Synthesis method of sulfonamide compound

Abstract

The invention relates to the field of synthesis of compounds, in particular to a synthesis method of sulfonamide compounds. Ammonia water and paratoluensulfonyl chloride are used as raw materials to synthesize an intermediate paratoluensulfonamide, and then the intermediate paratoluensulfonamide and diethylene glycol sulfate are subjected to nitrogen methylation reaction under the action of a catalyst to obtain N, N-bis (2-ethoxyl)-paratoluensulfonamide. The preparation method is simple, raw materials are cheap and easy to obtain, and a high-purity target product is easy to obtain.

Description

Technical Field

[0001] The present invention relates to the field of compound synthesis, and particularly to a method for synthesizing sulfonamide compounds. Background Art

[0002] N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide, with the molecular formula C 11 H 17 O2N1, has a melting point of 94 - 100 °C, appears as white powder crystals, and has stable properties.

[0003] N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide has been widely used in various fields. In the manufacturing industry, N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide can be used to synthesize various plasticizers, wood brighteners, and fungicides. In the pesticide industry, N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide can be used to synthesize various insecticides, fungicides, etc.; in the dye and fragrance industries, N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide can be used to synthesize fluorescent dyes. The market prospect of N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide is very broad. With the continuous development of the manufacturing, pesticide, dye, and fragrance industries, the demand for N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide will also continue to increase.

[0004] Currently, the synthesis methods reported in domestic and foreign literature mainly include the synthesis method of 4-methyl-N,N-bis(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)benzenesulfonamide, the one-step synthesis method of 4-methylbenzenesulfonyl azide and triethanolamine, the one-step synthesis method of p-toluenesulfonyl chloride and diethanolamine, etc.

[0005] The synthesis method of 4-methyl-N,N-bis(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)benzenesulfonamide uses 4-methyl-N,N-bis(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)benzenesulfonamide as the starting material, adds succinyl-15, and synthesizes N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide using methanol as the solvent. The raw materials of this process are not easily available and are expensive, and the final yield is only 87%.

[0006] The one-step synthesis method of 4-methylbenzenesulfonyl azide and triethanolamine is to add 1,4-dioxane to 4-methylbenzenesulfonyl azide and triethanolamine, and react at high temperature for 24 h to obtain N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide. The yield of this process is relatively low, only 46%.

[0007] It can be seen that the N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide prepared by the existing methods for preparing N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide has problems such as low yield and expensive raw materials. Therefore, there is an urgent need for a method with high yield and simple preparation process. Summary of the Invention

[0008] To this end, the present invention provides a synthesis method suitable for industrial production of N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide. The content of N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide in this method reaches more than 99%, and the yield reaches more than 85%, which has great production value.

[0009] The present invention provides a preparation method of a sulfonamide compound, and the sulfonamide compound is N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide, which comprises the following steps: Step 1: Add p-toluenesulfonyl chloride and ammonia water in a molar ratio of 1:(1 - 1.5) to water for amination reaction; Step 2: After the reaction is completed, post-treat the reaction solution to obtain p-toluenesulfonamide; Step 3: Add the p-toluenesulfonamide, diethylene glycol sulfate, and methylation catalyst to a solvent for methylation reaction, wherein the molar ratio of the addition amounts of p-toluenesulfonamide, diethylene glycol sulfate, and methylation catalyst is 1:(2.2 - 3.0):(0.01 - 0.03); Step 4: Post-treat the obtained reaction solution to obtain N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide.

[0010] Preferably, in Step 1, the concentration of ammonia water is 10 - 20 wt%, and the additional amount of water added is 0.2 - 0.8 times the mass of p-toluenesulfonyl chloride.

[0011] Preferably, the reaction in Step 1 is carried out at 50°C - 60°C for 1 - 3 hours with heat preservation. Preferably, the post-treatment steps in Step 2 include steps of cooling the reaction solution, centrifuging, alkali washing, and acid precipitation.

[0012] Preferably, the methylation catalyst used in Step 3 is one of potassium carbonate, potassium hydroxide, sodium hydride, and sodium carbonate; the solvent used in Step 3 is one or a mixture of several of water, dichloromethane, dichloroethane, methanol, and ethanol, and the mass ratio of p-toluenesulfonamide to the solvent is 1:(1 - 5).

[0013] Preferably, the reaction temperature of the methylation reaction in Step 3 is 30°C - 70°C, and the reaction time is 8 - 12 h.

[0014] Preferably, the post-treatment steps described in Step 4 include: Step 4-1: Cool the reaction solution to room temperature and then filter; Step 4-2: Wash the filter cake after filtration with water; Step 4-3: Wash the filter cake after water washing with dichloroethane; Step 4-4: Drying to obtain N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide.

[0015] Preferably, the content of N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide obtained in Step 4 reaches over 99%.

[0016] The preparation process route of N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide in the present invention is as follows: Reaction formula 1 Reaction formula 2 Compared with the prior art, the N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide obtained by the method provided by the present invention has a purity of over 99% and a yield of over 85%. Moreover, the preparation method is simple, the raw materials are cheap and easily available, and it is easy to obtain the target product with high purity, having extremely high application value. Description of the drawings

[0017] Figure 1 : Liquid-phase detection spectrogram of N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide prepared in Example 1. Detailed implementation manners

[0018] Example 1: Step 1: Add 381 g of p-toluenesulfonyl chloride, 466 g of 18 wt% ammonia water, and 190 g of water into a 3 L four-necked flask equipped with a thermometer and a mechanical stirrer. Heat up to the temperature in the flask of 55 °C and keep the reaction for 2 hours.

[0019] Step 2: After the reaction is completed, cool down the temperature in the flask to 30 °C, pour out the reactants and centrifuge. Add the centrifuged solid into 300 g of water, adjust the pH to 10 with 30% sodium hydroxide solution; heat up to 70 °C and stir for 30 min, then adjust the pH to 2 - 3 with hydrochloric acid, cool down to 30 °C, wash with water until neutral and then centrifuge. Transfer the solid material into an oven for drying, and the dried solid is p-toluenesulfonamide.

[0020] Step 3: Add 300 g of the obtained p-toluenesulfonamide, 816 g of diethylene glycol sulfate, 300 g of dichloroethane, and 1.9 g of potassium hydroxide into a 3 L four-necked flask equipped with a thermometer and a mechanical stirrer. Heat up to 60 °C and keep the reaction for 10 hours.

[0021] Step 4: After the heat preservation is completed, cool down the materials in the flask to room temperature, wash with water and then filter, and then wash the filter cake after water washing with dichloroethane. Dry the filter cake to finally obtain 400.4 g of N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide, with a molar yield of 88.2% and an HPLC-detected content of 99.5% (mass spectrometry detection: m / z = 189.99, and the liquid-phase detection spectrogram is shown in the appendix Figure 1 )

[0022] Example 2: The difference between the preparation method of N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide in this example and that in Example 1 lies in: Step 3: Add 300 g of the obtained p-toluenesulfonyl chloride, 1303 g of diethylene glycol sulfate, 300 g of dichloroethane, and 1.9 g of potassium hydroxide into a 3 L four-necked flask equipped with a thermometer and mechanical stirring. Heat up to 60 °C and keep the reaction at this temperature for 10 hours. Keep other steps unchanged. Obtain 387.6 g of N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide, with a molar yield of 85.4% and a content of 99.2% detected by HPLC.

[0023] Example 3: The difference between the preparation method of N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide in this example and that in Example 1 lies in: Step 3: Add 300 g of the obtained p-toluenesulfonyl chloride, 816 g of diethylene glycol sulfate, 300 g of methanol, and 1.9 g of potassium hydroxide into a 3 L four-necked flask equipped with a thermometer and mechanical stirring. Heat up to 60 °C and keep the reaction at this temperature for 10 hours. Keep other steps unchanged. Obtain 388.9 g of N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide, with a molar yield of 85.7% and a content of 99.3% detected by HPLC.

[0024] Example 4: The difference between the preparation method of N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide in this example and that in Example 1 lies in: Step 3: Add 300 g of the obtained p-toluenesulfonyl chloride, 816 g of diethylene glycol sulfate, 300 g of dichloroethane, and 3.7 g of sodium carbonate into a 3 L four-necked flask equipped with a thermometer and mechanical stirring. Heat up to 60 °C and keep the reaction at this temperature for 10 hours. Keep other steps unchanged. Obtain 395.7 g of N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide, with a molar yield of 87.2% and a content of 99.6% detected by HPLC.

[0025] Example 5: The difference between the preparation method of N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide in this example and that in Example 1 lies in: Step 4: After the heat preservation is completed, cool the materials in the flask to room temperature, wash them with water, then wash them with dichloroethane, and concentrate the solvent. Finally, obtain 390.7 g of N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide, with a molar yield of 86.1% and a content of 99.4% detected by HPLC.

[0026] The above is only the specific implementation manners of the present disclosure, but the protection scope of the present disclosure is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present disclosure can easily think of changes or substitutions, which should all be covered within the protection scope of the present disclosure. Therefore, the protection scope of the present disclosure should be subject to the protection scope of the claims.

Claims

1. A method for synthesizing a sulfonamide compound, characterized in that, The sulfonamide compound is N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide, and it includes the following steps: Step 1: Add p-toluenesulfonyl chloride and ammonia water in a molar ratio of 1:(1 - 1.5) to water for amination reaction; Step 2: After the reaction ends, post-treat the reaction solution to obtain p-toluenesulfonamide; Step 3: Add the p-toluenesulfonamide, diethylene glycol sulfate, and methylation catalyst to a solvent for methylation reaction, where the molar ratio of the added amounts of p-toluenesulfonamide, diethylene glycol sulfate, and methylation catalyst is 1:(2.2 - 3.0):(0.01 - 0.03); Step 4: Post-treat the obtained reaction solution to obtain N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide.

2. The method according to claim 1, wherein In Step 1, the concentration of ammonia water is 10 - 20 wt%, and the additional amount of water added is 0.2 - 0.8 times the mass of p-toluenesulfonyl chloride.

3. The method according to claim 1, characterized in that, The reaction in Step 1 is carried out at 50°C - 60°C and kept warm for 1 - 3 hours.

4. The method according to claim 1, wherein The post-treatment steps in Step 2 include cooling the reaction solution, centrifuging, alkali washing, and acid precipitation steps.

5. The method according to claim 1, wherein The methylation catalyst used in Step 3 is one of potassium carbonate, potassium hydroxide, sodium hydride, and sodium carbonate; the solvent used in Step 3 is one or a mixture of several of water, dichloromethane, dichloroethane, methanol, and ethanol, where the mass ratio of p-toluenesulfonamide to the solvent is 1:(1 - 5).

6. The method according to claim 1, wherein In Step 3, the reaction temperature of the methylation reaction is 30°C - 70°C, and the reaction time is 8 - 12 h.

7. The method according to claim 1, characterized in that, The post-treatment steps described in Step 4 include: Step 4-1: Cool the reaction solution to room temperature and then filter; Step 4-2: Wash the filter cake after filtration with water; Step 4-3: Wash the filter cake after water washing with dichloroethane; Step 4-4: Dry to obtain N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide.

8. The method according to any one of claims 1-7, characterized in that, The content of N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide obtained in Step 4 reaches more than 99%.

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