Production method of high-purity sulfanilamide

Abstract

The invention discloses a production method of high-purity sulfanilamide, and relates to the technical field of organic synthesis, the production method comprises the following steps: S1, chlorosulfonation reaction; and step S2, amination reaction. The production method of the high-purity sulfanilamide is simple and easy to implement, low in energy consumption, high in efficiency, small in dependence on equipment and suitable for continuous large-scale production; the sulfanilamide prepared by the production method is high in purity and total yield.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, in particular to a production method of high-purity sulfonamide. Background Art

[0002] Sulfonamide, also known as p-aminobenzenesulfonamide, has a molecular formula of C6H8N2O2S. It is an organic compound with medicinal value, commonly used in the pharmaceutical industry, and is the main raw material for the synthesis of sulfonamide drugs. Sulfonamide drugs are a type of antibacterial and anti-inflammatory drugs commonly used in modern medicine. Due to their good antibacterial effect, mature technology, easy availability of raw materials, and low prices, they have been used clinically for decades and still maintain a certain share. As a result, the market demand for sulfonamide is still large, and the requirements for its purity are getting higher and higher.

[0003] The traditional sulfonamide production method usually uses acetanilide as the raw material, prepares acetamidobenzenesulfonyl chloride through chlorosulfonic acid chlorination, and then obtains acetamidobenzenesulfonamide through ammonolysis reaction, and then hydrolyzes and recrystallizes to obtain the final product sulfonamide. This method has technical defects such as the yield and purity need to be further improved, and the production cost and environmental impact need to be further reduced. In order to solve the above problems, the Chinese invention patent with authorization announcement number CN105175294B discloses a method for synthesizing p-aminobenzenesulfonamide using chlorobenzene as a raw material, characterized in that it comprises the following steps: (a) adding dichloroethane, ammonium chloride and chlorosulfonic acid to a reactor, heating to 50-60°C, then dripping chlorobenzene and continuing to react for 2-5h, cooling to 15-20°C to obtain a first mixed solution; the mass ratio of the dichloroethane, the ammonium chloride, the chlorosulfonic acid and the chlorobenzene is 20-30:1:20-30:10- 15; (b) adding the first mixed solution dropwise to ammonia water with a mass concentration of 22-25%, stirring the reaction for 0.5-1 hour, heating to 40-42°C, continuing to stir the reaction for 1-2 hours, then transferring to a high-pressure reactor, adding a catalyst, heating to 160-200°C, reacting for 10-12 hours, cooling, depressurizing, steaming out excess ammonia, adjusting the pH to 6.5-6.7, precipitating solids, filtering and separating, and drying; the mass ratio of the ammonia water, the catalyst and the chlorobenzene is 120-150:1:8-15. Chlorosulfonic acid is used as a sulfonation and chlorination reagent to complete the synthesis of p-chlorobenzenesulfonyl chloride in one step, and p-chlorobenzenesulfonyl chloride is obtained by aminolysis, which is directly put into the autoclave for aminolysis without going through an intermediate separation process. The route is relatively short, the operation is easy, and the total yield of the product is high. However, there is still room for improvement in its purity and yield. Summary of the invention

[0004] The present invention aims to overcome the deficiencies of the prior art and to provide a method for producing high-purity sulfonamides, which is simple and easy to operate, has low energy consumption, high efficiency, low dependence on equipment, and is suitable for continuous large-scale production; the sulfonamides prepared by the production method have high purity and total yield.

[0005] To achieve the above object, the technical solution adopted by the present invention is: a method for producing high-purity sulfonamide, comprising the following steps:

[0006] Step S1, chlorosulfonation reaction: add chlorosulfonic acid and catalyst A to an organic solvent, mix well, place in a closed reaction kettle, add chlorobenzene dropwise at 48-58° C. while stirring, and add the mixture within 0.5-1 h. After the mixture is added, continue to keep the mixture warm for 1-3 h, and then cool to room temperature to obtain a reaction solution;

[0007] Step S2, amination reaction: adding ammonia water with a mass percentage concentration of 20wt%-26wt% to the reaction solution obtained in step S1, and the dripping is completed within 0.3-0.6h. After the dripping is completed, stirring and reacting for 0.8-1.2h, then heating to 45-50°C, keeping the temperature for reaction for 1.5-2.5h, then transferring to a high-pressure reactor, adding catalyst B, heating to 180-210°C, reacting for 8-10h, cooling after the reaction, releasing the pressure, steaming off excess ammonia, adjusting the pH to 6.4-6.8, precipitating solids, filtering and separating, and drying to obtain high-purity sulfonamide.

[0008] Preferably, the mass ratio of chlorosulfonic acid, catalyst A, organic solvent and chlorobenzene in step S1 is (20-30):1:(20-30):(10-15).

[0009] Preferably, the catalyst A is a mixture of phosphorus trichloride and an organic ion salt in a mass ratio of 1:(2-4).

[0010] Preferably, the organic ion salt is at least one of tetrabutylammonium bromide, tetrabutylammonium chloride, (1-butyl-3-methylimidazole) chloride, and 1-butyl-2,3-dimethylimidazole chloride.

[0011] Preferably, the organic solvent is at least one of dichloromethane and chloroform.

[0012] Preferably, the molar ratio of the chlorosulfonated product in the reaction solution in step S2, the ammonia gas in the ammonia water, and the catalyst B is 1:(1-1.02):(0.1-0.2).

[0013] Preferably, the catalyst B in step S2 is a mixture of copper acetate and molybdenum pentachloride in a mass ratio of (1-3):1. DETAILED DESCRIPTION

[0014] The preferred embodiments of the present invention will be described in detail below.

[0015] A method for producing high-purity sulfonamide comprises the following steps:

[0016] Step S1, chlorosulfonation reaction: add chlorosulfonic acid and catalyst A to an organic solvent, mix well, place in a closed reaction kettle, add chlorobenzene dropwise at 48-58° C. while stirring, and add the mixture within 0.5-1 h. After the mixture is added, continue to keep the mixture warm for 1-3 h, and then cool to room temperature to obtain a reaction solution;

[0017] Step S2, amination reaction: adding ammonia water with a mass percentage concentration of 20wt%-26wt% to the reaction solution obtained in step S1, and the dripping is completed within 0.3-0.6h. After the dripping is completed, stirring and reacting are continued for 0.8-1.2h, then the temperature is raised to 45-50°C, and the temperature is kept for reaction for 1.5-2.5h, and then transferred to a high-pressure reactor, catalyst B is added, the temperature is raised to 180-210°C, and the reaction is carried out for 8-10h. After the reaction is completed, the reaction is cooled, the pressure is released, and the excess ammonia is evaporated, the pH is adjusted to 6.4-6.8, and the solid is precipitated. After filtration and separation, it is dried to obtain high-purity sulfonamide.

[0018] Preferably, the mass ratio of chlorosulfonic acid, catalyst A, organic solvent and chlorobenzene in step S1 is (20-30):1:(20-30):(10-15).

[0019] Preferably, the catalyst A is a mixture of phosphorus trichloride and an organic ion salt in a mass ratio of 1:(2-4).

[0020] Preferably, the organic ion salt is at least one of tetrabutylammonium bromide, tetrabutylammonium chloride, (1-butyl-3-methylimidazole) chloride, and 1-butyl-2,3-dimethylimidazole chloride.

[0021] Preferably, the organic solvent is at least one of dichloromethane and chloroform.

[0022] Preferably, the molar ratio of the chlorosulfonated product in the reaction solution in step S2, the ammonia gas in the ammonia water, and the catalyst B is 1:(1-1.02):(0.1-0.2).

[0023] Preferably, the catalyst B in step S2 is a mixture of copper acetate and molybdenum pentachloride in a mass ratio of (1-3):1.

[0024] Due to the application of the above technical scheme, the patent of the present invention has the following advantages compared with the prior art: the present invention makes the production method simple and easy, with low energy consumption, high efficiency, low dependence on equipment, and suitable for continuous large-scale production through reasonable selection of catalyst types and preparation process parameters; the sulfonamide prepared by the production method has high purity and total yield.

[0025] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto:

[0026] Example 1

[0027] A method for producing high-purity sulfonamide comprises the following steps:

[0028] Step S1, chlorosulfonation reaction: add chlorosulfonic acid and catalyst A to an organic solvent, mix well, place in a closed reaction kettle, add chlorobenzene dropwise at 48°C while stirring, and complete the addition within 0.5h. After the addition is completed, continue to keep the temperature for reaction for 1h and then cool to room temperature to obtain a reaction solution;

[0029] Step S2, amination reaction: add ammonia water with a mass percentage concentration of 20wt% to the reaction solution obtained in step S1, and complete the dripping within 0.3h. After the dripping is completed, continue to stir and react for 0.8h, then raise the temperature to 45°C, keep the temperature for 1.5h, then transfer to a high-pressure reactor, add catalyst B, raise the temperature to 180°C, react for 8h, cool after the reaction, release the pressure, evaporate excess ammonia, adjust the pH to 6.4, precipitate solids, filter and separate, and then dry to obtain high-purity sulfonamide.

[0030] The mass ratio of chlorosulfonic acid, catalyst A, organic solvent and chlorobenzene in step S1 is 20:1:20:10; the catalyst A is a mixture of phosphorus trichloride and an organic ion salt in a mass ratio of 1:2; the organic ion salt is tetrabutylammonium bromide; and the organic solvent is dichloromethane.

[0031] The molar ratio of the chlorosulfonated product in the reaction solution, the ammonia gas in the ammonia water, and the catalyst B in step S2 is 1:1:0.1; the catalyst B in step S2 is a mixture of copper acetate and molybdenum pentachloride in a mass ratio of 1:1.

[0032] Example 2

[0033] A method for producing high-purity sulfonamide comprises the following steps:

[0034] Step S1, chlorosulfonation reaction: add chlorosulfonic acid and catalyst A to an organic solvent, mix well, place in a closed reaction kettle, add chlorobenzene dropwise at 50° C. while stirring, and complete the addition within 0.7 h. After the addition is completed, continue to keep the temperature for reaction for 1.5 h, and then cool to room temperature to obtain a reaction solution;

[0035] Step S2, amination reaction: add ammonia water with a mass percentage concentration of 22wt% to the reaction solution obtained in step S1, and complete the addition within 0.4h. After the addition is completed, continue to stir and react for 0.9h, then raise the temperature to 47°C, keep the temperature for 1.8h, then transfer to a high-pressure reactor, add catalyst B, raise the temperature to 190°C, react for 8.5h, cool after the reaction, release the pressure, evaporate excess ammonia, adjust the pH to 6.5, precipitate solids, filter and separate, and then dry to obtain high-purity sulfonamide.

[0036] The mass ratio of chlorosulfonic acid, catalyst A, organic solvent and chlorobenzene in step S1 is 22:1:23:12; the catalyst A is a mixture of phosphorus trichloride and an organic ion salt in a mass ratio of 1:2.5; the organic ion salt is tetrabutylammonium chloride; and the organic solvent is chloroform.

[0037] The molar ratio of the chlorosulfonate in the reaction solution, the ammonia gas in the ammonia water, and the catalyst B in step S2 is 1:1.01:0.13; the catalyst B in step S2 is a mixture of copper acetate and molybdenum pentachloride in a mass ratio of 1.5:1.

[0038] Example 3

[0039] A method for producing high-purity sulfonamide comprises the following steps:

[0040] Step S1, chlorosulfonation reaction: add chlorosulfonic acid and catalyst A to an organic solvent, mix well, place in a closed reaction kettle, add chlorobenzene dropwise at 54° C. while stirring, and complete the addition within 0.8 h. After the addition is completed, continue to keep the temperature for reaction for 2 h, and then cool to room temperature to obtain a reaction solution;

[0041] Step S2, amination reaction: add ammonia water with a mass percentage concentration of 24wt% to the reaction solution obtained in step S1, and complete the addition within 0.45h. After the addition is completed, continue to stir and react for 1h, then raise the temperature to 48°C, keep the temperature for 2h, then transfer to a high-pressure reactor, add catalyst B, raise the temperature to 200°C, react for 9h, cool after the reaction, release the pressure, evaporate excess ammonia, adjust the pH to 6.6, precipitate solids, filter and separate, and then dry to obtain high-purity sulfonamide.

[0042] The mass ratio of chlorosulfonic acid, catalyst A, organic solvent and chlorobenzene in step S1 is 25:1:25:13; the catalyst A is a mixture of phosphorus trichloride and an organic ion salt in a mass ratio of 1:3; the organic ion salt is chloride (1-butyl-3-methylimidazole); and the organic solvent is dichloromethane.

[0043] The molar ratio of the chlorosulfonate in the reaction solution, the ammonia gas in the ammonia water, and the catalyst B in step S2 is 1:1.01:0.15; the catalyst B in step S2 is a mixture of copper acetate and molybdenum pentachloride in a mass ratio of 2:1.

[0044] Example 4

[0045] A method for producing high-purity sulfonamide comprises the following steps:

[0046] Step S1, chlorosulfonation reaction: add chlorosulfonic acid and catalyst A to an organic solvent, mix well, place in a closed reaction kettle, add chlorobenzene dropwise at 56° C. while stirring, and complete the addition within 0.9 h. After the addition is completed, continue to keep the temperature for reaction for 2.5 h, and then cool to room temperature to obtain a reaction solution;

[0047] Step S2, amination reaction: add ammonia water with a mass percentage concentration of 25wt% to the reaction solution obtained in step S1, and complete the addition within 0.55h. After the addition is completed, continue to stir and react for 1.1h, then raise the temperature to 49°C, keep the temperature for 2.3h, then transfer to a high-pressure reactor, add catalyst B, raise the temperature to 205°C, react for 9.5h, cool after the reaction, release the pressure, evaporate excess ammonia, adjust the pH to 6.7, precipitate solids, filter and separate, and then dry to obtain high-purity sulfonamide.

[0048] The mass ratio of chlorosulfonic acid, catalyst A, organic solvent and chlorobenzene in step S1 is 28:1:29:14; the catalyst A is phosphorus trichloride and organic ion salt mixed in a mass ratio of 1:3.5; the organic ion salt is tetrabutylammonium bromide, tetrabutylammonium chloride, (1-butyl-3-methylimidazole) chloride and 1-butyl-2,3-dimethylimidazole chloride mixed in a mass ratio of 1:2:2:1; the organic solvent is dichloromethane and chloroform mixed in a mass ratio of 3:5.

[0049] The molar ratio of the chlorosulfonate in the reaction solution, the ammonia gas in the ammonia water, and the catalyst B in step S2 is 1:1.02:0.18; the catalyst B in step S2 is a mixture of copper acetate and molybdenum pentachloride in a mass ratio of 2.5:1.

[0050] Example 5

[0051] A method for producing high-purity sulfonamide comprises the following steps:

[0052] Step S1, chlorosulfonation reaction: add chlorosulfonic acid and catalyst A to an organic solvent, mix well, place in a closed reaction kettle, add chlorobenzene dropwise at 58° C. while stirring, and complete the addition within 1 hour. After the addition is completed, continue to keep the temperature for reaction for 3 hours and then cool to room temperature to obtain a reaction solution;

[0053] Step S2, amination reaction: add ammonia water with a mass percentage concentration of 26wt% to the reaction solution obtained in step S1, and complete the addition within 0.6h. After the addition is completed, continue to stir and react for 1.2h, then raise the temperature to 50°C, keep the temperature for 2.5h, then transfer to a high-pressure reactor, add catalyst B, raise the temperature to 210°C, react for 10h, cool after the reaction, release the pressure, evaporate excess ammonia, adjust the pH to 6.8, precipitate solids, filter and separate, and then dry to obtain high-purity sulfonamide.

[0054] The mass ratio of chlorosulfonic acid, catalyst A, organic solvent and chlorobenzene in step S1 is 30:1:30:15; the catalyst A is a mixture of phosphorus trichloride and an organic ion salt in a mass ratio of 1:4; the organic ion salt is 1-butyl-2,3-dimethylimidazolium chloride; and the organic solvent is dichloromethane.

[0055] The molar ratio of the chlorosulfonate in the reaction solution, the ammonia gas in the ammonia water, and the catalyst B in step S2 is 1:1.02:0.2; the catalyst B in step S2 is a mixture of copper acetate and molybdenum pentachloride in a mass ratio of 3:1.

[0056] Comparative Example 1

[0057] A method for producing high-purity sulfonamide is basically the same as that of Example 1, except that catalyst A is ammonium chloride.

[0058] Comparative Example 2

[0059] A method for producing high-purity sulfonamide is basically the same as Example 1, except that catalyst B is copper iodide.

[0060] In order to further illustrate the beneficial technical effects of each product, the purity and yield of the high-purity sulfonamide production method involved in each example were tested. The test method refers to the current national standard of my country or the conventional method in this field. The test results are shown in Table 1.

[0061] Table 1

[0062]

[0063]

[0064] It can be seen from Table 1 that the yield and purity of the sulfanilamide product produced by the production method of high-purity sulfanilamide in the embodiment of the present invention are higher, and the combined use of catalyst A and catalyst B is beneficial to improving the above-mentioned properties.

[0065] 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 this technology to understand the contents of the present invention and implement them accordingly. They cannot be used to limit the protection scope of the present invention. All 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 producing high-purity sulfonamide, characterized in that: The steps include: Step S1, chlorosulfonation reaction: adding chlorosulfonic acid and catalyst A to an organic solvent, mixing evenly, placing in a closed reaction kettle, adding chlorobenzene dropwise at 48-58° C. while stirring, and dripping the mixture within a certain period of time. After the dripping is completed, the mixture is kept warm for 1-3 hours and then cooled to room temperature to obtain a reaction solution; the catalyst A comprises phosphorus trichloride and an organic ion salt; Step S2, amination reaction: adding ammonia water with a mass percentage concentration of 20wt%-26wt% to the reaction liquid obtained in step S1, and the dripping is completed within 0.3-0.6h. After the dripping is completed, stirring and reacting for 0.8-1.2h, then heating to 45-50°C, keeping the temperature for reaction for 1.5-2.5h, then transferring to a high-pressure reactor, adding catalyst B, heating to a certain temperature, reacting for 8-10h, cooling after the reaction, releasing the pressure, steaming off excess ammonia, adjusting the pH, precipitating solids, filtering and separating, and drying to obtain high-purity sulfonamide; the catalyst B includes copper acetate and molybdenum pentachloride.

2. The method for producing high-purity sulfonamide according to claim 1, characterized in that: The mass ratio of chlorosulfonic acid, catalyst A, organic solvent and chlorobenzene in step S1 is (20-30):1: (20-30):(10-15).

3. The method for producing high-purity sulfonamide according to claim 1, characterized in that: The catalyst A is prepared by mixing phosphorus trichloride and an organic ion salt in a mass ratio of 1:(2-4).

4. The method for producing high-purity sulfonamide according to claim 3, characterized in that: The organic ion salt is at least one of tetrabutylammonium bromide, tetrabutylammonium chloride, (1-butyl-3-methylimidazole) chloride, and 1-butyl-2,3-dimethylimidazole chloride.

5. The method for producing high-purity sulfonamide according to claim 1, characterized in that: The organic solvent is at least one of dichloromethane and chloroform.

6. The method for producing high-purity sulfonamide according to claim 1, characterized in that: The molar ratio of the chlorosulfonated product in the reaction solution, the ammonia gas in the ammonia water, and the catalyst B in step S2 is 1:(1-1.02):(0.1-0.2).

7. The method for producing high-purity sulfonamide according to claim 1, characterized in that: The catalyst B is a mixture of copper acetate and molybdenum pentachloride in a mass ratio of (1-3):

1.

8. The method for producing high-purity sulfonamide according to claim 1, characterized in that: The certain time in step S1 is 0.5-1h.

9. The method for producing high-purity sulfonamide according to claim 1, characterized in that: The certain temperature in step S2 is 180-210°C.

10. The method for producing high-purity sulfonamide according to claim 1, characterized in that: The pH adjustment in step S2 is to adjust the pH to 6.4-6.8.

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