A process for the preparation of 2-aminosulfonyl-N,N-dimethylnicotinamide

Abstract

This invention relates to a method for preparing 2-aminosulfonyl-N,N-dimethylnicotinamide, belonging to the technical field of organic synthesis. The method includes the following steps: first, preparing an aqueous solution of 2-mercapto-N,N-dimethylnicotinamide; then, generating an intermediate aqueous solution under an oxidizing agent, transferring it to an organic solvent, cooling it, and then introducing chlorine gas; collecting the organic phase after post-treatment by separation; introducing ammonia gas into the organic phase to synthesize 2-aminosulfonyl-N,N-dimethylnicotinamide; after completion, adjusting the pH with hydrochloric acid to remove excess ammonia gas; filtering, washing with water, and drying to obtain the final product. This invention effectively improves the reaction yield and reduces production costs without requiring significant adjustments to existing batch reactor equipment.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, specifically to a method for preparing 2-aminosulfonyl-N,N-dimethylnicotinamide. Background Technology

[0002] Aminosulfonyl-N,N-dimethylnicotinamide is an important intermediate for nicosulfuron technical. The current industrial production route uses 2-chloro-N,N-dimethylnicotinamide as a raw material. First, it reacts with sulfur, sodium sulfide, and water to prepare 2-mercapto-N,N-dimethylnicotinamide. Its aqueous solution is then chlorinated with chlorine in the presence of an organic solvent to synthesize 3-(dimethylcarbamoyl)pyridine-2-sulfonyl chloride. Ammonia is then introduced into the organic solution of 3-(dimethylcarbamoyl)pyridine-2-sulfonyl chloride to prepare 2-aminosulfonyl-N,N-dimethylnicotinamide. The overall yield of the entire reaction process is between 70% and 80%, with the yields of the thiolation and amination steps both exceeding 98%. The key step affecting the yield is the reaction of 2-mercapto-N,N-dimethylnicotinamide with chlorine to synthesize the 3-(dimethylcarbamoyl)pyridine-2-sulfonyl chloride segment. Research has revealed that the reaction of 2-mercapto-N,N-dimethylnicotinamide with chlorine is actually a process of oxidation followed by chlorination. However, in current industrial-scale batch reactor reactions, the oxidation and chlorination stages occur almost simultaneously. The oxidation stage releases a large amount of heat, making temperature control difficult. Furthermore, the chlorination product, 3-(dimethylcarbamoyl)pyridine-2-sulfonyl chloride, is readily hydrolyzed in a high-temperature system with water present. This explains why the yield of batch reactor reactions is currently only 70%–80%. Therefore, reducing the hydrolysis of 3-(dimethylcarbamoyl)pyridine-2-sulfonyl chloride during the reaction is key to improving the yield of this step. Summary of the Invention

[0003] To address the problems of difficulty in controlling the reaction temperature and easy hydrolysis of chlorination products during the oxidation of 2-aminosulfonyl-N,N-dimethylnicotinamide in existing technologies, this invention provides a method for preparing 2-aminosulfonyl-N,N-dimethylnicotinamide. By separating the strongly exothermic oxidation stage, the heat accumulation during the chlorination stage is effectively reduced, and the hydrolysis of 3-(dimethylcarbamoyl)pyridine-2-sulfonyl chloride is avoided. This method effectively improves the reaction yield and reduces production costs without requiring significant adjustments to existing batch reactor equipment.

[0004] The technical solution of this invention is as follows:

[0005] A method for preparing 2-aminosulfonyl-N,N-dimethylnicotinamide, the reaction route is as follows:

[0006]

[0007] The preparation steps are as follows:

[0008] (1) 2-chloro-N,N-dimethylnicotinamide, sodium sulfide, elemental sulfur and water were reacted to obtain a reaction solution containing the sodium salt of 2-mercapto-N,N-dimethylnicotinamide;

[0009] (2) Add water to the reaction solution prepared in step (1) and adjust the pH of the reaction system to 1 to 1.5 using hydrochloric acid; then add activated carbon, heat to 70 to 80°C and stir to decolorize; filter to obtain an aqueous solution of 2-mercapto-N,N-dimethylnicotinamide;

[0010] (3) Transfer the aqueous solution of 2-mercapto-N,N-dimethylnicotinamide prepared in step (2) to a reaction vessel, cool it to 0°C, add a measured amount of oxidant dropwise, control the temperature of the reaction solution to 0-10°C during the dropwise addition process, and keep it at the temperature for 0.6-1h after the dropwise addition is completed; then transfer a measured amount of organic solvent to cool it to below -5°C, and pass chlorine gas until the starch potassium iodide test paper turns blue, indicating that the chlorination is complete. Control the temperature of the system to -5-0°C during the chlorination process; after the reaction is completed, let it stand and separate into layers, take the organic phase, and obtain 3-(dimethylcarbamoyl)pyridine-2-sulfonyl chloride;

[0011] (4) Cool the organic phase prepared in step (3) to below -5℃, and then introduce ammonia into the reaction solution. During this period, control the temperature to -5 to 0℃. When the pH of the reaction system is 8 to 9, keep it warm for 0.5 to 1 h. After the warming is completed, add a small amount of hydrochloric acid to adjust the pH to 4 to 6, centrifuge, and add water to rinse to obtain 2-aminosulfonyl-N,N-dimethylnicotinamide.

[0012] Furthermore, in step (3), the oxidant is either H2O2 or NaClO.

[0013] Furthermore, the oxidant is H2O2, and after the oxidation reaction is completed, 0.01 to 0.05 eq of sodium hydrosulfite is added to quench the excess H2O2.

[0014] Furthermore, in step (3), the amount of oxidant used is 1 to 1.05 mol / mol based on the amount of 2-chloro-N,N-dimethylnicotinamide used.

[0015] Furthermore, in step (3), the organic solvent is either dichloroethane or dichloromethane.

[0016] Furthermore, in step (3), the amount of organic solvent used is 5 to 7 g / g, calculated as 2-chloro-N,N-dimethylnicotinamide.

[0017] Furthermore, in step (3), the molar ratio of chlorine to 2-chloro-N,N-dimethylnicotinamide is 1.7 to 2:1.

[0018] Furthermore, in step (3), the chlorination reaction temperature is -5 to 0℃.

[0019] The beneficial effects of this invention are as follows:

[0020] (1) After the sodium salt of 2-mercapto-N,N-dimethylnicotinamide is prepared, the elemental sulfur in the solution can be effectively removed by adjusting the pH, so that the selectivity of the oxidation intermediate (intermediate II to II) reaches more than 98%. On the one hand, the elemental sulfur can be recovered with a high recovery rate for the next batch to reduce production costs. On the other hand, improving the quality of the mercapto aqueous solution and reducing the generation of sulfuric acid will effectively reduce the hydrolysis of 3-(dimethylcarbamoyl)pyridine-2-sulfonyl chloride during the chlorination reaction and improve the reaction yield.

[0021] (2) By adding an oxidant, the reaction of oxidation and chlorination in the traditional batch reaction is divided into an oxidation stage and a chlorination stage. The strongly exothermic oxidation stage is separated, which effectively reduces the heat accumulation in the chlorination stage and avoids the hydrolysis of 3-(dimethylcarbamoyl)pyridine-2-sulfonyl chloride. Without requiring major adjustments to the existing batch reaction equipment, the reaction yield is effectively improved and the production cost is reduced. Attached Figure Description

[0022] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0023] Figure 1 This is the liquid chromatography spectrum after adding sodium hypochlorite aqueous solution in Example 3.

[0024] Figure 2 This is the liquid phase detection spectrum after the oxidation reaction in Example 3 is completed.

[0025] Figure 3 This is the liquid phase detection spectrum after chlorine gas passage in Example 3.

[0026] Figure 4 This is the liquid phase detection spectrum after the ammonia gas was introduced in Example 3.

[0027] Figure 5 This is the liquid phase detection spectrum after chlorine gas was passed through in Comparative Example 3. Detailed Implementation

[0028] To enable those skilled in the art to better understand the technical solutions of this invention, the technical solutions of the embodiments of this invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this invention.

[0029] Example 1

[0030] A method for preparing 2-aminosulfonyl-N,N-dimethylnicotinamide includes the following steps:

[0031] (1) Preparation of sodium salt of 2-mercapto-N,N-dimethylnicotinamide

[0032] Add 500 kg of 2-chloro-N,N-dimethylnicotinamide (2-chloro-N,N-dimethylnicotinamide content is 95%, the same below), 225 kg of sodium sulfide, 88 kg of elemental sulfur, and 200 kg of water to a reaction vessel, and react at 135℃ for 3 h to obtain a reaction solution containing sodium salt of 2-mercapto-N,N-dimethylnicotinamide.

[0033] (2) Acidification to prepare 2-mercapto-N,N-dimethylnicotinamide

[0034] Add 2000 kg of water to the reaction solution prepared in step (1) and transfer it to an acidification reactor. Adjust the pH of the reaction system to 1-1.5 using 30% hydrochloric acid. Then add 25 kg of activated carbon, heat to 70-80 °C and stir for 1 h to decolorize. Filter the solution using a plate and frame filter to obtain an aqueous solution of 2-mercapto-N,N-dimethylnicotinamide. The activated carbon filter residue containing elemental sulfur in the plate and frame filter is dried with nitrogen and collected for use in the next batch.

[0035] (3) Oxidation, chlorination

[0036] The aqueous solution of 2-mercapto-N,N-dimethylnicotinamide prepared in step (2) was transferred to an oxidation and chlorination reactor, cooled to 0°C, and 292 kg of 30% H2O2 aqueous solution was added dropwise. The temperature of the reaction solution was controlled at 0-5°C during the dropwise addition process, and the dropwise addition time was 1 h. After the dropwise addition was completed, the solution was kept warm for 0.5 h. 5 kg of sodium hydrosulfite was added and stirred for 0.5 h.

[0037] 3500 kg of dichloromethane was transferred to the oxidation and chlorination reactors, and the temperature was lowered to -5°C. Chlorine gas was introduced until the starch-potassium iodide test paper turned blue. A total of 350 kg of chlorine gas was consumed. During this process, the system temperature was controlled between -5°C and 0°C. The system was allowed to stand and separate into layers. The aqueous phase was transferred to a wastewater storage tank, and the organic phase was transferred to an amination reactor to obtain 3-(dimethylcarbamoyl)pyridine-2-sulfonyl chloride.

[0038] (4)Amination

[0039] The organic phase prepared in step (3) was cooled to -5℃, and then ammonia gas was introduced into the reaction solution. During this period, the temperature was controlled between -5℃ and 0℃. When the pH of the reaction system was 8 to 9, it was kept at this temperature for 1 hour. After the temperature was kept at this temperature, a small amount of hydrochloric acid was added to adjust the pH to 4 to 6. After centrifugation, 500 kg of water was added to rinse the solution to obtain 2-aminosulfonyl-N,N-dimethylnicotinamide. After drying, the weight was 571.5 kg, the liquid phase quantitative content was 97.0%, and the total yield was 94%.

[0040] Example 2

[0041] A method for preparing 2-aminosulfonyl-N,N-dimethylnicotinamide includes the following steps:

[0042] (1) Preparation of sodium salt of 2-mercapto-N,N-dimethylnicotinamide

[0043] Add 500 kg of 2-chloro-N,N-dimethylnicotinamide, 225 kg of sodium sulfide, 88 kg of elemental sulfur, and 200 kg of water to a reaction vessel, and react at 135 °C for 3 h to obtain a reaction solution containing sodium salt of 2-mercapto-N,N-dimethylnicotinamide.

[0044] (2) Acidification to prepare 2-mercapto-N,N-dimethylnicotinamide

[0045] Add 2000 kg of water to the reaction solution prepared in step (1) and transfer it to an acidification reactor. Adjust the pH of the reaction system to 1-1.5 using 30% hydrochloric acid. Then add 25 kg of activated carbon, heat to 70-80 °C and stir for 1 h to decolorize. Filter the solution using a plate and frame filter to obtain an aqueous solution of 2-mercapto-N,N-dimethylnicotinamide. The activated carbon filter residue containing elemental sulfur in the plate and frame filter is dried with nitrogen and collected for use in the next batch.

[0046] (3) Oxidation, chlorination

[0047] The aqueous solution of 2-mercapto-N,N-dimethylnicotinamide prepared in step (2) was transferred to an oxidation and chlorination reactor, cooled to 0°C, and 303 kg of 30% H2O2 aqueous solution was added dropwise. The temperature of the reaction solution was controlled at 0-5°C during the dropwise addition process, and the dropwise addition time was 45 min. After the dropwise addition was completed, the solution was kept warm for 0.5 h. 18 kg of sodium hydrosulfite was added and stirred for 0.5 h.

[0048] 3500 kg of dichloromethane was transferred to the oxidation and chlorination reactors, and the temperature was lowered to -5°C. Chlorine gas was then introduced until the starch-potassium iodide test paper turned blue. A total of 365.9 kg of chlorine gas was consumed. During this process, the system temperature was controlled between -5°C and 0°C. The system was allowed to stand and separate into layers. The aqueous phase was transferred to a wastewater storage tank, and the organic phase was transferred to an amination reactor to obtain 3-(dimethylcarbamoyl)pyridine-2-sulfonyl chloride.

[0049] (4)Amination

[0050] The organic phase prepared in step (3) was cooled to -5℃, and then ammonia gas was introduced into the reaction solution. During this period, the temperature was controlled between -5℃ and 0℃. When the pH of the reaction system was 8 to 9, it was kept at this temperature for 1 hour. After the temperature was kept at this temperature, a small amount of hydrochloric acid was added to adjust the pH to 4 to 6. After centrifugation, 500 kg of water was added to rinse the solution to obtain 2-aminosulfonyl-N,N-dimethylnicotinamide. After drying, the weight was 580.5 kg, the liquid phase quantitative content was 96.0%, and the total yield was 94.5%.

[0051] Example 3

[0052] A method for preparing 2-aminosulfonyl-N,N-dimethylnicotinamide includes the following steps:

[0053] (1) Preparation of sodium salt of 2-mercapto-N,N-dimethylnicotinamide

[0054] Add 500 kg of 2-chloro-N,N-dimethylnicotinamide, 225 kg of sodium sulfide, 88 kg of elemental sulfur, and 200 kg of water to a reaction vessel, and react at 135 °C for 3 h to obtain a reaction solution containing sodium salt of 2-mercapto-N,N-dimethylnicotinamide.

[0055] (2) Acidification to prepare 2-mercapto-N,N-dimethylnicotinamide

[0056] Add 2000 kg of water to the reaction solution prepared in step (1) and transfer it to an acidification reactor. Adjust the pH of the reaction system to 1-1.5 using 30% hydrochloric acid. Then add 25 kg of activated carbon, heat to 70-80 °C and stir for 1 h to decolorize. Filter the solution using a plate and frame filter to obtain an aqueous solution of 2-mercapto-N,N-dimethylnicotinamide. The activated carbon filter residue containing elemental sulfur in the plate and frame filter is dried with nitrogen and collected for use in the next batch.

[0057] (3) Oxidation, chlorination

[0058] The aqueous solution of 2-mercapto-N,N-dimethylnicotinamide prepared in step (2) was transferred to an oxidation and chlorination reactor, cooled to 0°C, and 1994 kg of 10% sodium hypochlorite aqueous solution was added dropwise. The temperature of the reaction solution was controlled at 0-5°C during the dropwise addition process, and the dropwise addition time was 40 min. After the dropwise addition was completed, the solution was kept warm for 0.5 h.

[0059] 3500 kg of dichloromethane was transferred to the oxidation and chlorination reactors, and the temperature was lowered to -5°C. Chlorine gas was then introduced until the starch-potassium iodide test paper turned blue. A total of 311 kg of chlorine gas was consumed. During this process, the system temperature was controlled between -5°C and 0°C. The system was allowed to stand and separate into layers. The aqueous phase was transferred to a wastewater storage tank, and the organic phase was transferred to an amination reactor to obtain 3-(dimethylcarbamoyl)pyridine-2-sulfonyl chloride.

[0060] (4)Amination

[0061] The organic phase prepared in step (3) was cooled to -5℃, and then ammonia gas was introduced into the reaction solution. During this period, the temperature was controlled between -5℃ and 0℃. When the pH of the reaction system was 8 to 9, it was kept at this temperature for 1 hour. After the temperature was kept at this temperature, a small amount of hydrochloric acid was added to adjust the pH to 4 to 6. After centrifugation, 500 kg of water was added to rinse the solution to obtain 2-aminosulfonyl-N,N-dimethylnicotinamide. After drying, the weight was 577.5 kg, the liquid phase quantitative content was 97.5%, and the total yield was 95.5%.

[0062] Example 4

[0063] A method for preparing 2-aminosulfonyl-N,N-dimethylnicotinamide includes the following steps:

[0064] (1) Preparation of sodium salt of 2-mercapto-N,N-dimethylnicotinamide

[0065] Add 500 kg of 2-chloro-N,N-dimethylnicotinamide, 225 kg of sodium sulfide, 88 kg of elemental sulfur, and 200 kg of water to a reaction vessel, and react at 135 °C for 3 h to obtain a reaction solution containing sodium salt of 2-mercapto-N,N-dimethylnicotinamide.

[0066] (2) Acidification to prepare 2-mercapto-N,N-dimethylnicotinamide

[0067] Add 2000 kg of water to the reaction solution prepared in step (1) and transfer it to an acidification reactor. Adjust the pH of the reaction system to 1-1.5 using 30% hydrochloric acid. Then add 25 kg of activated carbon, heat to 70-80 °C and stir for 1 h to decolorize. Filter the solution using a plate and frame filter to obtain an aqueous solution of 2-mercapto-N,N-dimethylnicotinamide. The activated carbon filter residue containing elemental sulfur in the plate and frame filter is dried with nitrogen and collected for use in the next batch.

[0068] (3) Oxidation, chlorination

[0069] The aqueous solution of 2-mercapto-N,N-dimethylnicotinamide prepared in step (2) was transferred to an oxidation and chlorination reactor, cooled to 0°C, and 1935.5 kg of 10% sodium hypochlorite aqueous solution was added dropwise. The temperature of the reaction solution was controlled at 0-5°C during the dropwise addition process, and the dropwise addition time was 50 min. After the dropwise addition was completed, the solution was kept warm for 0.5 h.

[0070] 3500 kg of dichloromethane was transferred to the oxidation, oxidation, and chlorination reactors, and the temperature was lowered to -5°C. Chlorine gas was then introduced until the starch-potassium iodide test paper turned blue. A total of 330 kg of chlorine gas was consumed. During this process, the system temperature was controlled between -5°C and 0°C. The system was allowed to stand and separate into layers. The aqueous phase was transferred to a wastewater storage tank, and the organic phase was transferred to an amination reactor to obtain 3-(dimethylcarbamoyl)pyridine-2-sulfonyl chloride.

[0071] (4)Amination

[0072] The organic phase prepared in step (3) was cooled to -5℃, and then ammonia gas was introduced into the reaction solution. During this period, the temperature was controlled between -5℃ and 0℃. When the pH of the reaction system was 8 to 9, it was kept at this temperature for 1 hour. After the temperature was kept at this temperature, a small amount of hydrochloric acid was added to adjust the pH to 4 to 6. After centrifugation, 500 kg of water was added to rinse the solution to obtain 2-aminosulfonyl-N,N-dimethylnicotinamide. After drying, the weight was 577.5 kg, the liquid phase quantitative content was 97.0%, and the total yield was 95.0%.

[0073] Example 5

[0074] A method for preparing 2-aminosulfonyl-N,N-dimethylnicotinamide includes the following steps:

[0075] (1) Preparation of sodium salt of 2-mercapto-N,N-dimethylnicotinamide

[0076] Add 500 kg of 2-chloro-N,N-dimethylnicotinamide, 225 kg of sodium sulfide, 15 kg of elemental sulfur, activated carbon filter residue containing elemental sulfur recovered in Example 4, and 200 kg of water to the reactor, and react at 135°C for 3 h to obtain a reaction solution containing sodium salt of 2-mercapto-N,N-dimethylnicotinamide.

[0077] (2) Acidification to prepare 2-mercapto-N,N-dimethylnicotinamide

[0078] Add 1690 kg of water to the reaction solution prepared in step (1) and transfer it to an acidification vessel. Adjust the pH of the reaction system to 1-1.5 using 30% hydrochloric acid. Then add 10 kg of activated carbon, heat to 70-80 °C and stir for 1 h to decolorize. Filter the solution through a plate and frame filter to obtain an aqueous solution of 2-mercapto-N,N-dimethylnicotinamide.

[0079] (3) Oxidation, chlorination

[0080] The aqueous solution of 2-mercapto-N,N-dimethylnicotinamide prepared in step (2) was transferred to an oxidation and chlorination reactor, cooled to 0°C, and 1935.5 kg of 10% sodium hypochlorite aqueous solution was added dropwise. The temperature of the reaction solution was controlled at 0-5°C during the dropwise addition process, and the dropwise addition time was 1 h. After the dropwise addition was completed, the solution was kept warm for 0.5 h.

[0081] 3500 kg of dichloromethane was transferred to the oxidation and chlorination reactors, and the temperature was lowered to -5°C. Chlorine gas was introduced until the starch-potassium iodide test paper turned blue. A total of 329 kg of chlorine gas was consumed. During this process, the system temperature was controlled between -5°C and 0°C. The system was allowed to stand and separate into layers. The aqueous phase was transferred to a wastewater storage tank, and the organic phase was transferred to an amination reactor to obtain 3-(dimethylcarbamoyl)pyridine-2-sulfonyl chloride.

[0082] (4)Amination

[0083] The organic phase prepared in step (3) was cooled to -5℃, and then ammonia gas was introduced into the reaction solution. During this period, the temperature was controlled between -5℃ and 0℃. When the pH of the reaction system was 8 to 9, it was kept at this temperature for 1 hour. After the temperature was kept at this temperature, hydrochloric acid was added dropwise to adjust the pH to 4 to 6. After centrifugation, 500 kg of water was added to rinse the solution to obtain 2-aminosulfonyl-N,N-dimethylnicotinamide. After drying, the weight was 578 kg, the liquid phase quantitative content was 96.5%, and the total yield was 94.6%.

[0084] Comparative Example 1

[0085] A method for preparing 2-aminosulfonyl-N,N-dimethylnicotinamide includes the following steps:

[0086] (1) Preparation of sodium salt of 2-mercapto-N,N-dimethylnicotinamide

[0087] Add 500 kg of 2-chloro-N,N-dimethylnicotinamide, 225 kg of sodium sulfide, 88 kg of elemental sulfur, and 200 kg of water to a reaction vessel, and react at 135 °C for 3 h to obtain a reaction solution containing sodium salt of 2-mercapto-N,N-dimethylnicotinamide.

[0088] (2) Acidification to prepare 2-mercapto-N,N-dimethylnicotinamide

[0089] Add 2000 kg of water to the reaction solution prepared in step (1) and transfer it to an acidification vessel. Adjust the pH of the reaction system to 2-2.5 using 30% hydrochloric acid. Then add 25 kg of activated carbon, heat to 70-80°C and stir for 1 h to decolorize. Filter the solution using a plate and frame filter to obtain an aqueous solution of 2-mercapto-N,N-dimethylnicotinamide. The activated carbon filter residue containing elemental sulfur in the plate and frame filter is dried with nitrogen and collected for use in the next batch.

[0090] (3) Oxidation, chlorination

[0091] The aqueous solution of 2-mercapto-N,N-dimethylnicotinamide prepared in step (2) was transferred to an oxidation and chlorination reactor, cooled to 0°C, and 1994 kg of 10% sodium hypochlorite aqueous solution was added dropwise. The temperature of the reaction solution was controlled at 0-5°C during the dropwise addition process, and the dropwise addition time was 40 min. After the dropwise addition was completed, the solution was kept warm for 0.5 h.

[0092] 3500 kg of dichloromethane was transferred to the oxidation and chlorination reactors, and the temperature was lowered to -5°C. Chlorine gas was then introduced until the starch-potassium iodide test paper turned blue. A total of 311 kg of chlorine gas was consumed. During this process, the system temperature was controlled between -5°C and 0°C. The system was allowed to stand and separate into layers. The aqueous phase was transferred to a wastewater storage tank, and the organic phase was transferred to an amination reactor to obtain 3-(dimethylcarbamoyl)pyridine-2-sulfonyl chloride.

[0093] (4)Amination

[0094] The organic phase prepared in step (3) was cooled to -5℃, and then ammonia gas was introduced into the reaction solution. During this period, the temperature was controlled at -5 to 0℃. When the pH of the reaction system was 8 to 9, it was kept at this temperature for 1 hour. After the temperature was kept at this temperature, a small amount of hydrochloric acid was added to adjust the pH to 4 to 6. After centrifugation, 500 kg of water was added to rinse the solution to obtain 2-aminosulfonyl-N,N-dimethylnicotinamide. After drying, the weight was 565 kg, the liquid phase quantitative content was 95.0%, and the total yield was 91.0%.

[0095] The difference between Comparative Example 1 and Example 3 is that in step (2), the pH is adjusted to 2-2.5 with hydrochloric acid, while the rest is the same as in Example 3.

[0096] As can be seen from Comparative Example 1 and Example 3, when the pH of the reaction solution prepared in step (1) is adjusted to 2-2.5, compared with adjusting the pH to 1-1.5, the yield and purity of the product 2-aminosulfonyl-N,N-dimethylnicotinamide are significantly reduced. Through a large number of experiments, the present invention found that adjusting the pH of the reaction solution prepared in step (1) to 1-1.5 can effectively remove elemental sulfur from the mercapto aqueous solution, so that the selectivity of the oxidation intermediate (intermediate II-II) reaches more than 98%. On the one hand, the elemental sulfur can be recovered with a high recovery rate for the next batch to reduce production costs. On the other hand, improving the quality of the mercapto aqueous solution and reducing the production of sulfuric acid will effectively reduce the hydrolysis of 3-(dimethylcarbamoyl)pyridine-2-sulfonyl chloride during the chlorination reaction and improve the reaction yield.

[0097] Comparative Example 2

[0098] A method for preparing 2-aminosulfonyl-N,N-dimethylnicotinamide includes the following steps:

[0099] (1) Preparation of sodium salt of 2-mercapto-N,N-dimethylnicotinamide

[0100] Add 500 kg of 2-chloro-N,N-dimethylnicotinamide, 225 kg of sodium sulfide, 88 kg of elemental sulfur, and 200 kg of water to a reaction vessel, and react at 135 °C for 3 h to obtain a reaction solution containing sodium salt of 2-mercapto-N,N-dimethylnicotinamide.

[0101] (2) Acidification to prepare 2-mercapto-N,N-dimethylnicotinamide

[0102] Add 2000 kg of water to the reaction solution prepared in step (1) and transfer it to an acidification reactor. Adjust the pH of the reaction system to 1-1.5 using 30% hydrochloric acid. Then add 25 kg of activated carbon, heat to 70-80 °C and stir for 1 h to decolorize. Filter the solution using a plate and frame filter to obtain an aqueous solution of 2-mercapto-N,N-dimethylnicotinamide. The activated carbon filter residue containing elemental sulfur in the plate and frame filter is dried with nitrogen and collected for use in the next batch.

[0103] (3) Oxidation, chlorination

[0104] The aqueous solution of 2-mercapto-N,N-dimethylnicotinamide prepared in step (2) was transferred to an oxidation and chlorination reactor, and 3500 kg of dichloromethane was added. The temperature was lowered to -15°C, and chlorine gas was introduced until the starch potassium iodide test paper turned blue. A total of 460 kg of chlorine gas was consumed. During this period, the system temperature was controlled between -5°C and 0°C. The system was allowed to stand and separate into layers. The aqueous phase was transferred to a wastewater storage tank, and the organic phase was transferred to an amination reactor to obtain 3-(dimethylcarbamoyl)pyridine-2-sulfonyl chloride.

[0105] (4)Amination

[0106] The organic phase prepared in step (3) was cooled to -5℃, and then ammonia gas was introduced into the reaction solution. During this period, the temperature was controlled between -5℃ and 0℃. When the pH of the reaction system was 8 to 9, it was kept at this temperature for 1 hour. After the temperature was kept at this temperature, a small amount of hydrochloric acid was added to adjust the pH to 4 to 6. After centrifugation, 500 kg of water was added to rinse the solution to obtain 2-aminosulfonyl-N,N-dimethylnicotinamide. After drying, the weight was 524.7 kg, the liquid phase quantitative content was 95.5%, and the total yield was 85.0%.

[0107] The difference between Comparative Example 2 and Example 3 is that the oxidation reaction and chlorination reaction are carried out simultaneously in step (3), and the system temperature and chlorine amount before the reaction are adjusted accordingly. The rest is the same as Example 3.

[0108] As can be seen from Comparative Example 2 and Example 3, in Comparative Example 2, step (3) uses the traditional method of simultaneous oxidation and chlorination reactions, with a chlorine usage of 2.4 eq. Compared to performing the oxidation and chlorination reactions in stages, using chlorine as both the oxidant and chlorinator results in a decrease in the purity of the product 2-aminosulfonyl-N,N-dimethylnicotinamide and a significant reduction in yield. Furthermore, since step (3) involves simultaneous oxidation and chlorination, which generates a large amount of heat, the system temperature must be lowered to a very low level (-15°C) beforehand; otherwise, the reaction is difficult to control.

[0109] Comparative Example 3

[0110] A method for preparing 2-aminosulfonyl-N,N-dimethylnicotinamide includes the following steps:

[0111] (1) Preparation of sodium salt of 2-mercapto-N,N-dimethylnicotinamide

[0112] Add 500 kg of 2-chloro-N,N-dimethylnicotinamide, 225 kg of sodium sulfide, 88 kg of elemental sulfur, and 200 kg of water to a reaction vessel, and react at 135 °C for 3 h to obtain a reaction solution containing sodium salt of 2-mercapto-N,N-dimethylnicotinamide.

[0113] (2) Acidification to prepare 2-mercapto-N,N-dimethylnicotinamide

[0114] Add 2000 kg of water to the reaction solution prepared in step (1) and transfer it to an acidification vessel. Adjust the pH of the reaction system to 2-2.5 using 30% hydrochloric acid. Then add 25 kg of activated carbon, heat to 70-80°C and stir for 1 h to decolorize. Filter the solution using a plate and frame filter to obtain an aqueous solution of 2-mercapto-N,N-dimethylnicotinamide. The activated carbon filter residue containing elemental sulfur in the plate and frame filter is dried with nitrogen and collected for use in the next batch.

[0115] (3) Oxidation, chlorination

[0116] The aqueous solution of 2-mercapto-N,N-dimethylnicotinamide prepared in step (2) was transferred to an oxidation and chlorination reactor, and 3500 kg of dichloromethane was added. The temperature was lowered to -15°C, and chlorine gas was introduced until the starch potassium iodide test paper turned blue. A total of 460 kg of chlorine gas was consumed. During this period, the system temperature was controlled between -5°C and 0°C. The system was allowed to stand and separate into layers. The aqueous phase was transferred to a wastewater storage tank, and the organic phase was transferred to an amination reactor to obtain 3-(dimethylcarbamoyl)pyridine-2-sulfonyl chloride.

[0117] (4)Amination

[0118] The organic phase prepared in step (3) was cooled to -5℃, and then ammonia gas was introduced into the reaction solution. During this period, the temperature was controlled between -5℃ and 0℃. When the pH of the reaction system was 8 to 9, it was kept at this temperature for 1 hour. After the temperature was kept at this temperature, a small amount of hydrochloric acid was added to adjust the pH to 4 to 6. After centrifugation, 500 kg of water was added to rinse the solution to obtain 2-aminosulfonyl-N,N-dimethylnicotinamide. After drying, the weight was 500 kg. The liquid phase quantitative content was 95.0%, and the total yield was 80.6%.

[0119] The difference between Comparative Example 3 and Example 3 is that in step (2), the pH is adjusted to 2-2.5 with hydrochloric acid, and in step (3), the oxidation reaction and the chlorination reaction are carried out simultaneously. Based on this, the system temperature and the amount of chlorine gas used before the reaction are adjusted. The rest is the same as Example 3.

[0120] As can be seen from Comparative Example 3 and Example 3, the method of the present invention, by precisely controlling the pH in the acidification step and creatively dividing the traditional simultaneous oxidation and chlorination reactions into two steps of oxidation followed by chlorination in the oxidation and chlorination steps, unexpectedly improves the product yield and product purity.

[0121] Although the present invention has been described in detail with reference to the accompanying drawings and preferred embodiments, the present invention is not limited thereto. Various equivalent modifications or substitutions can be made to the embodiments of the present invention by those skilled in the art without departing from the spirit and essence of the invention, and such modifications or substitutions should all be within the scope of the present invention. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should also be covered within the protection scope of the present invention.

Claims

1. A method for preparing 2-aminosulfonyl-N,N-dimethylnicotinamide, characterized in that, The reaction route is as follows: ； The specific steps are as follows: (1) 2-chloro-N,N-dimethylnicotinamide, sodium sulfide, elemental sulfur and water were reacted to obtain a reaction solution containing the sodium salt of 2-mercapto-N,N-dimethylnicotinamide; (2) Add water to the reaction solution prepared in step (1) and adjust the pH of the reaction system to 1~1.5 using hydrochloric acid; then add activated carbon, heat to 70~80℃ and stir to decolorize; filter to obtain an aqueous solution of 2-mercapto-N,N-dimethylnicotinamide; (3) Transfer the aqueous solution of 2-mercapto-N,N-dimethylnicotinamide prepared in step (2) to a reaction vessel, cool it to 0°C, and add a quantitative amount of oxidant, which is either H2O2 or NaClO. The molar ratio of the oxidant to 2-chloro-N,N-dimethylnicotinamide is 1~1.05:

1. During the dropwise addition process, control the temperature of the reaction solution at 0~10°C and the dropwise addition time at 0.6~1h. After the dropwise addition is completed, keep it warm for 0.5~1h. Then transfer it to an organic solvent and cool it to below -5°C. Pass chlorine gas through it until the starch potassium iodide test paper turns blue, indicating that the chlorination is complete. Control the temperature of the system at -5~0°C during the chlorination. After the reaction is completed, let it stand and separate into layers. Take the organic phase to obtain 3-(dimethylcarbamoyl)pyridine-2-sulfonyl chloride. (4) Cool the organic phase prepared in step (3) to below -5℃, and then introduce ammonia into the reaction solution. During this period, control the temperature to -5~0℃. When the pH of the reaction system is 8~9, keep it warm for 1h. After the warming is completed, add hydrochloric acid to adjust the pH to 4~6, centrifuge, and add water to rinse to obtain 2-aminosulfonyl-N,N-dimethylnicotinamide.

2. The method for preparing 2-aminosulfonyl-N,N-dimethylnicotinamide as described in claim 1, characterized in that, The oxidant is H2O2. After the oxidation reaction is complete, 0.01~0.05 eq of sodium hydrosulfite is added to quench the excess H2O2.

3. The method for preparing 2-aminosulfonyl-N,N-dimethylnicotinamide as described in claim 1, characterized in that, In step (3), the organic solvent is either dichloroethane or dichloromethane.

4. The method for preparing 2-aminosulfonyl-N,N-dimethylnicotinamide as described in claim 1, characterized in that, In step (3), the amount of organic solvent used is 5~7 g / g based on 2-chloro-N,N-dimethylnicotinamide.

5. The method for preparing 2-aminosulfonyl-N,N-dimethylnicotinamide as described in claim 1, characterized in that, In step (3), the molar ratio of chlorine to 2-chloro-N,N-dimethylnicotinamide is 1.7~2:

1.

6. The method for preparing 2-aminosulfonyl-N,N-dimethylnicotinamide as described in claim 1, characterized in that, In step (3), the chlorination reaction temperature is -5~0℃.

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