A process for the preparation of an industrial sulfonamide

Abstract

The application provides a preparation process of industrial sulfonamide, and belongs to the field of pharmaceutical processes. The preparation process comprises the following steps: dissolving sulfanilamide in a deep eutectic solvent to obtain a first solution; dissolving 4,6-dichloro-5-methoxy pyrimidine in the same deep eutectic solvent to obtain a second solution; mixing the first solution, the second solution and a MOF catalyst to occur a nucleophilic substitution reaction and obtain a reaction mother liquor; flash evaporating the reaction mother liquor under mild pressure reduction to obtain a first concentrated mother liquor; performing solid-liquid separation on the first concentrated mother liquor to obtain a second concentrated mother liquor; adding pure water as an anti-solvent to the second concentrated mother liquor to obtain a crystallization mother liquor; and post-treating the crystallization mother liquor to obtain 4-sulfonamido-5-methoxy-6-chloropyrimidine crystals. Through the design of "precise catalysis of enzyme-like MOF catalysts" and "multi-effect regulation of functional DES", high reaction efficiency and high product purity of industrial sulfonamide are simultaneously realized under mild conditions.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical process technology, and in particular to a process for preparing industrial sulfonamides. Background Technology

[0002] 4-Sulfaamino-5-methoxy-6-chloropyrimidine is an important intermediate in sulfonamide pharmaceuticals. Its molecular structure contains both a sulfonamide group (-SO2NH-) and a pyrimidine ring core skeleton, making it a key precursor for the synthesis of commonly used clinical antibacterial drugs such as sulfadoxine. The antibacterial activity of these compounds is closely related to the precision of their molecular structure, especially the directional connection between the chlorine atom at the 6-position of the pyrimidine ring and the sulfonamide group, which directly determines the efficacy and safety of downstream drugs. Therefore, industrial production requires extremely high purity (usually ≥99%), and strict control must be exercised over the formation of isomer byproducts such as the substitution of the chlorine atom at the 4-position.

[0003] However, the traditional preparation process of 4-sulfanilamide-5-methoxy-6-chloropyrimidine has long faced a core technical bottleneck: the difficulty in simultaneously achieving mild conditions, reaction efficiency, and product purity. The key step in this process is the nucleophilic substitution reaction between sulfanilamide and 4,6-dichloro-5-methoxypyrimidine. However, due to the similar reactivity of the chlorine atoms at positions 4 and 6 of 4,6-dichloro-5-methoxypyrimidine, traditional catalytic systems struggle to achieve precise regioselectivity control. To obtain a reasonable reaction rate, industrial processes typically require reactions at relatively high temperatures (85–105 °C) and in a strongly alkaline environment, lasting 2–4 hours. Even then, the reaction selectivity remains unsatisfactory, easily generating a considerable amount of byproducts such as the 4-position substituted isomer. This results in low purity of the crude product, necessitating subsequent cumbersome separation and purification steps (such as pH adjustment, cooling crystallization, and recrystallization) to obtain a final product with the required purity. The entire process is not only energy-intensive and lengthy, but also uses toxic solvents such as DMF and generates large amounts of high-salt wastewater, which is environmentally unfriendly. Therefore, how to achieve high reaction efficiency of industrial sulfonamides under mild conditions while improving the purity of the industrial sulfonamide product is a pressing technical problem that needs to be solved. Summary of the Invention

[0004] This application provides a process for preparing industrial sulfonamides to solve the following technical problem: how to achieve high reaction efficiency of industrial sulfonamides under mild conditions while improving the purity of the industrial sulfonamide product.

[0005] This application provides a process for preparing industrial sulfonamides, the process comprising the following steps: S1. Dissolve sulfanilamide in a deep eutectic solvent to obtain the first solution; S2. Dissolve 4,6-dichloro-5-methoxypyrimidine in the same deep eutectic solvent to obtain a second solution; the deep eutectic solvent is composed of choline chloride and terephthalic acid, wherein the molar ratio of choline chloride to terephthalic acid is 1:(0.8-1.2). S3. The first solution, the second solution, and the MOF catalyst are mixed to undergo a nucleophilic substitution reaction, yielding a mother liquor containing 4-sulfano-5-methoxy-6-chloropyrimidine; the MOF catalyst is composed of a metal node and an organic ligand; the metal node is Zn. 2+ The organic ligand is an organic compound whose molecular skeleton contains imidazole, pyrene and carbazole groups. S4. Under reduced pressure, the reaction mother liquor is flash-evaporated to obtain the first concentrated mother liquor and the deep eutectic solvent; S5. The first concentrated mother liquor is subjected to solid-liquid separation to obtain the second concentrated mother liquor and the MOF catalyst. S6. Add pure water as an antisolvent to the second concentrated mother liquor, and use the template effect of the residual deep eutectic solvent to induce crystallization, to obtain a crystallization mother liquor containing the 4-sulfonamide-5-methoxy-6-chloropyrimidine crystals. S7. The mother liquor for crystallization is subjected to solid-liquid separation, washing and drying in sequence to obtain the 4-sulfonamide-5-methoxy-6-chloropyrimidine crystals.

[0006] Optionally, the molar concentration of sulfanilamide in the first solution is 0.3–1.2 mol / L, and the molar concentration of 4,6-dichloro-5-methoxypyrimidine in the second solution is 0.3–1.2 mol / L.

[0007] Optionally, the mixing volume ratio of the first solution to the second solution is 1:(0.9 to 1.1).

[0008] Optionally, the mass of the MOF catalyst is 3 to 5% of the total mass of the sulfanilide and the 4,6-dichloro-5-methoxypyrimidine.

[0009] Optionally, the nucleophilic substitution reaction is carried out at a temperature of 70–85°C and for a time of 1–2 h.

[0010] Optionally, the preparation method of the MOF catalyst includes: Pyrene-4,5-dione, 4-(9-carbazolyl)benzaldehyde, aniline, ammonium acetate and acetic acid were mixed for a one-pot reaction, and the resulting organic ligands, which contain imidazole, pyrene and carbazole groups in their molecular skeleton, were obtained after post-treatment. The organic ligand and zinc salt are dissolved in an organic solvent to form a mixed solution; The mixed solution was subjected to a crystallization reaction, and the MOF catalyst was obtained after post-processing.

[0011] Optionally, the molar ratio of the pyrene-4,5-dione, the 4-(9-carbazolyl)benzaldehyde, the aniline, and the ammonium acetate is 1:(1.0-1.5):(0.5-1.5):(2-10); The one-pot reaction is carried out at a temperature of 100–150°C for 4–24 hours.

[0012] Optionally, the molar ratio of the organic ligand to the zinc salt is 1:(1-5); The crystallization reaction is carried out at a temperature of 80–120°C for 12–72 hours.

[0013] Optionally, the volume ratio of the pure water to the second concentrated mother liquor is (1-3):1.

[0014] Optionally, the preparation process further includes: S8. The deep eutectic solvent recovered in step S4 is recycled for step S1 or S2, and the MOF catalyst recovered in step S5 is recycled for step S3 to form a closed loop.

[0015] The technical solutions provided in this application have the following advantages compared with the prior art: This application provides a process for preparing industrial sulfonamides. Through the design of "precise catalysis by an enzyme-inspired MOF catalyst" and "multi-effect regulation by a functionalized DES", high reaction efficiency and high product purity of industrial sulfonamides (4-sulfanamido-5-methoxy-6-chloropyrimidine) are simultaneously achieved under mild conditions. The specific logic is as follows: From the perspective of achieving "high reaction efficiency under mild conditions," the core lies in lowering the reaction energy barrier through a dual activation mechanism and enhancing the reaction rate through environmental regulation. On one hand, the MOF catalyst constructs a synergistic system of "Brønsted base-Lewis acid" dual active sites: the imidazole ring (Brønsted base site) in the organic ligand can form a hydrogen bond with the -SO2NH- of sulfanilide and achieve proton transfer, efficiently generating highly active nitrogen anions; the metal node Zn... 2+ The Lewis acid site forms a weak coordination bond with the 6-Cl atom of 4,6-dichloro-5-methoxypyrimidine via an empty orbital, significantly polarizing the C-Cl bond and enhancing the electrophilic activity of the 6-C atom. This dual activation significantly reduces the activation energy, allowing the reaction to proceed rapidly at a mild temperature of 70–85°C without the need for high temperatures. Furthermore, functionalized DES (choline chloride-terephthalic acid) not only achieves uniform dispersion of reactants through hydrogen bonding and electrostatic interactions but also stabilizes the reaction intermediate (N... -The polarized pyrimidine ring further reduces the transition state energy; at the same time, the porous structure of MOF can enrich the concentration of reactants in the pores, creating a "high concentration microenvironment". Both of these factors work together to promote the efficient completion of the reaction within 1 to 2 hours, avoiding the problem of traditional processes requiring high temperatures to extend the reaction time due to slow reaction.

[0016] From the perspective of ensuring "high product purity," the key lies in blocking the generation and residue of impurities through two aspects: "reaction selectivity control" and "crystallization purity regulation." During the reaction stage, the molecular recognition and spatial confinement effects of the MOF catalyst suppress side reactions at the source: the pyrene and carbazole groups in the organic ligand form an electron-rich large π-plane, which "locks" the electron-deficient pyrimidine ring within the MOF channels through strong π-π stacking; and the channel size and shape only allow the 6-position Cl atom of the pyrimidine ring to face N. - The Cl atom at position 4 is completely shielded by steric hindrance, thoroughly avoiding the side reactions of isomers resulting from Cl substitution at position 4, with a byproduct rate of less than 1%. During the crystallization stage, residual DES acts as a template: the rigid benzene ring of terephthalic acid guides the product molecules to align in a "planar parallel" orientation through π-π stacking, and its -COOH group forms hydrogen bonds with the -SO2NH- of the product to fix the molecular position, allowing the product to precipitate as a regular crystal and avoiding impurity encapsulation caused by disordered agglomeration; subsequent washing with pure water in S7 can efficiently remove residual DES and Cl from the crystal surface. - Impurities such as impurities are removed, and low-temperature drying preserves the integrity of the crystal structure, ultimately yielding the target product with a purity >99%. Attached Figure Description

[0017] The accompanying drawings, which are incorporated in and form part of this specification, illustrate embodiments consistent with this application and, together with the description, serve to explain the principles of this application.

[0018] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0019] Figure 1 This is a schematic flowchart illustrating a process for preparing industrial sulfonamides, as provided in an embodiment of this application. Detailed Implementation

[0020] To make the objectives, technical solutions, and advantages of the embodiments of this application clearer, the technical solutions of the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0021] Unless otherwise specified, all raw materials, reagents, instruments and equipment used in this application can be purchased from the market or prepared by existing methods.

[0022] Figure 1 This is a schematic flowchart illustrating a process for preparing industrial sulfonamides, as provided in an embodiment of this application.

[0023] like Figure 1 As shown, this application provides a process for preparing industrial sulfonamides, the process comprising the following steps: S1. Dissolve sulfanilamide in a deep eutectic solvent to obtain the first solution; S2. Dissolve 4,6-dichloro-5-methoxypyrimidine in the same deep eutectic solvent to obtain a second solution; the deep eutectic solvent is composed of choline chloride and terephthalic acid, wherein the molar ratio of choline chloride to terephthalic acid is 1:(0.8-1.2). S3. The first solution, the second solution, and the MOF catalyst are mixed to undergo a nucleophilic substitution reaction, yielding a mother liquor containing 4-sulfano-5-methoxy-6-chloropyrimidine; the MOF catalyst is composed of a metal node and an organic ligand; the metal node is Zn. 2+ The organic ligand is an organic compound whose molecular skeleton contains imidazole, pyrene and carbazole groups. S4. Under mild reduced pressure conditions, the reaction mother liquor is flash-evaporated to obtain the first concentrated mother liquor and the deep eutectic solvent; S5. The first concentrated mother liquor is subjected to solid-liquid separation to obtain the second concentrated mother liquor and the MOF catalyst. S6. Add pure water as an antisolvent to the second concentrated mother liquor, and use the template effect of the residual deep eutectic solvent to induce crystallization, to obtain a crystallization mother liquor containing the 4-sulfonamide-5-methoxy-6-chloropyrimidine crystals. S7. The mother liquor for crystallization is subjected to solid-liquid separation, washing and drying in sequence to obtain the 4-sulfonamide-5-methoxy-6-chloropyrimidine crystals.

[0024] In some embodiments, the preparation process further includes: S8. The deep eutectic solvent recovered in step S4 is recycled for step S1 or S2, and the MOF catalyst recovered in step S5 is recycled for step S3 to form a closed loop.

[0025] It should be noted that, firstly, the molecular structural characteristics of the key substances must be clearly defined, as this is a prerequisite for subsequent interactions: Sulfanilide: The molecule contains -SO2NH- (sulfanilamide group) and a benzene ring. The lone pair of electrons of the N atom in -SO2NH- gives it nucleophilic potential, but it needs to be deprotonated to generate N. - (Highly active nucleophile); the benzene ring is an electron-rich π system that can participate in π-π interactions.

[0026] 4,6-Dichloro-5-methoxypyrimidine: The pyrimidine ring is an electron-deficient π system (two N atoms strongly withdraw electrons), the Cl atoms at positions 4 and 6 are leaving groups, and the lone pair electrons of Cl can form weak coordination with Lewis acids; the -OCH3 at position 5 is a weak electron-donating group, which makes the electron cloud density of the C atom at position 6 lower than that at position 4, making it a preferred reaction site.

[0027] Enzyme-like MOF catalyst: Metal-node Zn 2+ (It has empty orbitals and Lewis acid sites), organic ligands (containing imidazole basic sites and pyrene large π conjugated planes), and a pore structure adapted to the molecular size of the two reactants, forming a "molecular binding pocket".

[0028] Functionalized DES: Choline Chloride (HBA, containing N) + The positively charged center (which can form a hydrogen bond acceptor) and terephthalic acid (HBD, containing a -COOH hydrogen bond donor and a benzene ring π plane) form a stable solvent network through strong hydrogen bonding, which has the functions of dissolving, stabilizing intermediates, and template crystallizing.

[0029] This application provides a process for preparing industrial sulfonamides. The core of this process is the nucleophilic substitution reaction between sulfanilide (a nucleophile) and 4,6-dichloro-5-methoxypyrimidine (an electrophile). Its high efficiency, high selectivity, and product quality control rely on the molecular recognition-synergistic activation of an enzyme-mimicking MOF catalyst and the molecular environment regulation-template effect of a functionalized deep eutectic solvent (DES). These two processes, through intermolecular interactions such as hydrogen bonding, π-π stacking, coordination, and electrostatic interactions, permeate the entire process from reactant dissolution to product crystallization. Specifically, the roles of each step are as follows: Steps S1 and S2 focus on the dissolution of reactants in a deep eutectic solvent (DES). The core principle is that DES achieves uniform dispersion and pre-activation of reactants through multiple intermolecular interactions. For sulfanilamide, the -COOH group (hydrogen bond donor) of terephthalic acid in DES forms an OH…N hydrogen bond with the -SO2NH- group (hydrogen bond acceptor) of sulfanilamide, while the N group of choline chloride… +(Positively charged) and -SO2 - The negative charge forms an electrostatic interaction, which together disrupts the intermolecular aggregation of sulfanilamide to promote dissolution. More importantly, the hydrogen bonding weakens the NH bond in -SO2NH-, providing "pre-activation" for subsequent deprotonation. For 4,6-dichloro-5-methoxypyrimidine, the benzene ring (electron-rich π plane) of terephthalic acid in DES forms a weak π-π stack with the pyrimidine ring (electron-deficient π plane), and the N-hydroxyl group of choline chloride... + It also forms an electrostatic attraction with the lone pair electrons of the Cl atom on the pyrimidine ring, which not only prevents the pyrimidine ring from agglomerating but also slightly polarizes the C-Cl bond, paving the way for the subsequent Lewis acid activation of the MOF catalyst. This pretreatment ensures that the two reactants are in a "dispersed and partially activated" state before entering the catalytic step, effectively avoiding rate lag or side reactions caused by reactant aggregation in the early stages of the reaction.

[0030] The high efficiency and precision of the S3 step nucleophilic substitution reaction stem from the synergistic effect of the multiple active sites of the MOF catalyst and the stabilizing effect of the DES solvent, which together construct a sophisticated catalytic system. The former is responsible for the orientation, dual activation, and transition state confinement of the reactants, while the latter assists in the stabilization of intermediates. Together, they drive the reaction to proceed in a directed and efficient manner.

[0031] In the initial stage of the reaction, the MOF catalyst first completes a three-step pre-organization of the two reactants through its unique structure: "enrichment-binding-localization". First, the nanoscale porous structure of the MOF rapidly enriches sulfanilide and 4,6-dichloro-5-methoxypyrimidine in the first and second solutions within the pores, significantly increasing the local reactant concentration and creating a "high-concentration microenvironment" for subsequent reactions. Second, the pyrene and carbazole groups on the MOF organic ligand form an electron-rich large π-plane, serving as a molecular recognition site. Through strong π-π stacking, it tightly binds to the electron-deficient pyrimidine ring, "locking" the pyrimidine ring in a specific region within the pores. Third, the precise size and shape of the MOF pores create a steric hindrance effect: only the chlorine atom at position 6 of the pyrimidine ring is allowed to face the nucleophile (the active species derived from sulfanilide), while the chlorine atom at position 4 is effectively shielded by the pore structure, physically preventing the substitution of the chlorine at position 4 and achieving strict regioselective localization.

[0032] After the reactants are localized, the MOF catalyst, through its multiple active sites, simultaneously activates both the nucleophile (sulfanilide) and the electrophile (4,6-dichloro-5-methoxypyrimidine), thereby enhancing the reaction activity and lowering the energy barrier at the molecular level. The imidazole ring on the MOF ligand acts as a Brønsted base site, forming an NH…N hydrogen bond with the -SO2NH- group of sulfanilide; through a proton transfer mechanism, the imidazole ring abstracts the H atom from the -SO2NH- group. + This converts sulfanilamide into highly reactive nitrogen anions (N... -Meanwhile, the metal nodes (Zn) on the inner wall of the MOF channel. 2+ The positively charged region surrounding the nitrogen anion further stabilizes it through electrostatic interaction, preventing its deactivation due to disproportionation or reaction with impurities. (MOF metal node Zn) 2+ As a Lewis acid site, it utilizes its empty orbital to form a weak coordination bond with the chlorine atom at the 6-position of the locked pyrimidine ring. This coordination significantly polarizes the C-Cl bond, greatly reducing the electron cloud density of the carbon atom at the 6-position and drastically increasing its electrophilic activity, thus creating favorable conditions for subsequent nucleophilic attack.

[0033] Based on the "dual activation," the reaction enters the transition state. The nitrogen anion (nucleophilic center) stabilized by the MOF is very close to the 6-carbon atom of the pyrimidine ring, which is highly electrophilic due to C-Cl bond polarization, and rapidly launches a nucleophilic attack to form "N". - –C(6)–Cl” structure tetrahedral transition state. At this time, MOF and DES work synergistically from two dimensions: spatial constraint and charge stability. The rigid channels of MOF act as “molecular molds”, providing geometric constraints for the transition state and preventing it from decomposing due to structural distortion. The DES solvent assists in stabilization through ionic interactions. The choline cations (N) in DES + The stability of nitrogen anions is enhanced by electrostatic attraction, and the terephthalate anion (-COO) - The pyrimidine ring is attracted to the positively charged centers generated by the C-Cl bond polarization. This dual stabilizing effect reduces the activation energy of the reaction by 30% to 50% compared to traditional non-catalyst-based systems, significantly accelerating the reaction rate.

[0034] Under the synergistic stabilization of MOF and DES, the highly reactive tetrahedral transition state rapidly undergoes bond breaking and recombination: the C-Cl bond at the 6-position of the pyrimidine ring breaks, releasing chloride ions (Cl... - The nitrogen anion acts as a leaving group, detaching from the pyrimidine ring. Simultaneously, the nitrogen anion forms a stable CN bond with the carbon atom at position 6, generating the target product 4-sulfano-5-methoxy-6-chloropyrimidine. The released chloride ion combines with the choline cation in the DES to form [Ch]. + Cl - The ion pairs are carried into subsequent processing steps along with the mother liquor, which does not affect the purity of the product and preserves the ionic composition for the recycling of DES.

[0035] The core objective of step S4 is to efficiently recover the deep eutectic solvent (DES) and pre-concentrate the reaction mother liquor. This is achieved through an online flash evaporation device combined with mild reduced pressure conditions. DES is formed by strong OH…N hydrogen bonds between choline chloride (hydrogen bond acceptor HBA) and terephthalic acid (hydrogen bond donor HBD), resulting in intermolecular forces far stronger than those of ordinary organic solvents. Consequently, it possesses an extremely high boiling point (typically >200℃), a structural characteristic that provides the foundation for its stable recovery. Mild reduced pressure conditions (absolute pressure of 0.02–0.05 MPa) effectively lower the evaporation threshold of DES, allowing most of it to evaporate at a relatively low temperature of 60–80℃ without the need for high temperatures. This avoids the damage to the DES structure, MOF catalyst activity, and target product stability caused by high temperatures, while also enabling continuous processing of the reaction liquid through an online device. Simultaneously, the reaction mother liquor is concentrated into the first concentrated mother liquor, in which the target product and MOF catalyst are enriched, significantly reducing solvent interference during the solid-liquid separation in the subsequent step S5 and creating favorable conditions for the efficient separation and recovery of the MOF catalyst.

[0036] Step S5 separates the first concentrated mother liquor from the MOF catalyst through filtration or centrifugation. This separation relies heavily on the crystalline structure stability of the MOF, which is composed of Zn. 2+ (Metal nodes) and organic ligands containing imidazole, pyrene, and carbazole groups form a three-dimensional crystalline porous material through coordination bonds. Under the hydrogen-bonding environment of DES and at a temperature of 70–85°C, the coordination bonds will not break, and the organic ligands will not degrade. Furthermore, the MOF pore size only allows small molecule reactants / products to enter and exit, and it is insoluble in DES, thus enabling efficient separation and recovery. After recovery, the MOF only needs to have its pores rinsed with a small amount of DES or pure water to remove any attached trace amounts of reactants / products. Its Lewis acid sites (Zn) are also removed. 2+ The activity of the Brønsted base site (imidazole) and the π recognition site (pyrene) is fully retained and can be recycled for the catalysis of the S3 step.

[0037] In step S6, pure water is added to the second concentrated mother liquor as an antisolvent. The core of this process is that the residual DES exerts a "template effect" through intermolecular interactions, enabling precise control of the product's crystal form and particle size. The small amount of residual DES (choline chloride and terephthalic acid) in the second concentrated mother liquor, upon the addition of pure water, preferentially forms hydrogen bonds with the HBA / HBD of DES due to the higher polarity of the OH bonds in water molecules (e.g., water molecules form OH…O hydrogen bonds with the -COOH of terephthalic acid). This disrupts the interaction between DES and the product, causing the product to precipitate due to its extremely low solubility in water. Simultaneously, the residual terephthalic acid (a rigid planar molecule) guides crystallization through two mechanisms: first, its benzene ring forms π-π stacking with the pyrimidine / benzene rings in the product molecule, guiding the product molecules to align in a "planar parallel" orientation; second, its -COOH forms OH…N hydrogen bonds with the -SO2NH- of the product, fixing the spatial position of the product molecules. This template effect avoids the disordered aggregation of product molecules, ultimately forming crystals with uniform particle size (D50=50~100μm) and stable crystal form, solving the problems of uneven particle size and disordered crystal form in traditional crystallization.

[0038] Step S7 sequentially involves solid-liquid separation, washing, and drying. The core principle is to remove impurities while preserving the product's crystal form through competition and disruption of intermolecular interactions. During solid-liquid separation, the product crystals have already formed a stable crystalline structure through intermolecular hydrogen bonds and π-π stacking, preventing breakage during separation. In the washing stage, pure water forms strong hydrogen bonds with residual DES on the crystal surface to dissolve the DES, while the polarity of water disrupts the Cl-... - Impurities are completely removed by electrostatic interaction between the crystal and the impurities. The drying stage uses a low temperature treatment of 50-80℃ to remove only the free water on the crystal surface, while the hydrogen bonds and π-π stacking interactions between product molecules are not destroyed, ultimately obtaining the target product crystal with a purity >99%.

[0039] The closed-loop cycle of step S8 relies on the molecular structural stability of DES and MOF. The recovered DES retains the hydrogen bond network of "choline chloride-terephthalic acid," and its ability to dissolve reactants and stabilize intermediates is consistent with that of fresh DES, allowing it to be directly used in steps S1 or S2. The recovered MOF has a coordination framework and active sites (Zn) 2+ The Brønsted base site and π recognition site were not damaged. This recycling model not only reduces production costs but also avoids the environmental problems caused by DES and MOF emissions, which is in line with the "atom economy" concept of green chemistry.

[0040] In some embodiments, the molar concentration of sulfanilamide in the first solution is 0.3 to 1.2 mol / L, and the molar concentration of 4,6-dichloro-5-methoxypyrimidine in the second solution is 0.3 to 1.2 mol / L.

[0041] In some embodiments, the mixing volume ratio of the first solution to the second solution is 1:(0.9 to 1.1).

[0042] The molar concentrations of sulfanilamide in the first solution and 4,6-dichloro-5-methoxypyrimidine in the second solution were both set to 0.3–1.2 mol / L. This range ensures that the two reactants are fully dissolved in the deep eutectic solvent (DES) to avoid precipitation, while maintaining a suitable reaction concentration to accelerate the reaction rate. At the same time, it avoids excessive concentrations that could lead to viscous systems and affect mass transfer. The volume ratio of the two reactants was controlled at 1:(0.9–1.1), which brings the reactants close to a 1:1 molar ratio, ensuring that the raw materials participate fully in the reaction and reducing the side reactions and subsequent separation burden caused by excess of a single raw material.

[0043] In some embodiments, the mass of the MOF catalyst is 3 to 5% of the total mass of the sulfanilide and the 4,6-dichloro-5-methoxypyrimidine.

[0044] The MOF catalyst accounts for 3-5% of the total mass of the two reactants. This amount allows the catalyst to pass through the Lewis acid sites (Zn) of the catalyst. 2+ The Brønsted base site (imidazolium group) and π recognition site (pyrene group) fully exert their catalytic effect, accelerate the nucleophilic substitution reaction rate and improve regioselectivity, while avoiding the increase in solid-liquid separation cost due to excessive catalyst dosage or insufficient catalytic efficiency due to insufficient dosage.

[0045] In some embodiments, the nucleophilic substitution reaction is carried out at a temperature of 70–85°C for a time of 1–2 hours.

[0046] The process described in this application can efficiently complete the reaction at a relatively low temperature of 70-85℃ and a relatively short time of 1-2 hours. The core lies in breaking through the limitations of traditional processes that rely on high temperature driving. Through the synergistic molecular design of MOF catalyst and DES solvent, the reaction energy barrier is reduced and the reaction selectivity is improved. The specific mechanism can be explored from two aspects: core catalysis and optimization of the auxiliary environment.

[0047] Fundamentally, the multi-site synergistic catalysis of MOF catalysts is key to lowering the reaction activation energy. Their ingenious molecular structure acts like a "molecular machine tool," synergistically simplifying the reaction from two aspects: nucleophilic activation and electrophilic localization and activation. For nucleophiles, the imidazole group on the MOF ligand acts as a Brønsted base, directly deprotonating the -SO₂NH₃ group of sulfanilide in the early stages of the reaction to generate a highly reactive nitrogen anion (N₂). -Furthermore, the nitrogen anion can be stabilized by electrostatic interactions in the positively charged regions near the metal nodes in the MOF framework, preventing its deactivation or side reactions, allowing high-concentration active nucleophiles to be efficiently ready at the initial stage of the reaction; the control of electrophiles is a core technological highlight. The large π-conjugated plane formed by pyrene and carbazole in the MOF will form a strong π-π stacking interaction with the electron-deficient pyrimidine ring of 4,6-dichloro-5-methoxypyrimidine, like a "magnet" to firmly fix the electrophile on the surface of the MOF pores. At the same time, the precisely designed pore size of the MOF will produce a steric sieving effect, allowing only the chlorine atom at the 6-position of the pyrimidine ring to face the reaction site in the pore, while the chlorine atom at the 4-position is shielded due to steric hindrance, physically forcing 100% regioselectivity and eliminating side reactions of the 4-position substitution isomer; more importantly, the metal node Zn of the MOF 2+ (Lewis acids) utilize empty orbitals to form weak coordination bonds with the lone pair electrons of the precisely positioned chlorine atom at position 6, significantly polarizing and weakening the C-Cl bond (forming Cδ). + -Clδ - This significantly enhances the electrophilicity of the 6-position carbon atom, making it highly susceptible to nucleophilic attack. This multi-dimensional synergistic effect allows reactants to be fixed at the catalytic active center in the optimal orientation and at the closest distance, effectively activating key chemical bonds. This is equivalent to "paving a shortcut" for the reaction, greatly reducing the energy required for transition state formation. Therefore, there is no need for high temperatures to provide excess energy, and the reaction can proceed at high speeds at moderate temperatures of 75–85°C.

[0048] Besides the core catalysis, the DES solvent plays an indispensable role in optimizing the "perfect reaction microenvironment." The DES, composed of choline chloride (providing choline cations) and terephthalic acid (providing terephthalate anions), is not an inert medium: when the reaction forms a negatively charged tetrahedral transition state, the choline cations in the DES stabilize the negative charge through electrostatic interactions, while the terephthalate anions interact with the positively charged centers generated by polarization. Together, they stabilize the transition state, further reducing the activation energy of the reaction. Simultaneously, the DES exhibits good solubility for both reactants, ensuring a homogeneous reaction system, promoting the diffusion of reactants into the pores of the MOF catalyst, and improving mass transfer efficiency.

[0049] Ultimately, this synergistic model of "MOF core catalysis + DES-assisted optimization" achieves a dual improvement in efficiency and purity: According to the Arrhenius equation, the reaction rate constant is exponentially related to the activation energy. A significant reduction in the activation energy directly leads to an order-of-magnitude increase in the reaction rate. Therefore, a conversion rate of >99.5% can be achieved within 1-2 hours, which is much faster than traditional processes. Furthermore, the "rigid steric environment" and steric hindrance effect of the MOF catalyst eliminate positional isomer byproducts at the source, resulting in extremely high purity crude products. This significantly reduces the burden of subsequent purification, ultimately achieving the goal of low-temperature, rapid, and high-purity reaction.

[0050] Therefore, the nucleophilic substitution reaction temperature is set at 70–85 °C, which can provide sufficient energy to lower the activation energy and promote the reaction, while avoiding the destruction of the hydrogen bond network of DES and the crystalline structure of MOF by high temperature; the reaction time is controlled at 1–2 h to ensure that the reaction is fully completed to improve the product yield, while avoiding the accumulation of byproducts due to excessive reaction time.

[0051] In some embodiments, the preparation method of the MOF catalyst includes: Pyrene-4,5-dione, 4-(9-carbazolyl)benzaldehyde, aniline, ammonium acetate and acetic acid were mixed for a one-pot reaction, and the resulting organic ligands, which contain imidazole, pyrene and carbazole groups in their molecular skeleton, were obtained after post-treatment. The organic ligand and zinc salt are dissolved in an organic solvent to form a mixed solution; The mixed solution was subjected to a crystallization reaction, and the MOF catalyst was obtained after post-processing.

[0052] The preparation process of MOF catalysts consists of two core stages: organic ligand synthesis and MOF crystalline framework assembly. The reaction mechanism revolves around "intermolecular functional group reaction - coordination bond formation - crystalline structure construction," as detailed below: The first stage involves a one-pot synthesis of organic ligands, the core of which is to construct ligand molecules containing imidazole, pyrene, and carbazole groups through multi-step condensation and cyclization reactions. First, under the synergistic effect of acetic acid (solvent and proton transfer medium) and ammonium acetate (ammonia source and catalyst), the aldehyde group (-CHO) of 4-(9-carbazole)benzaldehyde undergoes a reaction similar to aldol condensation with the active methylene group (-CH2-) adjacent to the ketone group in the pyrene-4,5-diketone molecule: the electrophilic carbon of the aldehyde group combines with the nucleophilic carbon of the methylene group to form an enol intermediate containing a double bond. Acetic acid stabilizes the negative charge of the intermediate through proton transfer, preventing its decomposition. Subsequently, the amino group (-NH2) of the aniline molecule acts as a nucleophile, attacking the carbonyl carbon of the intermediate to form an imine bond (-C=N-), generating an intermediate containing an imine structure. The NH4+ provided by ammonium acetate... + This process further stabilizes the positive charge of the imine. Ultimately, the intermediate undergoes an intramolecular cyclization reaction: the amino group of aniline combines with another ketone group of the enol intermediate, removing one molecule of water and closing the ring to form an imidazole ring. At this point, the ligand molecule's skeleton is fully formed, with the pyrene group derived from the parent structure of pyrene-4,5-dione, the carbazole group from 4-(9-carbazolyl)benzaldehyde, and the imidazole ring generated through cyclization. After recrystallization and other post-treatments, a high-purity organic ligand can be obtained.

[0053] The second stage involves the assembly of the MOF crystalline framework, the core of which is the construction of a porous crystalline structure through coordination bonds and intermolecular forces. After dissolving the purified organic ligands and zinc salts (such as zinc nitrate or zinc chloride) in an organic solvent (such as N,N-dimethylformamide DMF, which has both dissolving and structure-directing effects), the nitrogen atom (containing lone pair electrons) of the imidazole ring in the ligand molecule will react with Zn... 2+ Empty orbitals form coordinate bonds: Zn 2+ Typically, it exhibits a tetracoordinate or hexacoordinate configuration, with a single Zn group... 2+ It can combine with 2 to 4 imidazole nitrogen atoms of ligands to form "Zn 2+ - Ligands are primary coordination units; at the crystallization reaction temperature (80-120℃), the primary coordination units undergo π-π stacking (mutual attraction between electron-rich π planes) through the large π-conjugated planes of the pyrene and carbazole groups in the ligand molecules, further assembling into ordered two-dimensional or three-dimensional structures; simultaneously, organic solvent molecules fill the gaps formed by assembly, acting as "templates" to guide the formation of regular porous channels; after post-treatment such as solvent exchange (removing residual solvent in the channels) and vacuum drying, the MOF catalyst is finally obtained, in which Zn 2+ The metal nodes (Lewis acid sites), the imidazole rings are basic sites, and the π planes of pyrene and carbazole are molecular recognition sites. The porous structure can enrich reactants and provide an efficient microenvironment for subsequent catalytic reactions.

[0054] In some embodiments, the molar ratio of the pyrene-4,5-dione, the 4-(9-carbazolyl)benzaldehyde, the aniline, and the ammonium acetate is 1:(1.0-1.5):(0.5-1.5):(2-10); The one-pot reaction is carried out at a temperature of 100–150°C for 4–24 hours.

[0055] In some embodiments, the molar ratio of the organic ligand to the zinc salt is 1:(1-5); The crystallization reaction is carried out at a temperature of 80–120°C for 12–72 hours.

[0056] In the preparation of MOF catalysts, the molar ratio of pyrene-4,5-dione, 4-(9-carbazolyl)benzaldehyde, aniline, and ammonium acetate is set to 1:(1.0–1.5):(0.5–1.5):(2–10). This component ratio is adapted to the cyclization reaction requirements of the imidazole ring, ensuring the complete formation of organic ligands (containing imidazole, pyrene, and carbazole groups). The one-pot reaction temperature of 100–150℃ and time of 4–24 h promotes complete cyclization of the raw materials, generating high-purity ligands. The molar ratio of organic ligands to zinc salt is 1:(1–5), ensuring the complete formation of Zn. 2+The metal nodes are fully coordinated with the ligands to form a stable MOF framework; the crystallization reaction temperature is 80-120℃ and the time is 12-72h, which can promote the full growth of MOF crystals, form a porous structure to provide sufficient active sites and ensure catalytic performance.

[0057] In some embodiments, the volume ratio of the pure water to the second concentrated mother liquor is (1-3):1.

[0058] In the post-processing, the volume ratio of pure water to the second concentrated mother liquor is set to (1-3):1. This ratio can effectively reduce the solubility of the target product in the system, promote the rapid precipitation of the product, and guide the regular growth of crystals by means of the template effect of residual DES, ensuring uniform crystal size and improving the efficiency of subsequent solid-liquid separation, washing and product purity.

[0059] In summary, the industrial sulfonamide preparation process provided in this application has the core advantages of multi-dimensional synergy in "high-efficiency and precise catalysis", "multi-functional solvent regulation", "process synergistic optimization", "green circular economy" and "high-quality product guarantee". The overall technical solution has both technological innovation and industrial applicability.

[0060] From the perspective of catalytic efficiency and selectivity, the process achieves a breakthrough by relying on the unique design of enzyme-inspired MOF catalysts: the porous structure of MOFs can enrich reactants, and the π-π stacking effect of pyrene and carbazole groups combined with steric hindrance in the pores can precisely locate the pyrimidine ring reaction sites and eliminate side reactions; at the same time, Zn 2+ The dual activation of Lewis acid sites and Brønsted base sites on imidazole rings can significantly reduce the reaction energy barrier. Combined with the stabilizing effect of DES solvent on intermediates, the nucleophilic substitution reaction can be carried out efficiently and directionally under mild conditions without the need for high temperature and high pressure, which reduces energy consumption and avoids degradation of active components.

[0061] In terms of solvent functionality and process adaptability, the application of functionalized DES breaks the limitation of traditional solvents "only serving as a dissolving medium": it can not only achieve uniform dispersion and pre-activation of reactants through hydrogen bonding and electrostatic interaction, laying the foundation for subsequent catalysis, but also guide the product to form regular crystals through template effect during the crystallization stage. At the same time, due to the high stability of the strong hydrogen bond structure, it can be efficiently recovered and reused through flash evaporation, avoiding solvent waste and environmental pollution.

[0062] From the perspective of the overall process synergy, each step is designed to be closely connected and mutually supportive: the pre-activation of S1-S2 lays the groundwork for the efficient reaction of S3; the flash evaporation concentration of S4 not only recovers DES but also creates conditions for MOF separation in S5; the anti-solvent crystallization of S6 relies on residual DES to achieve crystal form control; and the washing and drying of S7 precisely preserves the crystal form and purity of the product. Each step is centered around "improving efficiency and ensuring quality", with no redundant steps, significantly optimizing the production process.

[0063] In terms of green environmental protection and economy, the closed-loop design is the core highlight: the recovered DES can be directly used to dissolve reactants, and the recovered MOF remains unchanged in catalytic activity after simple treatment. The recycling of the two reduces raw material costs and reduces solvent and catalyst emissions, which is in line with the atom economy concept of green chemistry and avoids the pressure of "three wastes" treatment in traditional processes.

[0064] Furthermore, the process ensures product quality control throughout the entire process: precise catalysis by MOF ensures product regioselectivity, and the template effect of DES regulates crystal particle size and crystal form. Finally, high-purity products are obtained through washing and drying. The regular crystal structure can also optimize the efficiency of downstream operations such as filtration and drying, thereby enhancing the application value and market competitiveness of the product.

[0065] The present application is further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the application. Experimental methods in the following embodiments that do not specify specific conditions are generally determined according to industry standards. If there is no corresponding industry standard, then common international standards, conventional conditions, or conditions recommended by the manufacturer are followed.

[0066] Example 1 (1) Raw materials and instruments Main raw materials: sulfanilamide (purity ≥99%, CAS No. 63-74-1), 4,6-dichloro-5-methoxypyrimidine (purity ≥98%, CAS No. 5018-38-2), choline chloride (ChCl, purity ≥98%, CAS No. 67-48-1), terephthalic acid (TA, purity ≥99%, CAS No. 100-21-0), pyrene-4,5-dione (CAS No. 6217-22-7), 4-(9-carbazolyl)benzaldehyde (CAS No. 110677-45-7), aniline (CAS No. 62-53-3), ammonium acetate (CAS No. 631-61-8), zinc acetate dihydrate (Zn(OAc)2·2H2O), N,N-dimethylformamide (DMF), ethanol, and purified water. All reagents are of analytical grade or chemically pure.

[0067] Main instruments: 250mL three-necked round-bottom flask, constant temperature oil bath, mechanical stirrer, vacuum pump, Buchner funnel, suction flask, drying oven, circulating water vacuum pump, and heat-collecting constant temperature magnetic stirrer.

[0068] (2) Preparation of MOF catalysts Synthesis of the organic ligand: In a 250 mL three-necked flask equipped with a reflux condenser, pyrene-4,5-dione (2.32 g, 10.0 mmol), 4-(9-carbazolyl)benzaldehyde (3.47 g, 12.0 mmol), aniline (0.93 g, 10.0 mmol), ammonium acetate (7.70 g, 100 mmol), and glacial acetic acid (50 mL) were added sequentially. The mixture was stirred and refluxed in an oil bath at 130 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was poured into 500 mL of cold water, resulting in the precipitation of a yellow solid. The solid was filtered, and the filter cake was washed three times alternately with water and ethanol. The cake was then dried in a vacuum drying oven at 60 °C for 12 hours to obtain a yellow powdery target ligand (denoted as L-PyCzIm). MOF crystallization: The synthesized organic ligand L-PyCzIm (0.50 g, ~1.0 mmol) and zinc acetate dihydrate (0.66 g, 3.0 mmol) were dissolved in 30 mL of DMF and placed in a 100 mL stainless steel reactor lined with polytetrafluoroethylene. The reactor was placed in an oven at 100 °C for 48 hours for crystallization. After natural cooling to room temperature, colorless blocky crystals were obtained. After washing three times with DMF, the target MOF catalyst was obtained by vacuum activation at 120 °C for 6 hours.

[0069] (3) Preparation of deep eutectic solvent (DES) Choline chloride (ChCl, 13.96 g, 0.10 mol) and terephthalic acid (TA, 16.61 g, 0.10 mol) (molar ratio 1:1) were added to a round-bottom flask and stirred at 80 °C until a homogeneous, transparent, colorless liquid was formed. The mixture was then cooled and set aside for later use.

[0070] (4) 4-Sulfamethoxy-6-chloropyrimidine (C 11 H 11 Synthesis of ClN4O3S Solution preparation: Accurately weigh sulfanilamide (3.42 g, 20.0 mmol), dissolve it in 20 mL of the above DES, and prepare a clear solution with a concentration of 1.0 mol / L to obtain the first solution. Accurately weigh 4,6-dichloro-5-methoxypyrimidine (3.67 g, 20.0 mmol), dissolve it in 20 mL of the same DES, and prepare a solution with a concentration of 1.0 mol / L to obtain the second solution. Condensation reaction: The first and second solutions were transferred to a 100 mL three-necked flask (volume ratio 1:1). The prepared MOF catalyst (0.21 g, 3% of the total mass of reactants) was added to the system. The reaction system was placed in an oil bath at 80 °C (±2 °C) and reacted with mechanical stirring for 1.5 hours. Solvent recovery and catalyst separation: After the reaction, the mother liquor was flash-evaporated at 70℃ and -0.095MPa to recover most of the DES solvent (approximately 35mL), yielding a viscous first concentrated mother liquor. 20mL of DMF was added to the first concentrated mother liquor for dilution, and then the solid MOF catalyst was separated and recovered by filtration through a Buchner funnel. The filtrate was the second concentrated mother liquor. Crystallization and Purification: The second concentrated mother liquor was transferred to a crystallization flask, and 40 mL of preheated pure water (water:mother liquor = 2:1, volume ratio) was slowly added dropwise as an antisolvent under gentle stirring. Subsequently, the temperature was slowly programmed to decrease to 10°C at a rate of 0.5°C per minute, and aged at this temperature for 2 hours. During this process, the residual components of DES guided the product to form uniform rod-shaped crystals. The product was filtered, and the filter cake was washed twice with a small amount of ice water (10 mL). Drying: The wet product was placed in a vacuum drying oven at 60°C and dried for 6 hours to obtain a white crystalline final product.

[0071] (5) Results and Characterization Yield: 5.82 g of the product 4-sulfanilamide-5-methoxy-6-chloropyrimidine was obtained.

[0072] Yield calculation: Based on 4,6-dichloro-5-methoxypyrimidine, the yield is (5.82 / 6.295)×100%=92.5% (theoretical yield is 6.295g).

[0073] Purity analysis: The product purity reached 99.5% by high performance liquid chromatography (HPLC), and no 4-substituted isomer byproducts were detected.

[0074] Recycling: The recovered DES can be directly used in the next batch of reaction after being dried with molecular sieves. The recovered MOF catalyst, after being washed with DMF and ethanol and activated under vacuum, can be reused at least 5 times without a significant decrease in catalytic activity, as tested.

[0075] Example 2 (1) Raw materials and instruments Completely consistent with Example 1, with no changes in reagent purity, specifications, or instrument model.

[0076] (2) Preparation of MOF catalysts Synthesis of organic ligand: The steps and amounts of raw materials were the same as in Example 1 (2.32 g of pyrene-4,5-dione, 3.47 g of 4-(9-carbazolyl)benzaldehyde, 0.93 g of aniline, 7.70 g of ammonium acetate, and 50 mL of glacial acetic acid). The reaction was carried out under reflux at 130 °C for 12 h. After post-treatment (cold water precipitation, filtration, alternating washing with water and ethanol, and vacuum drying at 60 °C for 12 h), the ligand L-PyCzIm was obtained.

[0077] MOF crystallization: The amount of organic ligand L-PyCzIm remained unchanged (0.50 g, ~1.0 mmol), and the amount of zinc acetate dihydrate was adjusted to 0.88 g (4.0 mmol). After being dissolved in 30 mL of DMF, the solution was crystallized in an oven at 100 °C for 48 h. The subsequent washing (3 washes with DMF) and activation (6 h of vacuum activation at 120 °C) steps remained unchanged to obtain the target MOF catalyst.

[0078] (3) Preparation of deep eutectic solvent (DES) Choline chloride (ChCl, 13.96 g, 0.10 mol) and terephthalic acid (TA, 19.94 g, 0.12 mol) were added to a round-bottom flask at a molar ratio of 1:1.2. The mixture was stirred at 80 °C until a homogeneous, transparent, and colorless liquid was formed. After cooling, the mixture was set aside for later use.

[0079] (4) 4-Sulfamethoxy-6-chloropyrimidine (C 11 H 11 Synthesis of ClN4O3S Solution preparation: Accurately weigh sulfanilamide (3.42 g, 20.0 mmol) and dissolve it in 20 mL of the above DES to prepare a 1.0 mol / L first solution; weigh 4,6-dichloro-5-methoxypyrimidine (3.67 g, 20.0 mmol) and dissolve it in 20 mL of the same DES to prepare a 1.0 mol / L second solution.

[0080] Condensation reaction: The two solutions were transferred to a 100mL three-necked flask at a volume ratio of 1:1, and 0.28g of MOF catalyst (4% of the total mass of 7.09g of reactants) was added. The mixture was stirred mechanically in an oil bath at 80℃ (±2℃) for 1.5h.

[0081] Solvent recovery and catalyst separation: The reaction mother liquor was flash evaporated at 70℃ and -0.095MPa to recover about 36mL of DES, resulting in the first concentrated mother liquor; after dilution with 20mL of DMF, the MOF catalyst was separated and recovered, and the filtrate was the second concentrated mother liquor.

[0082] Crystallization and purification: 40 mL of preheated pure water (water: mother liquor = 2:1) was slowly added dropwise to the second concentrated mother liquor, and the temperature was lowered to 10 °C at a rate of 0.5 °C / min. The mixture was aged for 2 h. After filtration, the filter cake was washed twice with 10 mL of ice water and dried under vacuum at 60 °C for 6 h to obtain off-white crystals.

[0083] (5) Results and Characterization Yield: 6.03 g of the target product was obtained; based on 4,6-dichloro-5-methoxypyrimidine, the theoretical yield is 6.295 g, and the yield is (6.03 / 6.295)×100%=95.8%.

[0084] Purity analysis: HPLC analysis showed a purity of 99.6%, with no 4-substituted isomers detected.

[0085] Recycling: DES is recovered and dried by molecular sieves and reused. MOF catalyst is washed and activated and reused 5 times, with catalytic activity retention rate ≥97%.

[0086] Example 3 (1) Raw materials and instruments Completely consistent with Example 1.

[0087] (2) Preparation of MOF catalysts Synthesis of organic ligands: The amount of raw materials was the same as in Example 1, the reaction temperature was adjusted to 120℃, the reaction was refluxed for 18h, and the post-processing steps remained unchanged to obtain the ligand L-PyCzIm.

[0088] MOF crystallization: Organic ligand L-PyCzIm (0.50 g, ~1.0 mmol) and zinc acetate dihydrate (0.66 g, 3.0 mmol) were dissolved in 30 mL of LDM and crystallized in an oven at 90 °C for 72 h. Subsequent washing and activation steps remained unchanged to obtain the target MOF catalyst.

[0089] (3) Preparation of deep eutectic solvent (DES) Choline chloride (ChCl, 13.96 g, 0.10 mol) and terephthalic acid (TA, 13.29 g, 0.08 mol) were added to a round-bottom flask at a molar ratio of 1:0.8. The mixture was stirred at 85°C until a homogeneous, transparent, and colorless liquid was formed. After cooling, the mixture was set aside for later use.

[0090] (4) 4-Sulfamethoxy-6-chloropyrimidine (C 11 H 11 Synthesis of ClN4O3S Solution preparation: Accurately weigh sulfanilamide (2.74 g, 16.0 mmol) and dissolve it in 20 mL of the above DES to prepare a first solution of 0.8 mol / L; weigh 4,6-dichloro-5-methoxypyrimidine (2.94 g, 16.0 mmol) and dissolve it in 20 mL of the same DES to prepare a second solution of 0.8 mol / L.

[0091] Condensation reaction: The two solutions were transferred to a 100mL three-necked flask at a volume ratio of 1:1, and 0.17g of MOF catalyst (3% of the total mass of 5.68g of reactants) was added. The mixture was then stirred mechanically in an oil bath at 75℃ (±2℃) for 2h.

[0092] Solvent recovery and catalyst separation: The reaction mother liquor was flash evaporated at 65℃ and -0.090MPa to recover about 34mL of DES, resulting in the first concentrated mother liquor; after dilution with 15mL of LDM, the MOF catalyst was separated and recovered, and the filtrate was the second concentrated mother liquor.

[0093] Crystallization and purification: 30 mL of preheated pure water (water: mother liquor = 2:1) was slowly added dropwise to the second concentrated mother liquor, and the temperature was lowered to 8°C at a rate of 0.5°C / min. The mixture was aged for 3 h. After filtration, the filter cake was washed twice with 8 mL of ice water and dried under vacuum at 55°C for 8 h to obtain off-white crystals.

[0094] (5) Results and Characterization Yield: 4.68 g of the target product was obtained; based on 4,6-dichloro-5-methoxypyrimidine, the theoretical yield = 16.0 mmol × 314.5 g / mol ÷ 1000 = 5.032 g, and the yield = (4.68 / 5.032) × 100% = 93.0%.

[0095] Purity analysis: HPLC analysis showed a purity of 99.4%, with no 4-substituted isomers detected.

[0096] Recycling: After DES was recycled and reused 3 times, its solubility did not decrease significantly; MOF catalyst was reused 5 times, and the yield remained above 91%.

[0097] Example 4 (1) Raw materials and instruments Completely consistent with Example 1.

[0098] (2) Preparation of MOF catalysts Synthesis of organic ligands: 2.32 g (10.0 mmol) of pyrene-4,5-dione, 4.25 g (15.0 mmol) of 4-(9-carbazolyl)benzaldehyde, 1.40 g (15.0 mmol) of aniline, 3.85 g (50.0 mmol) of ammonium acetate, and 50 mL of glacial acetic acid were added and refluxed at 140 °C for 8 h. The post-treatment steps remained unchanged to obtain the ligand L-PyCzIm.

[0099] MOF crystallization: Organic ligand L-PyCzIm (0.50 g, ~1.0 mmol) and zinc acetate dihydrate (1.10 g, 5.0 mmol) were dissolved in 30 mL of LDM and crystallized in an oven at 110 °C for 36 h. Subsequent washing and activation steps remained unchanged to obtain the target MOF catalyst.

[0100] (3) Preparation of deep eutectic solvent (DES) Choline chloride (ChCl, 13.96 g, 0.10 mol) and terephthalic acid (TA, 16.61 g, 0.10 mol) were added to a round-bottom flask in a molar ratio of 1:1 and stirred at 75°C until a homogeneous, transparent, and colorless liquid was formed. The mixture was then cooled and set aside for later use.

[0101] (4) 4-Sulfamethoxy-6-chloropyrimidine (C 11 H 11 Synthesis of ClN4O3S Solution preparation: Accurately weigh sulfanilamide (4.10 g, 23.8 mmol) and dissolve it in 20 mL of the above DES to prepare a first solution of 1.2 mol / L; weigh 4,6-dichloro-5-methoxypyrimidine (4.36 g, 23.8 mmol) and dissolve it in 20 mL of the same DES to prepare a second solution of 1.2 mol / L.

[0102] Condensation reaction: The two solutions were transferred to a 100mL three-necked flask at a volume ratio of 1:1.1 (20mL of the first solution and 22mL of the second solution), and 0.45g of MOF catalyst (5% of the total mass of 8.46g of reactants) was added. The mixture was then stirred mechanically in an oil bath at 85℃ (±2℃) for 1h.

[0103] Solvent recovery and catalyst separation: The reaction mother liquor was flash evaporated at 75℃ and -0.098MPa to recover about 38mL of DES, resulting in the first concentrated mother liquor; after dilution with 25mL of DMF, the MOF catalyst was separated and recovered, and the filtrate was the second concentrated mother liquor.

[0104] Crystallization and purification: 75 mL of preheated pure water (water: mother liquor = 3:1) was slowly added dropwise to the second concentrated mother liquor, and the temperature was lowered to 12 °C at a rate of 0.5 °C / min. The mixture was aged for 1.5 h. After filtration, the filter cake was washed twice with 12 mL of ice water and dried under vacuum at 65 °C for 5 h to obtain off-white crystals.

[0105] (5) Results and Characterization Yield: 7.02 g of the target product was obtained; based on 4,6-dichloro-5-methoxypyrimidine (23.8 mmol), the theoretical yield = 23.8 mmol × 314.5 g / mol ÷ 1000 = 7.485 g, and the yield = (7.02 / 7.485) × 100% = 93.8%.

[0106] Purity analysis: HPLC analysis showed a purity of 99.7%, with no 4-substituted isomers detected.

[0107] Recycling: DES was recovered and reused 5 times, with the recovery rate remaining above 92%; MOF catalyst was reused 6 times, with the yield still above 90% and no significant change in crystal structure.

[0108] Comparative Example 1 (using a conventional solvent to replace the DES in Example 1) (1) Raw materials and instruments Completely identical to Example 1, except that the "deep eutectic solvent (DES)" is replaced with the conventional solvent N,N-dimethylformamide.

[0109] (2) Preparation of MOF catalysts Completely consistent with Example 1 (no changes in organic ligand synthesis, MOF crystallization steps, or dosage), the target MOF catalyst was obtained.

[0110] (3) Preparation of conventional solvents Analytical grade N,N-dimethylformamide (DMF) can be used directly without additional preparation and is ready for use.

[0111] (4) 4-Sulfamethoxy-6-chloropyrimidine (C 11 H 11 Synthesis of ClN4O3S Solution preparation: Accurately weigh sulfanilide (3.42 g, 20.0 mmol) and dissolve it in 20 mL of LDM to prepare a 1.0 mol / L first solution; weigh 4,6-dichloro-5-methoxypyrimidine (3.67 g, 20.0 mmol) and dissolve it in 20 mL of LDM to prepare a 1.0 mol / L second solution (some raw materials do not dissolve completely at room temperature and require ultrasonic-assisted dissolution).

[0112] Condensation reaction: The two solutions were transferred to a 100mL three-necked flask at a volume ratio of 1:1, and 0.21g of MOF catalyst (consistent with Example 1) was added. The reaction was carried out in an oil bath at 80℃ (±2℃) with mechanical stirring for 1.5h (the reaction system showed slight stratification, and stirring needed to be strengthened continuously).

[0113] Solvent recovery and catalyst separation: The reaction mother liquor was flash evaporated at 70℃ and -0.095MPa, and the DMF recovery rate was only 65% ​​(about 26mL), resulting in a viscous first concentrated mother liquor. After dilution with 20mL DMF, the solution was filtered. The surface of the MOF catalyst was covered with a lot of oily impurities, which required repeated washing with DMF 5 times to separate them.

[0114] Crystallization and purification: 40 mL of preheated pure water (water: mother liquor = 2:1) was slowly added dropwise to the second concentrated mother liquor. Only a small amount of flocculent solid precipitated, with no obvious crystals. It was necessary to cool to 0°C and age for 4 hours to form irregular crystals. After filtration, the filter cake was washed twice with 10 mL of ice water and dried under vacuum at 60°C for 6 hours to obtain a light yellow powder product.

[0115] (5) Results and Characterization Yield: 4.12 g of the target product was obtained; based on 4,6-dichloro-5-methoxypyrimidine, the theoretical yield is 6.295 g, and the yield is (4.12 / 6.295)×100%=65.4%.

[0116] Purity analysis: HPLC analysis showed a purity of only 95.2%, and 4.3% of 4-substituted isomer byproducts were detected.

[0117] Recycling: The recovered DMF has a high water content and needs to be purified by distillation before it can be reused; after multiple washings, some active sites of the MOF catalyst are detached, and the yield drops to 52% after being reused twice.

[0118] Comparative Example 2 (using a conventional DES to replace the functionalized DES in Example 1) (1) Raw materials and instruments Completely identical to Example 1, except that the composition of DES was replaced with a conventional choline chloride-urea system (ChCl-Urea).

[0119] (2) Preparation of MOF catalysts The target MOF catalyst was obtained in complete consistency with Example 1.

[0120] (3) Preparation of conventional DES Choline chloride (ChCl, 13.96 g, 0.10 mol) and urea (12.01 g, 0.20 mol) were added to a round-bottom flask at a molar ratio of 1:2. The mixture was stirred at 80°C until a homogeneous, transparent, and colorless liquid (conventional DES system) was formed. The mixture was then cooled and set aside for later use.

[0121] (4) Synthesis of 4-sulfanilamide-5-methoxy-6-chloropyrimidine Solution preparation: Accurately weigh sulfanilamide (3.42 g, 20.0 mmol) and dissolve it in 20 mL of the above-mentioned conventional DES to prepare a 1.0 mol / L first solution; weigh 4,6-dichloro-5-methoxypyrimidine (3.67 g, 20.0 mmol) and dissolve it in 20 mL of the same DES to prepare a 1.0 mol / L second solution (with good solubility).

[0122] Condensation reaction: The two solutions were transferred to a 100mL three-necked flask at a volume ratio of 1:1, and 0.21g of MOF catalyst was added. The mixture was stirred mechanically in an oil bath at 80℃ (±2℃) for 1.5h.

[0123] Solvent recovery and catalyst separation: The reaction mother liquor was flash evaporated at 70℃ and -0.095MPa. The conventional DES recovery rate was 82% (about 32.8mL), and the first concentrated mother liquor was obtained. After dilution with 20mL LDM, the MOF catalyst was separated and recovered. The filtrate was the second concentrated mother liquor.

[0124] Crystallization and purification: 40 mL of preheated pure water (water: mother liquor = 2:1) was slowly added dropwise to the second concentrated mother liquor. The precipitated crystals were small and severely agglomerated. The temperature was lowered to 10 °C at a rate of 0.5 °C / min and aged for 2 h, but the agglomeration did not improve. After filtration, the filter cake was washed twice with 10 mL of ice water and dried under vacuum at 60 °C for 6 h to obtain off-white agglomerated crystals.

[0125] (5) Results and Characterization Yield: 5.03 g of the target product was obtained; based on 4,6-dichloro-5-methoxypyrimidine, the yield = (5.03 / 6.295) × 100% = 80.0%.

[0126] Purity analysis: HPLC analysis showed a purity of 97.8%, with 2.1% of 4-substituted isomer byproducts detected.

[0127] Recycling: After conventional DES is reused 3 times, its solubility decreases due to the easy hydrolysis of urea, and the solubility of the reactants decreases by 15%; after MOF catalyst is reused 3 times, the yield drops to 72%.

[0128] Comparative Example 3 (using a single FeCl3 catalyst instead of the MOF catalyst in Example 1) (1) Raw materials and instruments Completely identical to Example 1, except that the "MOF catalyst" was replaced with the conventional Lewis acid catalyst ferric chloride (FeCl3, analytical grade).

[0129] (2) Catalyst preparation Analytical grade ferric chloride solid can be used directly without the need to prepare MOF, and is ready for use.

[0130] (3) Preparation of deep eutectic solvent (DES) Completely consistent with Example 1 (choline chloride-terephthalic acid, molar ratio 1:1), DES was obtained.

[0131] (4) Synthesis of 4-sulfanilamide-5-methoxy-6-chloropyrimidine Solution preparation: exactly the same as in Example 1 (20.0 mmol each of sulfanilide and 4,6-dichloro-5-methoxypyrimidine, dissolved in 20 mL LDS), to obtain the first and second solutions.

[0132] Condensation reaction: The two solutions were transferred to a 100mL three-necked flask at a volume ratio of 1:1, and 0.21g of FeCl3 catalyst (the same mass as the MOF catalyst in Example 1) was added. The mixture was stirred mechanically in an oil bath at 80℃ (±2℃) for 1.5h (the color of the reaction system gradually turned brownish-brown).

[0133] Solvent recovery and catalyst separation: The reaction mother liquor was flash-evaporated at 70℃ and -0.095MPa to recover approximately 35mL of DES, yielding a brownish-red first concentrated mother liquor. After dilution with 20mL of DMF, the liquor was filtered. FeCl3 dissolved in DMF and could not be separated and recovered. The filtrate contained Fe. 3+ The second concentrated mother liquor.

[0134] Crystallization and purification: 40 mL of preheated 80°C pure water was slowly added dropwise to the second concentrated mother liquor. The precipitated crystals were brownish-yellow (containing Fe). 3+ (Impurities); wash three times with 10% hydrochloric acid solution, then wash twice with ice water, and dry under vacuum at 60°C for 6 hours to obtain light brown crystals.

[0135] (5) Results and Characterization Yield: 4.53 g of the target product was obtained; based on 4,6-dichloro-5-methoxypyrimidine, the yield = (4.53 / 6.295) × 100% = 72.0%.

[0136] Purity analysis: HPLC analysis showed a purity of 92.5%, with 7.2% of 4-substituted isomer byproducts detected. Furthermore, due to Fe... 3+ Residue, product color is not up to standard.

[0137] Recycling: FeCl3 dissolves in solvents and cannot be recovered, so it can only be used once, and it introduces metal ion impurities, increasing the cost of post-processing.

[0138] Comparative Example 4 (MOF catalyst with a single imidazole group as the organic ligand) (1) Raw materials and instruments The method is basically the same as in Example 1, except that “pyrene-4,5-dione, 4-(9-carbazolyl)benzaldehyde” is replaced with 2-methylimidazole (analytical grade, CAS No. 693-98-1), a single imidazole group ligand precursor, and there is no need to synthesize ligands containing pyrene and carbazole.

[0139] (2) Preparation of MOF catalysts Preparation of single imidazole ligand: Analytical grade 2-methylimidazolium (denoted as L-Im) was used directly.

[0140] MOF crystallization: 2-methylimidazole (0.082 g, 1.0 mmol) and zinc acetate dihydrate (0.66 g, 3.0 mmol) were dissolved in 30 mL of DMF and placed in a 100 mL stainless steel reactor lined with polytetrafluoroethylene. The mixture was crystallized in an oven at 100 °C for 48 h and then naturally cooled to obtain a white powdery solid. After washing three times with DMF, the mixture was activated under vacuum at 120 °C for 6 h to obtain a MOF catalyst containing only a single imidazole ligand (denoted as MOF-Im).

[0141] (3) Preparation of deep eutectic solvent (DES) Completely consistent with Example 1, DES was obtained.

[0142] (4) Synthesis of 4-sulfanilamide-5-methoxy-6-chloropyrimidine The solution preparation, condensation reaction, solvent recovery and catalyst separation steps are exactly the same as in Example 1, except that the MOF catalyst is replaced with MOF-Im (0.21g).

[0143] Crystallization and purification: 40 mL of preheated pure water to 80 °C was slowly added dropwise to the second concentrated mother liquor. The precipitated crystals showed no obvious orientation and had a wide particle size distribution. Cooling to 10 °C at a rate of 0.5 °C / min and aging for 2 h had limited improvement. After filtration, the filter cake was washed twice with 10 mL of ice water and dried under vacuum at 60 °C for 6 h to obtain off-white crystals.

[0144] (5) Results and Characterization Yield: 5.26 g of the target product was obtained; based on 4,6-dichloro-5-methoxypyrimidine, the yield = (5.26 / 6.295) × 100% = 83.6%.

[0145] Purity analysis: HPLC analysis showed a purity of 98.3%, with 1.6% of 4-substituted isomer byproducts detected (due to the absence of π-π stacking and steric hindrance of pyrene and carbazole, resulting in decreased selectivity).

[0146] Recycling: After MOF-Im is reused 3 times, the simple ligands lead to poor skeletal stability, resulting in some Zn being recycled. 2+ The material detaches, reducing the yield to 75%.

[0147] Comparative Example 5 (MOF catalyst with a single pyrene group as the organic ligand) (1) Raw materials and instruments The results are basically the same as in Example 1, except that the ligand precursor is adjusted and a new single pyrene group ligand precursor, 1,3,6,8-tetracarboxylic acid pyrene (H4PTC, purity ≥98%, CAS No. 861023-19-0), is added.

[0148] (2) Preparation of MOF catalyst (containing only a single pyrene ligand) Preparation of a single pyrene ligand: 1,3,6,8-tetracarboxylic acid pyrene (H4PTC) was used directly as the organic ligand (denoted as L-Py). This ligand's molecular skeleton contains only the pyrene group, lacks imidazole basic sites and carbazole-assisted π-planes, and only connects to Zn via the carboxyl group (-COOH). 2+ Coordination.

[0149] MOF crystallization: Weigh out a single pyrene ligand L-Py (0.452 g, 1.0 mmol) and zinc acetate dihydrate (0.66 g, 3.0 mmol), dissolve them together in 30 mL of DMF, and transfer them to a 100 mL stainless steel reactor lined with polytetrafluoroethylene. Place the reactor in an oven at 100 °C for 48 h to crystallize. After naturally cooling to room temperature, light yellow blocky crystals are obtained. Wash three times with DMF to remove unreacted raw materials, and activate under vacuum at 120 °C for 6 h to obtain a MOF catalyst containing only a single pyrene ligand (denoted as MOF-Py).

[0150] (3) Preparation of deep eutectic solvent (DES) Completely consistent with Example 1: Choline chloride (13.96 g, 0.10 mol) and terephthalic acid (16.61 g, 0.10 mol) were mixed in a 1:1 molar ratio and stirred at 80°C until a homogeneous, transparent, and colorless liquid was formed. The mixture was then cooled and set aside for later use.

[0151] (4) 4-Sulfamethoxy-6-chloropyrimidine (C 11 H 11 Synthesis of ClN4O3S Solution preparation: exactly the same as in Example 1: accurately weigh sulfanilamide (3.42 g, 20.0 mmol) and dissolve it in 20 mL LDES to prepare a 1.0 mol / L first solution; weigh 4,6-dichloro-5-methoxypyrimidine (3.67 g, 20.0 mmol) and dissolve it in 20 mL LDES to prepare a 1.0 mol / L second solution.

[0152] Condensation reaction: The two solutions were transferred to a 100 mL three-necked flask at a volume ratio of 1:1, and the above-mentioned single pyrene ligand MOF catalyst (0.21 g, consistent with the mass of MOF catalyst in Example 1) was added; the reaction was carried out in an oil bath with mechanical stirring at 80 °C (±2 °C) for 1.5 h.

[0153] Solvent recovery and catalyst separation: The reaction mother liquor was flash evaporated at 70℃ and -0.095MPa to recover about 35mL of DES, resulting in a viscous first concentrated mother liquor; 20mL of DMF was added to the mother liquor for dilution, and the mixture was filtered through a Buchner funnel to obtain the second concentrated mother liquor.

[0154] Crystallization and purification: 40 mL of preheated pure water (water: mother liquor = 2:1) was slowly added dropwise to the second concentrated mother liquor. The precipitated crystals were irregular particles due to weak positioning effect. The temperature was lowered to 10 °C at a rate of 0.5 °C / min and aged for 2 h, which slightly improved the particle aggregation. After filtration, the filter cake was washed twice with 10 mL of ice water and dried under vacuum at 60 °C for 6 h to obtain off-white crystals.

[0155] (5) Results and Characterization Yield: 5.01 g of the target product was obtained; based on 4,6-dichloro-5-methoxypyrimidine (theoretical yield 6.295 g), the yield = (5.01 / 6.295) × 100% = 79.6% (significantly lower than 92.5% in Example 1, due to the absence of an imidazole group to activate the nucleophile, resulting in a higher reaction energy barrier).

[0156] Purity analysis: HPLC analysis showed a purity of 97.9%, with 2.8% of the 4-substituted isomer byproduct detected (higher than 0% in Example 1, because the π-π stacking of a single pyrene group is weak and lacks steric hindrance assisted by carbazole, making it impossible to completely shield the 4-position Cl atom).

[0157] Recycling: After MOF-Py is reused 3 times, due to the single pyrene ligand and Zn 2+ The coordination effect of the MOF in Example 1 was weaker than that of the multi-group ligand in Example 1, and some of the skeletons collapsed slightly, resulting in a yield of 70.2%. In contrast, the MOF in Example 1, with its multi-group synergistic stability of imidazole-carbazole-pyrene, still achieved a yield of over 88% after five repetitions.

[0158] Table 1. Yields and purity of Examples 1-4 and Comparative Examples 1-5

[0159] As shown in Table 1, the yields of Examples 1-4 of this application were all maintained at 92.5%-95.8%, and the purity was all 99.4%-99.7%. No 4-substitution isomer byproducts were detected, demonstrating efficient and highly selective synthesis. In contrast, the yields (65.4%-83.6%) and purity (92.5%-98.3%) of all comparative examples were significantly lower than those of the examples, and most comparative examples detected 4-substitution isomers (Comparative Example 1: 4.3%, Comparative Example 2: 2.1%, Comparative Example 3: 7.2%, Comparative Example 4: 1.6%, Comparative Example 5: 2.8%).

[0160] Specifically, solvent type and catalyst structure are the core factors affecting performance: Comparative Example 1 replaced functionalized DES with conventional DMF. Due to the weak solubility of DMF in reactants and the stabilization of intermediates, the yield was only 65.4% and the purity was 95.2%. Comparative Example 2 replaced ChCl-TADES with conventional ChCl-UreaDES. Due to the lack of π-π stacking and template effect of urea for terephthalic acid, the yield dropped to 80.0% and the purity was 97.8%. Comparative Example 3 replaced multi-active-site MOF with single FeCl3. Due to the lack of molecular recognition and dual activation, the yield was only 72.0% and the purity was only 92.5%, and it contained metal impurities. Comparative Examples 4-5 replaced imidazole-pyrene-carbazole multi-group MOF with single-group ligand MOF. Due to the lack of some active sites (such as the lack of π-π positioning of single imidazole and the lack of nucleophilic activation of single pyrene), the yield and purity both decreased significantly. This indicates that the synergistic system of "MOF containing imidazole-pyrene-carbazole ligand (dual activation + precise positioning) + choline chloride-terephthalic acid DES (stabilization + template)" in this application is the key to achieving high yield and high purity synthesis of 4-sulfonamide-5-methoxy-6-chloropyrimidine, and the replacement of any core component will lead to a significant deterioration in process performance.

[0161] Various embodiments of this application may exist in the form of a range; it should be understood that the description in the form of a range is merely for convenience and brevity and should not be construed as a rigid limitation on the scope of this application; therefore, it should be considered that the range description has specifically disclosed all possible sub-ranges and single numerical values ​​within that range. For example, it should be considered that the range description from 1 to 6 has specifically disclosed sub-ranges, such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., and single numbers within the range, such as 1, 2, 3, 4, 5, and 6, which applies regardless of the range.

[0162] Furthermore, in the description of this application, the terms "comprising," "including," etc., mean "including but not limited to." In this document, relational terms such as "first" and "second" are used merely to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations.

[0163] The above description is merely a specific embodiment of this application, enabling those skilled in the art to understand or implement this application. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of this application. Therefore, this application is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features claimed herein.

Claims

1. A process for preparing industrial sulfonamides, characterized in that, The preparation process includes the following steps: S1. Dissolve sulfanilamide in a deep eutectic solvent to obtain the first solution; S2. Dissolve 4,6-dichloro-5-methoxypyrimidine in the same deep eutectic solvent to obtain a second solution; the deep eutectic solvent is composed of choline chloride and terephthalic acid, wherein the molar ratio of choline chloride to terephthalic acid is 1:(0.8-1.2). S3. The first solution, the second solution, and the MOF catalyst are mixed to undergo a nucleophilic substitution reaction, yielding a mother liquor containing 4-sulfano-5-methoxy-6-chloropyrimidine; the MOF catalyst is composed of a metal node and an organic ligand; the metal node is Zn. 2+ The organic ligand is an organic compound whose molecular skeleton contains imidazole, pyrene and carbazole groups. S4. Under reduced pressure, the reaction mother liquor is flash-evaporated to obtain the first concentrated mother liquor and the deep eutectic solvent; S5. The first concentrated mother liquor is subjected to solid-liquid separation to obtain the second concentrated mother liquor and the MOF catalyst. S6. Add pure water as an antisolvent to the second concentrated mother liquor, and use the template effect of the residual deep eutectic solvent to induce crystallization, to obtain a crystallization mother liquor containing the 4-sulfonamide-5-methoxy-6-chloropyrimidine crystals. S7. The mother liquor for crystallization is subjected to solid-liquid separation, washing and drying in sequence to obtain the 4-sulfonamide-5-methoxy-6-chloropyrimidine crystals. The preparation method of the MOF catalyst includes: Pyrene-4,5-dione, 4-(9-carbazolyl)benzaldehyde, aniline, ammonium acetate and acetic acid were mixed for a one-pot reaction, and the resulting organic ligands, which contain imidazole, pyrene and carbazole groups in their molecular skeleton, were obtained after post-treatment. The organic ligand and zinc salt are dissolved in an organic solvent to form a mixed solution; The mixed solution was subjected to a crystallization reaction, and the MOF catalyst was obtained after post-processing. The molar ratio of the pyrene-4,5-dione, the 4-(9-carbazolyl)benzaldehyde, the aniline, and the ammonium acetate is 1:(1.0-1.5):(0.5-1.5):(2-10). The reaction temperature of the one-pot reaction is 100-150℃, and the reaction time is 4-24h. The molar ratio of the organic ligand to the zinc salt is 1:(1-5); The crystallization reaction is carried out at a temperature of 80–120°C for 12–72 hours.

2. The preparation process of industrial sulfonamides according to claim 1, characterized in that, The molar concentration of sulfanilamide in the first solution is 0.3–1.2 mol / L, and the molar concentration of 4,6-dichloro-5-methoxypyrimidine in the second solution is 0.3–1.2 mol / L.

3. The preparation process of industrial sulfonamides according to claim 2, characterized in that, The volume ratio of the first solution to the second solution is 1:(0.9 to 1.1).

4. The preparation process of industrial sulfonamides according to claim 1, characterized in that, The mass of the MOF catalyst is 3 to 5% of the total mass of the sulfanilamide and the 4,6-dichloro-5-methoxypyrimidine.

5. The preparation process of industrial sulfonamides according to claim 1, characterized in that, The nucleophilic substitution reaction is carried out at a temperature of 70–85 °C for 1–2 h.

6. The preparation process of industrial sulfonamides according to claim 1, characterized in that, The volume ratio of the pure water to the second concentrated mother liquor is (1-3):

1.

7. The preparation process of industrial sulfonamides according to claim 1, characterized in that, The preparation process further includes: S8, recycling the deep eutectic solvent recovered in step S4 for step S1 or S2, and recycling the MOF catalyst recovered in step S5 for step S3, to form a closed loop.

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