A preparation method of tolbutamide

Abstract

The present invention specifically relates to a preparation method of tolbutamide, and the steps are as follows: p-toluenesulfonyl chloride and urea are jointly added into a solvent containing an acid-binding agent and mixed evenly; after adding p-toluenesulfonamide and 4-dimethylaminopyridine, the reaction system is sealed, heated to 100-130°C and reacted for 2-4 hours; an alkali solution is added to the cooled reaction system to adjust the pH to neutral and stirred continuously for a period of time, and the obtained solid by filtration is tolbutamide. The present invention uses p-toluenesulfonamide and 4-dimethylaminopyridine as a composite catalyst, which significantly improves the reaction activity of urea and increases the reaction yield. In addition, the acid-binding agent in the present invention can be regenerated by alkali treatment, realizing the recycling of waste filtrate and composite catalyst in production, significantly reducing wastewater discharge and lowering production costs.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of toluenesulfonylurea. Background Art

[0002] Disclosing the information of this background art section is only intended to enhance the overall understanding of the present invention, and it is not necessarily to be regarded as an admission or any form of implication that this information constitutes the prior art already known to those of ordinary skill in the art.

[0003] Toluenesulfonylurea can be used in the synthesis of hypoglycemic drugs such as gliclazide. In the prior art, there are many reports on the synthesis method of toluenesulfonylurea, mainly starting from p-toluenesulfonamide and p-toluenesulfonyl chloride. The invention patent CN111747872A relates to a synthesis method of toluenesulfonylurea, in which p-toluenesulfonamide and sodium cyanate are dissolved in a mixed solution of water and ethanol for reaction. After the reaction is completed, filtration is carried out, and the mother liquor obtained after filtration is acidified and filtered again to finally obtain toluenesulfonylurea. The above method has no by-products and ammonia production, the yield of the target product reaches more than 90%, the purity > 99%, the process is simple, and there is no waste gas production, but the cost of using sodium cyanate is relatively high. Patent CN110372545A proposes a preparation method and process of high-purity gliclazide intermediate toluenesulfonylurea. The reaction steps are as follows: First, nitrogen is filled into the reaction vessel, organic solvent and p-toluenesulfonyl isocyanate are added, ammonia is filled, and reaction is carried out at low temperature under stirring conditions to generate crude toluenesulfonylurea, then filtration is carried out, acetonitrile / water is added for reflux, centrifugation, and drying to obtain white crystal toluenesulfonylurea. This invention uses p-toluenesulfonyl isocyanate to react with ammonia in toluene to obtain toluenesulfonylurea, and the yield can be as high as 96.3%, and the product purity is above 99.9%. This method is simple to operate, the conditions are mild, it is easy to post-treat, with high purity and high yield, but the raw material p-toluenesulfonyl isocyanate is expensive and does not have market competitiveness. Currently, the industrial production process mainly adopts a technology similar to the invention of CN102557997A, using p-methylbenzenesulfonamide, inorganic base and urea as raw materials. First, p-methylbenzenesulfonamide and inorganic base are reacted in an organic solvent to obtain sodium p-toluenesulfonamide, then urea is added to react with sodium p-toluenesulfonamide to obtain sodium toluenesulfonylurea, and then the obtained sodium toluenesulfonylurea is acidified to obtain crude toluenesulfonylurea, and the crude product is further purified to obtain toluenesulfonylurea. This method has a simple process, high raw material utilization rate, and short reaction cycle. Its raw material p-methylbenzenesulfonamide is generally obtained by reacting p-toluenesulfonyl chloride with ammonia water. In order to reduce costs, most enterprises currently adopt a two-step method to prepare toluenesulfonylurea. First, p-toluenesulfonyl chloride is reacted with ammonia water to obtain methylbenzenesulfonamide, and then further reacted with urea to obtain toluenesulfonylurea; in the first reaction, the ammonium chloride generated by adding ammonia water is dissolved in dilute ammonia water, and the ammonia gas generated in the second reaction is mixed with the alkali solution used for neutralization and will also remain in the water phase, resulting in a large amount of high-salt ammonia-nitrogen wastewater being generated in both reactions, and evaporating and treating it will consume a large amount of energy. Therefore, although the product yield of the above method is high and the quality meets the requirements of drug synthesis, the treatment cost of the wastewater generated by the reaction is high, resulting in low overall economic benefits.

[0004] The inventor believes that the direct reaction of p-toluenesulfonyl chloride with urea is an ideal synthetic route. CN102219718A discloses a new method for synthesizing p-toluenesulfonylurea. p-Toluenesulfonyl chloride is added to a system of urea and dichloroethane for condensation reaction. Dichloroethane can also be replaced by one of toluene, xylene, benzene, dichloromethane, chloroform, etc. to produce p-toluenesulfonylurea. After the condensation reaction is completed, sodium hydroxide solution is added to neutralize the generated hydrogen chloride, and p-toluenesulfonylurea will precipitate out. After filtration, p-toluenesulfonylurea is obtained. However, after many experiments, even heating to 140 °C did not yield the product, indicating that direct mixing of the two for reaction is not feasible. Summary of the Invention

[0005] In view of the above research status, the object of the present invention is to provide a method for synthesizing p-toluenesulfonylurea with high product yield, simple process and no obvious waste products. To achieve the above technical object, the present invention designs and provides a one-step synthesis preparation process using p-toluenesulfonyl chloride and urea as raw materials. By introducing a composite catalyst, the defect of low reaction yield of p-toluenesulfonyl chloride and urea is overcome. For the wastewater produced by the above reaction, a recycling application scheme is also provided, realizing high-efficiency synthesis while reducing production costs and maximizing the production efficiency of enterprises.

[0006] Based on the above-mentioned technical effects achieved, the present invention provides the following technical solutions:

[0007] The present invention provides a method for preparing p-toluenesulfonylurea, comprising the following steps:

[0008] (1) Add p-toluenesulfonyl chloride and urea together into a solvent containing an acid-binding agent and mix well; wherein, the weight of the solvent is 3-10 times the weight of p-toluenesulfonyl chloride, and the molar ratio of p-toluenesulfonyl chloride, urea, and acid-binding agent is 1~1.2:1~1.2:1~1.5;

[0009] (2) After adding the composite catalyst, seal the reaction system and heat to 100~130 °C for reaction for 2~4 h; the composite catalyst is a mixture of p-toluenesulfonamide and 4-dimethylaminopyridine mixed according to a molar ratio of 1:0.8~1.2;

[0010] (3) Add an alkali solution to the cooled reaction system to adjust the pH to neutral and stir continuously for a period of time. The obtained solid by filtration is p-toluenesulfonylurea.

[0011] The present invention designs to synthesize p-toluenesulfonylurea by a one-step reaction using p-toluenesulfonyl chloride and urea as raw materials. The reaction route is shown as follows:

[0012]

[0013] However, when urea is heated to about 160 °C, a decomposition reaction occurs. Further heating will cause a condensation reaction, generating biuret, triuret, cyanuric acid, etc. When heated below 160 °C, urea is not very reactive, so the yield of the above reactions is very low. To solve this problem, the present invention first introduces a composite catalyst, p-toluenesulfonamide and 4-dimethylaminopyridine (DMAP). The pyridine ring of DMAP has a significantly enhanced basicity due to the dimethylamino group (a strong electron-donating group) at its 4-position, becoming a strong nucleophile. When sulfonyl chloride (RSO 2 Cl) participates in the reaction, the pyridine nitrogen atom of DMAP nucleophilically attacks the sulfur atom of sulfonyl chloride to form a highly reactive N-sulfonylpyridinium salt intermediate (RSO 2- DMAP⁺Cl⁻). The sulfonyl group of this intermediate is significantly activated (the S-O bond is polarized, and the positive charge of the sulfur atom is enhanced). Urea attacks the positively charged center of the sulfur atom in the active intermediate through the lone pair of electrons on nitrogen, replacing DMAP to generate a sulfonylurea product (RSO 2 NHCONH 2 ). After DMAP completes the transfer, it is regenerated (restores the free state) and continues to catalyze the next sulfonyl transfer process (catalytic cycle). When DMAP catalyzes the sulfonylation reaction, it usually needs to be paired with a basic reagent (such as triethylamine) to neutralize the released HCl and prevent HCl from protonating DMAP and inhibiting the reaction. DMAP can also activate p-toluenesulfonamide, making it easier for urea molecules to attack and form p-toluenesulfonylurea. The ammonia released by the reaction quickly reacts with p-toluenesulfonyl chloride to generate p-toluenesulfonamide again, and the cyclic catalysis realizes the acceleration of the reaction rate. In some embodiments verified in the present invention, the p-toluenesulfonamide and 4-dimethylaminopyridine are mixed in a molar ratio of 1:1.

[0014] In addition, the above preparation method also has the following preferred embodiments:

[0015] In step (1):

[0016] The acid-binding agent is preferably an organic amine, more preferably a tertiary amine, and further preferably a combination of one or more of triethylamine, tributylamine, trioctylamine, etc.

[0017] The solvent is an aromatic hydrocarbon with a boiling point above 100 °C, and is further selected from substituted benzene reagents, and further preferably a combination of one or more of toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, etc.

[0018] In step (2):

[0019] The molar ratio of the composite catalyst to p-toluenesulfonyl chloride is 0.01 - 0.10:1.

[0020] The heating temperature is further preferably 110 - 120 °C.

[0021] In step (3):

[0022] The alkali solution is preferably an inorganic base, such as one of the aqueous solutions of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate. The concentration of the alkali solution can be adjusted by those skilled in the art according to factors such as the reaction volume and reaction conditions. Feasible mass fractions are, for example, 5% - 40%.

[0023] In addition, in order to reduce the reagent consumption in the above preparation method and lower the production cost, the present invention also optimizes the filtrate generated by filtration in step (3), and provides a scheme for recycling the filtrate. In a more preferred embodiment, step (3) is as follows:

[0024] Adjust the reaction system to neutral and continue stirring for 20 - 60 min to obtain a feed liquid. Filter the feed liquid to obtain filter residue I and filtrate I. Add 5 - 10 times the weight of hot water (85 - 95 °C) to filter residue I, stir and filter to obtain filter residue II and filtrate II. Dry filter residue II to obtain the toluenesulfonylurea. The upper layer separated from the statically stratified filtrate I is used to replace the solvent and acid-binding agent in step (1), and the lower layer adjusted with alkali is used to replace the alkali solution in step (3). Cool filtrate II to below 40 °C for crystallization, filter to obtain crystals and put them into step (2) for continued use.

[0025] In the above step (3), after adjusting the pH of the feed liquid to neutral, the product toluenesulfonylurea and the composite catalyst precipitate at this pH. Since the composite catalyst has better solubility in water, it can be dissolved by hot water, so that the composite catalyst can be separated from the product toluenesulfonylurea, and after cooling, it precipitates and is put back into step (2) for use. Filtrate I mainly includes the solvent, acid-binding agent and alkaline water. The alkaline environment will promote the regeneration of the acid-binding agent. Therefore, the solvent and acid-binding agent are separated as the organic phase (upper phase) and can be put into step (1) for repeated use.

[0026] Compared with the prior art, the beneficial effects of the present invention are:

[0027] The present invention adopts a one-step reaction of toluenesulfonyl chloride and urea, which conforms to atom economy and maximally utilizes the raw materials. Toluenesulfonyl chloride and urea are difficult to react below 130 °C, and high temperature will cause the polymerization reaction of urea. The present invention solves the problem of the reaction between toluenesulfonyl chloride and urea through catalysis. The present invention adopts the regeneration and recycling of the organic acid-binding agent through the alkali solution, and no wastewater is discharged during the production process, with obvious environmental protection benefits. The present invention not only reduces the operation steps, but also greatly reduces the raw material, operation and wastewater treatment costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] The accompanying drawings forming a part of this specification are used to provide a further understanding of the present invention. The schematic embodiments and descriptions thereof of the present invention are used to explain the present invention and do not constitute an improper limitation of the present invention.

[0029] Figure 1 It is the infrared spectrum diagram of the toluenesulfonylurea product prepared in Example 1;

[0030] Figure 2 It is the nuclear magnetic resonance hydrogen spectrum diagram of the toluenesulfonylurea product prepared in Example 1;

[0031] Figure 3 It is the liquid chromatography diagram of the toluenesulfonylurea product prepared in Example 1. Detailed implementation manners

[0032] It should be noted that the following detailed descriptions are all illustrative and are intended to provide further explanations of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention belongs.

[0033] It should be noted that the terms used herein are only for describing specific implementation manners and are not intended to limit the exemplary implementation manners according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular forms are also intended to include the plural forms. In addition, it should also be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0034] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in combination with specific examples and comparative examples.

[0035] Example 1

[0036] In this example, a preparation method of toluenesulfonylurea is provided, including the following steps:

[0037] (1) Add 100 g of toluene and 15 g of triethylamine (0.1 mol) to the reaction device and mix evenly, and then add 20 g of p-toluenesulfonyl chloride (0.105 mol) and 6.3 g of urea (0.105 mol) to the reaction device in sequence, and stir and mix for half an hour;

[0038] (2) Add 1 g of composite catalyst (0.58 g of p-toluenesulfonamide and 0.42 g of 4-dimethylaminopyridine) to the reaction device and mix evenly, seal the reaction device, heat it to 110 °C under stirring, and keep it warm for 3 h, and then cool it to room temperature;

[0039] (3) Add sodium hydroxide solution with a mass fraction of 32% to the reaction mixture to adjust the reaction mixture to neutrality, and then continue stirring for 30 min; filter the neutralized material liquid to obtain Filter Residue 1 and Filtrate 1. Add 10 times the weight of hot water (90 °C) to Filter Residue 1, stir, and filter for the second time to obtain Filter Residue 2 and Filtrate 2. Dry Filter Residue 2 to obtain 21.5 g of the product p-toluenesulfonylurea, with a yield of 95.5%; cool Filtrate 2 (to 35 °C or below) to crystallize, and conduct the third filtration. The crystalline solid obtained by filtration is returned to step (2) for use; the filtration water from the third filtration is reused; let Filtrate 1 stand for stratification and separation. The separated upper layer is used in step (1) to replace the solvent and acid-binding agent, and the separated lower layer is adjusted with alkali for use in step (3) to replace the alkali solution.

[0040] The purity of the obtained p-toluenesulfonylurea product determined by liquid chromatography is 99.4%. The infrared spectrum is shown in the appendix Figure 1 , and the proton nuclear magnetic resonance spectrum is shown in the appendix Figure 2 , and the liquid chromatography spectrum is as Figure 3 .

[0041] Example 2

[0042] In this example, another preparation method of p-toluenesulfonylurea is provided, including the following steps:

[0043] (1) Add 60 g of chlorobenzene and 15 g of triethylamine to the reaction device and mix evenly. Then, sequentially add 20 g of p-toluenesulfonyl chloride and 6.3 g of urea to the reaction device, and stir and mix for half an hour;

[0044] (2) Add 2 g of a composite catalyst (1.16 g of p-toluenesulfonamide and 0.84 g of 4-dimethylaminopyridine) to the reaction device and mix evenly. Seal the reaction device, heat it to 100 °C under stirring, and keep it warm for 4 h, and then cool it to room temperature;

[0045] (3) Add sodium hydroxide solution with a mass fraction of 28% to the reaction mixture to adjust the reaction mixture to neutrality, and then continue stirring for 30 min; filter the neutralized material liquid to obtain Filter Residue 1 and Filtrate 1. Add 10 times the weight of hot water (90 °C) to Filter Residue 1, stir, and filter for the second time to obtain Filter Residue 2 and Filtrate 2. Dry Filter Residue 2 to obtain 21.7 g of the product, with a yield of 96.4%; cool Filtrate 2 (to 35 °C) to crystallize, and conduct the third filtration. The crystalline solid obtained by the third filtration is returned to step (2) for use; the filtration water from the third filtration is reused; let Filtrate 1 stand for stratification and separation. The separated upper layer is used in step (1) to replace the solvent and acid-binding agent, and the separated lower layer is adjusted with alkali for use in step (3) to replace the alkali solution.

[0046] The purity of the obtained product determined by liquid chromatography is 99.2%.

[0047] Example 3

[0048] In this embodiment, another preparation method of tolbutamide is provided, which includes the following steps:

[0049] (1) Add 200 g of xylene and 27.5 g of tributylamine to the reaction device and mix evenly. Then, add 20 g of p-toluenesulfonyl chloride and 6.3 g of urea to the reaction device in sequence, and stir and mix for half an hour;

[0050] (2) Add 0.5 g of composite catalyst (0.29 g of p-toluenesulfonamide and 0.21 g of 4-dimethylaminopyridine) to the reaction device and mix evenly. Seal the reaction device, heat it to 120 °C under stirring, and keep it warm for 2 h, then cool it to room temperature;

[0051] (3) Add a potassium hydroxide solution with a mass fraction of 40% to the reaction mixture to adjust the reaction mixture to neutral, and then continue to stir for 30 min; Filter the neutralized feed liquid to obtain filter residue one and filtrate one. Add 8 times the weight of hot water (90 °C) to filter residue one, stir, and filter for the second time to obtain filter residue two and filtrate two. Dry filter residue two to obtain 21.3 g of the product, with a yield of 94%; Cool filtrate two (35 °C) to crystallize, and perform the third filtration. The crystalline solid obtained from the third filtration is returned to step (2) for use; The filtered water from the third filtration is reused; Let filtrate one stand for stratification and separation. The separated upper layer is used in step (1) to replace the solvent and acid-binding agent, and the separated lower layer is adjusted with alkali for use in step (3) to replace the alkali solution.

[0052] The purity of the obtained product determined by liquid chromatography is 99.3%.

[0053] Example 4

[0054] In this embodiment, another preparation method of tolbutamide is provided, which includes the following steps:

[0055] (1) Add 100 g of toluene and 27.5 g of tributylamine to the reaction device and mix evenly. Then, add 20 g of p-toluenesulfonyl chloride and 6.3 g of urea to the reaction device in sequence, and stir and mix for half an hour;

[0056] (2) Add 0.5 g of composite catalyst (0.29 g of p-toluenesulfonamide and 0.21 g of 4-dimethylaminopyridine) to the reaction device and mix evenly. Seal the reaction device, heat it to 120 °C under stirring, and keep it warm for 3 h, then cool it to room temperature;

[0057] (3) Add sodium hydroxide solution with a mass fraction of 32% to the reaction mixture to adjust the reaction mixture to neutrality, and then continue stirring for 30 min; Filter the neutralized feed liquid to obtain a filter residue and a filtrate. Add 10 times the weight of hot water (95 °C) to the filter residue, stir, and filter a second time to obtain a second filter residue and a second filtrate. Dry the second filter residue to obtain 21.0 g of product, with a yield of 93.3%; Cool the second filtrate (40 °C) to crystallize, and perform a third filtration. The crystalline solid obtained from the third filtration is returned to step (2) for use; The filtrate from the third filtration is reused; Let the first filtrate stand for liquid separation, and separate. The upper layer separated is used in step (1) to replace the solvent and the acid-binding agent, and the lower layer separated is adjusted with alkali for use in step (3) to replace the alkali solution.

[0058] The purity of the obtained product was determined by liquid chromatography to be 99.5%.

[0059] Example 5

[0060] In this example, another preparation method of tolbutamide is provided, including the following steps:

[0061] (1) Add the upper layer (organic phase) of the first filtrate recovered in Example 4 to the reaction device, and then sequentially add 20 g of tosyl chloride and 6.3 g of urea to the reaction device, and stir and mix for half an hour;

[0062] (2) Add the crystalline solid (composite catalyst) recovered in Example 4 to the reaction device and mix evenly. Seal the reaction device, heat it to 110 °C under stirring, and keep it warm for 3 h, and then cool it to room temperature;

[0063] (3) Add the lower aqueous phase of the first filtrate to the reaction mixture, use sodium hydroxide solution with a mass fraction of 40% to adjust the reaction mixture to neutrality, and then continue stirring for 30 min; Filter the neutralized feed liquid to obtain a first filter residue and a first filtrate. Add 10 times the weight of hot water (85 °C) to the first filter residue, stir, and filter a second time to obtain a second filter residue and a second filtrate. Dry the second filter residue to obtain 21.1 g of product, with a yield of 93.8%; Cool the second filtrate (35 °C) to crystallize, and perform a third filtration. The crystalline solid obtained from the third filtration is returned to step (2) for use; The filtrate from the third filtration is reused; Let the first filtrate stand for liquid separation, and separate. The upper layer separated is used in step (1) to replace the solvent and the acid-binding agent, and the lower layer separated is adjusted with alkali for use in step (3) to replace the alkali solution.

[0064] The purity of the obtained product was determined by liquid chromatography to be 99.2%.

[0065] Comparative Example

[0066] A comparison was made according to the method of direct reaction between p-toluenesulfonyl chloride and urea provided in CN102219718A. 39 g (0.65 mol) of urea and 79 g (0.8 mol) of dichloroethane were added to the condensation reaction tank, and the temperature was raised to 60 °C. Then, a solution of 95 g (0.5 mol) of p-toluenesulfonyl chloride in 79 g (0.8 mol) of dichloroethane was added dropwise. The temperature was maintained at about 60 - 65 °C. After the dropwise addition was completed, the temperature was raised to 70 - 72 °C, and the reaction was carried out under insulation for 3.5 h. Then, it was cooled to room temperature, and the prepared sodium hydroxide aqueous solution was added to make the reaction solution neutral. Then, dichloroethane was recovered by distillation until no dichloroethane was distilled out. After cooling and crystallization, centrifugation, and washing with water, the crude wet product of p-toluenesulfonylurea was obtained. Detection by liquid chromatography showed that no product was found. When heated under reflux at the reactant ratio and controlled at 110, 120, 130, and 140 °C, no product was detected either.

[0067] After consulting the literature, it was found that the reaction activity of urea is very low, and p-toluenesulfonyl chloride cannot directly react with urea without a catalyst.

[0068] In summary, the present invention believes that it is difficult for p-toluenesulfonyl chloride and urea to directly undergo an addition reaction below 130 °C. Urea has inactive properties and low yield. In the process provided by the present invention, when the reaction temperature is controlled at 130 °C and below, urea basically does not undergo side reactions. By introducing a composite catalyst, the activity of urea is significantly improved. In the above examples, the product yield of p-toluenesulfonylurea is over 90%, and the product purity is relatively high, belonging to products with high market value.

[0069] The above are only the preferred embodiments of the present invention and are not used to limit the present invention. For those skilled in the art, various changes and modifications can be made to the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for preparing p-toluenesulfonylurea, characterized in that: The steps include: (1) adding p-toluenesulfonyl chloride and urea to a solvent containing an acid binding agent and mixing them thoroughly; wherein the weight of the solvent is 3-10 times the weight of p-toluenesulfonyl chloride, and the molar ratio of p-toluenesulfonyl chloride, urea and acid binding agent is 1-1.2:1-1.2:1-1.5; (2) After adding the composite catalyst, the reaction system is sealed and heated to 100-130° C. for reaction for 2-4 hours; the composite catalyst is a mixture of p-toluenesulfonamide and 4-dimethylaminopyridine in a molar ratio of 1:0.8-1.2; (3) Adding alkaline solution to the reaction system after cooling to adjust the pH to neutral and continue stirring for a period of time. The solid obtained by filtering is p-toluenesulfonylurea.

2. The method for preparing p-toluenesulfonylurea as claimed in claim 1, characterized in that: In step (1): the acid binding agent is selected from one or a combination of triethylamine, tributylamine and trioctylamine.

3. The method for preparing p-toluenesulfonylurea as claimed in claim 1, characterized in that: In step (1): the solvent is selected from one or a combination of toluene, xylene, trimethylbenzene, chlorobenzene and dichlorobenzene.

4. The method for preparing p-toluenesulfonylurea as claimed in claim 1, characterized in that: In step (2): the molar ratio of the composite catalyst to p-toluenesulfonyl chloride is 0.01-0.10:

1.

5. The method for preparing p-toluenesulfonylurea as claimed in claim 1, characterized in that: In step (2): the p-toluenesulfonamide and 4-dimethylaminopyridine are mixed in a molar ratio of 1:

1.

6. The method for preparing p-toluenesulfonylurea as claimed in claim 1, characterized in that: In step (3): the alkali solution is selected from an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.

7. The method for preparing p-toluenesulfonylurea as claimed in claim 6, characterized in that: The mass fraction of the alkali solution is 5% to 40%.

8. The method for preparing p-toluenesulfonylurea as claimed in claim 1, characterized in that: The specific implementation method of step (3) is as follows: After the reaction system is adjusted to neutral, stirring is continued for 20-60 minutes to obtain a feed liquid, the feed liquid is filtered to obtain a filter residue 1 and a filtrate 1, 5-10 times the weight of hot water is added to the filter residue 1, stirred and filtered to obtain a filter residue 2 and a filtrate 2, and the filter residue 2 is dried to obtain the p-toluenesulfonyl urea; the filtrate 1 is allowed to stand for stratification and separation, the separated upper layer part replaces the solvent and the acid binding agent in step (1), and the separated lower layer is partially prepared with alkali to replace the alkali solution in step (3); the filtrate 2 is cooled and crystallized, and the crystals obtained by filtering are put into step (2) for further use.

9. The method for preparing p-toluenesulfonylurea as claimed in claim 8, characterized in that: The hot water temperature is 85-95°C.

10. The method for preparing p-toluenesulfonylurea as claimed in claim 8, characterized in that: The temperature of the cooling crystallization is 40° C. or below.

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