A sulfonamide and a method for preparing the same

Abstract

The application belongs to the technical field of fine chemical industry and synthesis of pharmaceutical intermediates, and particularly relates to a preparation method of sulfonamides. 2 When the nitrogen atom in the aniline is in the sp hybridization state, it can spontaneously crystallize in the chlorosulfonation reaction in the chlorosulfonating agent, thereby avoiding the generation of waste inorganic acid, and the remaining chlorosulfonation reagent after the reaction can be directly subjected to a recyclable application after being added with a chlorinating agent and a sulfonating agent; thus, the generation of waste inorganic acid in the preparation of sulfonamides is avoided; wherein, the specific protecting agent is mildly hydrolyzed in an ammonia water system after the protection is completed, and the protecting agent is released to become the raw material, thereby realizing the recycling of the protecting agent and greatly reducing the consumption of the protecting agent.

Description

Technical Field

[0001] This invention belongs to the field of fine chemical and pharmaceutical intermediate synthesis technology, specifically relating to a method for preparing sulfonamides. Background Technology

[0002] Sulfonamides (p-aminobenzenesulfonamide, chemical formula C6H8N2O2S) are the first class of synthetic antibacterial drugs in human history to be mass-produced industrially and widely used in clinical treatment. Since Domagk's discovery of Prontosil in the 1930s, dozens of important derivative drugs have been developed, including sulfadiazine, sulfamethoxazole, sulfadiazine, sulfadoxine, sulfamethoxypyrimidine, sulfasalazine, and acetazolamide. They are widely used in the treatment of bacterial infections, parasitic diseases, glaucoma, diabetes, and diuresis. The sulfonamide molecule contains both a free aromatic primary amino group (-NH2) and a sulfonamide group (-SO2NH2), which are key intermediates in the synthesis of the above-mentioned sulfonamide drugs. They are also important raw materials for the synthesis of azo dyes, reactive dyes, pesticide herbicides, rubber vulcanization accelerators, surfactants, and functional polymer materials. With the rapid development of the global pharmaceutical, pesticide and fine chemical industries, the demand for sulfonamides and their derivatives continues to grow. Developing efficient, green, low-cost, and industrially scalable sulfonamide preparation processes has always been a key focus of research and industrial upgrading in this field.

[0003] Currently, the classic synthetic route for the industrial production of sulfonamides uses inexpensive and readily available aniline as the starting material, proceeding through four steps: amino protection, chlorosulfonation, ammonolysis, and deprotection hydrolysis, known as the "acetanilide method." Specifically, the first step involves acetylation of the primary amino group of aniline with acetic anhydride or glacial acetic acid as a protecting agent to obtain acetanilide, thus preventing the amino group from being oxidized, sulfonated, or protonated and deactivated under subsequent strongly acidic chlorosulfonation conditions. The second step uses excess chlorosulfonic acid (ClSO3H) as the chlorosulfonating agent to undergo an electrophilic substitution reaction with acetanilide at low temperature, yielding p-acetaminobenzenesulfonyl chloride. The third step involves quenching the excess chlorosulfonic acid in ice water, separating the solid intermediate, and then ammonolyzing it with concentrated ammonia to obtain p-acetaminobenzenesulfonamide. The fourth step involves high-temperature hydrolysis under strongly alkaline conditions to remove the acetyl group, followed by purification operations such as neutralization, activated carbon decolorization, crystallization, washing, and drying to obtain the sulfonamide product. Although this process has been industrialized for many years and is relatively mature, it still has the following significant shortcomings.

[0004] First, and most critically significant and difficult-to-overcome engineering flaw lies in the "solventization + water quenching" mode of the chlorosulfonation step. In the acetanilide process, chlorosulfonic acid is not only the reagent for the chlorosulfonation reaction but also acts as a reaction solvent. A large excess of chlorosulfonic acid (often 4-6 times or even higher molar ratio to the substrate) must be used to ensure that the benzene ring is fully chlorosulfonated. The resulting p-acetamidobenzenesulfonyl chloride (i.e., the chlorosulfonation intermediate) dissolves in the excess chlorosulfonic acid system and cannot be directly separated into solid and liquid phases by filtration. To precipitate the intermediate from the system, the reaction solution must be slowly poured into a large amount of ice water for water quenching, resulting in a violent exothermic reaction: ClSO3H + H2O → H2SO4 + HCl. Consequently, the production of one ton of sulfonamide product generates several tons of waste inorganic acid. The waste inorganic acid has an extremely complex composition, typically consisting of approximately 25% sulfuric acid, 5% hydrochloric acid, 2% acetic acid, 3% organic matter, and more than 1000 ppm Kjeldahl nitrogen. It is a multi-component mixed strong acid waste liquid containing sulfur, chlorine, and nitrogen, making it difficult to achieve harmless treatment and resource utilization through conventional and simple methods. According to current environmental compliance requirements, the treatment cost for this type of waste inorganic acid is approximately 1500 yuan / ton. Converted to the product, 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 has become a fundamental constraint making the acetanilide process unsustainable under the new circumstances.

[0005] Secondly, the acetyl group, as an amino protecting group, presents a dilemma regarding stability. On the one hand, the acetyl group is not stable enough in chlorination systems using thionyl chloride as the chlorinating agent, and cannot withstand the attack of the thionyl chloride chlorination system. The acetyl bond is easily broken during the reaction, leading to the re-exposed aniline amino group, which undergoes protonation, sulfonation, or oxidation under strong acid conditions. This fundamentally limits the acetanilide process to a route that uses excess chlorosulfonic acid as both a chlorosulfonating agent and a solvent, and cannot be switched to a thionyl chloride-sulfonating agent composite system with less excess, easier byproduct recovery, and higher atom economy. Consequently, it cannot escape the aforementioned dilemma of water quenching and waste acid generation. On the other hand, the acetyl group is too stable in the subsequent deprotection stage. Hydrolysis usually requires harsh conditions such as liquid alkali, high temperature, and long duration (several hours or even tens of hours), resulting in high energy consumption, severe equipment corrosion, and easy hydrolysis of the sulfonamide group itself to form p-aminobenzenesulfonic acid byproduct, causing a decrease in product yield, an increase in impurities, and a darker color.

[0006] Third, after the acetyl group is destroyed in the deprotection hydrolysis stage, it is converted into sodium acetate and enters the aqueous phase. The protective reagent is actually a disposable consumable in the whole process and is not feasible to be recycled. The high unit consumption further increases the production cost.

[0007] To address the aforementioned issues, researchers in this field have attempted to reduce emissions of waste gas, wastewater, and solid waste, shorten reaction cycles, and improve atom utilization through various methods, such as replacing the protecting group (e.g., replacing the acetyl group with formate, carbamate, or sulfonyl protecting groups), improving the chlorosulfonation reagent system, and optimizing ammonolysis-hydrolysis operating parameters. However, these improved solutions still fail to simultaneously meet the triple requirements of "sufficient stability in the chlorination system, easy removal during the hydrolysis stage, and recyclability after removal" in actual industrial scale-up. They also fail to fundamentally eliminate the engineering bottleneck that requires water quenching to precipitate the chlorosulfonation intermediate, resulting in a large amount of waste inorganic acid. Consequently, it is difficult to achieve a cleaner, more circular, and more economical sulfonamide synthesis process.

[0008] Therefore, developing a new process for sulfonamide preparation that can stably exist in mild chlorination systems such as thionyl chloride, can be mildly removed during hydrolysis and recycled as an independent phase, and allows the chlorosulfonation intermediate to spontaneously crystallize in the reaction system and achieve simple solid-liquid separation, thereby eliminating the water quenching process and the generation of waste inorganic acids from the source, is of great practical significance and industrial application value for significantly reducing the emissions and energy consumption of sulfonamide production, greatly reducing the cost of waste acid treatment, improving atom economy and process economy, and promoting the green manufacturing of sulfonamide raw materials and their downstream derivatives. Summary of the Invention

[0009] This invention provides a sulfonamide and its preparation method to solve the problems of waste inorganic acid generation, low sulfonamide yield, and high cost of recovering amino protecting reagents during the preparation of sulfonamides.

[0010] In a first aspect, the present invention provides a method for preparing sulfonamides, comprising the following steps: S1 reacts aniline with a protecting reagent to undergo an amino protection reaction, yielding an N-protected aniline intermediate; The protective reagent has the following structure: O=CR-NR1R2; The amino group in aniline, after a protection reaction, becomes a group with 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 10The substituents in aryl or substituted 5-6 membered heteroaryl groups containing 1-2 heteroatoms selected from N, O, and S are selected from halogens, C1-C4 alkyl groups, C1-C4 alkoxy groups, and C6-C4 heteroatoms. 10 Aryl or cyano; S2 involves reacting the N-protected aniline intermediate from step S1 with a chlorosulfonating reagent to spontaneously crystallize, followed by solid-liquid separation to obtain the chlorosulfonated intermediate. The chlorosulfonated filtrate is then recycled after adding sulfonating and chlorinating reagents in stoichiometric ratio. S3 involves reacting the chlorosulfonation intermediate with ammonia water to undergo ammoniation and deprotection hydrolysis reactions, yielding a solution containing a protecting reagent and sulfonamide. The protecting reagent and sulfonamide are then recovered separately, and the recovered protecting reagent can be directly used in the reaction in S1.

[0011] In an alternative embodiment, thionyl chloride is also added during the amino protection reaction of aniline with the protecting agent.

[0012] In one alternative embodiment, the molar ratio of aniline to thionyl chloride is 1:(1-5); for example, 1:2, 1:3, 1:4 or 1:5, or within any of the above values.

[0013] In one alternative embodiment, the molar ratio of aniline to the protecting agent is 1:(1-2); for example, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.6, 1:1.8 or 1:2, or within any of the above values.

[0014] In one alternative embodiment, the amino protection reaction is carried out in a solvent.

[0015] In one alternative embodiment, the solvent includes thionyl chloride and N,N-dimethylformamide.

[0016] Understandably, the amount of solvent has little effect on amino protection and can be disregarded. In one alternative embodiment, the molar ratio of aniline to solvent can be 1:(0.1-10); for example, 1:0.1, 1:0.5, 1:1, 1:2, 1:5, 1:8 or 1:10, or within any of the above values.

[0017] It is understandable that the protecting reagent in step S3 is the same compound as the protecting reagent in step S1.

[0018] During their research on sulfonamide synthesis, the inventors discovered that by transforming the nitrogen atom of aniline from sp3 to sp2 hybridization (forming an N=X type double bond), the lone pair electrons of the nitrogen atom participate in the π bond system, fundamentally eliminating nucleophilicity. This allows it to withstand strong acid chlorosulfonation conditions without protection. Furthermore, experiments have confirmed that N-protected aniline intermediates with sp2 nitrogen atoms can spontaneously precipitate as solid crystals in specific chlorosulfonating reagents, thus achieving solid-liquid separation without the need for water addition. This unique physical phenomenon fundamentally eliminates the cause of waste acid generation.

[0019] The inventors discovered that a protective reagent with a specific structure can meet the following conditions in a chlorination system: it is sufficiently stable, easily removed during the hydrolysis stage, and can be recycled and reused in the preparation of sulfonamides in this application, thus realizing the recycling of the protective reagent.

[0020] In one optional embodiment, the process of recovering the protective reagent and sulfonamide involves removing NH3 from the solution containing the protective reagent and sulfonamide, cooling to crystallize, filtering to obtain a solution containing the protective reagent and crude sulfonamide; extracting the protective reagent from the solution containing the protective reagent; and washing and drying the crude sulfonamide to obtain sulfonamide.

[0021] The protective reagent can be recovered by distillation or by solvent extraction followed by distillation of the solution containing the protective reagent.

[0022] In one optional embodiment, the process of recovering the protective reagent and sulfonamide involves allowing the solution containing the protective reagent and sulfonamide to stand to obtain an oil phase and an aqueous phase, wherein the oil phase is the protective reagent; the aqueous phase is then subjected to NH3 removal, cooling to crystallize, filtration, washing, and drying to obtain sulfonamide.

[0023] The process of removing NH3 from a solution containing a protective reagent and sulfonamide is a heating process, with a heating temperature of 90-100℃.

[0024] The process of removing NH3 from the aqueous phase is a heating process, with a heating temperature of 90-100℃.

[0025] It is understandable that when the oil phase is used as a protective reagent, it is insoluble or sparingly soluble in water.

[0026] In one optional embodiment, R1 is a C1-C4 alkyl group, and R2 is a C6-C4 alkyl group. 10 Aryl or C7-C 12 Aryl groups; In one alternative embodiment, R1 is a C1-C4 alkyl group and R2 is a C1-C4 alkyl group.

[0027] 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.

[0028] In one alternative implementation, R1 is C6-C. 10 Aryl, R2 is C6-C 10 Aryl.

[0029] 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; In one alternative embodiment, R1 and R2 together with the nitrogen atom to which they are attached constitute a pyrrolidinyl, piperidinyl, or morpholinyl group.

[0030] In one alternative embodiment, R1 is methyl, 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.

[0031] In one optional embodiment, the chlorosulfonating agent includes a chlorinating agent and a sulfonating agent; 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.

[0032] 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.

[0033] In one alternative embodiment, the chlorosulfonating agent comprises thionyl chloride and sulfuric acid.

[0034] In one optional embodiment, the molar ratio of chlorinating agent to sulfonating agent in the chlorosulfonating agent is (1-5):1; In one optional embodiment, the molar ratio of aniline to sulfonating agent is 1:(1-2); In one optional embodiment, the chlorosulfonation reaction temperature is -20℃ to 100℃, and the reaction time is 1-6 hours. As an example, the chlorosulfonation reaction temperature can be -20℃, -15℃, -10℃, 0℃, 10℃, 25℃, 50℃, 60℃, 80℃, or 100℃, or any range thereof; the reaction time can be 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours, or any range thereof. In one optional embodiment, the concentration of ammonia in step S3 is 20 wt%-40 wt%; as an example, the concentration can be 20 wt%, 25 wt%, 30 wt%, 35 wt%, or 40 wt%, or any range thereof.

[0035] 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 within any range of the above values; the reaction time is 1 hour, 2 hours, or 3 hours, or within any range of the above values.

[0036] In one optional 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 within any range of the above values; the reaction time is 2 hours, 3 hours, 4 hours, 5 hours or 6 hours, or within any range of the above values.

[0037] In one optional embodiment, the molar ratio of NH3 in ammonia water to sulfonyl chloride in the chlorosulfonation intermediate is (2-7):1; In one alternative implementation, the settling time is 10-30 minutes.

[0038] Secondly, the present invention provides a sulfonamide prepared by the preparation method described above.

[0039] The technical solution of this invention has the following advantages: This invention provides a method for preparing sulfonamides, comprising the following steps: S1, reacting aniline with a protecting reagent to undergo an amino protection reaction to obtain an N-protected aniline intermediate; the protecting reagent has the following structure: O=CR-NR1R2; wherein the amino group in the aniline, after the protection reaction, becomes a group with the following structure: -N=CR-NR1R2; wherein R is H or a C1-C4 alkyl group; R1 and R2 are each independently selected from C1-C6 straight-chain alkyl, C3-C6 branched alkyl, C3-C8 cycloalkyl, C7-C6 cycloalkyl, C8-C9 cycloalkyl, C9 ... 12 Aryl, substituted or unsubstituted C6-C 10 Aromatic, 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; wherein, substituted C6-C 10The substituents in the aryl or substituted 5-6 membered heteroaryl groups containing 1-2 heteroatoms selected from N, O, and S are selected from halogens, C1-C4 alkyl groups, C1-C4 alkoxy groups, or cyano groups; S2: The N-protected aniline intermediate from step S1 is subjected to chlorosulfonation reaction with a chlorosulfonating reagent, and after spontaneous crystallization, the solid and liquid are separated to obtain the chlorosulfonated intermediate. The chlorosulfonated filtrate is replenished with sulfonating and chlorinating reagents according to the stoichiometric ratio and then recycled; S3: The chlorosulfonated intermediate is subjected to ammoniation and deprotection hydrolysis reaction with ammonia water to obtain a solution containing the protecting reagent and sulfonamide. The protecting reagent and sulfonamide are recovered separately. The recovered protecting reagent can be directly used in the reaction in S1.

[0040] In the preparation method provided by this invention, the nitrogen atom in aniline is sp after an amino protection reaction. 2 In its hybrid state, it can spontaneously crystallize during the chlorosulfonation reaction in chlorosulfonating reagent, thus avoiding the generation of waste inorganic acid. Furthermore, the remaining chlorosulfonating reagent after the reaction can be directly recycled after adding chlorination and sulfonation reagents. This avoids the generation of waste inorganic acid during the preparation of sulfonamides. In particular, after the protection is completed, the specific protective reagent is gently hydrolyzed in an ammonia system to release the protective reagent as a raw material, thereby realizing the recycling of the protective reagent and greatly reducing the consumption of the protective reagent.

[0041] Furthermore, the preparation method provided in this application can reduce the production cost of sulfonamides. Detailed Implementation

[0042] 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.

[0043] Unless otherwise specified, the experimental steps or conditions in the examples were performed in accordance with conventional experimental procedures and conditions in the art. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0044] The sulfonamide yields in the examples and comparative examples were calculated based on the amount of aniline added.

[0045] Unless otherwise specified, the molar equivalents or equivalents in the examples and comparative examples are based on the amount of aniline added.

[0046] The room temperature in the comparative example refers to 25°C.

[0047] Unless otherwise specified, the purity of sulfonamides in the examples and comparative examples was measured using chemical titration.

[0048] Example 1 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 that, the crystals were filtered, washed and dried (the filtrate contained DMF) to obtain sulfonamide with a yield of 80% and no waste inorganic acid was generated. Product Quality Appearance: White to off-white crystalline powder (comparison: Acetanilide process product is pale yellow to pale brown); HPLC purity: ≥99.5% Melting point: 164.8±1℃ (Industry standard: 163-166℃) Characteristic impurity C: 4-(CH3)2NSO2-C6H4-NH2, content 0.01-0.10% Impurity E (acetanilide method labeling, N-acetaminosulfanilamide): Not detected (<0.01%) (4) DMF is obtained by distillation of the filtrate containing DMF, with a recovery rate of 92% and a purity of 99%, and is used in the reaction in step (1).

[0049] Example 2 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 protection was removed and hydrolyzed at 80℃ for 6h. After the reaction was completed, NH3 was removed at 95℃, and then the temperature was lowered to 25℃ to crystallize. After that, the crystals were filtered, washed and dried (the filtrate contained 1-formylpiperidine) to obtain sulfonamide with a yield of 82% and no waste inorganic acid was generated. Product Quality Appearance: White to off-white crystalline powder (comparison: Acetanilide process product is pale yellow to pale brown); HPLC purity: ≥99.5%; Melting point: 165.1±0.4℃ (industry standard: 163-166℃); Characteristic impurity C: 4-(C5H) 10 )NSO2-C6H4-NH2, content 0.01-0.10%; Impurity E (acetanilide method labeling, N-acetaminosulfonamide): Not detected (<0.01%); (4) The filtrate containing 1-formylpiperidine was subjected to salting-out cyclohexane extraction and cyclohexane was removed by distillation to obtain 1-formylpiperidine with a recovery rate of 86% and a purity of 99%, which was used in the reaction in step (1).

[0050] Example 3 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 ammoniated 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 protection was removed and hydrolyzed at 80℃ for 6h. The hydrolysis released N-methyl-N-benzylformamide. After the reaction was completed, the mixture was allowed to stand for 30min to separate into layers. The organic phase N-methyl-N-benzylformamide was recovered with a recovery rate of 98% and a purity of 99.7% (GC). It was used in the reaction in step (1). The recovered organic phase was directly added to the next batch of step (1). The cycle was repeated 10 times. The overall yield was maintained at 87.2±1%, and the HPLC purity of the product was maintained at 99.7±0.2%, proving the feasibility of the closed-loop circulation of the protecting group. The aqueous phase was further treated at 95°C to remove NH3, then cooled to 25°C to crystallize, followed by filtration, washing, and drying to obtain sulfonamide with a yield of 86% and no waste inorganic acid was generated. Product Quality Appearance: White to off-white crystalline powder (comparison: Acetanilide process product is pale yellow to pale brown); HPLC purity: ≥99.5% Melting point: 165.3±0.4℃ (Industry standard: 163-166℃) Characteristic impurity C: 4-(CH3)(CH2Ph)NSO2-C6H4-NH2, content 0.01-0.10% Impurity E (acetanilide method labeling, N-acetaminosulfanilamide): Not detected (<0.01%) Compared with Example 1, N-methyl-N-benzylformamide exhibits stronger hydrophobicity (logP≈1.8) after standing and stratification, automatically separating from the aqueous phase for phase separation and recovery, and can be directly recycled without distillation; while DMF in Example 1 has logP≈-1.0, is in a water-soluble state, and requires distillation for recovery.

[0051] Example 4 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 the ammonia water to 4-chlorosulfonylphenyl-N,N-diphenylmethanemididine was 5:1) at a reaction temperature of 30℃; subsequently, the protection was removed and hydrolyzed at 80℃ for 6h, releasing N,N-diphenylformamide. After the reaction was completed, the mixture was allowed to stand for 30min to separate into layers, and the organic phase N,N-diphenylformamide was recovered with a recovery rate of 98.2% and a purity of 99.5% (GC), which was used in the reaction in step (1). The aqueous phase was cooled to 25℃ to remove NH3, and then filtered, washed and dried to obtain sulfonamide with a yield of 84% and no waste inorganic acid was generated. Product Quality Appearance: White to off-white crystalline powder (comparison: Acetanilide process product is pale yellow to pale brown); HPLC purity: ≥99.5% Melting point: 165.3±0.5℃ (Industry standard: 163-166℃) Characteristic impurity C: 4-(Ph)2NSO2-C6H4-NH2, content 0.01-0.10% Impurity E (acetanilide method labeling, N-acetaminosulfanilamide): Not detected (<0.01%) Comparative Example 1 This comparative example provides a method for preparing sulfonamides, comprising 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 deprotection hydrolysis reaction was carried out at a temperature of 80℃ for 6h (protection reagent could not be reused). 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 were performed to obtain sulfonamide with a yield of 64% and a purity of 98%, and no waste inorganic acid was generated.

[0052] Comparative Example 2 This comparative example provides a method for preparing sulfonamides, comprising 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℃ / 100 mmHg), and chlorobenzene was distilled off under reduced pressure (68-75℃ / 100 mmHg). Finally, the fraction at 90-95℃ / 15 mmHg 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 (protection reagent could not be reused). 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 were performed to obtain sulfonamide with a yield of 71% and a purity of 98%, and no waste inorganic acid was generated.

[0053] Comparative Example 3 (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 equivalents (relative to aniline)) to the mixture obtained in step (1) and react at 0°C for 4 h, then raise the temperature to 50°C 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 by hydrolysis at a temperature of 80℃ for 2h (protection reagent could not be reused). 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 were performed to obtain sulfonamide with a yield of 78% and a purity of 99%, and no waste inorganic acid was generated.

[0054] Comparative Example 4 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%.

[0055] (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.

[0056] (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.

[0057] 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 reacts aniline with a protecting reagent to undergo an amino protection reaction, yielding an N-protected aniline intermediate; The protective reagent has the following structure: O=CR-NR1R2; The amino group in aniline, after a protection reaction, becomes a group with 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 The substituents in aryl or substituted 5-6 membered heteroaryl groups containing 1-2 heteroatoms selected from N, O, and S are selected from halogens, C1-C4 alkyl groups, C1-C4 alkoxy groups, and C6-C4 heteroatoms. 10 Aryl or cyano; S2 involves reacting the N-protected aniline intermediate from step S1 with a chlorosulfonating reagent to spontaneously crystallize, followed by solid-liquid separation to obtain the chlorosulfonated intermediate. The chlorosulfonated filtrate is then recycled after adding sulfonating and chlorinating reagents in stoichiometric ratio. S3 involves reacting the chlorosulfonation intermediate with ammonia water to undergo ammoniation and deprotection hydrolysis reactions, yielding a solution containing a protecting reagent and sulfonamide. The protecting reagent and sulfonamide are then recovered separately, and the recovered protecting reagent can be directly used in the reaction in S1.

2. The preparation method according to claim 1, characterized in that, The process of recovering the protective reagent and sulfonamide involves removing NH3 from the solution containing the protective reagent and sulfonamide, cooling to crystallize, filtering to obtain a solution containing the protective reagent and crude sulfonamide; extracting the protective reagent from the solution containing the protective reagent; and washing and drying the crude sulfonamide to obtain sulfonamide. Preferably, the process of recovering the protective reagent and sulfonamide involves allowing the solution containing the protective reagent and sulfonamide to stand to obtain an oil phase and an aqueous phase, wherein the oil phase is the protective reagent; and then removing NH3 from the aqueous phase, cooling to crystallize, filtering, washing and drying to obtain sulfonamide.

3. The preparation method according to claim 1 or 2, characterized in that, R1 is a C1-C4 alkyl group, and R2 is a C6-C4 alkyl group. 10 Aryl or C7-C 12 Aryl alkyl groups; Preferably, R1 is a C1-C4 alkyl group and R2 is a C1-C4 alkyl group; Preferably, R1 and R2 together with the nitrogen atom they are attached to 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; Preferably, R1 and R2 together with the nitrogen atom to which they are attached constitute a pyrrolidinyl, piperidinyl, or morpholinyl group.

4. The preparation method according to any one of claims 1-3, characterized in that, R1 is methyl, 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.

5. The preparation method according to any one of claims 1-4, 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.

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

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

8. The preparation method according to any one of claims 1-7, 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); Preferably, the chlorosulfonation reaction is carried out at a temperature of -20°C to 100°C for 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 sulfonyl chloride in the chlorosulfonation intermediate is (2-7):1; Preferably, the settling time is 10-30 minutes.

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