Fine sulfanilamide synthesis method beneficial to impurity inhibition
By optimizing the synthesis method of sulfanilamide and adopting technologies such as deep dehydration of 3A molecular sieve, directional catalysis of composite catalysts and supercritical carbon dioxide dissolution crystallization, the problems of low yield and environmental protection in the synthesis of sulfanilamide were solved, and a high-purity and low-pollution green synthesis was achieved.
Patent Information
- Application Number
- CN202510850164.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-24
- Publication Date
- 2025-09-19
AI Technical Summary
Existing methods for synthesizing sulfonamides have problems such as low yield and environmental pollution, including impurities triggering side reactions, serious loss of target products, the use of toxic reagents, and difficulty in completely removing pollutants, leading to environmental pollution.
By adopting technologies such as deep dehydration of 3A molecular sieve, directional catalysis of composite catalysts, infrared spectroscopy monitoring, and supercritical carbon dioxide dissolution crystallization, and by optimizing reaction parameters and purification processes, combined with nanofiltration membrane treatment and low-oxygen nitrogen protection, high-purity synthesis of sulfonamides can be achieved.
The purity of sulfanilamide was significantly improved to 99.8%, pollutant emissions were reduced, the reliability and adaptability of the synthesis process were improved, and it met the requirements of green synthesis.
Smart Images
Figure QLYQS_1 
Figure QLYQS_2
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of sperm sulfonamide synthesis, in particular to a sperm sulfonamide synthesis method which is advantageous for inhibiting impurities. Background Art
[0002] Sulfanilamide is a key pharmaceutical intermediate for the synthesis of sulfonamides and diuretics. The two-step synthesis method of m-chloroaniline, which is currently commonly used in industry, by chlorosulfonation and amination, has the following drawbacks: First, the yield is low: the dehydration of m-chloroaniline is insufficient, the chlorosulfonic acid lacks deep impurity removal, and impurities trigger side reactions that consume raw materials; the reaction process relies on experience-based control and there is no effective monitoring method. The chlorosulfonation reaction has low selectivity, with the meta-product accounting for 2-3%. The ammonia concentration in the amination reaction is out of control, resulting in polyamines; separation and purification make it difficult to recover raw materials and intermediates, resulting in serious losses of target products.
[0003] Second, it is not environmentally friendly: a large amount of toxic reagents such as chlorosulfonic acid and phosphorus trichloride are used in the synthesis, and side reactions produce waste gases such as hydrogen chloride and sulfur dioxide; the recovery rate of organic solvents such as ethanol is less than 90%; however, traditional waste treatment methods cannot completely remove organic pollutants and heavy metal ions, posing a threat to the water, soil and atmospheric environment.
[0004] Therefore, there is an urgent need to develop a new method for the synthesis of efficient and green sulfonamides. Summary of the Invention
[0005] The present invention solves one of the above technical problems, and the technical solution adopted is: a method for synthesizing sulfanilamide that is beneficial to suppressing impurities, comprising the following steps: Step 1: deep dehydration of m-chloroaniline through 3A molecular sieve to a water content of ≤0.05 wt %, and purification of chlorosulfonic acid by vacuum distillation to ≥99.5%.
[0006] Step 2: Under the action of a composite catalyst, chlorosulfonic acid and phosphorus trichloride are reacted in a molar ratio of 1:1.2-1.3, m-chloroaniline is added at a temperature of 30-40° C. at a rate of 0.6-0.8 g / min, and the reaction is carried out at 100-110° C. for 3-4 hours. The absorption peak intensity ratio is monitored by infrared spectroscopy, and the reaction parameters such as the reaction temperature and the rate of addition of m-chloroaniline are adjusted as needed. The reaction is terminated when the absorption peak intensity ratio drops to 3%-7% of the initial value.
[0007] Step 3: The reaction solution is thawed at a water-to-ice ratio of 1:1.05-1.15 and 10-20° C. for 1-1.5 h, and 0.12%-0.18% of a surfactant is added.
[0008] Step 4: Add liquid ammonia at 0.35-0.45 MPa and 50-60° C. to react for 4-5 hours. During the reaction, adjust the ammonia concentration as needed to maintain it at 0.3-0.4 mol / L.
[0009] Step 5: The reaction product is placed in a decolorization kettle and decolorized with activated carbon, finely filtered, concentrated under reduced pressure and crystallized, and finally dissolved and crystallized by supercritical carbon dioxide to obtain sulfonamide seed crystals with a purity of >99.8%.
[0010] Step 6: The filtrate produced by the above reaction is treated with a 250-450Da nanofiltration membrane at an operating pressure of 2.2-2.8MPa and a membrane surface flow rate of 3.5-4.5m / s, and is recovered by ethanol distillation. The entire process is carried out under nitrogen protection with an oxygen content of less than 5ppm.
[0011] Step 7, further crystallizing, growing, separating and drying the obtained sulfanilamide seed crystals to obtain the sulfanilamide product.
[0012] Based on any of the above technical solutions, further optimization is as follows: in step 5, the amount of activated carbon is 0.8%-1.2% of the product mass, the wet product particle size is <100μm during supercritical carbon dioxide dissolution and crystallization, and the pressure is first reduced to 7-9MPa / min at 0.4-0.6MPa / min and maintained for 12-18min, and then reduced to normal pressure at 0.1-0.3MPa / min.
[0013] Based on any of the above technical solutions, a further optimization is achieved: during the pressure drop to 8 MPa, the temperature is periodically pulsed at a rate of ±1°C, with a pulse period of 3 minutes and a pressure fluctuation range of ±0.1 MPa. When the pressure drops to 8 MPa, 5-10 μm sulfanilamide seed crystals are added at a rate of 0.1-0.5 g / min. The crude sulfanilamide product is purified by crystallization through supercritical carbon dioxide dissolution, while impurities remain in the mother liquor.
[0014] Based on any of the above technical solutions, further optimized is that the molar ratio of m-chloroaniline to chlorosulfonic acid is 2.1-2.3:1.
[0015] On the basis of any of the above technical solutions, further optimized is that: in the activation reaction of chlorosulfonic acid and phosphorus trichloride in step 2, the specific reaction of chlorosulfonic acid and phosphorus trichloride is as follows: under the action of the composite catalyst, the chlorosulfonic acid purified in step 1 first undergoes an activation reaction with phosphorus trichloride to generate a sulfonyl chloride intermediate, and the specific chemical reaction formula is: .
[0016] The above reaction converts chlorosulfonic acid into a highly active sulfonyl chloride intermediate, which provides an active intermediate for the subsequent sulfonation reaction of m-chloroaniline.
[0017] Selective sulfonation reaction of m-chloroaniline: The activated sulfonyl chloride intermediate further undergoes electrophilic substitution reaction with m-chloroaniline to selectively generate the precursor of the target product. The specific chemical reaction formula is: .
[0018] The above reaction directionally generates para-sulfonated products under the action of the composite catalyst, effectively inhibiting the generation of ortho- and polysulfonated impurities.
[0019] Based on any of the above technical solutions, further optimized is that: the composite catalyst in step 2 is formed by loading an active component on a carrier, the active component is composed of cuprous chloride and triethylamine in a molar ratio of 1:0.7-0.8, and the carrier is one or more of SBA-15 mesoporous silica and KIT-6 mesoporous silica.
[0020] Based on any of the above technical solutions, further optimized is that the preparation method of the composite catalyst is as follows: placing the carrier in a muffle furnace, pretreating at 300-350°C for 4-6 hours to remove surface adsorbed water and impurities, and cooling to room temperature for use.
[0021] According to the required active component loading, cuprous chloride and triethylamine were calculated and measured, and dissolved in anhydrous ethanol to prepare an ethanol solution with a cuprous chloride concentration of 0.1-0.2 mol / L and a triethylamine concentration of 0.07-0.16 mol / L. The solution was stirred evenly to ensure that the active component was fully dissolved.
[0022] The pretreated carrier is completely immersed in the above ethanol solution at a solid-liquid ratio of 1g:10-20mL, placed in a constant temperature water bath, and subjected to an immersion reaction at 65-75°C and a stirring speed of 200-300r / min for 2.5-3.5 hours to allow the active components to be fully adsorbed on the surface and pores of the carrier.
[0023] After the impregnation is completed, the vacuum degree is maintained at 0.08-0.095 MPa, and the solid product loaded with active components is separated by reduced pressure filtration and washed with anhydrous ethanol 3-5 times, with the amount of washing liquid used each time being 3-5 times the volume of the solid, to remove the active components not adsorbed on the surface.
[0024] The washed solid product was transferred to a forced air drying oven and dried at 105-115° C. for 4.5-5.5 hours to remove residual ethanol and moisture and to fully dry the solid product.
[0025] The dried product is transferred to a tubular furnace, and under a nitrogen protective atmosphere, the temperature is raised to 320-380°C at a heating rate of 2-5°C / min, and calcined for 2.2-2.8 hours. The active component and the carrier are firmly bonded through a chemical bonding process. After naturally cooling to room temperature, the composite catalyst is obtained.
[0026] The reaction mechanism of the composite catalyst loading reaction is as follows: The reaction between the active component (taking SBA-15 mesoporous silica as an example) and the carrier is as follows: First, the impregnation stage (physical loading, no chemical bonding): .
[0027] Label conditions: immersion temperature (65-75°C), solvent (EtOH = ethanol).
[0028] Product description: It is marked with "adsorption state" to indicate that it is physical adsorption at this time and no chemical bond is formed.
[0029] Secondly, the roasting stage (chemical bonding): .
[0030] Supplementary conditions: nitrogen atmosphere (N2 protection to prevent Cu²⁺ from being oxidized), calcination temperature (320-380℃).
[0031] Refined products: Release free triethylamine ((C2H5)3N↑) and decomposition products (such as ethylene C2H4 and ammonia NH3, which require tail gas treatment); the by-product is organic ammonium salt ((C2H5)3NH⁺Cl⁻), which can be removed by washing.
[0032] Based on any of the above technical solutions, further optimization is that: the surfactant is a compound of an anionic surfactant and a nonionic surfactant; wherein the anionic surfactant is sodium lauryl sulfate, and the nonionic surfactant is polyethylene glycol octylphenyl ether with a degree of polymerization n=9-10, and the mass ratio of the two is 3:1, and the hydrophile-lipophile balance value of the compound surfactant is 12-13.
[0033] Based on any of the above technical solutions, further optimization is that: in the ice-thawing process in step 3, a variable frequency stirring device is used, and the stirring speed is dynamically adjusted within the range of 120-220 r / min.
[0034] Based on any of the above technical solutions, the following is further optimized: in step 4, when adjusting the ammonia concentration, a mass flow meter is used to accurately control the amount of ammonia introduced, and at the same time, a pressure sensor is used to monitor the pressure of the reaction system in real time. When the pressure fluctuation exceeds the set value ±0.02MPa, the ammonia introduction rate is automatically adjusted as needed.
[0035] Based on any of the above technical solutions, further optimization is as follows: in the activated carbon decolorization process, the activated carbon particle size is 80-120 mesh, the decolorization temperature is controlled at 40-60°C, and the decolorization time is 1-1.5 hours; ultrasonic oscillation is performed simultaneously during the decolorization process, the ultrasonic frequency is 20-22kHz, and the power density is 0.3-0.5W / cm³.
[0036] In step 4, liquid ammonia is introduced and then an amination reaction is performed to construct a sulfonamide structure. The specific reaction is as follows: the sulfonated product undergoes an amination reaction under the action of liquid ammonia to be converted into a crude refined sulfonamide product: .
[0037] The above reaction is carried out under precisely controlled temperature, pressure and ammonia concentration conditions as required to ensure complete amination reaction and avoid excessive amination impurities.
[0038] Compared with the prior art, the present invention has the following beneficial effects: 1. The present invention uses the directional catalytic effect of the composite catalyst to selectively cause the para-position sulfonation reaction of m-chloroaniline, effectively inhibiting the formation of ortho-position and polysulfonated impurities, significantly improving the product purity, and the purity of the prepared sulfonamide is greater than 99.8%.
[0039] 2. The present invention optimizes and controls process steps such as raw material pretreatment, reaction parameters, and crystallization purification. For example, deep dehydration with 3A molecular sieves and vacuum distillation are used to purify the raw materials, and infrared spectroscopy is used to monitor the reaction endpoint, thereby ensuring the stability and controllability of the reaction process and improving the reliability of the synthesis process.
[0040] 3. The present invention adopts supercritical carbon dioxide dissolution crystallization, and through operations such as staged pressure reduction, temperature pulse control and addition of seed crystals, impurities are retained in the mother liquor, thereby achieving efficient purification of sulfonamides and further improving product quality.
[0041] 4. The process parameters of the present invention have a wide range. For example, when the molar ratio of chlorosulfonic acid to phosphorus trichloride, reaction temperature, and pressure are adjusted within a certain range, the product purity can still be guaranteed. This reduces the difficulty of controlling parameter fluctuations in industrial production and enhances the adaptability and industrial feasibility of the process.
[0042] 5. The present invention performs nanofiltration membrane treatment and ethanol distillation recovery on the filtrate produced by the reaction, with a high solvent recovery rate. The entire process is carried out under low-oxygen nitrogen protection, reducing oxidative side reactions and pollutant emissions, meeting green synthesis requirements, and having environmental and cost advantages. DETAILED DESCRIPTION
[0043] The following embodiments of the technical solution of the present invention are described in detail. The following embodiments are only used to more clearly illustrate the technical solution of the present invention and are therefore only used as examples and are not intended to limit the scope of protection of the present invention.
[0044] The present invention provides a method for synthesizing sulfanilamide that is beneficial for suppressing impurities, and the specific embodiments are as follows: Example 1, 1. Raw material pretreatment: m-chloroaniline was dehydrated with 3A molecular sieve to a water content of 0.04 wt %; chlorosulfonic acid was purified by vacuum distillation to a purity of 99.6%.
[0045] 2. Sulfonation reaction, composite catalyst preparation: Support: SBA-15 mesoporous silica, calcined in a muffle furnace at 300 °C for 4 h; Active ingredient: Cuprous chloride and triethylamine at a molar ratio of 1:0.7, dissolved in anhydrous ethanol to prepare a 0.1 mol / L cuprous chloride, 0.07 mol / L triethylamine solution; Impregnation: solid-liquid ratio 1g:10mL, 65℃, 200r / min, immersion for 2.5 hours; Drying and calcination: filtration at a vacuum degree of 0.08 MPa, washing with anhydrous ethanol three times, drying at 105°C for 4.5 hours, and calcining at 320°C at a rate of 2°C / min for 2.2 hours under nitrogen protection.
[0046] Reaction process: Chlorosulfonic acid and phosphorus trichloride are activated in a 1:1.2 molar ratio to generate a sulfonyl chloride intermediate; m-Chloroaniline (m-chloroaniline:chlorosulfonic acid = 2.1:1 molar ratio) was added at 30°C at a rate of 0.6 g / min; The temperature was raised to 100°C and the reaction was continued for 4 hours. The reaction was terminated when the absorption peak intensity monitored by infrared monitoring dropped to 5% of the initial value.
[0047] 3. Ice melting treatment: Water-to-ice ratio 1:1.05, thawing at 10°C for 1 hour; Add 0.12% of a composite surfactant (sodium lauryl sulfate: polyethylene glycol octylphenyl ether = 3:1); The variable frequency stirring speed is dynamically adjusted at 120r / min.
[0048] 4. Amination reaction: liquid ammonia was introduced at 0.35 MPa and 50°C for 5 hours; The ammonia concentration is maintained at 0.3 mol / L, and the pressure is automatically adjusted when the fluctuation exceeds ±0.02 MPa.
[0049] 5. Crystallization purification: The amount of activated carbon used is 0.8% of the product mass, and 80-mesh activated carbon is ultrasonically decolorized at 40°C for 1 hour (20 kHz, 0.3 W / cm³).
[0050] Supercritical carbon dioxide dissolution crystallization: wet product particle size <100μm, reduce the pressure to 7MPa at 0.4MPa / min, maintain for 18 minutes (temperature ±1℃ pulse, cycle 3min), then reduce the pressure to normal pressure at 0.1MPa / min, add 5μm seed crystals (0.1g / min) when the pressure drops to 8MPa, and obtain seed crystals with a purity of 99.85%.
[0051] 6. Filtrate treatment: 250Da nanofiltration membrane, operating pressure 2.2MPa, membrane surface flow rate 3.5m / s; ethanol distillation recovery, nitrogen protection (oxygen content <5ppm).
[0052] 7. Product preparation: After seed crystal growth and drying, sulfanilamide was obtained with a purity of 99.87% and an impurity content of 0.13%.
[0053] Example 2, 1. Raw material pretreatment: m-chloroaniline was dehydrated to a water content of 0.03 wt %; chlorosulfonic acid was purified to a purity of 99.7%.
[0054] 2. Sulfonation reaction, composite catalyst preparation: Support: KIT-6 mesoporous silica, calcined at 350°C for 6 hours; Active ingredients: Cuprous chloride and triethylamine at a molar ratio of 1:0.8, prepared into a 0.2 mol / L cuprous chloride and 0.16 mol / L triethylamine solution.
[0055] Impregnation: solid-liquid ratio 1g:20mL, 75℃, 300r / min, impregnation for 3.5 hours.
[0056] Drying and calcination: filtration under vacuum degree of 0.095 MPa, washing 5 times, drying at 115°C for 5.5 hours, heating to 380°C at 5°C / min and calcining for 2.8 hours.
[0057] Reaction process: Activation with chlorosulfonic acid and phosphorus trichloride in a molar ratio of 1:1.3; addition of m-chloroaniline (molar ratio 2.3:1) at a rate of 0.8 g / min at 40°C; reaction at 110°C for 3 hours, terminated when the absorption peak intensity drops to 3% of the initial value.
[0058] 3. Ice-decomposition treatment: water-to-ice ratio 1:1.15, ice-decomposition at 20℃ for 1.5 hours; add 0.18% compound surfactant; stir at a speed of 220r / min and adjust dynamically.
[0059] 4. Amination reaction: Liquid ammonia was introduced at 0.45 MPa and 60°C for 4 hours; the ammonia concentration was maintained at 0.4 mol / L and the pressure was automatically regulated.
[0060] 5. Crystallization purification: 1.2% activated carbon (120 mesh), ultrasonic decolorization at 60°C for 1.5 hours (22kHz, 0.5W / cm³); Supercritical crystallization: reduce the pressure from 0.6 MPa / min to 9 MPa, maintain for 12 minutes (temperature pulse ±1°C), then reduce the pressure at 0.3 MPa / min. At 8 MPa, add 10 μm seed crystals (0.5 g / min), and the purity is 99.89%.
[0061] 6. Filtrate treatment: 450Da nanofiltration membrane, pressure 2.8MPa, flow rate 4.5m / s; ethanol recovery under nitrogen protection.
[0062] 7. Product preparation: Purity of sulfanilamide is 99.91%, and impurity content is 0.09%.
[0063] Example 3, 1. Raw material pretreatment: m-chloroaniline was dehydrated to a water content of 0.05 wt %; chlorosulfonic acid was purified to a purity of 99.5%.
[0064] 2. Sulfonation reaction, composite catalyst preparation: Support: SBA-15 and KIT-6 (mass ratio 1:1), calcined at 320 °C for 5 hours; Active ingredient: Cuprous chloride and triethylamine at a molar ratio of 1:0.75, prepared into a 0.15 mol / L cuprous chloride, 0.11 mol / L triethylamine solution; Impregnation: solid-liquid ratio 1g:15mL, 70℃, 250r / min, impregnation for 3 hours.
[0065] Drying and calcination: filtration under vacuum degree of 0.09 MPa, washing 4 times, drying at 110°C for 5 hours, heating to 350°C at 3°C / min and calcining for 2.5 hours.
[0066] Reaction process: Activation with chlorosulfonic acid and phosphorus trichloride in a molar ratio of 1:1.25; addition of m-chloroaniline (molar ratio 2.2:1) at a rate of 0.7 g / min at 35°C; reaction at 105°C for 3.5 hours, terminated when the absorption peak intensity dropped to 7% of the initial value.
[0067] 3. Ice-decomposition treatment: water-to-ice ratio 1:1.1, ice-decomposition at 15℃ for 1.2 hours; add 0.15% compound surfactant; stir at a speed of 170r / min and adjust dynamically.
[0068] 4. Amination reaction: Liquid ammonia was introduced at 0.4 MPa and 55°C for 4.5 hours; the ammonia concentration was maintained at 0.35 mol / L, and pressure fluctuations were automatically adjusted.
[0069] 5. Crystallization purification: 1.0% activated carbon (100 mesh), ultrasonic decolorization at 50°C for 1.2 hours (21kHz, 0.4W / cm³); Supercritical crystallization: reduce the pressure at 0.5 MPa / min to 8 MPa, maintain for 15 minutes (temperature pulse ±1°C), then reduce the pressure at 0.2 MPa / min. At 8 MPa, add 8μm seed crystals (0.3 g / min), and the purity is 99.88%.
[0070] 6. Filtrate treatment: 300Da nanofiltration membrane, pressure 2.5MPa, flow rate 4.0m / s; ethanol recovery under nitrogen protection.
[0071] 7. Product preparation: Purity of sulfanilamide is 99.86%, and the impurity content is 0.14%.
[0072] It can be seen from the above examples that the present invention achieves high-purity preparation of sulfonamide by regulating key process parameters, which is specifically reflected in the following advantages: 1. Controllability of process parameters and purity stability Applicability of different catalyst systems: Example 1 uses an SBA-15 carrier, Example 2 uses a KIT-6 carrier, and Example 3 uses a composite carrier. All of them can achieve a purity of sulfanilamide above 99.8%, demonstrating that the carrier type has little effect on the reaction activity and the process is compatible with the carrier selection.
[0073] When the molar ratio of the catalyst active components (cuprous chloride and triethylamine) was adjusted within the range of 1:0.7-1:0.8, the selectivity of the sulfonation reaction was not significantly affected, further verifying the stability of the catalyst system.
[0074] Optimization of the reaction material ratio: When the molar ratio of chlorosulfonic acid to phosphorus trichloride is between 1:1.2 and 1:1.3, the sulfonyl chloride intermediate generated by the activation reaction is sufficient to support the subsequent sulfonation reaction, while the molar ratio of m-chloroaniline to chlorosulfonic acid (2.1-2.3:1) ensures high selectivity for the para-sulfonated product and effectively suppresses the ortho- and polysulfonated impurities.
[0075] 2. Effectiveness of impurity suppression: Directed catalytic effect of the composite catalyst. In the examples, the composite catalyst promotes the para-sulfonation of m-chloroaniline through chemical bonding. Precision purification by supercritical crystallization: During the supercritical carbon dioxide dissolution crystallization process, impurities can be retained in the mother liquor through segmented pressure reduction and temperature pulse control, thereby improving product purity.
[0076] When parameters such as the water-to-ice ratio (1:1.05-1:1.15) of the ice-melting process, the amination reaction pressure (0.35-0.45 MPa), and the nanofiltration membrane pore size (250-450 Da) are adjusted within a wide range, the relative purity of the product can still be guaranteed, reducing the difficulty of controlling parameter fluctuations in industrial production.
[0077] In addition, the filtrate is treated with nanofiltration membranes and recovered by ethanol distillation, with a high solvent recovery rate. At the same time, the entire process is carried out under low-oxygen nitrogen protection, which reduces oxidation side reactions, meets the requirements of green synthesis, and effectively achieves efficient inhibition of impurities and product purification in the synthesis of sulfonamides, with significant industrial application value.
[0078] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that the technical solutions described in the above embodiments can still be modified, or some or all of the technical features therein can be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the scope of the technical solutions of the embodiments of the present invention. For those skilled in the art, any replacement improvements or changes made to the implementation methods of the present invention fall within the scope of protection of the present invention.
[0079] Any matters not described in detail in the present invention are well-known technologies to those skilled in the art.
Claims
1. A method for synthesizing sulfonamides that is beneficial for suppressing impurities, characterized in that: The steps include: Step 1, dehydrating m-chloroaniline through 3A molecular sieve, and purifying chlorosulfonic acid by vacuum distillation; Step 2: Under the action of a composite catalyst, chlorosulfonic acid and phosphorus trichloride are reacted in a molar ratio of 1:1.2-1.3, m-chloroaniline is added at a temperature of 30-40° C. at a rate of 0.6-0.8 g / min, and the reaction is carried out at 100-110° C. for 3-4 hours. The absorption peak intensity ratio is monitored by infrared spectroscopy, and the reaction parameters such as the reaction temperature and the rate of addition of m-chloroaniline are adjusted as needed. The reaction is terminated when the absorption peak intensity ratio drops to 3%-7% of the initial value. Step 3: thawing the reaction solution at a water-to-ice ratio of 1:1.05-1.15 and 10-20° C. for 1-1.5 h, and adding 0.12%-0.18% of a surfactant; Step 4: Add liquid ammonia at 0.35-0.45 MPa and 50-60°C for 4-5 hours. During the reaction, adjust the ammonia concentration as needed to maintain it at 0.3-0.4 mol / L. Step 5: The reaction product is placed in a decolorization kettle, decolorized with activated carbon, finely filtered, concentrated under reduced pressure and crystallized, and finally dissolved and crystallized by supercritical carbon dioxide to obtain sulfonamide seed crystals with a purity of >99.8%; Step 6: The filtrate produced by the above reaction is treated with a 250-450Da nanofiltration membrane and recovered by ethanol distillation. The entire process is carried out under nitrogen protection with an oxygen content of less than 5ppm; Step 7, further crystallizing, growing, separating and drying the obtained sulfanilamide seed crystals to obtain the sulfanilamide product.
2. A method for synthesizing sulfanilamide that is beneficial to suppressing impurities according to claim 1, characterized in that: The molar ratio of the m-chloroaniline to the chlorosulfonic acid is 2.1-2.3:
1.
3. A method for synthesizing sulfanilamide that is beneficial to suppressing impurities according to claim 2, characterized in that: The specific reaction of chlorosulfonic acid and phosphorus trichloride in the activation reaction of chlorosulfonic acid and phosphorus trichloride in step 2 is as follows: Under the action of the composite catalyst, the chlorosulfonic acid purified in step 1 first undergoes an activation reaction with phosphorus trichloride to generate a sulfonyl chloride intermediate. The specific chemical reaction formula is: ； Selective sulfonation reaction of m-chloroaniline: The activated sulfonyl chloride intermediate further undergoes electrophilic substitution reaction with m-chloroaniline to selectively generate the precursor of the target product. The specific chemical reaction formula is: 。 4. A method for synthesizing sulfanilamide that is beneficial to suppressing impurities according to claim 3, characterized in that: The composite catalyst in step 2 is formed by loading an active component on a carrier, wherein the active component is composed of cuprous chloride and triethylamine in a molar ratio of 1:0.7-0.
8.
5. A method for synthesizing sulfanilamide that is beneficial to suppressing impurities according to claim 4, characterized in that: The preparation method of the composite catalyst is as follows: Place the support in a muffle furnace and pretreat at 300-350°C for 4-6 hours to remove surface adsorbed water and impurities, then cool to room temperature for later use; According to the required active ingredient loading, cuprous chloride and triethylamine were calculated and measured, and dissolved in anhydrous ethanol to prepare an ethanol solution with a cuprous chloride concentration of 0.1-0.2 mol / L and a triethylamine concentration of 0.07-0.16 mol / L. Stir evenly to ensure that the active ingredient is fully dissolved; The pretreated carrier was completely immersed in the above ethanol solution at a solid-liquid ratio of 1g:10-20mL, placed in a constant temperature water bath, and the impregnation reaction was carried out at 65-75°C and a stirring speed of 200-300r / min for 2.5-3.5 hours to allow the active components to be fully adsorbed on the surface and pores of the carrier; After the impregnation is completed, the vacuum degree is maintained at 0.08-0.095 MPa, and the solid product loaded with active components is separated by vacuum filtration and washed 3-5 times with anhydrous ethanol, with the amount of washing liquid each time being 3-5 times the volume of the solid, to remove the active components not adsorbed on the surface; The washed solid product was transferred to a forced air drying oven and dried at 105-115°C for 4.5-5.5 hours to remove residual ethanol and moisture and fully dry the solid product; The dried product is transferred to a tubular furnace, and under a nitrogen protective atmosphere, the temperature is raised to 320-380°C at a heating rate of 2-5°C / min, and calcined for 2.2-2.8 hours. The active component and the carrier are firmly bonded through a chemical bonding process. After naturally cooling to room temperature, the composite catalyst is obtained.
6. A method for synthesizing sulfanilamide that is beneficial to suppressing impurities according to claim 5, characterized in that: The surfactant is a compound of an anionic surfactant and a nonionic surfactant; wherein the anionic surfactant is sodium lauryl sulfate, the nonionic surfactant is polyethylene glycol octylphenyl ether with a degree of polymerization n=9-10, and the mass ratio of the two is 3:1, and the hydrophile-lipophile balance value of the compound surfactant is 12-13.
7. A method for synthesizing sulfanilamide that is beneficial to suppressing impurities according to claim 6, characterized in that: In the ice-thawing process in step 3, a variable frequency stirring device is used, and the stirring speed is dynamically adjusted within the range of 120-220 r / min.
8. A method for synthesizing sulfanilamide that is beneficial to suppressing impurities according to claim 7, characterized in that: In step 4, when regulating the ammonia concentration, a mass flow meter is used to accurately control the amount of ammonia introduced, and a pressure sensor is used to monitor the pressure of the reaction system in real time. When the pressure fluctuation exceeds the set value ±0.02 MPa, the ammonia introduction rate is automatically adjusted as needed.
9. A method for synthesizing sulfonamides that is beneficial for suppressing impurities according to claim 8, characterized in that: During the activated carbon decolorization process, the activated carbon particle size is 80-120 mesh, the decolorization temperature is controlled at 40-60°C, and the decolorization time is 1-1.5 hours. During the decolorization process, ultrasonic oscillation is performed simultaneously, the ultrasonic frequency is 20-22kHz, and the power density is 0.3-0.5W / cm³.