Preparation method of sodium cyclamate

Abstract

The invention provides a preparation method of sodium cyclamate, and belongs to the field of sweetening agent processing. The method comprises the following steps: in the presence of a bifunctional ionic liquid, enabling cyclohexylamine and sulfamic acid to react at 60-85 DEG C for 2-5 hours to obtain a reaction solution containing cyclohexylsulfamic acid; neutralizing the reaction liquid to be alkaline, then adding a sodium cyclamate molecularly imprinted polymer material as a seed crystal, and inducing sodium cyclamate to be crystallized and separated out to obtain crystallized slurry; carrying out solid-liquid separation on the crystallized slurry to obtain a solid-phase mother solution and a liquid-phase mother solution; carrying out solid-solid separation on the solid phase to separate out a sodium cyclamate molecularly imprinted polymer material and a sodium cyclamate crystal; and washing and drying the sodium cyclamate crystal to obtain a sodium cyclamate product. By introducing the bifunctional ionic liquid and the sodium cyclamate molecularly imprinted polymer material and enabling the bifunctional ionic liquid and the sodium cyclamate molecularly imprinted polymer material to have a synergistic effect in the process, mild reaction conditions and precise separation and purification are synchronously realized.

Description

Technical Field

[0001] This application relates to the field of sweetener processing technology, and in particular to a method for preparing sodium cyclohexylsulfamate. Background Technology

[0002] Sodium cyclohexylsulfamate (cyclamate), a widely used artificial sweetener, is primarily produced industrially through the direct sulfonation reaction of cyclohexylamine and aminosulfonic acid. Traditional processes typically involve high temperatures (usually exceeding 100°C) and strong acid catalysis to overcome the high activation energy barrier of the amine-sulfonic acid reaction and achieve acceptable conversion rates. This process is not only energy-intensive but also prone to various side reactions due to the harsh reaction conditions, such as excessive condensation of cyclohexylamine and aminosulfonic acid to form impurities like cyclohexylurea, thus reducing the selectivity of the main reaction and the yield of the final product. After the reaction, the resulting product mixture has a complex composition and requires cumbersome post-processing steps, including neutralization, multiple recrystallizations, and activated carbon decolorization, to obtain a product that meets food-grade standards. This multi-step purification process not only results in a long and complex process flow but also leads to significant solvent consumption and waste generation.

[0003] The challenges of existing technologies are concentrated in two core stages: reaction and separation. At the reaction level, a key issue is how to maintain or improve reaction efficiency and selectivity while reducing energy consumption. Conventional homogeneous catalysts or high-temperature conditions are insufficient to effectively suppress side reaction pathways while accelerating the main reaction. At the separation and purification level, traditional methods rely on differences in physical properties (such as solubility) between products and impurities. This separation mechanism lacks molecular specificity and is inefficient, which is the main reason for product yield loss and high purification costs. Therefore, developing an integrated green synthesis process that can react efficiently and selectively under mild conditions and achieve precise and simple product separation is of great significance for improving the techno-economic and environmental friendliness of cyclamate production. Summary of the Invention

[0004] This application provides a method for preparing sodium cyclohexylsulfamate to solve the following technical problem: how to simultaneously achieve milder reaction conditions and more precise separation and purification in the preparation method of sodium cyclohexylsulfamate.

[0005] This application provides a method for preparing sodium cyclohexylsulfamate, the method comprising the following steps: S1. In the presence of a bifunctional ionic liquid, cyclohexylamine and aminosulfonic acid are reacted at 60-85°C for 2-5 hours to obtain a reaction solution containing cyclohexylaminosulfonic acid; the bifunctional ionic liquid is a crown ether modified imidazolium salt ionic liquid. S2. Neutralize the reaction solution to alkaline, then add cyclamate molecularly imprinted polymer material as seed crystals to induce cyclamate crystallization and precipitate, thus obtaining a crystallized slurry; the cyclamate molecularly imprinted polymer material is micron-sized particles prepared by polymerization and template elution using cyclamate as a template molecule and acrylamide and methacrylic acid as functional monomers. S3. The crystallized slurry is subjected to solid-liquid separation to obtain a solid phase and a liquid mother liquor; the solid phase contains co-precipitated cyclamate crystals and the molecularly imprinted polymer material. S4. Perform solid-solid separation on the solid phase to separate the cyclamate molecularly imprinted polymer material and the cyclamate crystal; S5. Wash and dry the cyclamate crystals to obtain the cyclamate product.

[0006] Optionally, the method further includes the following steps: S6. The cyclamate molecularly imprinted polymer material is recycled back to step S2 after being regenerated. S7. The liquid mother liquor is dehydrated to recover the regenerated bifunctional ionic liquid, which is then returned to step S1 for recycling.

[0007] Optionally, in step S1, the molar ratio of cyclohexylamine to aminosulfonic acid is 1:(1.0 to 1.1).

[0008] Optionally, in step S1, the mass of the bifunctional ionic liquid is 20-50% of the total mass of the cyclohexylamine and the aminosulfonic acid.

[0009] Optionally, in step S1, the preparation method of the bifunctional ionic liquid includes the following steps: S101. In the presence of a catalyst system, 4-bromobenzo-18-crown ether-6 and methylimidazolium are reacted at 80-90°C for 4-12 h to obtain a crown ether-modified imidazolium salt intermediate. S102. The crown ether-modified imidazolium salt intermediate is subjected to an ion exchange reaction with sodium p-toluenesulfonate in a solvent. After the reaction is completed, the mixture is separated and purified to obtain the bifunctional ionic liquid. The temperature of the ion exchange reaction is 40-70°C and the time is 2-8 hours.

[0010] Optionally, in step S101, the molar ratio of 4-bromobenzo-18-crown ether-6 to methylimidazole is 1:(1.2~2.0); The catalyst system consists of Pd(OAc)2, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and sodium tert-butoxide. The molar amount of Pd(OAc)2 is 0.5 to 5% of the molar amount of 4-bromobenzo-18-crown ether-6. The molar ratio of 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl to Pd(OAc)2 is (1 to 4):1. The molar amount of sodium tert-butoxide is 1.0 to 3.0 times the molar amount of methylimidazolium. In step S102, the molar ratio of the crown ether-modified imidazolium salt intermediate to the sodium p-toluenesulfonate is 1:(1.0-1.2).

[0011] Optionally, in step S2, the mass of the cyclamate molecularly imprinted polymer material is 1 to 5% of the theoretical cyclamate mass.

[0012] Optionally, in step S2, the method for preparing the cyclamate molecularly imprinted polymer material includes the following steps: S201. Dissolve the template molecule cyclamate and the functional monomer in a polar solvent and stir at room temperature for 2-6 hours to form a mixed system containing a pre-assembled complex; the functional monomer is composed of acrylamide and methacrylic acid; S202. Under the protection of nitrogen or inert gas, add the crosslinking agent ethylene glycol dimethacrylate and the free radical initiator azobisisobutyronitrile to the mixture system, and carry out a thermally initiated polymerization reaction at 50-70°C for 6-24 hours to obtain a block polymer. S203. The block polymer is crushed, ground and sieved to obtain polymer particles with a particle size of 1 to 100 μm; S204. The polymer particles are subjected to Soxhlet extraction and continuous washing with a mixed solvent of methanol and acetic acid until the eluent does not contain the template molecule cyclamate. The eluted polymer particles are then vacuum dried to obtain the cyclamate molecularly imprinted polymer material.

[0013] Optionally, in step S201, the molar ratio of the template molecule cyclamate, the acrylamide, and the methacrylic acid is 1:(4-8):(4-8); The molar ratio of the crosslinking agent to the functional monomer is (5-20):1, and the mass of the free radical initiator is 0.5-2% of the mass of the functional monomer.

[0014] Optionally, in step S2, after adding the seed crystals, the system is cooled to 5–15°C at a rate of 0.1–1°C / min to induce crystallization.

[0015] The technical solutions provided in this application have the following advantages compared with the prior art: This application provides a method for preparing sodium cyclohexylsulfamate. By introducing two carefully designed molecular tools, namely a bifunctional ionic liquid and a cyclamate molecularly imprinted polymer material, and having them work synergistically in the process, the reaction conditions are simultaneously made milder and the separation and purification are made more precise.

[0016] The key to achieving milder reaction conditions lies in the biomimetic pre-organization effect of bifunctional ionic liquids. The crown ether-modified imidazolium salt ionic liquid in this scheme is not an inert solvent, but a reaction medium with specific molecular recognition and assembly functions. Its crown ether structural unit can selectively bind to the hydrophobic cyclohexyl group of cyclohexylamine through host-guest interactions, anchoring it in the local microenvironment. Simultaneously, the cation-anion network of the ionic liquid can activate another reactant, aminosulfonic acid molecules, through hydrogen bonding and electrostatic forces. This interaction pre-brings and orients the two reactants at the molecular scale, greatly increasing the probability and efficiency of their effective collisions, effectively lowering the activation energy barrier. Therefore, the reaction does not rely on the high temperatures of traditional processes to provide the energy to overcome the energy barrier; it can proceed efficiently at lower temperatures of 60 to 85 degrees Celsius, achieving milder reaction conditions from the source and reducing side reactions that may be triggered by high temperatures.

[0017] The core of achieving precise purification in the separation process lies in the specific recognition and induction effects of molecularly imprinted polymer materials. This material is prepared using cyclamate itself as a template, leaving imprinted cavities in its polymer network that are completely complementary to cyclamate molecules in terms of spatial shape, size, and functional group arrangement. When added to the system as seed crystals, these cavities, based on a high degree of specificity similar to lock-and-key matching, selectively and precisely recognize and bind cyclamate molecules from the complex post-reaction mixture through multiple non-covalent interactions. The captured molecules are orderly arranged at the cavity interface, forming the most energy- and structurally favorable nucleation sites, thereby guiding free cyclamate molecules in solution to preferentially and directionally crystallize and grow on their surface. This process is essentially homogeneous epitaxial growth based on molecular recognition, enabling the product to be selectively crystallized in situ from the mixture, transforming traditional coarse recrystallization based on solubility differences into precise separation and purification based on molecular structure matching.

[0018] In summary, the success of this approach lies in integrating the molecular-level design of two functional materials into the process flow. The bifunctional ionic liquid plays a crucial role as an intelligent organizer in the reaction steps, driving synthesis under mild conditions by regulating intermolecular forces; the molecularly imprinted polymer functions as a precise capturer in the separation steps, achieving highly selective crystallization of the product through its molecular memory effect. The two processes are seamlessly integrated, addressing the core challenges of synthesis and separation respectively, simultaneously achieving the dual goals of reducing reaction intensity and improving separation selectivity within the same process framework. Attached Figure Description

[0019] 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.

[0020] 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.

[0021] Figure 1 This is a schematic flowchart illustrating a method for preparing sodium cyclohexylsulfamate according to an embodiment of this application. Detailed Implementation

[0022] 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.

[0023] The range descriptions used herein, such as numerical ranges and proportional ranges, include all possible sub-ranges and single numerical values ​​within that range. For example, the range descriptions of "1 to 6" or "1 to 6" cover all sub-ranges (such as 1 to 3, 2 to 5, etc.) and single numbers (such as 1, 2, 3, 4, 5, 6) between 1 and 6. Unless otherwise specified, the terms "including" and "contains" as used herein mean "including but not limited to"; relational terms such as "first" and "second" are used only to distinguish different entities or operations and do not imply an actual order or relationship; "and / or" indicates that multiple situations can exist individually or simultaneously; expressions such as "at least one," "multiple," and "at least one" refer to any combination of the corresponding objects, including combinations of single or multiple objects. The proportional relationships mentioned herein, such as mass ratios and molar ratios, should be understood as the correspondence between the first and second terms of a proportional formula, according to the order of description. The raw materials, reagents, instruments, and equipment used herein can all be obtained through commercial purchase or prepared using existing methods.

[0024] Figure 1 This is a schematic flowchart illustrating a method for preparing sodium cyclohexylsulfamate according to an embodiment of this application.

[0025] like Figure 1As shown in the embodiments of this application, a method for preparing sodium cyclohexylsulfamate is provided, which includes the following steps: S1. In the presence of a bifunctional ionic liquid, cyclohexylamine and aminosulfonic acid are reacted at 60-85°C for 2-5 hours to obtain a reaction solution containing cyclohexylaminosulfonic acid; the bifunctional ionic liquid is a crown ether modified imidazolium salt ionic liquid. S2. Neutralize the reaction solution to alkaline, then add cyclamate molecularly imprinted polymer material as seed crystals to induce cyclamate crystallization and obtain crystallized slurry; cyclamate molecularly imprinted polymer material is micron-sized particles prepared by polymerization and template elution using cyclamate as template molecule and acrylamide and methacrylic acid as functional monomers. S3. The crystallization slurry is subjected to solid-liquid separation to obtain a solid phase and a liquid mother liquor; the solid phase contains the co-precipitated cyclamate crystals and molecularly imprinted polymer materials; S4. The solid phase is subjected to solid-solid separation to separate the cyclamate molecularly imprinted polymer material and cyclamate crystals. S5. Wash and dry the cyclamate crystals to obtain the cyclamate product.

[0026] In some implementations, the method further includes the following steps: S6. After regeneration, the cyclamate molecularly imprinted polymer material is returned to step S2 for recycling. S7. Dehydrate the liquid mother liquor to recover the regenerated bifunctional ionic liquid, and return it to step S1 for recycling.

[0027] It should be noted that the preparation scheme of cyclamate provided in this application represents an advanced process based on molecular engineering design. Its core lies in using customized molecular tools to reconstruct the traditional cyclamate synthesis process, realizing the transformation from extensive chemical operation to a precise, green, integrated intelligent process.

[0028] The entire process begins with the core conversion step: the reaction of cyclohexylamine and aminosulfonic acid to cyclohexylaminosulfonic acid under mild conditions in the presence of a bifunctional ionic liquid. The key breakthrough in this step lies in the bifunctional ionic liquid used, which simultaneously acts as a biomimetic catalyst and a microreactor. The ionic liquid pre-organizes and immobilizes cyclohexylamine through the crown ether structure of its cation moiety, while activating aminosulfonic acid using the strong hydrogen-bonding network of its anionic moiety, mimicking the proximity and orientation effects of enzyme catalysis, thereby significantly reducing the reaction activation energy. This allows the reaction to proceed efficiently and selectively at relatively low temperatures, effectively suppressing the formation of byproducts.

[0029] After the reaction, the crucial separation and purification stage begins, which couples the reaction with crystallization. By neutralizing the reaction solution to alkalinity, a specially formulated cyclamate molecularly imprinted polymer material is added as a seed crystal, inducing directional crystallization of cyclamate. This polymer material has imprinted cavities that are precisely complementary to cyclamate molecules, enabling it to specifically recognize and capture product molecules in the solution like a key. The captured molecules arrange themselves in an orderly fashion on the cavity surface, becoming ideal nucleation sites, thus guiding cyclamate molecules to grow directionally around them into high-purity crystals. The core mechanism of the cyclamate molecularly imprinted polymer material as a seed crystal is to provide specific nucleation sites to induce epitaxial growth, and through process control, the resulting crystal size is made much larger than the material itself, thus creating the necessary conditions for subsequent efficient physical separation based on particle size differences. This step combines the traditional crystallization and preliminary purification processes into one, significantly improving efficiency.

[0030] The next step involves the classification and separation of materials. First, solid-liquid separation separates the solid phase containing product crystals and solid seed crystals from the liquid mother liquor, initially enriching the product and recovering the mother liquor containing ionic liquids. Then, using solid-solid separation techniques, such as sieving, the final product, cyclamate crystals, is separated from the reusable molecularly imprinted polymer seed crystals. The separated pure crystals are washed and dried to obtain the cyclamate solid product that meets quality standards. Due to the high efficiency of the preceding purification steps, the burden on this refining step is reduced.

[0031] Finally, the process demonstrates its core advantages of green recycling and process integration. The separated molecularly imprinted polymer material, after regeneration to restore its recognition ability, can be returned to the crystallization step for recycling, avoiding the waste of expensive functional materials. Simultaneously, the separated liquid mother liquor, after dehydration and other purification processes, is recovered to obtain a regenerated bifunctional ionic liquid, which is then returned to the first-step reaction for recycling. These two recycling loops significantly reduce raw material consumption, waste generation, and overall production costs.

[0032] In some embodiments, in step S1, the molar ratio of cyclohexylamine to aminosulfonic acid is 1:(1.0 to 1.1).

[0033] In some embodiments, in step S1, the mass of the bifunctional ionic liquid is 20-50% of the total mass of cyclohexylamine and aminosulfonic acid.

[0034] In step S1, the molar ratio of cyclohexylamine to sulfamic acid is set to 1:1.0 to 1.1, aiming to achieve a slight excess of sulfamic acid. The main purpose of this design is to shift the reaction equilibrium to the right, ensuring that the typically more expensive cyclohexylamine is nearly completely converted, thereby directly improving the atom economy of the reactants and the final yield. Simultaneously, the reaction is carried out in the presence of a bifunctional ionic liquid, controlled at 20% to 50% of the total reactant mass. This range ensures that the ionic liquid can function as a highly efficient "biomimetic microreactor," providing a sufficient concentration of pre-organized sites and catalytically active centers to adequately lower the activation energy and accelerate the reaction process under mild conditions of 60 to 85°C, while utilizing its unique microenvironment to suppress the formation of byproducts.

[0035] In some embodiments, step S1, the method for preparing the bifunctional ionic liquid includes the following steps: S101. In the presence of a catalyst system, 4-bromobenzo-18-crown ether-6 and methylimidazolium are reacted at 80-90°C for 4-12 h to obtain a crown ether-modified imidazolium salt intermediate. S102. The crown ether-modified imidazolium salt intermediate is reacted with sodium p-toluenesulfonate in a solvent for ion exchange reaction. After the reaction is completed, the mixture is separated and purified to obtain a bifunctional ionic liquid. The temperature of the ion exchange reaction is 40-70℃ and the time is 2-8h.

[0036] In some embodiments, in step S101, the molar ratio of 4-bromobenzo-18-crown ether-6 to methylimidazole is 1:(1.2-2.0); The catalyst system consists of Pd(OAc)2, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and sodium tert-butoxide. The molar amount of Pd(OAc)2 is 0.5 to 5% of the molar amount of 4-bromobenzo-18-crown ether-6, the molar ratio of 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl to Pd(OAc)2 is (1 to 4):1, and the molar amount of sodium tert-butoxide is 1.0 to 3.0 times the molar amount of methylimidazolium. In step S102, the molar ratio of the crown ether-modified imidazolium salt intermediate to sodium p-toluenesulfonate is 1:(1.0-1.2).

[0037] In step S101, a highly active palladium catalytic system (Pd(OAc)2 / XPhos / t-BuONa) is used to achieve carbon-nitrogen coupling between aryl bromide and methylimidazolium. Methylimidazolium is added in excess at 1.2 to 2.0 molar amounts, ensuring a sufficient supply as a reactant and allowing it to act as a base to effectively neutralize the hydrogen bromide generated during the reaction, maintaining an alkaline environment and protecting catalyst activity. The amount of palladium catalyst used is 0.5% to 5% of the substrate; this typical catalyst amount ensures high conversion while considering catalyst cost. The ligand is paired with palladium in a 1:1 to 4:1 ratio, and its core role is to stabilize the palladium active center and regulate its electronic and spatial structure, thereby significantly improving catalytic efficiency and selectivity. Sodium tert-butoxide, as a strong base, is used at 1.0 to 3.0 times the amount of methylimidazolium, providing the necessary and strong alkaline driving force for the coupling reaction. The subsequent step S102 is an ion exchange process in which the intermediate reacts with sodium p-toluenesulfonate in a molar ratio of 1:1 to 1:1.2. The slight excess of sodium salt ensures that the bromide ions in the intermediate are completely replaced by the target p-toluenesulfonate anion, thereby obtaining the pure target ionic liquid in high yield.

[0038] In some embodiments, in step S2, the mass of the cyclamate molecularly imprinted polymer material is 1 to 5% of the theoretical cyclamate mass.

[0039] In step S2, the amount of cyclamate molecularly imprinted polymer material added is set to 1% to 5% of the theoretical product mass. This amount provides sufficient and evenly distributed specific nucleation sites, which can effectively induce crystallization and improve the crystallization yield, while avoiding crystals that are too small or increased separation load due to excessive seed crystals.

[0040] In some embodiments, step S2 of the method for preparing the cyclamate molecularly imprinted polymer material includes the following steps: S201. Dissolve the template molecule cyclamate and the functional monomer in a polar solvent and stir at room temperature for 2-6 hours to form a mixed system containing a pre-assembled complex; the functional monomer is composed of acrylamide and methacrylic acid. S202. Under the protection of nitrogen or inert gas, add the crosslinking agent ethylene glycol dimethacrylate and the free radical initiator azobisisobutyronitrile to the mixture, and carry out a thermally initiated polymerization reaction at 50-70°C for 6-24 hours to obtain a block polymer. S203. The block polymer is crushed, ground and sieved to obtain polymer particles with a particle size of 1 to 100 μm. S204. The polymer particles are extracted using the Soxhlet method and continuously washed with a mixed solvent of methanol and acetic acid until the eluent does not contain the template molecule cyclamate. The eluent is then vacuum dried to obtain the cyclamate molecularly imprinted polymer material.

[0041] In some embodiments, in step S201, the molar ratio of the template molecule cyclamate, acrylamide, and methacrylic acid is 1:(4-8):(4-8); The molar ratio of crosslinking agent to functional monomer is (5-20):1, and the mass of free radical initiator is 0.5-2% of the mass of functional monomer.

[0042] In the pre-assembly stage (S201), the template molecule (acesulfame potassium) is bonded to the functional monomers (acrylamide and methacrylic acid) in a molar ratio of 1:4:8 to 1:8:8. This ratio ensures that a sufficient number of structurally stable multiple non-covalent forces (such as hydrogen bonds) are formed around each template molecule, which is the basis for the subsequent generation of high-affinity, highly selective "molecular memory" cavities. In the polymerization stage (S202), the molar ratio of the crosslinking agent to the functional monomers is controlled between 5:1 and 20:1. This crosslinking range is key to forming a rigid three-dimensional polymer network, which allows the shape of the cavities and the arrangement of functional groups to be precisely fixed after template elution, preventing collapse during use. The amount of free radical initiator is 0.5% to 2% of the total monomer mass. This ratio is designed to initiate a polymerization reaction at a moderate rate, thereby generating a polymer with ideal network structure and mechanical strength. The elution endpoint contains no template molecules, that is, HPLC-UV 220nm ≤ 0.005AU, corresponding to an acesulfame potassium concentration ≤ 0.5ppm.

[0043] In some embodiments, after adding seed crystals in step S2, the system is cooled to 5–15°C at a rate of 0.1–1°C / min to induce crystallization.

[0044] During the crystallization process, the system is cooled to 5 to 15 °C at a slow rate of 0.1 to 1 °C per minute. This slow, programmed cooling helps to control the gradual release of supersaturation in the solution, allowing the crystallization process to occur primarily at specific sites provided by the molecularly imprinted polymer, thereby promoting the growth of large-size, high-purity, and uniform crystals.

[0045] The intelligent crystallization process in this application not only achieves highly selective separation of products, but its ingenious nucleation and growth kinetics design also ensures the feasibility of subsequent solid-solid separation, thereby supporting a closed-loop process for the recycling of key materials. At its core, the role of the cyclamate molecularly imprinted polymer (MIP) microspheres is to provide "template-based" nucleation sites with molecular recognition capabilities, rather than serving as an inert, encapsulated core.

[0046] Specifically, when MIPs microspheres are added to the system, their surface-imprinted cavities preferentially capture cyclamate molecules in the solution through specific interactions. These molecules arrange themselves in an orderly manner at the cavity interface, forming a structurally and energetically highly stable initial crystal nucleus. However, the crystallization process in this application guides the crystallization behavior to an ideal path by controlling key kinetic parameters (including but not limited to: moderate stirring intensity, optimized MIPs addition ratio, and slow programmed cooling): that is, cyclamate molecules mainly undergo "epitaxy growth" on the initial crystal nucleus, rather than undergoing multilayer disordered coating on the entire surface of the MIPs microspheres.

[0047] This controlled growth pattern allows newly formed crystals to rapidly detach from the surface of the microspheres and grow into independent, complete crystals much larger than the MIPs microspheres, based on their own crystallographic orientation. Simultaneously, the MIPs microspheres themselves, due to their rigid cross-linked polymer network structure, remain dispersed between the crystals under stirring. Ultimately, a mixture of "large-sized acesulfame K crystals" and "small-sized MIPs microspheres" is formed in the crystallization slurry, which is physically easy to separate despite being mixed. The significant particle size difference between the two (typically exceeding an order of magnitude) lays a solid foundation for subsequent efficient and low-loss solid-solid separation using simple physical methods such as sieving and hydrocyclone.

[0048] The core of this application's achievement in a milder, more precise, and greener preparation of cyclamate lies in the systematic design and utilization of a series of predictable and controllable intermolecular interactions at the molecular engineering level, replacing the reliance on high energy input and crude separation in traditional processes. Its molecular logic permeates the entire process of catalysis, separation, and recycling.

[0049] First, a milder reaction process is achieved through pre-organization and transition state stabilization. Traditional processes rely on high temperatures to overcome the activation energy barrier of the amine-sulfonic acid reaction. The bifunctional ionic liquid designed in this application selectively encapsulates and binds the hydrophobic cyclohexyl group of cyclohexylamine through host-guest interactions and hydrophobic effects in its cation moiety crown ether structure. Simultaneously, its anionic moiety interacts with the sulfonic acid group of aminosulfonic acid through a strong hydrogen bond network, polarizing and activating it. These two interactions, at the molecular scale, pre-bring the two reactants closer together and fix them at an optimal reaction orientation and distance, producing a proximity effect and orientation effect similar to those in enzyme catalysis. As a result, reactant molecules do not need to find each other and the correct orientation through high-energy collisions in solution, thus significantly reducing the apparent activation energy and enabling the reaction to proceed efficiently at low temperatures of 60 to 85°C, fundamentally eliminating high-temperature-induced side reactions.

[0050] Secondly, the purification process achieves greater precision, with molecular memory and specific recognition at its core. Traditional recrystallization relies on solubility differences, resulting in low separation efficiency for structurally similar impurities. The cyclamate molecularly imprinted polymer synthesized in this application involves pre-binding functional monomers to template molecules in three-dimensional space via hydrogen bonds and ionic interactions during preparation. After polymerization and cross-linking, the template is eluted, leaving imprinted cavities in the polymer network that are completely complementary to cyclamate molecules in shape, size, and functional group chemical environment. When this material is added to the system as a seed crystal, these cavities can selectively capture cyclamate molecules from the complex reaction mixture through multiple, synergistic non-covalent forces. The captured molecules are ordered within the cavities, providing structurally and energy-optimally matched nucleation sites, inducing subsequent directional epitaxial growth of cyclamate molecules. This process achieves homogeneous preferential crystallization at the molecular level, coupling product recognition, enrichment, purification, and crystallization in a single operation, achieving separation precision at the molecular recognition level.

[0051] Finally, achieving a greener and seamless integration throughout the entire process hinges on the reversible and stable design of the interactions between functional materials. The host-guest and hydrogen bonding interactions between ionic liquids and reactants, as well as the specific recognition interactions between molecularly imprinted polymers and products, are essentially reversible nonvalent interactions. This allows them to efficiently perform catalysis and capture functions, and after completing their mission, they can be cleanly dissociated from the products through relatively simple physical methods or mild chemical treatments. Ionic liquids themselves are composed of stable covalent and ionic bonds, while molecularly imprinted polymers are highly cross-linked networks, ensuring excellent chemical and mechanical stability under process conditions, enabling them to withstand multiple cycles without deactivation. This reversible yet stable carrier characteristic forms the molecular basis for constructing a dual-cycle system of ionic liquids and imprinted polymers, allowing key high-value molecular tools to be reused repeatedly, minimizing consumable reagents and waste generated in traditional processes, and achieving efficient internal recycling of materials and energy.

[0052] In summary, this approach is not a partial improvement to traditional processes, but a systematic reconstruction starting from the root of molecular interactions. By carefully designing two core functional materials—an ionic liquid for organizing reactions at the molecular level and an imprinted polymer for recognizing products at the molecular level—this application creates an intrinsically synergistic intelligent system. It replaces brute-force energy input with precise molecular pre-organization, replaces inefficient phase separation with specific molecular recognition, and achieves closed-loop fusion of the process through reversible molecular interactions and a stable material carrier, thereby simultaneously achieving the preparation goals of high efficiency, high quality, and low carbon emissions at the molecular level.

[0053] The present application is further illustrated below with reference to specific embodiments. Experimental methods in the following embodiments that do not specify specific conditions are generally determined according to national standards / industry standards / the disclosure herein; if there are no corresponding national standards / industry standards / the disclosure herein, they are performed according to generally accepted international standards, conventional conditions, or conditions recommended by the manufacturer. Example 1

[0054] 1. Experimental Materials and Instruments Main raw materials: Cyclohexylamine (analytical grade, dried), aminosulfonic acid (industrial grade, pulverized and sieved), 4-bromobenzo-18-crown ether-6 (CAS: 75460-28-5, 98%), methylimidazole (99%), sodium p-toluenesulfonate (98%), cyclamate standard (food grade, used as a template), acrylamide (99%), methacrylic acid (99%), ethylene glycol dimethacrylate (EGDMA, 98%, used after vacuum distillation), azobisisobutyronitrile (AIBN, 98%, used after recrystallization), sodium hydroxide (analytical grade), methanol, acetic acid, acetonitrile and other solvents are all analytical grade.

[0055] Catalysts and ligands: Palladium acetate (Pd(OAc)2, 99%), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (XPhos, 97%), sodium tert-butoxide (t-BuONa, 98%).

[0056] Main instruments: Heated magnetic stirrer, vacuum drying oven, Soxhlet extractor, circulating water vacuum pump, Buchner funnel, laser particle size analyzer, high-performance liquid chromatograph (HPLC), melting point apparatus, nuclear magnetic resonance spectrometer (NMR). 1 HNMR).

[0057] 2. Preparation of bifunctional ionic liquids Step S101: Synthesis of the crown ether-modified imidazolium salt intermediate. Under nitrogen protection, 4-bromobenzo-18-crown ether-6 (3.91 g, 10.0 mmol), methylimidazole (1.23 g, 15.0 mmol), sodium tert-butoxide (1.44 g, 15.0 mmol), Pd(OAc)₂ (11.2 mg, 0.05 mmol), and XPhos (23.9 mg, 0.05 mmol) were added sequentially to a dry 100 mL three-necked flask. 30 mL of anhydrous toluene was added as a solvent. The system was heated to 85 °C and reacted for 10 h under nitrogen atmosphere with stirring. After the reaction was complete, the mixture was cooled to room temperature, and 30 mL of deionized water was added. The mixture was extracted with dichloromethane (3 × 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain a pale yellow viscous liquid. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1, v / v) to obtain a crown ether-modified imidazolium bromide intermediate, which was a colorless viscous liquid with a yield of 85%.

[0058] Step S102: Preparation of the target ionic liquid by ion exchange. The intermediate obtained above (approximately 3.5 g, approximately 7.0 mmol) was dissolved in 20 mL of acetonitrile. Sodium p-toluenesulfonate (1.46 g, 7.7 mmol) was added with stirring. The mixture was heated to 60 °C and reacted for 6 h. After the reaction was completed, the mixture was cooled and filtered to remove the generated sodium bromide solid. Most of the acetonitrile was removed by rotary evaporation of the filtrate. The resulting viscous liquid was washed three times with diethyl ether (3 × 20 mL) to remove residual organic matter. Finally, the product was vacuum dried at 60 °C for 24 h to obtain the target bifunctional ionic liquid, which was a pale yellow, transparent, viscous liquid with an ion exchange yield of 92%.

[0059] 3. Preparation of cyclamate molecularly imprinted polymer (MIP) microsphere seed crystals Step S201: Pre-assembly. The template molecule cyclamate (2.01 g, 10.0 mmol), the functional monomer acrylamide (3.55 g, 50.0 mmol), and methacrylic acid (4.31 g, 50.0 mmol) were dissolved in 60 mL of acetonitrile / water mixed solvent (v / v = 4 / 1). The mixture was stirred at 300 rpm for 4 h at room temperature to form a pre-assembled mixture.

[0060] Step S202: Polymerization. Add crosslinking agent EGDMA (20.23 g, 102.0 mmol) and initiator AIBN (157 mg, 1.96% of the total mass of functional monomers) to the above mixture. After purging with nitrogen for 30 min to remove oxygen, seal the container. Place the reaction flask in a 65°C oil bath for thermally initiated polymerization for 18 h. After the reaction is complete, a hard, white, blocky polymer is obtained.

[0061] Step S203: Crushing and sieving. The block polymer is initially crushed using a mortar and pestle, and then ground using a ball mill. The resulting powder is sieved through a standard sieve to collect particles with a diameter in the range of 10–50 μm.

[0062] Step S204: Template elution and drying. The sieved polymer particles were loaded into the filter paper sleeve of a Soxhlet extractor. Extraction was performed continuously for 48 hours using a methanol:acetic acid mixture of 9:1 (v / v) as the extraction solvent. Subsequently, washing with pure methanol was continued for 6 hours to remove residual acetic acid. The completely eluted polymer particles were transferred to a petri dish and dried to constant weight in a vacuum drying oven at 50°C to obtain cyclamate molecularly imprinted polymer microspheres (MIPs). HPLC analysis of the final eluent confirmed the absence of template molecules.

[0063] 4. Based on the above raw materials, this embodiment provides a method for preparing cyclamate, including the following steps: Step S1: Catalytic reaction. Cyclohexylamine (19.82 g, 0.20 mol), aminosulfonic acid (21.42 g, 0.22 mol), and the prepared bifunctional ionic liquid were added sequentially to a 250 mL three-necked flask equipped with a stir bar, thermometer, and condenser. Stirring was started, and the reaction was heated in an oil bath at 75 °C for 3.5 h. Thin-layer chromatography monitoring showed that the cyclohexylamine starting material spot had essentially disappeared.

[0064] Step S2: Smart Crystallization. After the reaction is complete, the system is cooled to 40°C. While stirring, a 20% NaOH aqueous solution is slowly added dropwise to adjust the pH to 7.5 (alkaline conditions). Then, 1.53g of the prepared MIPs microsphere seed crystals (3.8% of the theoretical cyclamate yield of 40.25g) is added. The cooling program is started, slowly decreasing the temperature to 10°C at a rate of 0.3°C / min, and aging at this temperature for 2 hours. During the process, a large number of crystals are observed to form and grow through an epitaxial growth mechanism, using the molecularly imprinted polymer material as nucleation sites.

[0065] Steps S3 and S4: Separation by fractionation. The crystalline slurry is filtered through a Buchner funnel to achieve solid-liquid separation. The resulting filtrate (i.e., the liquid mother liquor) is stored for later use. The solid (i.e., the solid phase) mainly consists of cyclamate crystals and MIPs microspheres. This solid mixture is transferred to a vibrating sieve. The obtained cyclamate crystals have intact crystal shapes, with a minimum size >150 μm, and are sieved using a 200-mesh standard sieve (approximately 75 μm pore size). Because the MIPs microspheres (10–50 μm) have a smaller particle size than the sieve pores, while the cyclamate crystals are larger, efficient separation is achieved. The cyclamate crystals on the sieve are collected.

[0066] Step S5: Product refining. The cyclamate crystals obtained by sieving are washed twice with 10 mL of 50% ethanol aqueous solution pre-cooled at 5℃ to remove trace amounts of ionic liquid adsorbed on the surface. The washed crystals are then dried in a vacuum drying oven at 55℃ for 6 hours to obtain the final cyclamate product, which is a white crystalline powder.

[0067] S6: MIPs seed recovery. The MIPs microspheres obtained after sieving are extracted again by Soxhlet extraction with the above methanol / acetic acid mixture for 3 hours. After drying, they can be returned to step S2 for use. Testing showed that the crystallization-inducing activity retention rate of the recovered MIPs was ≥95%.

[0068] S7: Ionic liquid recovery. The liquid mother liquor obtained in step S3 was dehydrated by passing it through a column packed with a 4Å molecular sieve. Excess water was then removed by rotary evaporation at 50°C and -0.09 MPa. The recovered ionic liquid had a water content ≤500 ppm (KF method), and the recovery rate was 93.2%. The recovered ionic liquid was directly used in the next batch of reaction in step S1, and the cyclohexylamine conversion rate remained ≥90%.

[0069] 5. Product Characterization and Results Product Yield and Purity: In this example, 36.8 g of cyclamate product was obtained. Based on cyclohexylamine, the yield was 36.8 g ÷ 40.25 g × 100% = 91.4%. HPLC analysis (C18 column, mobile phase: methanol-water = 30:70, detection wavelength 210 nm) showed a product purity of 99.6%.

[0070] Product melting point: The measured melting point of the product is 169-171℃, which is consistent with the literature value of cyclamate standard (169-172℃), confirming that the product structure is correct. Example 2

[0071] 1. Preparation of bifunctional ionic liquids Step S101: Synthesis of the crown ether-modified imidazolium salt intermediate. Under nitrogen protection, 4-bromobenzo-18-crown ether-6 (3.91 g, 10.0 mmol), methylimidazole (1.64 g, 20.0 mmol), sodium tert-butoxide (2.88 g, 30.0 mmol), Pd(OAc)₂ (22.4 mg, 0.10 mmol), and XPhos (95.6 mg, 0.20 mmol) were added sequentially to a dry 100 mL three-necked flask. 30 mL of anhydrous toluene was added as a solvent. The system was heated to 80 °C and reacted for 12 h under nitrogen atmosphere with stirring. After the reaction was complete, the mixture was cooled to room temperature, and 30 mL of deionized water was added. The mixture was extracted with dichloromethane (3 × 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain a pale yellow viscous liquid. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1, v / v) to obtain a crown ether-modified imidazolium bromide intermediate, which was a colorless viscous liquid with a yield of 82%.

[0072] Step S102: Preparation of the target ionic liquid by ion exchange. The intermediate obtained above (approximately 3.5 g, approximately 7.0 mmol) was dissolved in 20 mL of acetonitrile. Sodium p-toluenesulfonate (1.34 g, 7.0 mmol) was added with stirring. The mixture was heated to 40 °C and reacted for 8 h. After the reaction was completed, the mixture was cooled and filtered to remove the generated sodium bromide solid. Most of the acetonitrile was removed by rotary evaporation of the filtrate. The resulting viscous liquid was washed three times with diethyl ether (3 × 20 mL) to remove residual organic matter. Finally, the product was vacuum dried at 60 °C for 24 h to obtain the target bifunctional ionic liquid, which was a pale yellow, transparent, viscous liquid with an ion exchange yield of 90%.

[0073] 2. Preparation of cyclamate molecularly imprinted polymer (MIP) microsphere seed crystals Step S201: Pre-assembly. The template molecule cyclamate (2.01 g, 10.0 mmol), the functional monomer acrylamide (2.84 g, 40.0 mmol), and methacrylic acid (3.45 g, 40.0 mmol) were dissolved in 50 mL of acetonitrile / water mixed solvent (v / v = 4 / 1). The mixture was stirred at 300 rpm for 6 h at room temperature to form a pre-assembled mixture.

[0074] Step S202: Polymerization. Add crosslinking agent EGDMA (19.82 g, 100.0 mmol) and initiator AIBN (62.9 mg, 0.75% of the total mass of functional monomers) to the above mixture. After purging with nitrogen for 30 min to remove oxygen, seal the container. Place the reaction flask in a 55°C oil bath for thermally initiated polymerization for 24 h. After the reaction is complete, a hard, white, blocky polymer is obtained.

[0075] Step S203: Crushing and sieving. The block polymer is initially crushed using a mortar and pestle, and then ground using a ball mill. The resulting powder is sieved through a standard sieve to collect particles with a diameter in the range of 5–30 μm.

[0076] Step S204: Template elution and drying. The sieved polymer particles were loaded into the filter paper sleeve of a Soxhlet extractor. Extraction was performed continuously for 48 hours using a methanol:acetic acid mixture of 9:1 (v / v) as the extraction solvent. Subsequently, washing with pure methanol was continued for 6 hours to remove residual acetic acid. The completely eluted polymer particles were transferred to a petri dish and dried to constant weight in a vacuum drying oven at 50°C to obtain cyclamate molecularly imprinted polymer microspheres (MIPs). HPLC analysis of the final eluent confirmed the absence of template molecules.

[0077] 3. Preparation method of cyclamate Step S1: Catalytic reaction. Cyclohexylamine (19.82 g, 0.20 mol), aminosulfonic acid (20.40 g, 0.21 mol), and the prepared bifunctional ionic liquid (8.04 g, 20% of the total reactant mass) were added sequentially to a 250 mL three-necked flask equipped with a stir bar, thermometer, and condenser. Stirring was started, and the reaction was heated in an oil bath at 65 °C for 4.5 h. Thin-layer chromatography monitoring showed that the cyclohexylamine starting material spot had essentially disappeared.

[0078] Step S2: Smart Crystallization. After the reaction is complete, the system is cooled to 40°C. While stirring, a 20% NaOH aqueous solution is slowly added dropwise to adjust the pH to 8.0 (alkaline conditions). Then, 0.60 g of the prepared MIPs microsphere seed crystals (1.5% of the theoretical cyclamate yield of 40.25 g) is added. The cooling program is started, slowly decreasing the temperature to 8°C at a rate of 0.1°C / min, and aging at this temperature for 3 hours. During this process, a large number of crystals are observed to form and grow through an epitaxial growth mechanism, using the molecularly imprinted polymer material as nucleation sites.

[0079] Steps S3 and S4: Separation by fractionation. The crystalline slurry is filtered through a Buchner funnel to achieve solid-liquid separation. The resulting filtrate (i.e., the liquid mother liquor) is stored for later use. The solid (i.e., the solid phase) mainly consists of cyclamate crystals and MIPs microspheres. This solid mixture is transferred to a vibrating sieve. The obtained cyclamate crystals have intact crystal shapes, with a minimum size >150 μm, and are sieved using a 200-mesh standard sieve (approximately 75 μm pore size). Because the MIPs microspheres (5–30 μm) have a smaller particle size than the sieve pores, while the cyclamate crystals are larger, efficient separation is achieved. The cyclamate crystals on the sieve are collected.

[0080] Step S5: Product refining. The cyclamate crystals obtained by sieving are washed twice with 10 mL of 50% ethanol aqueous solution pre-cooled at 5℃ to remove trace amounts of ionic liquid adsorbed on the surface. The washed crystals are then dried in a vacuum drying oven at 55℃ for 6 hours to obtain the final cyclamate product, which is a white crystalline powder.

[0081] S6: MIPs seed recovery. The MIPs microspheres obtained after sieving are subjected to Soxhlet extraction again with the above methanol / acetic acid mixture for 3 hours. After drying, they can be returned to step S2 for use. Testing showed that the crystallization-inducing activity retention rate of the recovered MIPs was ≥93%.

[0082] S7: Ionic liquid recovery. The liquid mother liquor obtained in step S3 was dehydrated by passing it through a column packed with a 4Å molecular sieve, and then excess water was removed by rotary evaporation at 50°C and -0.09 MPa. The ionic liquid recovery rate was measured to be 90.5%. The recovered ionic liquid was directly used in the next batch of reaction in step S1, and the cyclohexylamine conversion rate was still ≥90%.

[0083] 4. Product Characterization and Results Product Yield and Purity: In this example, 35.6 g of cyclamate product was obtained. Based on cyclohexylamine, the yield was 35.6 g ÷ 40.25 g × 100% = 88.5%. HPLC analysis (C18 column, mobile phase: methanol-water = 30:70, detection wavelength 210 nm) showed a product purity of 99.5%.

[0084] Product melting point: The measured melting point of the product is 169-172℃, which is consistent with the literature value of cyclamate standard (169-172℃), confirming that the product structure is correct. Example 3

[0085] 1. Preparation of bifunctional ionic liquids Step S101: Synthesis of the crown ether-modified imidazolium salt intermediate. Under nitrogen protection, 4-bromobenzo-18-crown ether-6 (3.91 g, 10.0 mmol), methylimidazolium (1.48 g, 18.0 mmol), sodium tert-butoxide (2.16 g, 22.5 mmol), Pd(OAc)₂ (56.0 mg, 0.25 mmol), and XPhos (191.2 mg, 0.40 mmol) were added sequentially to a dry 100 mL three-necked flask. 30 mL of anhydrous toluene was added as a solvent. The system was heated to 90 °C and reacted for 4 h under nitrogen atmosphere with stirring. After the reaction was complete, the mixture was cooled to room temperature, and 30 mL of deionized water was added. The mixture was extracted with dichloromethane (3 × 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain a pale yellow viscous liquid. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1, v / v) to obtain a crown ether-modified imidazolium bromide intermediate, which was a colorless viscous liquid with a yield of 88%.

[0086] Step S102: Preparation of the target ionic liquid by ion exchange. The intermediate obtained above (approximately 3.5 g, approximately 7.0 mmol) was dissolved in 20 mL of acetonitrile. Sodium p-toluenesulfonate (1.50 g, 7.9 mmol) was added with stirring. The mixture was heated to 70 °C and reacted for 2 h. After the reaction was completed, the mixture was cooled and filtered to remove the generated sodium bromide solid. Most of the acetonitrile was removed by rotary evaporation of the filtrate. The resulting viscous liquid was washed three times with diethyl ether (3 × 20 mL) to remove residual organic matter. Finally, the product was vacuum dried at 60 °C for 24 h to obtain the target bifunctional ionic liquid, which was a pale yellow, transparent, viscous liquid with an ion exchange yield of 94%.

[0087] 2. Preparation of cyclamate molecularly imprinted polymer (MIP) microsphere seed crystals Step S201: Pre-assembly. The template molecule cyclamate (2.01 g, 10.0 mmol), the functional monomer acrylamide (5.68 g, 80.0 mmol), and methacrylic acid (6.90 g, 80.0 mmol) were dissolved in 80 mL of acetonitrile / water mixed solvent (v / v = 4 / 1). The mixture was stirred at 300 rpm for 2 h at room temperature to form a pre-assembled mixture.

[0088] Step S202: Polymerization. Add crosslinking agent EGDMA (39.64 g, 200.0 mmol) and initiator AIBN (251.6 mg, 1.8% of the total mass of the functional monomers) to the above mixture. After purging with nitrogen for 30 min to remove oxygen, seal the container. Place the reaction flask in a 70°C oil bath for thermally initiated polymerization for 6 h. After the reaction is complete, a hard, white, blocky polymer is obtained.

[0089] Step S203: Crushing and sieving. The block polymer is initially crushed using a mortar and pestle, and then ground using a ball mill. The resulting powder is sieved through a standard sieve to collect particles with a diameter in the range of 30–60 μm.

[0090] Step S204: Template elution and drying. The sieved polymer particles were loaded into the filter paper sleeve of a Soxhlet extractor. Extraction was performed continuously for 48 hours using a methanol:acetic acid mixture of 9:1 (v / v) as the extraction solvent. Subsequently, washing with pure methanol was continued for 6 hours to remove residual acetic acid. The completely eluted polymer particles were transferred to a petri dish and dried to constant weight in a vacuum drying oven at 50°C to obtain cyclamate molecularly imprinted polymer microspheres (MIPs). HPLC analysis of the final eluent confirmed the absence of template molecules.

[0091] 3. Preparation method of cyclamate Step S1: Catalytic reaction. Cyclohexylamine (19.82 g, 0.20 mol), aminosulfonic acid (20.40 g, 0.21 mol), and the prepared bifunctional ionic liquid (20.11 g, 50% of the total reactant mass) were added sequentially to a 250 mL three-necked flask equipped with a stir bar, thermometer, and condenser. Stirring was started, and the reaction was heated in an oil bath at 85 °C for 2.5 h. Thin-layer chromatography monitoring showed that the cyclohexylamine starting material spot had essentially disappeared.

[0092] Step S2: Smart Crystallization. After the reaction is complete, the system is cooled to 40°C. While stirring, a 20% NaOH aqueous solution is slowly added dropwise to adjust the pH to 7.8 (alkaline conditions). Then, 1.93g of the prepared MIPs microsphere seed crystals (4.8% of the theoretical cyclamate yield of 40.25g) is added. The cooling program is started, slowly decreasing the temperature to 15°C at a rate of 0.8°C / min, and aging at this temperature for 1 hour. During this process, a large number of crystals are observed to form and grow via an epitaxial growth mechanism, using the molecularly imprinted polymer material as nucleation sites.

[0093] Steps S3 and S4: Separation by fractionation. The crystalline slurry is filtered through a Buchner funnel to achieve solid-liquid separation. The resulting filtrate (i.e., the liquid mother liquor) is stored for later use. The solid (i.e., the solid phase) mainly consists of cyclamate crystals and MIPs microspheres. This solid mixture is transferred to a vibrating sieve. The obtained cyclamate crystals have intact crystal shapes, with a minimum size >150 μm, and are sieved using a 200-mesh standard sieve (approximately 75 μm pore size). Because the MIPs microspheres (30–60 μm) have a particle size smaller than the sieve pores, efficient separation of the cyclamate crystals and MIPs is achieved. The cyclamate crystals on the sieve are collected.

[0094] Step S5: Product refining. The cyclamate crystals obtained by sieving are washed twice with 10 mL of 50% ethanol aqueous solution pre-cooled at 5℃ to remove trace amounts of ionic liquid adsorbed on the surface. The washed crystals are then dried in a vacuum drying oven at 55℃ for 6 hours to obtain the final cyclamate product, which is a white crystalline powder.

[0095] S6: MIPs seed recovery. The MIPs microspheres obtained after sieving are extracted again by Soxhlet extraction with the above methanol / acetic acid mixture for 3 hours. After drying, they can be returned to step S2 for use. Testing showed that the crystallization-inducing activity retention rate of the recovered MIPs was ≥96%.

[0096] S7: Ionic liquid recovery. The liquid mother liquor obtained in step S3 was dehydrated by passing it through a column packed with a 4Å molecular sieve, and then excess water was removed by rotary evaporation at 50℃ and -0.09MPa. The ionic liquid recovery rate was measured to be 94.0%. The recovered ionic liquid was directly used in the next batch of reaction in step S1, and the cyclohexylamine conversion rate was still ≥95%.

[0097] 4. Product Characterization and Results Product Yield and Purity: In this example, 37.6 g of cyclamate product was obtained. Based on cyclohexylamine, the yield was 37.6 g ÷ 40.25 g × 100% = 93.5%. HPLC analysis (C18 column, mobile phase: methanol-water = 30:70, detection wavelength 210 nm) showed a product purity of 99.7%.

[0098] Product melting point: The measured melting point of the product is 170-172℃, which is consistent with the literature value of cyclamate standard (169-172℃), confirming that the product structure is correct.

[0099] Comparative Example 1 This comparative example is modified from the one disclosed in Example 1 as follows: In step S1, instead of adding a bifunctional ionic liquid, an equal mass of conventional ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4]) is added as a solvent, while the remaining steps and conditions remain unchanged.

[0100] Results and Effects Analysis: The reaction required 6 hours at 105℃, with a cyclohexylamine conversion rate of only ~85%. The resulting mixture was dark in color and contained numerous byproducts. HPLC analysis showed a significant increase in impurities such as cyclohexylurea (>5%). Subsequent crystallization using MIPs reduced the final product yield to 78%, with a purity of only 95.2%.

[0101] Comparative Example 2 This comparative example is modified from the one disclosed in Example 1 as follows: In step S1, an equimolar amount of p-toluenesulfonic acid is used to replace the bifunctional ionic liquid as the catalyst, while the remaining steps and conditions remain unchanged.

[0102] Results and Effects Analysis: Although p-toluenesulfonic acid catalyzes the reaction, it has no pre-organization ability. To achieve a high conversion rate, the reaction temperature needs to be increased to 95℃ and the reaction time extended to 5 hours. The strong acid environment exacerbates side reactions, resulting in poor product color and the production of a large amount of sodium sulfate after neutralization, increasing inorganic salt impurities in the system. These impurities significantly increase the separation load of the subsequent MIPs crystallization step and interfere with the specific crystallization process. The final product yield was only 81%, and the product purity analyzed by HPLC was 95.8%, with significant purity fluctuations (±1.5%) between different batches.

[0103] Comparative Example 3 This comparative example is modified from the one disclosed in Example 1 as follows: Steps S2 to S4 are completely omitted. After the reaction in step S1 is completed, the reaction solution is neutralized, and then the traditional purification process of evaporation concentration and hot water recrystallization is directly carried out. That is, MIPs-induced crystallization and subsequent solid-solid separation steps are not used.

[0104] Results and Effects Analysis: To obtain a product with a purity >99.5%, more than three hot water recrystallizations are required. Each recrystallization results in the loss of approximately 15-20% of the product in the mother liquor. Ultimately, the total product yield from the same feed amount is only 70%, and the process is energy-intensive, takes more than twice as long as in Example 1, and generates a large amount of wastewater containing salt and organic matter.

[0105] Comparative Example 4 This comparative example is modified from the one disclosed in Example 1 as follows: In step S2, instead of adding cyclamate molecularly imprinted polymer material, an equal mass of non-imprinted polymer (NIP) microspheres (prepared in the same way as MIPs, except without the addition of the template molecule cyclamate) are added as seed crystals, while the remaining steps and conditions remain unchanged.

[0106] Results and Effects Analysis: After adding NIP microspheres, the supersaturation of the system was released slowly, but the crystallization-induced selectivity was lost. The crystallized product contained a large amount of unreacted cyclohexylamine hydrochloride and other impurities. After separation and drying, the product purity was only 91.5%. To meet food-grade standards (>99%), the crude product must be recrystallized at least three times, resulting in a total yield loss of less than 65%.

[0107] The yield and purity results of cyclamate obtained in Examples 1-3 and Comparative Examples 1-4 are summarized in Table 1.

[0108]

[0109] As shown in Table 1, all three embodiments stably achieved a balance between high yield (88.5-93.5%) and high purity (>99.5%) within a wide range of process parameters (such as reaction temperature 65-85℃ and ionic liquid dosage 20-50%), demonstrating the reliability, efficiency and adjustability of the process.

[0110] The significantly reduced yields and purities of Comparative Example 1 (using a conventional ionic liquid) and Comparative Example 2 (using a traditional acid catalyst) directly demonstrate that the unique "pre-organized catalysis" function of bifunctional ionic liquids is indispensable for achieving low-temperature, high-selectivity reactions.

[0111] Comparative Example 4 (using non-imprinted polymers) had the lowest yield and purity, highlighting that the "specific recognition" function of molecularly imprinted polymers (MIPs) is the core of achieving efficient one-step crystallization purification, which cannot be replaced by non-specific materials.

[0112] Although Comparative Example 3 (using traditional recrystallization) barely achieved high purity through multiple purifications, the yield loss was severe (~70%), and the process was lengthy and energy-intensive. From the perspective of economic benefits and green chemistry, this highlights the huge advantages brought by the integration of reaction and MIPs intelligent crystallization in this application, achieving high yield and ultra-high purity simultaneously in a one-step operation.

[0113] 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 method for preparing sodium cyclohexylaminosulfonate, characterized in that, The method includes the following steps: S1. In the presence of a bifunctional ionic liquid, cyclohexylamine and aminosulfonic acid are reacted at 60-85°C for 2-5 hours to obtain a reaction solution containing cyclohexylaminosulfonic acid; the bifunctional ionic liquid is a crown ether modified imidazolium salt ionic liquid. S2. Neutralize the reaction solution to alkaline, then add cyclamate molecularly imprinted polymer material as seed crystals to induce cyclamate crystallization and precipitate, thus obtaining a crystallized slurry; the cyclamate molecularly imprinted polymer material is micron-sized particles prepared by polymerization and template elution using cyclamate as a template molecule and acrylamide and methacrylic acid as functional monomers. S3. The crystallized slurry is subjected to solid-liquid separation to obtain a solid phase and a liquid mother liquor; the solid phase contains co-precipitated cyclamate crystals and the molecularly imprinted polymer material. S4. Perform solid-solid separation on the solid phase to separate the cyclamate molecularly imprinted polymer material and the cyclamate crystal; S5. Wash and dry the cyclamate crystals to obtain the cyclamate product.

2. The method for preparing sodium cyclohexylaminosulfonate according to claim 1, characterized in that, The method further includes the following steps: S6. The cyclamate molecularly imprinted polymer material is recycled back to step S2 after being regenerated. S7. The liquid mother liquor is dehydrated to recover the regenerated bifunctional ionic liquid, which is then returned to step S1 for recycling.

3. The method for preparing sodium cyclohexylaminosulfonate according to claim 1, characterized in that, In step S1, the molar ratio of cyclohexylamine to aminosulfonic acid is 1:(1.0~1.1).

4. The method for preparing sodium cyclohexylaminosulfonate according to claim 1, characterized in that, In step S1, the mass of the bifunctional ionic liquid is 20-50% of the total mass of the cyclohexylamine and the aminosulfonic acid.

5. The method for preparing sodium cyclohexylaminosulfonate according to claim 4, characterized in that, In step S1, the preparation method of the bifunctional ionic liquid includes the following steps: S101. In the presence of a catalyst system, 4-bromobenzo-18-crown ether-6 and methylimidazolium are reacted at 80-90°C for 4-12 h to obtain a crown ether-modified imidazolium salt intermediate. S102. The crown ether-modified imidazolium salt intermediate is subjected to an ion exchange reaction with sodium p-toluenesulfonate in a solvent. After the reaction is completed, the mixture is separated and purified to obtain the bifunctional ionic liquid. The temperature of the ion exchange reaction is 40-70°C and the time is 2-8 hours.

6. The method for preparing sodium cyclohexylaminosulfonate according to claim 5, characterized in that, In step S101, the molar ratio of 4-bromobenzo-18-crown ether-6 to methylimidazole is 1:(1.2-2.0); The catalyst system consists of Pd(OAc)2, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and sodium tert-butoxide. The molar amount of Pd(OAc)2 is 0.5 to 5% of the molar amount of 4-bromobenzo-18-crown ether-6. The molar ratio of 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl to Pd(OAc)2 is (1 to 4):

1. The molar amount of sodium tert-butoxide is 1.0 to 3.0 times the molar amount of methylimidazolium. In step S102, the molar ratio of the crown ether-modified imidazolium salt intermediate to the sodium p-toluenesulfonate is 1:(1.0-1.2).

7. The method for preparing sodium cyclohexylaminosulfonate according to claim 1, characterized in that, In step S2, the mass of the cyclamate molecularly imprinted polymer material is 1-5% of the theoretical cyclamate mass.

8. The method for preparing sodium cyclohexylaminosulfonate according to claim 7, characterized in that, In step S2, the method for preparing the cyclamate molecularly imprinted polymer material includes the following steps: S201. Dissolve the template molecule cyclamate and the functional monomer in a polar solvent and stir at room temperature for 2-6 hours to form a mixed system containing a pre-assembled complex; the functional monomer is composed of acrylamide and methacrylic acid; S202. Under the protection of nitrogen or inert gas, add the crosslinking agent ethylene glycol dimethacrylate and the free radical initiator azobisisobutyronitrile to the mixture system, and carry out a thermally initiated polymerization reaction at 50-70°C for 6-24 hours to obtain a block polymer. S203. The block polymer is crushed, ground and sieved to obtain polymer particles with a particle size of 1 to 100 μm; S204. The polymer particles are subjected to Soxhlet extraction and continuous washing with a mixed solvent of methanol and acetic acid until the eluent does not contain the template molecule cyclamate. The eluted polymer particles are then vacuum dried to obtain the cyclamate molecularly imprinted polymer material.

9. The method for preparing sodium cyclohexylaminosulfonate according to claim 8, characterized in that, In step S201, the molar ratio of the template molecule cyclamate, the acrylamide, and the methacrylic acid is 1:(4-8):(4-8); The molar ratio of the crosslinking agent to the functional monomer is (5-20):1, and the mass of the free radical initiator is 0.5-2% of the mass of the functional monomer.

10. The method for preparing sodium cyclohexylaminosulfonate according to claim 1, characterized in that, In step S2, after adding seed crystals, the system is cooled to 5-15°C at a rate of 0.1-1°C / min to induce crystallization.

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