A method for synthesizing 2-(2-chloroethoxy)benzenesulfonamide

Abstract

The application relates to the technical field of chemical synthesis, in particular to a synthesis method of 2-(2-chloroethoxy) benzene sulfonamide, which comprises the following steps: S100: adding ortho-nitrophenol, 1,2-dichloroethane, an acid binding agent and a catalyst A into a solvent A to carry out a reaction, and preparing a compound IV; S200: adding the compound IV into a solvent B, carrying out a reduction reaction under the catalysis of Raney nickel, and preparing a compound V; the raw materials used in the synthesis method are conventional and easy to obtain; in the process design, diazotization, chlorosulfonation and amination reaction are ingeniously integrated into continuous operation; the high-activity intermediate can be directly subjected to amination to prepare the final product without being separated from the reaction system, so that the process operation flow is objectively simplified, and the safety risk in the intermediate transfer process is reduced.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, specifically to a method for synthesizing 2-(2-chloroethoxy)benzenesulfonamide. Background Technology

[0002] Developed and marketed by Novartis (now Syngenta) in 1987, bensulfuron-methyl is a second-generation sulfonylurea herbicide. It is primarily used in fields of cereal crops such as wheat and barley to control annual broadleaf weeds and some grassy weeds. It is characterized by low dosage, broad spectrum of weed control, and crop safety. Its target is acetolactate synthase (ALS) in plants, inhibiting the biosynthesis of branched-chain amino acids (valine, leucine, and isoleucine), thus blocking cell division and causing weed death. This herbicide is widely accepted in the market due to its high weed control efficacy, crop safety, and the fact that its application time is not limited by the weed's growth stage.

[0003] (2-Chloroethoxy)benzenesulfonamide is a key intermediate in the synthesis of benzyl ether, and its structural formula is as follows:

[0004] Existing production processes for 2-(2-chloroethoxy)benzenesulfonamide: Chinese patent CN116640074 discloses a process using p-chlorophenol as a starting material, involving dichloroethane etherification, chlorosulfonic acid sulfonation, ammonia amination, rehydrogenation dechlorination, and recrystallization to obtain 2-(2-chloroethoxy)benzenesulfonamide. The use of chlorosulfonic acid and thionyl chloride for sulfonation results in a vigorous reaction, difficult temperature control, and the use of highly corrosive chlorosulfonic acid, generating large amounts of hydrogen chloride gas. This process carries high risks and places stringent requirements on the equipment. The yield of this process is 50%.

[0005] Chinese patent CN103508968 discloses a method for synthesizing 2-(2-chloroethoxy)benzenesulfonic acid from 2-acetoxybenzenesulfonic acid with 2-chloroethanol, followed by reaction with phosgene and ammonia to obtain 2-(2-chloroethoxy)benzenesulfonamide. Although the route is simple, the main raw materials are expensive and difficult to procure, and the use of highly toxic phosgene poses high risks during storage, transportation, and reaction, with serious consequences from leaks, making it unsuitable for large-scale production. Summary of the Invention

[0006] To achieve the above objectives, the present invention provides the following technical solution: This invention provides a method for synthesizing 2-(2-chloroethoxy)benzenesulfonamide, comprising the following steps: S100: o-nitrophenol, 1,2-dichloroethane, an acid-binding agent and catalyst A are added to solvent A to react and obtain compound IV; S200: Compound IV is added to solvent B, and hydrogen is introduced under Raney nickel catalysis to carry out a reduction reaction to obtain compound V; S300: Compound V is added to dilute hydrochloric acid, sodium nitrite solution is added to prepare diazonium salt, and then sodium bisulfite solution, catalyst B and catalyst C are added to react in solvent C to obtain intermediate VI; S400: Without separating the intermediate VI from the reaction system, ammonia water is directly added to the reaction system to carry out the amination reaction, thereby obtaining the 2-(2-chloroethoxy)benzenesulfonamide.

[0007] Furthermore, the types of reaction reagents in step S100 respectively satisfy the following conditions: Solvent A is selected from one of 1,2-dichloroethane, DMF, DMAc, DEF, DMSO, NMP, and 1,4-dioxane; The acid-binding agent is selected from one of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and DBU. The catalyst A is selected from one of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, benzyltriethylammonium chloride, 18-crown-6, and 15-crown-5. The types of reaction reagents are further narrowed down to: Solvent A is preferably one of 1,2-dichloroethane, DMF, and DMAc; acid binder is preferably one of potassium carbonate, sodium hydroxide, and DBU; catalyst A is preferably one of tetrabutylammonium chloride, tetrabutylammonium bromide, and 18-crown-6.

[0008] Furthermore, the quantitative proportions of each reactant in step S100 are limited as follows: The molar ratio of o-nitrophenol, 1,2-dichloroethane and acid-binding agent is 1:1~2:1~5; The molar ratio of o-nitrophenol to catalyst A is 1:0.01~0.1; The mass ratio of o-nitrophenol to solvent A is 1:4~6.

[0009] Furthermore, the etherification reaction in step S100 is carried out under the following dynamic process conditions: the system temperature is maintained at 30-100°C, and the reaction is carried out with stirring for 1-12 hours. The process conditions are optimized as follows: the temperature is controlled at 85-90℃, and the time for heat preservation and stirring is shortened to 1-5 hours.

[0010] Furthermore, the material composition and static mass ratio of the reduction reaction system in step S200 satisfy the following linkage constraints: Solvent B is selected from one of methanol, ethanol, isopropanol, DMF, DMAc, NMP, and DMSO; The mass ratio of compound IV to Raney nickel is 1:0.01~0.5; and the mass ratio of compound IV to solvent B is 1:3~10; The solvents in the static mass ratio system are selected as follows: Solvent B is preferably one of methanol, ethanol, and DMF; In step S200, hydrogenation reduction is carried out through the coordinated control of thermodynamic and kinetic parameters. The dynamic process control parameters are limited to: the reaction control temperature is 20-60℃, the reaction control pressure is 0.25-1.0MPa, and the holding and stirring time is 1-12 hours. The process control parameters are finely reduced to a high-gain process control domain: the control temperature is adjusted to 50-60℃, the control pressure is adjusted to 0.8-1.0MPa, and the heat preservation and stirring time is shortened to 5-10 hours.

[0011] Furthermore, the material selection for the reaction medium and catalytic system involved in step S300 respectively meets the following functional classification requirements: Component 1: The solvent C, which serves as the reaction medium, is selected from one of dichloromethane, dichloroethane, chlorobenzene, chloroform, toluene, and xylene; Component 2: Catalyst B, which serves as the first catalyst, is selected from cuprous chloride and cupric chloride; Component 3: The catalyst C, which serves as the second catalyst, is selected from one of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, benzyltriethylammonium chloride, 18-crown-6, and 15-crown-5.

[0012] Furthermore, the reaction medium and the catalytic system achieve synergistic catalysis through the following optimal combination: the solvent C is preferably one of dichloromethane, dichloroethane, and toluene; the catalyst B is preferably copper chloride; and the catalyst C is preferably one of tetrabutylammonium chloride, tetrabutylammonium bromide, and 18-crown-6.

[0013] Furthermore, taking the amount of compound V as the absolute reference, the quantitative addition ratio of each material in step S300 satisfies the following matrix constraint: The molar ratio of compound V to sodium nitrite is 1:1 to 1.1; The molar ratio of compound V to catalyst B is 1:0.01~0.1; The molar ratio of compound V to catalyst C is 1:0.01~0.1; The mass ratio of compound V to solvent C is 1:5~10; The preparation of diazonium salt and subsequent reactions in step S300 are carried out under the following synergistic process window: the system temperature is maintained at 0-30°C and the reaction time is 1-10 hours with stirring. The collaborative process window is further narrowed to the following high yield control zone: the control temperature is adjusted to 0-10℃, and the heat preservation and stirring time is shortened to 1-5 hours.

[0014] Furthermore, the specific amination reagent for the amination reaction in step S400 is limited to: ammonia water with a mass fraction of 25%; The process control conditions for the one-pot continuous amination reaction without separating intermediate VI are limited to: cooling the reaction system to below 10°C, adding the ammonia water dropwise, and maintaining the temperature for 1 hour.

[0015] Furthermore, after the reaction in step S400 is completed, a post-processing step of purifying and extracting the target product is included, the specific process of which is as follows: After the reaction solution was allowed to stand and separate into layers, the organic phase was washed with water, then distilled under reduced pressure to a small volume, and n-heptane was added for stirring and crystallization. Finally, the solution was filtered and dried to obtain the 2-(2-chloroethoxy)benzenesulfonamide.

[0016] Beneficial effects This invention utilizes conventional and readily available raw materials for synthesis. The process design cleverly integrates diazotization, chlorosulfonation, and amination reactions into a continuous operation, eliminating the need to separate highly reactive intermediates from the reaction system before directly amination to obtain the final product. This objectively simplifies the process and reduces safety risks during intermediate transfer. Furthermore, through the synergistic effect of a specific solvent and catalyst system, along with rational control of temperature and pressure, the overall reaction conditions are relatively mild and atom-economical. This ensures high product yield and purity while effectively controlling production costs, providing a safe, stable, and industrially viable optimized route for the preparation of this compound. Attached Figure Description

[0017] Figure 1 This is the overall process flow diagram of the present invention; Figure 2 This is a flowchart illustrating the specific operation of the etherification reaction of the present invention; Figure 3 This is a flowchart illustrating the specific operation of hydrogenation reduction according to the present invention; Figure 4 The flowchart of the one-pot continuous process system for steps S300 and S400 of the present invention is shown. Detailed Implementation

[0018] To enable those skilled in the art to better understand the present invention, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of the present invention.

[0019] It should be noted that the terms "first," "second," etc., in the specification, claims, and accompanying drawings of this invention are used to distinguish similar objects and are not necessarily used to describe a specific order or sequence. It should be understood that such data can be interchanged where appropriate so that the embodiments of the invention described herein can be implemented in orders other than those illustrated or described herein. Furthermore, the terms "comprising" and "having," and any variations thereof, are intended to cover a non-exclusive inclusion; for example, a process, method, system, product, or apparatus that comprises a series of steps or units is not necessarily limited to those steps or units explicitly listed, but includes other steps or units not explicitly listed or inherent to such processes, methods, products, or apparatus.

[0020] The present invention will now be described in further detail with reference to the accompanying drawings: Example: like Figure 1-4 As shown, a method for synthesizing 2-(2-chloroethoxy)benzenesulfonamide includes the following steps: S100: o-nitrophenol, 1,2-dichloroethane, acid-binding agent and catalyst A are added to solvent A to react and obtain compound IV; S200: Compound IV was added to solvent B, and hydrogen gas was introduced under Raney nickel catalysis to carry out a reduction reaction to obtain compound V; S300: Compound V is added to dilute hydrochloric acid, sodium nitrite solution is added to prepare diazonium salt, and then sodium bisulfite solution, catalyst B and catalyst C are added to react in solvent C to obtain intermediate VI; S400: Without separating intermediate VI from the reaction system, ammonia is directly added to the reaction system to carry out the amination reaction, thus obtaining 2-(2-chloroethoxy)benzenesulfonamide.

[0021] Furthermore, the specific implementation process of step S100 is as follows: This embodiment examines the specific effects of different types of solvent A on the efficiency, product yield, and purity of the nucleophilic substitution etherification reaction. The entire reaction system was carried out in a 500 mL four-necked flask equipped with a mechanical stirrer, a double-pass inert gas inlet, a thermocouple temperature controller, and a reflux condenser.

[0022] First, open the double vent valve of the flask and introduce high-purity argon gas to purge the system. Repeat this process three times to completely remove air and moisture from the reaction system, maintaining a slightly positive pressure argon protective environment throughout the entire reaction. Next, add 160g of solvent A to the flask in a measured amount. While stirring at room temperature, add 40g (0.288mol) of o-nitrophenol (compound II) and an excess of 57g (0.576mol) of 1,2-dichloroethane (compound III) to the solvent, continuing stirring until the solid raw materials are completely dissolved, forming a homogeneous liquid phase system. Then, add 80g (0.579mol) of anhydrous potassium carbonate solid as an acid-binding agent and 2.0g (0.0072mol) of tetrabutylammonium chloride, a phase transfer catalyst, to the above solution in a single step.

[0023] After the feed is complete, turn on the mechanical stirrer and adjust and fix the stirring speed to 280 rpm to 320 rpm to ensure that the insoluble anhydrous potassium carbonate solid particles are uniformly suspended in the liquid medium, increasing the contact area and mass transfer rate of the solid-liquid multiphase system. Use a temperature-controlled heating mantle to program the temperature up to the range of 85°C to 90°C, and maintain the reaction under constant temperature and reflux with stirring. During the reaction, periodically extract trace amounts of the reaction solution for high-performance liquid chromatography (HPLC) analysis. When the peak area percentage of the starting material o-nitrophenol (II) in the chromatogram decreases to below 1.0%, the nucleophilic substitution reaction is considered complete, and heating is stopped.

[0024] After the reaction was completed, the reaction solution was allowed to cool naturally to a temperature range of 30°C to 40°C. To remove reaction byproducts (mainly potassium bicarbonate and potassium chloride solid salts) and unreacted excess potassium carbonate, the reaction suspension was filtered under reduced pressure using a Buchner funnel. After filtration, the filter cake was washed three times with 20 mL of 1,2-dichloroethane to recover the target product entrained within the solid salts, and the washes were combined with the mother liquor. The combined filtrate was transferred to a rotary evaporator and concentrated under reduced pressure distillation at a water bath temperature of 60°C and a system pressure of -0.095 MPa. Distillation was stopped when the solvent distillate reached 75% to 80% of the original volume, the residue in the reaction flask was a viscous fluid, and no significant solvent distillation was observed.

[0025] 400 mL of deionized water was slowly added to the concentrated residue in one go, while maintaining medium-speed stirring during the addition. After the water addition was complete, the emulsion system was slowly cooled. When the temperature reached 0°C, it was kept at a constant temperature for static crystallization for 1 hour to promote the full crystallization and growth of compound IV. After crystallization, the precipitate was collected by vacuum filtration. The resulting wet filter cake was transferred to a vacuum oven and dried at constant weight under conditions of system pressure less than -0.09 MPa and temperature of 30°C to finally obtain compound IV as a pale yellow solid powder.

[0026] To investigate the specific moderating effect of different solvents A on the reaction results, parallel experiments were conducted using 1,2-dichloroethane, dimethylformamide (DMF), and dimethylacetamide (DMAc) as solvent A, while maintaining identical molar ratios of other materials, stirring speeds, and post-treatment conditions. Reaction times were dynamically adjusted based on HPLC endpoint detection. The specific yields, percentages, and purity of compound IV are shown in Table 1.

[0027] The obtained product was analyzed by proton nuclear magnetic resonance spectroscopy. Structural characterization and confirmation were performed under the following conditions: 400 MHz, DMSO-d6 solvent. The specific spectral data are as follows: The chromatogram values ​​were 7.88–7.86 (d, J = 8.0 Hz, 1H), 7.68–7.63 (t, 1H), 7.40–7.38 (d, J = 8.0 Hz, 1H), 7.18–7.13 (t, 1H), 4.46–4.44 (t, 2H), and 3.97–3.94 (t, 2H). Characterization results confirmed that the solid was indeed the target compound IV.

[0028] The Influence of Different Types of Acid-Binding Agents on the Preparation of Compound IV and Process Details: The equipment configuration and inert gas protection operation in this embodiment are exactly the same as in Example 1. In a 500mL four-necked flask purged with argon, 160g of DMF, the optimal solvent selected in Example 1, was first added. Then, under stirring, 40g (0.288mol) of o-nitrophenol, 57g (0.576mol) of 1,2-dichloroethane, and 2.0g (0.0072mol) of tetrabutylammonium chloride were added sequentially, and the mixture was gently stirred to ensure complete miscibility of the reaction substrates.

[0029] Different feeding and control processes are adopted depending on the type of acid-binding agent. Details are as follows: When solid inorganic potassium carbonate is used as an acid-binding agent, the material input is 80g (0.579mol, molar ratio of 2.0 times), which is added to the reactor all at once, and the mechanical stirring speed is set to 300rpm. When using solid strong base sodium hydroxide as an acid-binding agent, considering the significant exothermic effect that occurs when strong bases and phenols form salts, to prevent excessive local temperature from causing over-etherification side reactions, 43.2g of solid sodium hydroxide (1.08mol, molar ratio of 1.5) was divided into five equal parts. One part was added dropwise every 10 minutes while the material was at room temperature of 20℃ to 25℃. During this period, the internal temperature fluctuation of the reaction was closely monitored and the stirring speed was controlled at 350rpm. When using the strong organic base 1,8-diazabicycloundec-7-ene (DBU) as an acid-binding agent, since DBU is liquid at room temperature, 96.4 g (0.633 mol, molar ratio of 2.2) of it is pre-loaded into a constant pressure dropping funnel and slowly added to the flask over 30 minutes, maintaining a dropping speed of 250 rpm.

[0030] After all acid-binding agents are added, the reaction system is uniformly heated to a reflux range of 85℃ to 90℃ and maintained at this temperature for further reaction. The consumption rate of o-nitrophenol is monitored online by HPLC to determine the reaction endpoint (percentage of starting material peak area <1.0%).

[0031] The post-reaction processing steps were carried out according to the standard procedure of Example 1, including cooling to 30-40°C, filtering to separate inorganic salts, washing and recovering the filter cake with a small amount of 1,2-dichloroethane, rotary evaporating the filtrate at 60°C and -0.095 MPa to a fluid state, adding 400 mL of deionized water, gradually cooling to 0°C for freezing and crystallization for 1 hour, filtration and dehydration, and vacuum drying at 30°C to constant weight. The effects of different acid-binding agents on the reaction performance are shown in the table below:

[0032] The influence of different phase transfer catalysts A on the preparation of compound IV and process details: This embodiment was carried out in a 500mL four-necked flask, with argon flow used for purging and maintenance. DMF 160g, o-nitrophenol 40g (0.288mol), and 1,2-dichloroethane 57g (0.576mol) were added sequentially to the flask, followed by anhydrous potassium carbonate solid 80g (0.579mol) as a solid acid-binding agent. Then, different types of phase transfer catalyst A were introduced. When tetrabutylammonium chloride is used, the amount added is 4.0 g (0.0144 mol, corresponding to a molar ratio of catalyst to compound II of 0.05). When tetrabutylammonium bromide is used, the amount added is 4.64 g (0.0144 mol, corresponding to a molar ratio of 0.05). When using the macrocyclic polyether catalyst 18-crown-6, due to the extremely high matching degree between its complexation cavity and potassium ions and the large complexation constant, its dosage was reduced to 1.52 g (0.00576 mol, corresponding to a molar ratio of catalyst to compound II of 0.02).

[0033] Mechanical stirring was started on all the above catalytic systems at 300 rpm, and the heating device was activated to rapidly raise the internal temperature of the system to the reaction control range of 85°C to 90°C. The reaction was monitored using HPLC until the starting material o-nitrophenol was completely converted (peak area percentage <1.0%).

[0034] The standard extraction and purification process was then performed: cooling, filtering out insoluble solids, rinsing the filter cake with 1,2-dichloroethane, combining the filtrates and removing most of the solvent under vacuum at 60°C, adding 400 mL of deionized water to the residue to precipitate crystals, freezing at 0°C for 1 hour to allow crystals to grow, collecting the solid by suction filtration and drying it in a vacuum oven at 30°C until its mass no longer changes. The experimental output parameters for each catalyst A are shown in the table below: Effects of different catalysts A on the synthesis parameters of compound IV:

[0035] Furthermore, the specific implementation process of step S200 is as follows: This embodiment illustrates the specific adjustment rules for the rate, product yield, and purity of the Raney nickel catalytic hydrogenation reduction of nitro compounds in step S200 using different types of solvent B. Since hydrogenation reduction is a typical high-pressure, gas-liquid-solid three-phase heterogeneous catalytic reaction, to eliminate gas-liquid mass transfer resistance and ensure operational safety, the reaction is carried out in a 1000mL stainless steel high-pressure reactor equipped with an anchor-type mechanical stirrer, a high-pressure gas feed valve, a safety rupture disc, a high-pressure sampling inner tube, and a jacketed heating and cooling linkage temperature control system.

[0036] First, under normal temperature and pressure, 50g (0.248mol) of intermediate compound IV prepared in step S100 and 500g of solvent B were sequentially and quantitatively added to the high-pressure reactor. Then, 5g of active Raney nickel catalyst was weighed and added to the reactor as the hydrogenation catalyst. To prevent the highly pyrophosphate-prone Raney nickel catalyst from spontaneously combusting upon contact with air, a small amount of solvent B was used to rinse and wet the reactor walls during the feeding process, ensuring that the catalyst particles were completely submerged below the liquid surface. After the feeding was completed, the high-pressure reactor lid was immediately tightened, and all external valves were confirmed to be tightly closed.

[0037] To completely eliminate residual oxygen in the gas phase space inside the reactor, the exhaust valve and nitrogen inlet valve at the top of the reactor were opened, and high-purity nitrogen was introduced to pressurize and purge the reactor. After the nitrogen pressure reached 0.5 MPa, the inlet valve was closed, and then the exhaust valve was slowly opened to release pressure to atmospheric pressure. This pressurization and depressurization process was repeated at least three times, using an online oxygen analyzer at the exhaust port at the top of the reactor to ensure that the oxygen volume percentage inside the reactor dropped below 0.05%. After purging, the exhaust valve was closed, and high-purity hydrogen was introduced to purge the hydrogen system. This process was repeated twice, pressurizing to 0.3 MPa and then releasing the pressure, to completely establish a high-purity hydrogen reaction environment.

[0038] Subsequently, hydrogen gas was continuously introduced into the reactor through the hydrogen feed valve until the pressure gauge reading inside the high-pressure reactor reached the set range of 0.8 MPa to 1.0 MPa. At this point, the hydrogen feed valve was closed, and the mechanical agitator was turned on. The agitation speed was adjusted and fixed at 450 rpm to 500 rpm. The high-speed agitation forced the hydrogen gas to form microbubbles in the liquid phase, uniformly suspending the solid Raney nickel catalyst in the reaction liquid and constructing a highly efficient three-phase mass transfer interface. Then, the jacketed electric heating system was turned on to perform programmed temperature rise, raising the temperature of the reactants in the reactor to the controlled range of 50°C to 60°C. Under this condition, the heat-maintaining and stirring reaction began.

[0039] Since the hydrogenation reduction of nitro compounds is a strongly exothermic reaction, the material inside the reactor releases a large amount of heat in the first one to two hours of the reaction. The jacketed cooling water system needs to be automatically connected to suppress internal temperature overshoot and maintain the reaction temperature within the set range. Simultaneously, as hydrogen is rapidly consumed, the pressure inside the reactor will show a significant downward trend. Whenever the pressure drops to 0.25 MPa to 0.3 MPa, the hydrogen feed valve needs to be reopened to replenish hydrogen into the reactor, restoring the pressure and maintaining it between 0.8 MPa and 1.0 MPa. After 5 to 10 hours of heated and stirred reaction, the pressure gauge reading inside the reactor stops decreasing, indicating that the hydrogen absorption rate is approaching zero. At this point, a trace amount of the reaction solution is extracted through the high-pressure sampling tube for high-performance liquid chromatography (HPLC) detection. When the detection results show that the peak area percentage of the starting compound IV decreases to below 1.0%, the reduction reaction is considered to have reached its endpoint, and heating is stopped.

[0040] After the reaction is complete, the jacket heating is turned off and cold water is introduced into the jacket to allow the material inside the reactor to cool naturally to room temperature (20°C to 30°C). Mechanical stirring is stopped, and the exhaust valve at the top of the reactor is opened to slowly vent the remaining residual hydrogen gas to a safe area through a sealed pipeline and depressurize it to atmospheric pressure. Subsequently, to ensure that the Raney nickel catalyst does not come into contact with air and pose a risk of spontaneous combustion, 0.1 MPa of low-pressure nitrogen gas is introduced into the reactor. The pressure difference is used to filter the reaction liquid inside the reactor through a microporous filter element at the bottom of the reactor. The solid Raney nickel catalyst is intercepted and sealed inside the reactor bottom to maintain a moist state for later use, while the supernatant filtered out is collected in a sealed receiving bottle.

[0041] The collected clear supernatant was transferred to a vacuum distillation apparatus. The vacuum pump was turned on to reduce the system pressure to -0.095 MPa, and the water bath heating temperature was controlled at 40°C for vacuum distillation. Since the target product compound V is sensitive to high temperatures, the external heating source was strictly controlled to not exceed 45°C. As solvent B was completely distilled off, the residue in the reaction flask gradually concentrated into a solid until no significant liquid distillation occurred and the mass remained constant. Distillation was then stopped, ultimately yielding compound V as a solid powder.

[0042] To investigate the specific moderating effect of different solvents B on the hydrogenation reduction reaction performance, parallel hydrogenation experiments were conducted using methanol, ethanol, and dimethylformamide (DMF) as solvent B, while maintaining consistent amounts of compound IV (50 g), Raney nickel (5 g), solvent B (500 g), stirring speed (450-500 rpm), and temperature and pressure control ranges. Reaction times were dynamically recorded based on pressure stability and HPLC endpoint detection. The specific yield, reaction rate, and purity of the obtained compound V are shown in the table below. The effect of different solvents B on the synthesis parameters of compound V:

[0043] The obtained product was characterized and confirmed by proton nuclear magnetic resonance spectroscopy. The test conditions were 400 MHz and the solvent was DMSO-d6. The specific spectral data are as follows: 9.91 (brs, 2H). The chromatogram values ​​were 7.43–7.41 (d, J = 8.0 Hz, 1H), 7.35–7.31 (t, 1H), 7.25–7.23 (d, J = 8.0 Hz, 1H), 7.07–7.03 (t, 1H), 4.39–4.37 (t, 2H), and 4.02–3.99 (t, 2H). Characterization results confirmed that the solid was indeed the target product compound V.

[0044] Furthermore, the specific implementation process of step S300 is as follows: This embodiment illustrates the specific process of using different solvents C as the reaction medium in step S300 and carrying out a non-separation one-pot amination reaction in step S400. This process involves intense exothermic reactions and gas release; therefore, the entire process is conducted in a reactor equipped with a cryogenic system, high-efficiency condensers, and a tail gas absorption device.

[0045] (1) Preparation of diazonium salt solution: In a 1000mL reaction flask (diazo reactor) equipped with a mechanical stirrer, 150g of deionized water and 100g of 36% concentrated hydrochloric acid were added sequentially. The mechanical stirrer was turned on and the speed was set to 300rpm. Then, 120g of compound V prepared in step S200 was slowly added in batches, stirring to ensure complete salt formation and dissolution in the acidic aqueous phase. The ice-salt bath cryogenic system was turned on to lower the internal temperature of the system to 0-5℃. Within this temperature range, 110g of 40% sodium nitrite aqueous solution was slowly added dropwise through a constant pressure dropping funnel. During the dropwise addition, the internal temperature was strictly controlled not to exceed 5℃ to prevent the generated nitrite from decomposing and producing reddish-brown nitrogen oxide gas. After the dropwise addition was completed, the mixture was kept at 0-5℃ and stirred for 1 hour to ensure the diazotization reaction was complete. The diazotization reaction was confirmed to have reached its endpoint when the peak area percentage of the starting compound V was <1.0% by high performance liquid chromatography (HPLC), yielding a light yellow diazonium salt solution, which was maintained at a low temperature throughout the process for later use.

[0046] (2) In-situ generation of sulfur dioxide and chlorosulfonation coupling reaction: In another 2000mL reaction vessel (coupling vessel) equipped with a high-power stirrer and internal baffles, 900g of solvent C and 120g of solid sodium bisulfite were added sequentially and quantitatively. Stirring was then activated to ensure uniform mixing of the solid and liquid. Subsequently, the cryogenic cooling system was activated to lower the internal temperature of the vessel to below 0°C. While maintaining the internal temperature below 0°C, 160g of concentrated hydrochloric acid was slowly added dropwise. During this process, sodium bisulfite reacts with the strong acid to release sulfur dioxide in situ. The cryogenic conditions below 0°C significantly increase the solubility of sulfur dioxide in solvent C, preventing the escape of effective gaseous components.

[0047] After the addition was complete, 5g of catalyst B (copper chloride) and 5g of catalyst C (tetrabutylammonium bromide) were added sequentially to the reactor, and the mixture was stirred continuously for 15 minutes to ensure uniform dispersion of the catalytic system. Subsequently, the prepared and refrigerated diazonium salt solution was slowly added dropwise to the coupling reactor using a diaphragm pump. Because the coupling process of the diazonium group converting to the sulfonyl chloride group releases nitrogen gas violently and is accompanied by a large amount of exothermic reaction, the dropping rate needs to be dynamically matched according to the bubble escape rate and the heat exchange efficiency of the refrigerant. The temperature inside the reactor must be strictly controlled between 0-5℃ to prevent the risk of material overflow due to nitrogen boiling. After the addition was complete, the mixture was kept at 0-5℃ and stirred for 1-5 hours until almost no more tiny bubbles emerged from the reaction solution. Using HPLC central control detection, when the residual amount of diazonium salt was <1.0%, it indicated that the chlorosulfonation reaction was complete and the target intermediate VI (2-(2-chloroethoxy)benzenesulfonyl chloride) was generated in the system. According to the one-pot design concept of this invention, the highly active intermediate VI is not subjected to any separation or purification operations, but is directly introduced into the following amination process in situ.

[0048] Furthermore, the specific implementation process of step S400 is as follows: One-pot continuous amination and product extraction without separation of intermediate VI: (1) Amination reaction: Continue operating the cooling system of the coupling vessel to cool the reaction solution containing intermediate VI to below 10°C. Then, slowly add 600g of 25% ammonia solution dropwise into the system using a dropping funnel. Both the neutralization reaction of ammonia with the free acid and the amination substitution reaction with sulfonyl chloride are strongly exothermic processes; therefore, the dropping rate must be controlled to maintain the internal temperature below 15°C. After the addition is complete, remove the ice bath and maintain the temperature under natural conditions with stirring for 1 hour. Perform HPLC analysis on a sample; the amination reaction is considered complete when the peak area percentage of intermediate VI is <1.0%.

[0049] (2) Product purification and extraction (antisolvent crystallization technology): Stop stirring and transfer the reaction solution to a separatory funnel. Let it stand for 30 minutes to allow for complete phase separation. Separate the lower organic phase (the lower layer when using dichloromethane or dichloroethane), and discard the aqueous phase containing a large amount of inorganic ammonium salts. Add 500g of deionized water to the collected organic phase for a second washing to remove residual inorganic salt impurities. After standing, separate again to obtain a high-purity organic phase.

[0050] The organic phase was transferred to a rotary evaporator and distilled under reduced pressure (pressure < -0.09 MPa) at 40°C in a water bath to remove most of the solvent C. Distillation was stopped when the liquid in the flask was concentrated to approximately 1 / 4 to 1 / 5 of the original organic phase volume (i.e., a small volume). After releasing the vacuum, 500 g of n-heptane was added to the concentrate as a countersolvent. Since the target product has extremely low solubility in n-heptane, the addition of n-heptane disrupted the original solubility equilibrium, causing the target product to rapidly precipitate as a supersaturated solution. The mixture was stirred at 200 rpm for 1 hour to allow the crystals to fully age and grow. Finally, the crystals were filtered under reduced pressure through a Buchner funnel, and the resulting wet crystals were dried to constant weight in a vacuum oven at 45°C to obtain the white to slightly yellow final product, 2-(2-chloroethoxy)benzenesulfonamide (compound I).

[0051] To investigate the effects of different solvents C on the core processes described above, parallel experiments were conducted using toluene, dichloromethane, and dichloroethane, respectively. The holding time was dynamically adjusted according to the reaction progress. The results are detailed in the table below: Effects of different solvents C on the synthesis parameters of 2-(2-chloroethoxy)benzenesulfonamide:

[0052] The final product was characterized by proton NMR spectroscopy at 400 MHz using DMSO-d6 solvent. The spectral data are as follows: 7.77-7.75 (d, J = 8.0 Hz, 1H), 7.58 (t, 1H), 7.27-7.25 (d, J = 8.0 Hz, 1H), 7.13-7.09 (t, 1H), 4.44-4.41 (t, 2H), 4.09-4.06 (t, 2H). This confirms that it is indeed 2-(2-chloroethoxy)benzenesulfonamide.

[0053] The effects of different dual-catalyst systems (B and C) on intermediate VI and the final product: The operation process, feed amount, and physical parameter control (diazotization temperature control 0-5℃, in-situ sulfur dioxide release temperature control <0℃, amination temperature control <10℃, and n-heptane antisolvent crystallization) of this embodiment are completely consistent with those of Example 5. The difference is that "dichloromethane," which performed best in Example 5, is used as solvent C (900g), and the specific effects of changing the combination of the two catalysts (catalyst B and catalyst C) on the chlorosulfonation coupling yield are investigated in parallel.

[0054] After the reaction of sodium bisulfite with concentrated hydrochloric acid to produce sulfur dioxide, 5g of catalyst B (copper chloride was used uniformly) and 5g of different types of phase transfer catalyst C (replaced by equal mass with tetrabutylammonium chloride, tetrabutylammonium bromide, and 18-crown-6, respectively) were added to change the lipid-water partition coefficient and ion pair transport capacity of the phase transfer system. Specific catalyst ratios and experimental results are detailed in the table below: Effects of different catalysts C on the synthesis parameters of 2-(2-chloroethoxy)benzenesulfonamide:

[0055] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions will not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing 2-(2-chloroethoxy)benzenesulfonamide, characterized in that, Includes the following steps: S100: o-nitrophenol, 1,2-dichloroethane, acid-binding agent and catalyst A are added to solvent A to react and obtain compound IV; S200: Compound IV is added to solvent B, and hydrogen is introduced under Raney nickel catalysis to carry out a reduction reaction to obtain compound V; S300: Compound V is added to dilute hydrochloric acid, sodium nitrite solution is added to prepare diazonium salt, and then sodium bisulfite solution, catalyst B and catalyst C are added to react in solvent C to obtain intermediate VI; S400: Without separating the intermediate VI from the reaction system, ammonia water is directly added to the reaction system to carry out the amination reaction, thereby obtaining the 2-(2-chloroethoxy)benzenesulfonamide.

2. The method for synthesizing 2-(2-chloroethoxy)benzenesulfonamide according to claim 1, characterized in that, The types of reaction reagents in step S100 respectively meet the following conditions: Solvent A is selected from one of 1,2-dichloroethane, DMF, DMAc, DEF, DMSO, NMP, and 1,4-dioxane; The acid-binding agent is selected from one of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and DBU. The catalyst A is selected from one of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, benzyltriethylammonium chloride, 18-crown-6, and 15-crown-5. The types of reaction reagents are further narrowed down to: Solvent A is preferably one of 1,2-dichloroethane, DMF, and DMAc; acid binder is preferably one of potassium carbonate, sodium hydroxide, and DBU; catalyst A is preferably one of tetrabutylammonium chloride, tetrabutylammonium bromide, and 18-crown-6.

3. The method for synthesizing 2-(2-chloroethoxy)benzenesulfonamide according to claim 2, characterized in that, The quantitative proportions of each reactant in step S100 are limited as follows: The molar ratio of o-nitrophenol, 1,2-dichloroethane and acid-binding agent is 1:1~2:1~5; The molar ratio of o-nitrophenol to catalyst A is 1:0.01~0.1; The mass ratio of o-nitrophenol to solvent A is 1:4~6.

4. The method for synthesizing 2-(2-chloroethoxy)benzenesulfonamide according to claim 3, characterized in that, The etherification reaction in step S100 is carried out under the following dynamic process conditions: the system temperature is maintained at 30-100°C, and the reaction is carried out with stirring for 1-12 hours. The process conditions are optimized as follows: the temperature is controlled at 85-90℃, and the time for heat preservation and stirring is shortened to 1-5 hours.

5. The method for synthesizing 2-(2-chloroethoxy)benzenesulfonamide according to claim 4, characterized in that, The material composition and static mass ratio of the reduction reaction system in step S200 satisfy the following linkage constraints: Solvent B is selected from one of methanol, ethanol, isopropanol, DMF, DMAc, NMP, and DMSO; The mass ratio of compound IV to Raney nickel is 1:0.01~0.5; and the mass ratio of compound IV to solvent B is 1:3~10; The solvents in the static mass ratio system are selected as follows: Solvent B is preferably one of methanol, ethanol, and DMF; In step S200, hydrogenation reduction is carried out through the coordinated control of thermodynamic and kinetic parameters. The dynamic process control parameters are limited to: the reaction control temperature is 20-60℃, the reaction control pressure is 0.25-1.0MPa, and the holding and stirring time is 1-12 hours. The process control parameters are finely reduced to a high-gain process control domain: the control temperature is adjusted to 50-60℃, the control pressure is adjusted to 0.8-1.0MPa, and the heat preservation and stirring time is shortened to 5-10 hours.

6. The method for synthesizing 2-(2-chloroethoxy)benzenesulfonamide according to claim 5, characterized in that, The selection of materials for the reaction medium and catalytic system involved in step S300 respectively meets the following functional classification requirements: Component 1: The solvent C, which serves as the reaction medium, is selected from one of dichloromethane, dichloroethane, chlorobenzene, chloroform, toluene, and xylene; Component 2: Catalyst B, which serves as the first catalyst, is selected from cuprous chloride and cupric chloride; Component 3: The catalyst C, which serves as the second catalyst, is selected from one of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, benzyltriethylammonium chloride, 18-crown-6, and 15-crown-5.

7. The method for synthesizing 2-(2-chloroethoxy)benzenesulfonamide according to claim 6, characterized in that, The reaction medium and the catalytic system are synergistically catalyzed through the following optimal combination: the solvent C is preferably one of dichloromethane, dichloroethane, and toluene; the catalyst B is preferably copper chloride; and the catalyst C is preferably one of tetrabutylammonium chloride, tetrabutylammonium bromide, and 18-crown-6.

8. The method for synthesizing 2-(2-chloroethoxy)benzenesulfonamide according to claim 7, characterized in that, Using the amount of compound V as the absolute reference, the quantitative addition ratio of each material in step S300 satisfies the following matrix constraints: The molar ratio of compound V to sodium nitrite is 1:1 to 1.1; The molar ratio of compound V to catalyst B is 1:0.01~0.1; The molar ratio of compound V to catalyst C is 1:0.01~0.1; The mass ratio of compound V to solvent C is 1:5~10; The preparation of diazonium salt and subsequent reactions in step S300 are carried out under the following synergistic process window: the system temperature is maintained at 0-30°C and the reaction time is 1-10 hours with stirring. The collaborative process window is further narrowed to the following high yield control zone: the control temperature is adjusted to 0-10℃, and the heat preservation and stirring time is shortened to 1-5 hours.

9. The method for synthesizing 2-(2-chloroethoxy)benzenesulfonamide according to claim 8, characterized in that, The specific amination reagent for the amination reaction in step S400 is limited to: ammonia water with a mass fraction of 25%; The process control conditions for the one-pot continuous amination reaction without separating intermediate VI are limited to: cooling the reaction system to below 10°C, adding the ammonia water dropwise, and maintaining the temperature for 1 hour.

10. The method for synthesizing 2-(2-chloroethoxy)benzenesulfonamide according to claim 9, characterized in that, After the reaction in step S400 is completed, a post-processing step of purifying and extracting the target product is further included. The specific process is as follows: After the reaction solution was allowed to stand and separate into layers, the organic phase was washed with water, then distilled under reduced pressure to a small volume, and n-heptane was added for stirring and crystallization. Finally, the solution was filtered and dried to obtain the 2-(2-chloroethoxy)benzenesulfonamide.

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