A sulfonamide and a method for preparing the same

Abstract

The present application relates to the technical field of organic synthesis, and in particular to a sulfonamide and a preparation method thereof. 2 The nitrogen atom in the aniline compound is in sp 2 hybridization state after the amino protection reaction, and can spontaneously crystallize in the chlorosulfonation reaction in chlorosulfonating reagent, thereby avoiding the generation of waste inorganic acid, and the remaining chlorosulfonation reagent after the reaction can be directly used in the recyclable process after adding chlorinating reagent and sulfonating reagent; thus, the generation of waste inorganic acid in the preparation of sulfonamide is avoided. In summary, the preparation method of the sulfonamide provided by the present application can effectively avoid the generation of waste inorganic acid.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a sulfonamide and its preparation method. Background Technology

[0002] p-Aminobenzenesulfonamide (sulfonamide, CAS: 63-74-1, molecular weight 172.21), as a multifunctional basic intermediate containing aromatic ring, amino, and sulfonamide groups, is a core supporting raw material for sulfonamide drugs, agrochemicals, and fine chemicals. With its unique molecular structure and excellent modifiability, it occupies an irreplaceable strategic position in many fields. Its downstream applications are extensive and its demand is prominent, resulting in a continuously expanding market size and providing a solid guarantee for the stable development of related industries such as pharmaceuticals, pesticides, and fine chemicals.

[0003] In the pharmaceutical field, sulfonamides are the lead nucleus and core starting material of the entire sulfonamide antibacterial drug system. The amino and sulfonamide groups in their molecules can be structurally modified through reactions such as acylation, substitution, and condensation, resulting in hundreds of clinically commonly used sulfonamide antibacterial drugs, including sulfadiazine, sulfamethoxazole, sulfisoxazole, sulfadimidine, and sodium sulfacetamide. These are widely used in human clinical anti-infective treatment, covering various bacterial infections such as respiratory tract infections, urinary tract infections, and intestinal infections, and are an indispensable and important component of the clinical anti-infective drug system. Simultaneously, sulfonamides themselves possess certain antibacterial activity and can be directly used to formulate preparations for superficial skin infections, playing an important role in primary healthcare and routine anti-infective care. In the veterinary pharmaceutical field, sulfonamide derivatives are mainstream veterinary drug raw materials for the prevention and treatment of bacterial diseases in livestock, poultry, and aquaculture, meeting the essential needs of large-scale farming for disease prevention and effectively ensuring the healthy development of the livestock industry, thus becoming one of the core raw materials of the veterinary drug industry.

[0004] In the fields of pesticides and agrochemicals, sulfonamides are key intermediates for synthesizing highly efficient, low-toxicity, and environmentally friendly agrochemicals, playing an irreplaceable role, especially in the synthesis of sulfonylurea herbicides, fungicides, and plant growth regulators. Using sulfonamides as raw materials, structural modification can lead to the development of various pesticide products tailored to the needs of modern agriculture. These products possess advantages such as broad-spectrum weed control, good fungicidal effects, high crop safety, and low environmental residues. They are widely used in weed control and disease prevention for various field crops such as rice, wheat, corn, and cotton, as well as cash crops such as fruits, vegetables, and flowers, effectively improving crop yield and quality, supporting the green and sustainable development of modern agriculture, and serving as an important basic raw material in the agrochemical industry chain.

[0005] In the fields of fine chemicals and new materials, sulfonamides, with their multifunctional functional group structure, demonstrate excellent application potential and are important supporting raw materials for the synthesis of fine chemical products and the modification of new materials. In the dye industry, sulfonamides can be used as intermediates to synthesize various acid dyes and reactive dyes, which are used in textiles, printing and dyeing industries to improve the color stability and adhesion of dyes. In the field of functional auxiliaries, sulfonamides can be used to prepare optical brighteners, resin modifying auxiliaries, leather tanning agents, etc., and are widely used in plastics, rubber, leather, papermaking and other industries to improve product performance. At the same time, sulfonamides can also be used as metal complexing and chelating agents in water treatment, metal extraction and separation and other fields. In addition, their structure can be used to modify special polymer materials, which helps the research and development and application of functional new materials, and plays an important connecting and supporting role in the fine chemical and new materials industry chain.

[0006] From an industry market perspective, sulfonamides are basic bulk fine chemical intermediates. Downstream sectors such as pharmaceuticals, pesticides, veterinary drugs, and fine chemicals are all pillar industries of the national economy, with inelastic and stable demand and no significant substitutes. Their market size is closely linked to the development of downstream industries. Currently, the sulfonamide industry has mature upstream and downstream supporting facilities, continuously optimized production technology, and consistently improving product quality, capable of meeting the diversified needs of various sectors. Annual demand has remained at a high level for a long time, and the market size is stable with the potential for continued growth. As a key raw material in the pharmaceutical and agrochemical industry chain, a stable supply of sulfonamides not only ensures the normal production of downstream industries but also plays a vital role in promoting the upgrading of related industries and enhancing the overall competitiveness of the industry, possessing extremely high industrial value and strategic importance.

[0007] Currently, the main method for preparing sulfonamides in existing technologies is the acetanilide method, which mainly includes the following steps: Aniline + Acetic anhydride → Acetaniline Acetaniline + chlorosulfonic acid → acetaminobenzenesulfonyl chloride Acetaminobenzenesulfonyl chloride + ammonia → acetaminobenzenesulfonamide Acetaminobenzenesulfonamide + liquid alkali → Sodium sulfadiazine Sodium sulfadiazine + hydrochloric acid → sulfadiazine.

[0008] In the acetanilide process described above, chlorosulfonic acid acts as both a reagent and a solvent in the chlorosulfonation step, using a large amount of excess chlorosulfonic acid to fully chlorosulfonate the benzene ring. Acetaminobenzenesulfonyl chloride (the chlorosulfonation intermediate) dissolves in the excess chlorosulfonic acid system and cannot be directly separated by filtration. To precipitate the intermediate, a large amount of water must be added to the system: ClSO3H + H2O → H2SO4 + HCl. Producing one ton of sulfonamide generates several tons of waste inorganic acid; this waste inorganic acid is a complex mixed acid (approximately 25% sulfuric acid, 5% hydrochloric acid, 2% acetic acid, 3% organic matter, and Kjeldahl nitrogen >1000 ppm). The current compliant treatment cost is approximately 1500 yuan / ton of waste inorganic acid, and the waste acid treatment cost for each ton of sulfonamide exceeds 10,000 yuan. Furthermore, the treatment process easily generates secondary pollutants, posing a high environmental risk. This is the most critical engineering flaw of the acetanilide process.

[0009] Other existing sulfonamide preparation processes all have similar problems in generating waste inorganic acids. Summary of the Invention

[0010] This invention provides a sulfonamide and its preparation method to solve the problem of waste inorganic acid generation during the preparation of sulfonamide.

[0011] In a first aspect, the present invention provides a method for preparing sulfonamides, comprising the following steps: S1 involves an amino protection reaction of aniline to obtain an N-protected aniline intermediate; wherein the nitrogen in the amino group of aniline is converted to sp after the protection reaction. 2 Hybridized nitrogen atoms; S2 involves reacting the N-protected aniline intermediate from step S1 with a chlorosulfonating reagent via a chlorosulfonation reaction, followed by spontaneous crystallization and solid-liquid separation to obtain the chlorosulfonated intermediate. S3 involves reacting the chlorosulfonation intermediate with ammonia water through ammoniation and deprotection hydrolysis, followed by cooling to crystallize, filtration, washing, and drying to obtain sulfonamide.

[0012] During their research on sulfonamide synthesis, the inventors discovered that changing the nitrogen atom in aniline from sp3 to sp... 2 In the hybridized state (forming an N=X type double bond), the lone pair electrons of the nitrogen atom participate in the π-bond system, fundamentally eliminating nucleophilicity, and allowing it to withstand strong acid chlorosulfonation conditions without protection; and experiments have confirmed that it possesses sp... 2 The nitrogen-protected aniline intermediate is very stable in a specific chlorosulfonating reagent and spontaneously precipitates as solid crystals in the chlorosulfonation system, thus achieving solid-liquid separation without the need for water addition. This unique physical phenomenon fundamentally eliminates the cause of waste acid generation.

[0013] In one optional embodiment, the solid after solid-liquid separation in step S2 is a chlorosulfonation intermediate, and the liquid is a chlorosulfonation filtrate, which can be recycled after adding sulfonating and chlorinating reagents according to the stoichiometric ratio.

[0014] In one alternative embodiment, the nitrogen group in the amino group of aniline is protected to form a sulfinylimide type group.

[0015] In one alternative embodiment, the sulfinimide type group is selected from -N=S=O.

[0016] In one alternative embodiment, the nitrogen group in the amino group of aniline is protected to become an N=C type group.

[0017] In one optional embodiment, the N=C type group is selected from -N=CR-Z, wherein R is selected from H, halogen, C1-C4 alkyl, and Z is selected from halogen, nitrogen-containing substituent.

[0018] In one alternative embodiment, the nitrogen-containing substituent has the following structure: -N=CR-NR1R2; Wherein, R is H or C1-C4 alkyl; R1 and R2 are each independently selected from substituted or unsubstituted C1-C6 straight-chain alkyl, substituted or unsubstituted C3-C6 branched alkyl, C3-C8 cycloalkyl, C7-C 12 Aryl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-6 membered heteroaryl groups containing 1-2 heteroatoms selected from N, O, and S; or R1 and R2 together with the nitrogen atom they are attached to form a 4-7 membered saturated nitrogen-containing heterocycle; Among them, substituted C1-C6 straight-chain alkyl, substituted C3-C6 branched alkyl, substituted C6-C 10 Aryl or substituted 5-6 membered heteroaryl groups containing 1-2 heteroatoms selected from N, O, and S are substituents selected from halogens, C1-C4 alkyl groups, C6-C4 alkyl groups, and C6-C4 alkyl groups. 10 Aryl, C1-C4 alkoxy, or cyano.

[0019] R1 is a C1-C4 alkyl group, and R2 is a C6-C4 alkyl group. 10 Aryl or C7-C 12 Aryl group.

[0020] In one alternative embodiment, R1 is a C1-C4 alkyl group and R2 is a C1-C4 alkyl group.

[0021] In one alternative embodiment, R1 is a C1-C4 alkyl group, and R2 is a C6-C4 alkyl group. 10 Aryl-substituted C1-C4 alkyl groups.

[0022] In one alternative implementation, R1 is C6-C. 10 Aryl, R2 is C6-C 10 Aryl.

[0023] In one alternative embodiment, R1 and R2 together with the nitrogen atom to which they are attached form a 4-7 member saturated nitrogen-containing heterocycle; the 4-7 member saturated nitrogen-containing heterocycle optionally contains an additional heteroatom selected from O, N, and S.

[0024] In one alternative embodiment, R1 and R2 together with the nitrogen atom to which they are attached constitute a pyrrolidinyl, piperidinyl, or morpholinyl group.

[0025] In one alternative embodiment, R1 is ethyl or phenyl, and R2 is phenyl, benzyl, substituted phenyl or C1-C4 alkyl, wherein the substituent in the substituted phenyl is selected from halogen, C1-C4 alkyl, C1-C4 alkoxy or cyano.

[0026] In one alternative embodiment, the chlorosulfonating agent includes a chlorinating agent and a sulfonating agent.

[0027] In one optional embodiment, the chlorinating agent is selected from thionyl chloride; In one alternative embodiment, the sulfonating agent is selected from at least one of sulfuric acid, sulfur trioxide, and chlorosulfonic acid.

[0028] In one optional embodiment, the chlorosulfonation reaction system of the N-protected aniline intermediate and the chlorosulfonating agent in step S1 is an anhydrous system.

[0029] In one optional embodiment, the chlorosulfonating agent comprises thionyl chloride and sulfuric acid; In one alternative embodiment, the chlorosulfonating agent comprises thionyl chloride and chlorosulfonic acid.

[0030] In one optional embodiment, the molar ratio of chlorinating agent to sulfonating agent in the chlorosulfonating agent is 1-5:1; In one alternative embodiment, the molar ratio of aniline to the sulfonating agent is 1:(1-2).

[0031] In one optional embodiment, the chlorosulfonation reaction is carried out at a temperature of -20°C to 100°C for a reaction time of 1-6 hours. As an example, the chlorosulfonation reaction temperature may be -20°C, -15°C, -10°C, 0°C, 10°C, 25°C, 50°C, 60°C, 80°C, or 100°C, or any range thereof; the reaction time may be 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours, or any range thereof.

[0032] In one optional embodiment, the concentration of ammonia in step S3 is 20wt%-40wt%. As an example, the concentration is 20wt%, 25wt%, 30wt%, 35wt%, or 40wt%, or within any range of the above values.

[0033] In one alternative embodiment, the ammoniation reaction time is 1-3 hours, and the reaction temperature is -20°C to 60°C. As an example, the ammoniation reaction temperature is -20°C, -15°C, -10°C, 0°C, 10°C, 25°C, 50°C, or 60°C, or any range thereof; the reaction time is 1 hour, 2 hours, or 3 hours, or any range thereof.

[0034] In one alternative embodiment, the deprotection hydrolysis reaction time is 2-6 hours, and the reaction temperature is 60°C to 105°C. As an example, the deprotection hydrolysis reaction temperature is 60°C, 70°C, 80°C, 90°C, 100°C, or 105°C, or any range thereof; the reaction time is 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours, or any range thereof.

[0035] In one alternative embodiment, the molar ratio of NH3 in the ammonia water to the chlorosulfonation intermediate is (2-7):1.

[0036] In one alternative implementation, after the deprotection hydrolysis reaction and before cooling and crystallization, a process for removing NH3 is also included.

[0037] In one alternative implementation, the temperature for removing NH3 is 90-100°C.

[0038] Secondly, the present invention provides a sulfonamide, prepared by the preparation method described above. The technical solution of this invention has the following advantages: The present invention provides a method for preparing sulfonamides, comprising the following steps: S1, subjecting aniline to an amino protection reaction to obtain an N-protected aniline intermediate; wherein the nitrogen in the amino group of aniline is sp after the protection reaction. 2 Hybridized nitrogen atoms; S2 The N-protected aniline intermediate from step S1 is reacted with a chlorosulfonating reagent to spontaneously crystallize, and then the solid and liquid are separated to obtain the chlorosulfonated intermediate; S3 The chlorosulfonated intermediate is reacted with ammonia water to undergo ammoniation and deprotection hydrolysis, followed by cooling to crystallize, filtration, washing and drying to obtain sulfonamide.

[0039] In the preparation method provided by this invention, the nitrogen atom in aniline is sp after an amino protection reaction. 2In its hybrid state, it can spontaneously crystallize during the chlorosulfonation reaction in a chlorosulfonating reagent, thus avoiding the generation of waste inorganic acids. Furthermore, the remaining chlorosulfonating reagent after the reaction can be directly recycled after adding chlorination and sulfonation reagents; thereby preventing the generation of waste inorganic acids during the preparation of sulfonamides. In summary, the sulfonamide preparation method provided by this invention can effectively avoid the generation of waste inorganic acids. Detailed Implementation

[0040] The following embodiments are provided to better understand the present invention, but the following embodiments do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the scope of protection of the present invention.

[0041] Unless otherwise specified, all experimental steps or conditions in the examples were performed according to conventional experimental procedures and conditions in the art. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0042] The sulfonamide yields in the examples and comparative examples were calculated based on the amount of aniline added.

[0043] Unless otherwise specified, the molar equivalents or equivalents in the examples and comparative examples are based on the amount of aniline added.

[0044] The room temperature in the comparative example refers to 25°C.

[0045] Unless otherwise specified, the purity of sulfonamides in the examples and comparative examples was measured using chemical titration.

[0046] Example 1 This embodiment provides a method for preparing sulfonamides, including the following steps: (1) Aniline was reacted with triethyl orthoformate (HC(OEt)3, 1.1 molar equivalent) at 80 °C for 4 h, with ethanol continuously distilled off during the reaction to obtain N-ethoxymethylene aniline (Ph-N=CH-OEt), with a yield of 85% and a purity of 96%. N-ethoxymethylene aniline is liquid and stable at room temperature; (2) N-ethoxymethyleneaniline was reacted with a chlorosulfonating agent at 0°C for 3 h. After spontaneous crystallization, the solid and liquid phases were separated to obtain 4-(chlorosulfonyl)phenylimine amide chloride (4-ClSO2-Ph-N=CH-Cl). The chlorosulfonation filtrate could be recycled. The chlorosulfonating agent included chlorosulfonic acid and thionyl chloride, with a molar ratio of 1:5. The molar ratio of N-ethoxymethyleneaniline to chlorosulfonic acid was 1:1.05. The yield was 88% and the purity was 92%. (3) 4-(chlorosulfonyl)phenylimine chloride was aminated in 25wt% ammonia water for 3h (the molar ratio of NH3 in ammonia water to 4-(chlorosulfonyl)phenylimine chloride was 5:1) at a reaction temperature of 30℃; then, the temperature was raised to remove protection and hydrolyze for 6h at a reaction temperature of 80℃. After the reaction was completed, NH3 was removed at 95℃, and then the temperature was lowered to 25℃ to crystallize. After filtration, washing and drying, sulfonamide was obtained with a yield of 64% and a purity of 98%, and no waste inorganic acid was generated.

[0047] Example 2 This embodiment provides a method for preparing sulfonamides, including the following steps: (1) Aniline was reacted dropwise with triphosgene (BTC, 0.35 molar equivalents) and triethylamine (2.2 molar equivalents) in anhydrous toluene (500 mL / mol aniline) at 0 °C for 1.5 h, and then the temperature was raised to 80 °C and refluxed for 1.5 h. During the reaction, a white precipitate of triethylamine hydrochloride was continuously formed. After hot filtration to remove the precipitate, the filtrate was distilled at atmospheric pressure at 110-115 °C to recover toluene. The fraction collected at 50-55 °C / 15 mmHg was collected by vacuum distillation to obtain phenyl isocyanate (Ph-N=C=O) with a yield of 93% and a purity of 98%. The phenyl isocyanate was reacted with phosphorus pentachloride (PCl5, 1.2 molar equivalents) in anhydrous chlorobenzene (500 mL / mol Ph-N=C=O) at 70 °C for 4 h. After the reaction was complete, POCl3 was distilled off under reduced pressure in stages (35-40℃ / 100mmHg), and chlorobenzene was distilled off under reduced pressure (68-75℃ / 100mmHg). Finally, the fraction at 90-95℃ / 15mmHg was collected by reduced pressure distillation to obtain a light yellow liquid dichloromethyleneaniline (Ph-N=CCl2), with a yield of 88% and a purity of 97%. (2) Dichloromethyleneaniline was reacted with a chlorosulfonating agent at 0°C for 3 h. After spontaneous crystallization, the solid and liquid phases were separated to obtain 4-(chlorosulfonyl)phenylimine dichloride (4-ClSO2-Ph-N=CCl2). The chlorosulfonation filtrate could be recycled. The chlorosulfonating agent included chlorosulfonic acid and thionyl chloride, with a molar ratio of 1:5. The molar ratio of dichloromethyleneaniline to chlorosulfonic acid was 1:1.05. The yield was 92% and the purity was 95%. (3) 4-(chlorosulfonyl)phenylimine dichloride was ammonified in 25wt% ammonia water for 3h (the molar ratio of NH3 in ammonia water to 4-(chlorosulfonyl)phenylimine dichloride was 5:1) at a reaction temperature of 30℃; then, the deprotection hydrolysis reaction was carried out at a temperature of 80℃ for 6h. After the reaction was completed, NH3 was removed at 95℃, and then the temperature was lowered to 25℃ to crystallize. After filtration, washing and drying, sulfonamide was obtained with a yield of 71% and a purity of 98%, and no waste inorganic acid was generated.

[0048] Example 3 This embodiment provides a method for preparing sulfonamides, including the following steps: (1) Aniline was reacted with SOCl2 (the molar ratio of aniline to SOCl2 was 1:5, where SOCl2 was both a reactant and a solvent, and the catalyst in the reaction was DMF, which was used at 1% of the molar amount of aniline) and the reaction was carried out at 0°C for 2 hours to obtain a mixture containing Ph-N=S=O and SOCl2. (2) Add sulfuric acid (1.05 molar equivalent) to the mixture obtained in step (1) and react at 0℃ for 4 h, then raise the temperature to 50℃ and continue the reaction for 2 h. After spontaneous crystallization, the solid and liquid are separated to obtain 4-(chlorosulfonyl)-N-sulfinylaniline (4-ClSO2-C6H4-N=S=O). The chlorosulfonation filtrate can be recycled. The yield of 4-(chlorosulfonyl)-N-sulfinylaniline is 82%, and the purity is 96%. (3) 4-(chlorosulfonyl)-N-sulfinylaniline was aminated in 25wt% ammonia water for 3h (the molar ratio of NH3 in ammonia water to 4-(chlorosulfonyl)-N-sulfinylaniline was 5:1) at a reaction temperature of 30℃. Then, the protection was removed and hydrolyzed at 80℃ for 2h. After the reaction was completed, NH3 was removed at 95℃. Then the temperature was lowered to 25℃ to crystallize. After filtration, washing and drying, sulfonamide was obtained with a yield of 78% and a purity of 99%, and no waste inorganic acid was generated.

[0049] Example 4 This embodiment provides a method for preparing sulfonamides, including the following steps: (1) Aniline and DMF (1.2 molar equivalents) were reacted in SOCl2 (5 molar equivalents) at 60°C for 3 hours, with SOCl2 acting as both a reactant and a solvent, to obtain a mixture containing Ph-N=CH-N(CH3)2. Ph-N=CH-N(CH3)2 dissolved in SOCl2 in a solution state. (2) Add sulfuric acid (1.05 molar equivalent) to the mixture obtained in step (1) and react at 0℃ for 4 h, then raise the temperature to 50℃ and continue the reaction for 2 h. After spontaneous crystallization, the solid and liquid are separated to obtain 4-chlorosulfonylphenyl-N',N'-dimethylformamidin (4-ClSO2-C6H4-N=CH-N(CH3)2). The chlorosulfonation filtrate can be recycled. The yield of 4-chlorosulfonylphenyl-N',N'-dimethylformamidin is 84%, and the purity is 97%. (3) 4-Chlorosulfonylphenyl-N',N'-dimethylformamide was aminated in 25wt% ammonia water for 3h (the molar ratio of NH3 in ammonia water to 4-chlorosulfonylphenyl-N',N'-dimethylformamide was 5:1) at a reaction temperature of 30℃; then, the deprotection hydrolysis reaction was carried out at a temperature of 80℃ for 6h. After the reaction was completed, NH3 was removed at 95℃, and then the temperature was lowered to 25℃ to crystallize. After filtration, washing and drying, sulfonamide was obtained with a yield of 80% and a purity of 99%, and no waste inorganic acid was generated.

[0050] Example 5 This embodiment provides a method for preparing sulfonamides, including the following steps: (1) Aniline and 1-formylpiperidine (1.2 molar equivalents) were reacted in SOCl2 (5 molar equivalents) at 70°C for 3 h, with SOCl2 acting as both the reactant and solvent, to obtain a product containing Ph-N=CH-N(C5H 10 A solution of ) (2) Under anhydrous conditions, in step (1) a substance containing Ph-N=CH-N(C5H) is obtained. 10 Sulfuric acid (1.2 molar equivalents, which is the amount of aniline added in step (1)) was added dropwise to the solution, and the reaction was carried out at 25°C for 3 h. After spontaneous crystallization, solid-liquid separation was performed to obtain 4-chlorosulfonylphenyl-piperidine formamidinium, 4-ClSO2-Ph-N=CH-N(C5H 10 The yield was 87%, and the purity was 98%. (3) 4-Chlorosulfonylphenyl-piperidine formamidine was aminated in 25wt% ammonia water for 3h (the molar ratio of NH3 in ammonia water to 4-chlorosulfonylphenyl-piperidine formamidine was 5:1) at a reaction temperature of 30℃; then, the deprotection hydrolysis reaction was carried out at a temperature of 80℃ for 6h. After the reaction was completed, NH3 was removed at 95℃, and then the temperature was lowered to 25℃ to crystallize. After filtration, washing and drying, sulfonamide was obtained with a yield of 82% and a purity of 99%, and no waste inorganic acid was generated.

[0051] Example 6 This embodiment provides a method for preparing sulfonamides, including the following steps: (1) Aniline was reacted with N-methyl-N-benzylformamide (1.2 molar equivalents) in SOCl2 (5 molar equivalents), with SOCl2 as both reactant and solvent. The reaction was carried out at 70°C for 3 hours to obtain a solution containing Ph-N=CH-N(CH3)(CH2Ph). (2) Under anhydrous conditions, sulfuric acid (1.2 molar equivalents (the amount of aniline added in step (1)) was added dropwise to the solution containing Ph-N=CH-N(CH3)(CH2Ph) obtained in step (1). The reaction was carried out at 50°C for 3 hours. After spontaneous crystallization, solid-liquid separation was performed to obtain 4-chlorosulfonylphenyl-N-methyl-N-benzylformamidinium, 4-ClSO2-Ph-N=CH-N(CH3)(CH2Ph), with a yield of 92% and a purity of 98%. (3) 4-Chlorosulfonylphenyl-N-methyl-N-benzylformamidin was aminated in 25wt% ammonia water for 3h (the molar ratio of NH3 in ammonia water to 4-chlorosulfonylphenyl-N-methyl-N-benzylformamidin was 5:1) at a reaction temperature of 30℃. Subsequently, the deprotection hydrolysis reaction was carried out at a temperature of 80℃ for 6h. After the reaction was completed, the mixture was allowed to stand for 30min to separate into an oil phase and an aqueous phase. The aqueous phase was further subjected to NH3 removal at 95℃, and then cooled to 25℃ to crystallize. After filtration, washing and drying, sulfonamide was obtained with a yield of 86% and a purity of ≥99%, without the generation of waste inorganic acid.

[0052] Example 7 This embodiment provides a method for preparing sulfonamides, including the following steps: (1) Aniline and N,N-diphenylformamide (1.2 molar equivalents) were reacted in SOCl2 (5 molar equivalents) at 70°C for 3 hours to obtain a solution containing Ph-N=CH-N(Ph)2. (2) Under anhydrous conditions, sulfuric acid (1.2 molar equivalents (the amount of aniline added in step (1)) was added dropwise to the solution containing Ph-N=CH-N(Ph)2 obtained in step (1). The reaction was carried out at 50°C for 3 hours. After spontaneous crystallization, solid-liquid separation was performed to obtain 4-chlorosulfonylphenyl-N,N-diphenylformamidinium, 4-ClSO2-Ph-N=CH-N(Ph)2, with a yield of 90% and a purity of 97%. (3) 4-Chlorosulfonylphenyl-N,N-diphenylmethanemididine was aminated in 25wt% ammonia water for 3h (the molar ratio of NH3 in ammonia water to 4-chlorosulfonylphenyl-N,N-diphenylmethanemididine was 5:1) at a reaction temperature of 30℃. Subsequently, the deprotection hydrolysis reaction was carried out at a temperature of 80℃ for 6h. After the reaction was completed, the mixture was allowed to stand for 30min to separate into an aqueous phase and an oil phase. The aqueous phase was dehydrated at 95℃ to remove NH3, and then cooled to 25℃ to crystallize. After filtration, washing and drying, sulfonamide was obtained with a yield of 84% and a purity of ≥99%, without the generation of waste inorganic acid.

[0053] Comparative Example 1 This comparative example provides a method for preparing sulfonamides, comprising the following steps: (1) Aniline (186 g, 2.0 mol) and acetic anhydride (256 g, 2.5 mol) were reacted in 500 ml of acetic acid solvent at room temperature for 2 hours. The temperature was then raised to 110 °C and reacted for 2 hours. Acetic acid was recovered under negative pressure, and the mixture was cooled to crystallize. Acetaniline was obtained by filtration and washing, with a yield of 97%.

[0054] (2) The acetanilide obtained in step (1) was reacted with chlorosulfonic acid (1165 g, 10.0 mol, with chlorosulfonic acid as both the reagent and solvent) at 30°C for 4 h, and then the temperature was raised to 50°C for another 2 h. The reaction solution was poured into 4000 g of ice water and quickly filtered to obtain wet acetaminobenzenesulfonyl chloride.

[0055] (3) The wet product of p-acetaminobenzenesulfonyl chloride obtained in step (2) was ammonified in 1000ml of 25% ammonia water at 50°C for 3 hours. Then, 600ml of 32wt% liquid alkali was added for hydrolysis at 95°C for 4 hours. Then, it was neutralized with hydrochloric acid to pH=6.5-7, cooled to 25°C to crystallize, and then filtered, washed and dried to obtain sulfonamide with a yield of 78% and a purity of about 98%. 16 tons of waste inorganic acid were produced per ton of sulfonamide.

[0056] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A method for preparing sulfonamides, characterized in that, Includes the following steps: S1 involves an amino protection reaction of aniline to obtain an N-protected aniline intermediate; wherein the nitrogen in the amino group of aniline is converted to sp after the protection reaction. 2 Hybridized nitrogen atoms; S2 involves reacting the N-protected aniline intermediate from step S1 with a chlorosulfonating reagent via a chlorosulfonation reaction, followed by spontaneous crystallization and solid-liquid separation to obtain the chlorosulfonated intermediate. S3 involves reacting the chlorosulfonation intermediate with ammonia water through ammoniation and deprotection hydrolysis, followed by cooling to crystallize, filtration, washing, and drying to obtain sulfonamide.

2. The preparation method according to claim 1, characterized in that, The nitrogen group in the amino group of aniline is protected to form a sulfinimide type group; Preferably, the sulfinimide type group is selected from -N=S=O.

3. The preparation method according to claim 1, characterized in that, The nitrogen group in the amino group of aniline becomes an N=C type group after a protection reaction; Preferably, the N=C type group is selected from -N=CR-Z, wherein R is selected from H, halogen, C1-C4 alkyl, and Z is selected from halogen, nitrogen-containing substituent.

4. The preparation method according to any one of claims 1-3, characterized in that, The chlorosulfonating agent includes a chlorinating agent and a sulfonating agent; Preferably, the chlorinating agent is selected from thionyl chloride; Preferably, the sulfonating agent is selected from at least one of sulfuric acid, sulfur trioxide, and chlorosulfonic acid.

5. The preparation method according to any one of claims 1-4, characterized in that, The chlorosulfonation reaction system of the N-protected aniline intermediate and the chlorosulfonating reagent in step S1 is an anhydrous system.

6. The preparation method according to any one of claims 1-5, characterized in that, The chlorosulfonating agent includes thionyl chloride and sulfuric acid; Preferably, the chlorosulfonating agent includes thionyl chloride and chlorosulfonic acid.

7. The preparation method according to any one of claims 1-6, characterized in that, The molar ratio of chlorinating agent to sulfonating agent in the chlorosulfonating agent is (1-5):1; Preferably, the molar ratio of aniline to sulfonating agent is 1:(1-2).

8. The preparation method according to any one of claims 1-7, characterized in that, The chlorosulfonation reaction is carried out at a temperature of -20℃ to 100℃ for a reaction time of 1-6 hours.

9. The preparation method according to any one of claims 1-7, characterized in that, The concentration of ammonia in step S3 is 20wt%-40wt%; Preferably, the ammoniation reaction time is 1-3 hours and the reaction temperature is -20℃ to 60℃; Preferably, the deprotection hydrolysis reaction time is 2-6 hours and the reaction temperature is 60℃ to 105℃; Preferably, the molar ratio of NH3 in ammonia water to the chlorosulfonation intermediate is (2-7):

1.

10. A sulfonamide, characterized in that, It is prepared by the preparation method according to any one of claims 1-9.