Method for preparing high-quality p-acetamidobenzene sulfonyl chloride

Abstract

The invention provides a method for preparing high-quality p-acetamidobenzene sulfonyl chloride, which comprises the following steps: (a) carrying out sulfonation reaction on N-acetanilide and a sulfonating agent at 48-52 DEG C to obtain a mixture containing sulfonyl chloride; (b) transferring the mixture containing the sulfonyl chloride into a vacuum flask, and standing for further reaction to obtain sulfonation reaction liquid; (c) dropwise adding the sulfonation reaction solution into an organic solvent, and controlling the temperature in the dropwise adding process to be less than or equal to 25 DEG C, so that a solid is separated out from a system; raising the temperature of the system to be greater than or equal to 30 DEG C to ensure that the separated solid is completely dissolved; the dripping speed is 10 to 20 ml / min; and (d) layering the product obtained in the step (c), separating out concentrated sulfuric acid on the upper layer, adding water into the organic phase on the lower layer, washing, and layering again. And finally, the acetamidobenzene sulfonyl chloride with the purity of 99.8% is obtained, the method is suitable for industrial production with high quality requirements, and the quality guarantee period of the product is prolonged and can reach 1 year.

Description

Technical Field

[0001] The invention belongs to the field of organic chemistry and relates to a method for preparing 4-acetamidobenzenesulfonyl chloride, in particular to a method for preparing high-quality 4-acetamidobenzenesulfonyl chloride. Background Art

[0002] N-acetyl-4-aminobenzenesulfonyl chloride is an important organic intermediate widely used in the fields of medicine and chemical industry, especially in the production of sulfonamide drugs, dyes and other organic synthetic chemicals. The preparation of this compound usually uses N-acetanilide as raw material to generate sulfonyl chloride through sulfonation reaction. However, due to the harsh reaction conditions and the difficulty of purification, the traditional process often cannot obtain high-purity N-acetyl-4-aminobenzenesulfonyl chloride, which limits its industrial application.

[0003] In order to obtain high-purity acetamidobenzenesulfonyl chloride, the existing process often requires the use of a large amount of solvent for recrystallization and purification. The Chinese invention patent with publication number CN102304070A discloses a production process of acetamidobenzenesulfonyl chloride, which uses acetanilide as a raw material, adds chlorosulfonic acid and dehydrated water to obtain sulfonated oil through chlorosulfonation reaction, adds water to the obtained sulfonated oil, and performs hydrolysis reaction. The sulfonated oil after hydrolysis undergoes a suction filtration process, and one part produces hydrogen chloride gas, and the hydrogen chloride gas is recycled and absorbed to obtain dilute hydrochloric acid. The other part of the obtained product acetamidobenzenesulfonyl chloride is dissolved in a dissolving kettle, and then crystallized, centrifuged, and dried to obtain the acetamidobenzenesulfonyl chloride finished product. Dichloroethane solvent is added during the dissolution process, and the finished product obtained after centrifugation is dried by air flow, and then vacuum packaged. In the production process, the mass ratio of dichloroethane solvent to raw material acetanilide is 4~8:1, and air flow drying is adopted. The shelf life of the obtained finished product can reach 180 days, and the finished product is more stable. However, multiple recrystallization purification steps cannot avoid the loss of some active ingredients and are prone to produce residual solvents, affecting the quality and shelf life of the final product. Summary of the invention

[0004] In order to solve the above technical problems, the object of the present invention is to provide a method for preparing high-quality 4-acetamidobenzenesulfonyl chloride.

[0005] In order to achieve the above technical problem, the present invention provides a method for preparing high-quality 4-acetamidobenzenesulfonyl chloride, comprising the following steps: (a) subjecting N-acetanilide to a sulfonation reaction with a sulfonating agent at 48 to 52° C. to obtain a mixture containing sulfonyl chloride; (b) transferring the mixture containing sulfonyl chloride into a thermos bottle and allowing it to stand for further reaction to obtain a sulfonation reaction solution; (c) adding the sulfonation reaction solution dropwise to an organic solvent, controlling the temperature during the dropping process to ≤25°C, so that a solid precipitates in the system; heating the system to ≥30°C to ensure that the precipitated solid is completely dissolved; the dropping speed is 10-20 ml / min; (d) The product of step (c) is subjected to a layering operation, the upper layer of concentrated sulfuric acid is separated, water is added to the lower organic phase for washing and the layering operation is performed again; the obtained organic phase is concentrated, cooled to room temperature, and the solid crude product is collected by filtration; and the solid crude product is then subjected to reduced pressure distillation.

[0006] Optimally, in step (a), the molar ratio of N-acetanilide to the sulfonating agent is 1:1.5-2.

[0007] Furthermore, in step (a), the sulfonation reaction time is 2 to 5 hours.

[0008] Furthermore, in step (a), the sulfonating agent is chlorosulfonic acid; and the gaseous product of the sulfonation reaction is collected and absorbed.

[0009] Optimally, in step (b), the static storage time is 5 to 10 hours.

[0010] Optimally, in step (c), the organic solvent is dichloromethane, chloroform, dichloroethane or isopropyl ether.

[0011] Furthermore, in step (c), stirring is continued at room temperature for 0.5 to 2 hours after the dropwise addition is completed.

[0012] Optimally, in step (d), the product of step (c) is subjected to a layer separation operation using an extractant.

[0013] Furthermore, in step (d), the obtained organic phase is concentrated to recover 65-80% of the organic solvent.

[0014] The method for preparing high-quality 4-acetamidobenzenesulfonyl chloride provided by the invention strictly controls the temperature conditions of the sulfonation reaction and adds a standing step, the reaction conditions are mild, no excessively high temperature and pressure are required, the reaction operation is simple, the equipment requirements are low, and the safety factor is greatly increased; the post-treatment is simple, dichloromethane is used as a solvent and an extractant is used to improve the liquid separation efficiency, the traditional recrystallization and multi-step purification process are simplified, and the process complexity is reduced; finally, 4-acetamidobenzenesulfonyl chloride (ASC) with a purity of up to 99.8% is obtained, which is suitable for industrial production with high quality requirements, and the product shelf life is increased to 1 year. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 The chemical reaction formula involved in the method for preparing high-quality 4-acetamidobenzenesulfonyl chloride of the present invention; Figure 2 The process flow chart of the method for preparing high-quality 4-acetamidobenzenesulfonyl chloride of the present invention; Figure 3 It is the liquid phase spectrum of 4-acetamidobenzenesulfonyl chloride in Example 1. DETAILED DESCRIPTION

[0016] The method for preparing high-quality 4-acetamidobenzenesulfonyl chloride comprises the following steps: (a) subjecting N-acetanilide and a sulfonating agent to a sulfonation reaction at 48-52° C. to obtain a mixture containing sulfonyl chloride; (b) transferring the mixture containing sulfonyl chloride to a thermos bottle, standing it for further reaction to obtain a sulfonation reaction liquid; (c) dripping the sulfonation reaction liquid into an organic solvent, controlling the temperature during the dripping process to be ≤25° C., so that a solid is precipitated in the system; heating the system to ≥30° C. to ensure that the precipitated solid is completely dissolved; the dripping speed is 10-20 ml / min; (d) performing a layering operation on the product of step (c), separating the concentrated sulfuric acid in the upper layer, adding water to the lower organic phase for washing and performing a layering operation again; performing a concentration operation on the obtained organic phase, cooling it to room temperature, filtering and collecting a solid crude product; and performing a reduced pressure distillation on the solid crude product. The temperature conditions of the sulfonation reaction are strictly controlled, a standing step is added, and an efficient extraction crystallization purification step is combined. The reaction conditions are mild, and excessively high temperature and pressure are not required. The reaction operation is simple, the equipment requirements are low, and the safety factor is greatly increased. The post-treatment is simple, dichloromethane is used as a solvent and an extractant is used to improve the separation efficiency, simplify the traditional recrystallization and multi-step purification process, and reduce the complexity of the process. Finally, acetaminobenzenesulfonyl chloride with a purity of up to 99.8% is obtained, which is suitable for industrial production with high quality requirements and improves the product shelf life to 1 year.

[0017] In step (a), the molar ratio of N-acetanilide to the sulfonating agent is 1:1.5-2; the time of the sulfonation reaction is 2-5 hours; the sulfonating agent is chlorosulfonic acid; and the gaseous product of the sulfonation reaction is collected and absorbed. In step (b), the static storage time is 5-10 hours. In step (c), the organic solvent is dichloromethane, chloroform, dichloroethane or isopropyl ether. After the dropwise addition is completed, stirring is continued at room temperature for 0.5-2 hours. In step (d), the product of step (c) is layered using an extractant (dichloromethane, chloroform and other organic solvents). In step (d), the obtained organic phase is concentrated to recover 65-80% of the organic solvent.

[0018] The present invention will be further described below in conjunction with the embodiments shown in the accompanying drawings. Example 1

[0019] This embodiment provides a method for preparing high-quality acetamidobenzenesulfonyl chloride, such as Figure 1 and Figure 2 As shown, the following steps are included: (a) Add 60g (0.44mol) of N-acetanilide (Compound 1) to a 50ml three-necked flask, and add 150g of chlorosulfonic acid dropwise under stirring to carry out sulfonation reaction (the sulfonation reaction is carried out under a constant temperature strictly controlled at 50±2°C); to ensure the adequacy of the reaction, keep the temperature for 180 minutes to obtain a mixture containing sulfonyl chloride. In this process, N-acetanilide reacts with chlorosulfonic acid to generate an intermediate product, sulfonyl chloride; collect and absorb the gaseous product of the sulfonation reaction to obtain hydrochloric acid (such as Figure 1 and Figure 2 shown); (b) After the reaction is completed, the reaction solution (sulfonation solution, i.e., the aforementioned mixture containing sulfonyl chloride) is transferred to a thermos bottle and allowed to stand for 8 hours to obtain a sulfonation reaction solution to ensure that the sulfonation reaction is further completed.

[0020] (c) The sulfonation reaction liquid is slowly added dropwise to the dichloromethane solvent (the total amount of the solvent is 1050 ml); to avoid drastic temperature fluctuations and local uneven concentration, the addition process is carried out in an environment with a temperature below 30°C (usually room temperature 25°C), and the dropping speed is strictly controlled (20 ml / min); as the sulfonation liquid is added dropwise, solids gradually precipitate in the system, and then the system is heated to 30°C to ensure that all solids are completely dissolved; after the addition is completed, stirring is continued at room temperature for 1 hour.

[0021] (d) The product of step (c) (i.e., the mixed solution in which the solid is completely dissolved) is subjected to a layering operation to separate the concentrated sulfuric acid in the upper layer; after the layering, 150 ml of water (about 2.5 times the mass of the sulfonated liquid) is added to the lower organic phase for washing, and the layering operation is performed again (dichloromethane, about 1 times the amount of the sulfonated liquid (100 ml), is added to improve the efficiency of the liquid separation). After the layering is completed, the obtained organic layer (i.e., the combined organic layer) is placed in a reduced pressure evaporator for atmospheric concentration operation (40° C.), and the concentration is stopped when about 70% of the dichloromethane is recovered (during the concentration process, a large amount of solids precipitate from the solution), and after the system is cooled to room temperature, the solid product (about 85 g) is collected by filtration.

[0022] The obtained product is then placed in a vacuum drying oven to further remove the residual solvent. Finally, a 99.8% pure acetamidobenzenesulfonyl chloride solid is obtained. Through gas chromatography analysis, the purity of the product is determined to be more than 99.8%, the single impurity is less than 0.1%, the acidity is less than 0.2%, the content is 99.5%, and the yield is 89.7% (such as Figure 3 as shown).

[0023] The solid 4-acetamidobenzenesulfonyl chloride was also subjected to a storage test, and the test indicators thereof are shown in Table 1. The product has a shelf life of 1 year.

[0024] Table 1 Shelf life test indicators index Acidity (calculated as HCL) Moisture (FK) purity content Require ≦0.2% ≦0.2% ≥99.8% ≥99% Comparative Example 1 This example provides a method for preparing 4-acetamidobenzenesulfonyl chloride in a noted table, which is basically the same as that in Example 1, except that: in step (a), the temperature is controlled at 55-60°C; the purity of the product is measured to reach 98.1%, the content is 95%, the yield is 90%, and the shelf life is one month.

[0025] Comparative Example 2 This example provides a method for preparing 4-acetamidobenzenesulfonyl chloride, which is basically the same as that in Example 1, except that: in step (a), the temperature is controlled at 35-40°C; the purity of the product is measured to reach 98.5%, the content is 96%, the yield is 87%, and the shelf life is one month.

[0026] Comparative Example 3 This example provides a method for preparing 4-acetamidobenzenesulfonyl chloride, which is basically the same as that in Example 1, except that step (b) is not performed. The purity of the final product is measured to be 99%, the content is 97.5%, the yield is 83%, and the shelf life is two months.

[0027] Comparative Example 4 This example provides a method for preparing 4-acetamidobenzenesulfonyl chloride, which is basically the same as that in Example 1, except that in step (d), no extractant is added, and the purity of the final product is measured to be 92%, the content is 89%, the yield is 92%, and the shelf life is one week.

[0028] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing high-quality 4-acetamidobenzenesulfonyl chloride, characterized in that: The following steps are involved: (a) subjecting N-acetanilide to a sulfonation reaction with a sulfonating agent at 48 to 52° C. to obtain a mixture containing sulfonyl chloride; (b) transferring the mixture containing sulfonyl chloride into a thermos bottle and allowing it to stand for further reaction to obtain a sulfonation reaction solution; (c) adding the sulfonation reaction solution dropwise to an organic solvent, controlling the temperature during the dropping process to ≤25°C, so that a solid precipitates in the system; heating the system to ≥30°C to ensure that the precipitated solid is completely dissolved; the dropping speed is 10-20 ml / min; (d) The product of step (c) is subjected to a layering operation, the upper layer of concentrated sulfuric acid is separated, water is added to the lower organic phase for washing and the layering operation is performed again; the obtained organic phase is concentrated, cooled to room temperature, and the solid crude product is collected by filtration; and the solid crude product is then subjected to reduced pressure distillation.

2. The method for preparing high-quality 4-acetamidobenzenesulfonyl chloride according to claim 1, characterized in that: In step (a), the molar ratio of N-acetanilide to the sulfonating agent is 1:1.5-2.

3. The method for preparing high-quality 4-acetamidobenzenesulfonyl chloride according to claim 1 or 2, characterized in that: In step (a), the sulfonation reaction time is 2 to 5 hours.

4. The method for preparing high-quality 4-acetamidobenzenesulfonyl chloride according to claim 3, characterized in that: In step (a), the sulfonating agent is chlorosulfonic acid; and the gaseous product of the sulfonation reaction is collected and absorbed.

5. The method for preparing high-quality 4-acetamidobenzenesulfonyl chloride according to claim 1, characterized in that: In step (b), the static storage time is 5 to 10 hours.

6. The method for preparing high-quality 4-acetamidobenzenesulfonyl chloride according to claim 1, characterized in that: In step (c), the organic solvent is dichloromethane, chloroform, dichloroethane or isopropyl ether.

7. The method for preparing high-quality 4-acetamidobenzenesulfonyl chloride according to claim 6, characterized in that: In step (c), stirring is continued at room temperature for 0.5 to 2 hours after the dropwise addition is completed.

8. The method for preparing high-quality 4-acetamidobenzenesulfonyl chloride according to claim 1, characterized in that: In step (d), the product of step (c) is subjected to a layer separation operation using an extractant.

9. The method for preparing high-quality 4-acetamidobenzenesulfonyl chloride according to claim 1 or 8, characterized in that: In step (d), the obtained organic phase is concentrated to recover 65-80% of the organic solvent.

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