid thereto, stir and mix, heat to 95°C, and keep warm for 2 hours. After the reaction is completed, a mixed solution is obtained, which is cooled to 20°C and filtered. The filter cake is dried to obtain 284.0g of p-methylsulfonyltoluene, with a yield of 97.2% and a liquid phase purity of 99.4%.
[0069] The mass concentration of the sodium p-toluenesulfinate aqueous solution in Examples 1 to 5 was detected by a liquid phase external standard quantitative method, and the detection conditions are shown in Table 1. The liquid phase spectrum of the product p-methylsulfonyltoluene is shown in Figure 1 shown.
[0070] Table 1 Detection conditions of mass concentration of reaction solution
[0071]
Claims
1. A method for synthesizing p-methylsulfonyltoluene, characterized in that: The following steps are involved: The supported AlCl3 catalyst is added to a fixed bed reactor and nitrogen is introduced for protection, and toluene and sulfur dioxide gas are introduced into the fixed bed reactor at 70-80°C at the same time. After the reaction is completed, a reaction mixture is obtained, and the reaction mixture enters a gas-liquid separation device, and unreacted sulfur dioxide is gasified and separated to obtain a reaction liquid; The mass ratio of the supported AlCl3 catalyst, toluene and sulfur dioxide gas is 1:92-100:6-13; The supported AlCl3 catalyst is Al2O3-AlCl3 loaded on the honeycomb ceramic ball or / and SiO2-AlCl3 loaded on the honeycomb ceramic ball; ② Add sodium hydroxide aqueous solution to the reaction solution to adjust the pH to 7-8, stir the reaction at 20-35°C for 0.5-1 hour, filter, and obtain an aqueous solution of sodium p-toluenesulfinate; ③ Add chloroacetic acid to the aqueous solution of sodium p-toluenesulfinate obtained in step ②, stir and mix, heat to 95-105° C., keep warm for 1-2 hours, and after the reaction is completed, obtain a mixed solution, cool to 20-35° C., filter, and dry the filter cake to obtain p-methylsulfonyltoluene; The molar ratio of sodium p-toluenesulfinate to chloroacetic acid in the sodium p-toluenesulfinate aqueous solution obtained in step ② is 1:1-1.
2.
2. The synthetic method of p-methylsulfonyltoluene according to claim 1, wherein: The supported AlCl3 catalyst is prepared according to the following steps: Mix oxide powder, water and concentrated nitric acid, ball-mill to obtain active oxide slurry, coat the obtained active oxide slurry on honeycomb ceramic balls, dry at 100-140° C. for 3-5 hours, calcine at 800-850° C. for 3-5 hours, cool to 20-35° C., obtain an activated carrier, and set aside; The mass ratio of oxide powder, water, concentrated nitric acid and honeycomb ceramic balls is 1-3:1-3:0.05-0.15:3-5; The oxide powder is aluminum oxide and / or silicon dioxide; Under the protection of inert gas, toluene, anhydrous aluminum chloride and the activated carrier are added into the reactor, stirred for 2 to 4 hours, filtered under the protection of inert gas, and the obtained filter cake is vacuum dried at 60 to 70° C. for 3 to 4 hours to obtain a supported AlCl3 catalyst; The mass ratio of toluene, anhydrous aluminum chloride and activated carrier is 10-15:1:4-8.
3. The synthetic method of p-methylsulfonyltoluene according to claim 1, characterized in that: The feeding rate of toluene is 4-6 g / min.
4. The method for synthesizing p-methylsulfonyltoluene according to claim 1, wherein: The mass concentration of the sodium hydroxide aqueous solution is 3-5%.
5. The method for synthesizing p-methylsulfonyltoluene according to claim 1, wherein: The supported AlCl3 catalyst is SiO2-AlCl3 supported on honeycomb ceramic balls.
6. The method for synthesizing p-methylsulfonyltoluene according to claim 2, wherein: The inert gas is nitrogen or argon.
7. The method for synthesizing p-methylsulfonyltoluene according to claim 2, wherein: The mass ratio of oxide powder, water, concentrated nitric acid and honeycomb ceramic balls is 2-3:1-2:0.05-0.1:4-5.
8. The method for synthesizing p-methylsulfonyltoluene according to claim 2, wherein: The mass ratio of toluene, anhydrous aluminum chloride and activated carrier is 10-12:1:5-6.