Magnetic nanosplitting agent platform for chiral compound crystallization resolution

Abstract

The application discloses a magnetic nano-resolving agent platform for chiral compound crystallization resolution. The magnetic nano-resolving agent platform takes hydrophobic ligand stabilized magnetic nanoparticles and block copolymer containing non-covalent binding sites as assembly units, forms polymer composite nanoparticles with magnetic responsiveness through solution co-assembly, and then constructs the magnetic nano-resolving agent through electrostatic or hydrogen bond complexation between chiral small molecules and the nanoparticle crown layer, so as to be used for crystallization resolution of racemic compounds. The preparation process does not need to synthesize chiral block polymers in advance, and can obtain magnetic nano-resolving agents suitable for different chiral compound crystallization resolution systems by changing chiral small molecules, adjusting polymer structure, magnetic nanoparticle proportion and assembly morphology. The application focuses on providing a modular preparation process of a kind of magnetic nano-resolving agent, which is suitable for crystallization resolution of various chiral compounds in aqueous phase and organic solvent system.

Description

Technical Field

[0001] This invention belongs to the field of chiral separation and nanomaterials, specifically relating to a magnetic nano-resolution agent platform for the crystallization and resolution of chiral compounds, its preparation method, and its application. Background Technology

[0002] Single enantiomers of chiral compounds have important applications in pharmaceuticals, pesticides, fragrances, fine chemicals, and functional materials, making the acquisition of high-purity single enantiomers crucial. However, traditional asymmetric synthesis or salt-forming resolution routes are often limited by cost and scale-up challenges. Therefore, developing efficient, low-cost, and scalable chiral resolution technologies is of great significance for the industrial production and safe use of chiral drugs.

[0003] Crystallization resolution is an important method for obtaining high-optical-purity chiral compounds, offering advantages such as simple operation, low cost, and ease of scale-up. For racemic mixture crystal systems, single enantiomers can be obtained through spontaneous crystallization resolution, preferential crystallization resolution, and reverse crystallization resolution. However, Pasteurized spontaneous crystallization resolution typically relies on manual identification and sorting of enantiomer crystals, which often have similar sizes, appearances, and physical properties, making rapid and quantitative sorting difficult. Preferential crystallization resolution often requires repeated heating, cooling, filtration, feeding, and recrystallization, making the operation cumbersome, demanding high process control, and resulting in low single-crystallization efficiency.

[0004] In recent years, the strategy of using magnetic nanomaterials to assist crystallization separation has provided a new approach to solving the above problems. After composite magnetic particles enter or bind to a specific crystal, they can endow the crystal with magnetic responsiveness, enabling it to rapidly separate from non-magnetic crystals under an applied magnetic field. This transforms the traditional crystal selection process into a physical separation process similar to "magnetic separation." Nat. Commun. 2019, 10 , 1964; J. Am. Chem. Soc. 2025, 147 (37265). However, existing magnetic nanoparticle resolving agent systems typically rely on the co-assembly of pre-synthesized chiral block polymers with magnetic nanoparticles. When the substrate to be resolved is changed, the original chiral polymer recognition shell may not be compatible with the new crystal surface, often requiring the redesign and synthesis of new chiral polymers. This limits their platform-based application and substrate expansion capabilities. Therefore, there is an urgent need to develop a magnetic nanoparticle resolving agent platform that is easy to prepare, structurally tunable, and allows for modular replacement of chiral recognition units. Summary of the Invention

[0005] The purpose of this invention is to address the problem of limited substrate adaptability of existing magnetic nano-resolving agents in the chiral crystallization resolution process, and to provide a magnetic nano-resolving agent platform for the chiral compound crystallization resolution, its modular preparation method, and its application in the chiral compound crystallization resolution. This method is currently applicable to chiral compound systems that crystallize and precipitate in the form of racemic mixtures (conglomerates).

[0006] The magnetic nano-resolving agent platform provided by the present invention has a core-shell structure, with magnetic nanoparticles as the core and a polymer assembly layer as the shell; that is, the magnetic nano-resolving agent platform includes magnetic nanoparticles and a polymer assembly layer that coats or is composited on the outside of the magnetic nanoparticles.

[0007] The magnetic nanoparticles may be Fe, Co, FePt, CoPt, Fe3O4, etc. γ- Fe2O3 or MFe2O4, wherein M is at least one of Zn, Mn, Ni or Co, and its particle size can be 5-100 nm; preferably, it is oleic acid-stabilized Fe3O4 nanoparticles with a particle size of 20-30 nm.

[0008] The polymer assembly layer is formed from block copolymers containing coordination or ion-binding sites.

[0009] The block copolymer is a block copolymer containing poly(4-vinylpyridine) segments; Preferably, the block copolymer is poly(4-vinylpyridine)-block-polystyrene or polystyrene-block-poly(4-vinylpyridine), wherein the poly(4-vinylpyridine) segments can undergo protonation, electrostatic interaction, hydrogen bonding or coordination with chiral acidic small molecules, and the polystyrene segments are used to stabilize hydrophobic magnetic nanoparticles and participate in the formation of composite micelle structures.

[0010] The present invention also provides a magnetic nano-resolving agent.

[0011] The magnetic nano-resolving agent is formed by non-covalent compounding of the above-mentioned magnetic nano-resolving agent with chiral small molecules.

[0012] The chiral small molecule can non-covalently recombine with poly(4-vinylpyridine) segments and provide a chiral recognition interface; The chiral small molecule may be a chiral sulfonic acid, a chiral carboxylic acid, or a salt thereof; specifically, it may be... L -Sulfoalanine, R - Mandelic acid, L - Camphor sulfonic acid, R -NAP ( R -Naproxen or its salts.

[0013] The magnetic nano-resolving agent described in this invention (the morphology of the magnetic nano-resolving agent platform is almost identical before and after composite chiral small molecules) can exhibit cherry-like, patchy, fused, worm-like, or other composite micelle morphologies; preferably, it is a cherry-like magnetic micelle that combines good dispersibility, magnetic responsiveness, and crystal interface interaction capabilities. The morphology can be controlled by adjusting the block copolymer composition, the mass ratio of magnetic nanoparticles to polymer, the solvent composition, the feeding method, and the dialysis conditions.

[0014] The present invention also provides a method for preparing the above-mentioned magnetic nano-resolving agent.

[0015] The method for preparing magnetic nano-resolution agents provided by this invention includes the following steps: (1) Dissolve the block copolymer containing poly(4-vinylpyridine) segments in a good solvent to obtain a polymer solution; (2) Add a hydrophobic ligand-stabilized magnetic nanoparticle dispersion to the polymer solution and mix thoroughly; (3) Under stirring conditions, a selective solvent or precipitation-inducing solvent is slowly added to the mixed solution to cause the magnetic nanoparticles and block copolymers to co-assemble and form magnetic polymer composite micelles. (4) Remove unassembled components and organic solvents, and transfer the system to the aqueous or alcohol phase; (5) Add chiral small molecules to the obtained magnetic polymer composite micelles and construct a chiral interface layer on the outer layer of the micelles through non-covalent composite; (6) Remove the uncomposite chiral small molecules to obtain magnetic nano-resolving agent.

[0016] This invention proposes a method for first co-assembling hydrophobically ligand-stabilized magnetic nanoparticles with a polystyrene-poly(4-vinylpyridine) block copolymer to form a magnetic nano-resolving agent platform with a poly(4-vinylpyridine) shell. This platform is then non-covalently compounded with chiral small molecules to form a magnetic nano-resolving agent. This method eliminates the need for pre-synthesizing chiral block polymers and allows for the acquisition of magnetic nano-resolving agents suitable for different crystallization resolution systems by changing the chiral small molecules, adjusting the composition of the block copolymer, and modifying the proportion of magnetic nanoparticles.

[0017] In step (1) of the above method, the good solvent may be chloroform, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, dioxane or a combination thereof; In step (3), the selective solvent or precipitation-inducing solvent may be ethanol, methanol, isopropanol, water, acidic water or a combination thereof.

[0018] The mass ratio of the magnetic nanoparticles to the block copolymer can be 0.25-5:1, preferably 3:1; The amount of the chiral small molecule relative to the poly(4-vinylpyridine) repeating unit can be 0.1-5.0 equivalents, preferably 0.5-2.0 equivalents, and more preferably 1.0 equivalents.

[0019] The present invention also provides the application of the above-mentioned magnetic nano-resolving agent platform or magnetic nano-resolving agent in the crystallization and resolution of chiral compounds.

[0020] In the application described, the chiral compound may include any one of chiral amino acids and their hydrates, chiral amino acid derivatives, chiral alcohols, chiral acids, and chiral esters that are crystallized in the form of racemic mixtures.

[0021] Specifically, it can be... DL- Asparagine monohydrate, DL- Threonine, DL- Allothreonine, racemic hydrogenated benzoin, naproxen methyl ester, etc.

[0022] The present invention also provides a method for crystallization and resolution of chiral compounds.

[0023] The method for crystallizing and separating chiral compounds includes: preparing a supersaturated solution or a solution to be crystallized from the chiral compound to be separated; adding the magnetic nano-resolving agent and dispersing it evenly; precipitating crystals by isothermal crystallization, cooling crystallization, seed crystal-induced crystallization, or solvent evaporation crystallization; after crystallization, using an external magnetic field to separate the magnetically responsive crystals from the non-magnetic or weakly magnetic crystals; and collecting the magnetic and non-magnetic crystals separately, thereby achieving the crystallization and separation of the chiral compound.

[0024] The present invention has the following advantages: 1. This invention constructs a magnetic nano-resolving agent through "co-assembly of magnetic nanoparticles and block copolymers - non-covalent composite of chiral small molecules", which eliminates the need for pre-synthesizing chiral block polymers and has a simple preparation process with a high degree of modularity.

[0025] 2. This invention can quickly adjust the chiral interface layer by replacing chiral small molecules, thereby adapting to different substrate crystal surfaces, which is beneficial for forming a scalable chiral crystallization separation platform.

[0026] 3. This invention combines crystallization separation with magnetic field sorting, which can reduce manual crystal picking, repeated filtering and multiple recrystallization operations, providing a new technical path for the rapid, automated and scalable separation of chiral compounds. Attached Figure Description

[0027] Figure 1 (a) shows the advantages of this strategy; (b) is a schematic diagram of the preparation of magnetic nano-resolving agents using a solution co-assembly-chiral small molecule post-composite step.

[0028] Figure 2In the middle (a), (a–c) Fe3O4-OA and Fe3O4@PS magnetic nanoparticles are shown. 91 -P4VP 58 and Fe3O4@PS 91 -P4VP 58 / L - TEM image of CA. (d) DLS particle size distribution. (e) TGA curve. (f) FTIR spectrum. (g) Fe3O4@PS 91 -P4VP 58 and Fe3O4@PS 91 -P4VP 58 / L - High-resolution XPS spectra of CA in the S 2p region. (h) VSM curves show that the superparamagnetism is maintained after co-assembly and complexation of small molecules.

[0029] Figure 3 Fe3O4-OA and P4VP 58 - b -PS n TEM image of the assembly obtained by co-assembling block copolymers.

[0030] Figure 4 Typical HPLC spectrum of non-magnetic crystals obtained by resolving asparagine monohydrate.

[0031] Figure 5 Typical HPLC spectrum of magnetic crystals obtained by resolving asparagine monohydrate.

[0032] Figure 6 Typical HPLC spectrum of non-magnetic crystals obtained by resolving threonine.

[0033] Figure 7 Typical HPLC spectrum of magnetic crystals obtained by resolving threonine. Detailed Implementation

[0034] The present invention will now be described in further detail with reference to specific embodiments. The given embodiments are merely illustrative of the invention and not intended to limit its scope. The embodiments provided below can serve as a guide for further improvements by those skilled in the art and do not constitute a limitation on the invention in any way.

[0035] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0036] Example 1, P4VP 58-PS 91 Platform-type magnetic nanomicelles were prepared by co-assembly with Fe3O4-OA. Add P4VP to a 50 mL round-bottom flask 58 -PS 91 (10 mg) was dissolved completely in chloroform (20 mL) to obtain a block copolymer solution. A chloroform solution of Fe3O4-OA (containing 30 mg of Fe3O4-OA, 1.0 mL, with an average particle size of 25 nm) was added to the above solution and stirred until homogeneous. Under stirring conditions, ethanol (60 mL) was slowly added dropwise over 30 min to assemble the solution.

[0037] After assembly, the resulting solution was transferred to a dialysis bag with a molecular weight cutoff of 12,000-14,000 Da. The solution was first dialyzed with ethanol for 24 h to obtain an ethanol dispersion of the magnetic polymer composite micelles. Then, it was dialyzed with acidic water (pH=3) for 24 h to obtain an aqueous dispersion of the magnetic polymer composite micelles.

[0038] Figure 3 Fe3O4-OA and P4VP 58 - b -PS n TEM image of the assembly obtained by co-assembling block copolymers.

[0039] Example 2: Preparation of magnetic nano-resolving agents by composite chiral small molecules In this embodiment, the magnetic polymer composite micelles prepared in Example 1 are used as a precursor. Magnetic nano-resolving agents for different crystallization systems are prepared by non-covalently combining them with different chiral small molecules. Depending on the solvent system used for subsequent crystallization and resolution, the chiral small molecule composite process can be carried out in an aqueous phase or an organic phase. Figure 1 As shown in (b).

[0040] (I) Preparation of magnetic nano-resolving agents by aqueous chiral small molecule composite Take the aqueous dispersion of the magnetic polymer composite micelles obtained in Example 1, and add... L -Sulfoalanine aqueous solution (0.70 mL, containing 7.0 mg) L -Sulfoalanine). L The amount of sulfoalanine added was one equivalent relative to the poly(4-vinylpyridine) repeating unit. The resulting mixture was stirred at room temperature for 12 h to allow it to mature. L -Sulfoalanine electrostatically recombines with the P4VP canopy on the surface of the magnetic polymer composite micelles, thereby forming a chiral recognition interface on the surface of the magnetic polymer composite micelles.

[0041] After the complexation was completed, the resulting dispersion was placed in a dialysis bag and dialyzed with water for 12 h to remove unreacted free L-sulfoalanine. The dialyzed dispersion was centrifuged, and the brownish-black solid at the bottom was collected. The resulting solid was redispersed with water and then freeze-dried to obtain... L -Sulfoalanine-based magnetic nano-resolving agent Fe3O4@PS 91 -P4VP 58 / L -CA, product mass 26 mg.

[0042] Figure 2 In the middle (a), (a–c) Fe3O4-OA and Fe3O4@PS magnetic nanoparticles are shown. 91 -P4VP 58 and Fe3O4@PS 91 -P4VP 58 / L - TEM image of CA. (d) DLS particle size distribution. (e) TGA curve. (f) FTIR spectrum. (g) Fe3O4@PS 91 -P4VP 58 and Fe3O4@PS 91 -P4VP 58 / L - High-resolution XPS spectra of CA in the S 2p region. (h) VSM curves show that the superparamagnetism is maintained after co-assembly and complexation of small molecules.

[0043] The obtained Fe3O4@PS 91 -P4VP 58 / L -CA can be used for the crystallization resolution of aqueous chiral compounds, such as asparagine monohydrate, threonine, allothreonine and other racemic systems.

[0044] (II) Preparation of Magnetic Nanoparticle Resolving Agents by Organic-Phase Chiral Small Molecule Composites Take the cherry-type magnetic polymer composite micelles Fe3O4@PS obtained in Example 1 91 -P4VP 58 An ethanol dispersion. Specifically, Fe3O4@PS was added to a 100 mL flask. 91 -P4VP 58 40 mL of ethanol dispersion containing Fe3O4@PS 91 -P4VP 58 The mass is 80 mg.

[0045] Under stirring conditions, add to the above ethanol dispersion R- An ethanolic solution of mandelic acid (7.8 mg, corresponding to 1 equivalent of the P4VP binding site). After addition, the reaction was continued with stirring at room temperature for 24 h. R Mandelic acid undergoes a non-covalent complexation with the P4VP segment. The resulting dispersion is centrifuged, and the black solid is collected. The black solid is dried to obtain... R - Mandelic acid-based magnetic nano-resolving agent Fe3O4@PS 91 -P4VP 58 / R-MA.

[0046] The obtained Fe3O4@PS 91 -P4VP 58 / R-MA can be used for the crystallization and resolution of chiral compounds in organic solvent systems, such as hydrogenated benzoin.

[0047] (III) Complexation with other chiral small molecules remove L- sulfoalanine and R- Besides mandelic acid, other chiral small molecule acids with a single chiral configuration can also be used to composite with the magnetic polymer micelles obtained in Example 1. The chiral small molecule acid can be a chiral sulfonic acid, a chiral carboxylic acid, or a salt thereof.

[0048] Example 3: Effect of the ratio of magnetic nanoparticles to polymer on assembly morphology Following the methods of Examples 1 and 2, the Fe3O4-OA and PS were adjusted. 91 -P4VP 58 Magnetic nano-resolving agents with different morphologies were prepared by mass ratio of 0.25:1 to 5:1, preferably 3:1. The resulting assemblies can exhibit cherry-like, patchy, fused, or worm-like morphologies. Their structure, particle size, organic component content, chiral small molecule complexation, and magnetic response properties were characterized by transmission electron microscopy, dynamic light scattering, thermogravimetric analysis, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and vibrating sample magnetometer.

[0049] Example 4: Magnetic nano-resolving agent used for the crystallization separation of asparagine monohydrate In this embodiment, the magnetic nano-resolving agent (Fe3O4@PS) prepared in Example 2 is used. 91 -P4VP 58 / L -CA) is used for the aqueous phase crystallization resolution of racemic asparagine monohydrate.

[0050] The specific operating method is as follows: (1) Add racemic asparagine monohydrate to a 20 mL vial rac-Add 0.55 g of Asn·H₂O and 5.0 mL of deionized water. Heat and stir the resulting mixture in a 70°C oil bath until the solid is completely dissolved, yielding a clear solution.

[0051] (2) Filter the solution obtained in step (1) while it is still hot to remove insoluble impurities or undissolved solids. Transfer the filtered clear solution to a 25 mL beaker.

[0052] (3) Add 11 mg of the magnetic nano-resolving agent solid powder prepared in Example 2 to the clear solution obtained in step (2). The amount added is 2 wt% of the mass of racemic asparagine monohydrate. After addition, the system is ultrasonically dispersed to make the magnetic nano-resolving agent uniformly dispersed in the crystallization solution.

[0053] (4) Place the above solution containing the magnetic nano-resolving agent in a water bath and slowly cool it from 70°C to 25°C. After cooling to near the crystallization temperature, add a small amount of... D Asn·H₂O seed crystals were used to induce the crystallization of asparagine monohydrate. The crystals were then allowed to stand at 25°C for 24 hours to crystallize.

[0054] (5) After crystallization, the upper mother liquor is poured off and the resulting crystal mixture is collected. The crystals are washed with an ethanol / water mixed solvent (ethanol to water volume ratio of 2:1) to remove residual mother liquor and free magnetic nano-resolving agent from the crystal surface. The washed crystals are dried under vacuum to obtain a crystal mixture containing magnetic and non-magnetic crystals.

[0055] (6) Place the dried crystal mixture obtained in step (5) near an external magnetic field, and separate the magnetic crystal components by adsorption with a magnet; collect the crystals that are not adsorbed by the magnet as non-magnetic crystal components. Collect the magnetic crystal components and non-magnetic crystal components separately, and perform weighing and chiral HPLC tests on the ee value.

[0056] Figure 4 and Figure 5 The results showed that the yield of the non-magnetic crystalline component was 17.6%, with an ee value of 95.7%; the yield of the magnetic crystalline component was 19.3%, with an ee value of 89.6%. These results indicate that the magnetic nano-resolving agent prepared in Example 2 can selectively impart magnetic responsiveness to one of the enantiomers during the crystallization of racemic asparagine monohydrate. After crystallization, the magnetic crystalline component can be separated from the non-magnetic crystalline component by applying an external magnetic field, thereby achieving the crystallization separation of racemic asparagine monohydrate.

[0057] Example 6: Magnetic nano-resolving agent for the crystallization and resolution of threonine In this embodiment, the magnetic nano-resolving agent Fe3O4@PS prepared in Example 2 is used. 91-P4VP 58 / L -CA is used for the aqueous phase crystallization resolution of racemic threonine.

[0058] The specific operating method is as follows: (1) Add racemic threonine to a 20 mL vial rac- Add 1.4 g of thallium sulfate and 4.0 g of deionized water. Heat the resulting mixture at 75 degrees Celsius with stirring until the solid is completely dissolved, yielding a clear solution.

[0059] (2) Filter the solution obtained in step (1) while it is still hot to remove insoluble impurities or undissolved solids. Transfer the filtered clear solution to a 25 mL beaker.

[0060] (3) Add the magnetic nano-resolving agent prepared in Example 2 to the clear solution obtained in step (2). The amount of magnetic nano-resolving agent added is 2 wt% of the mass of racemic threonine, that is, 28 mg of magnetic nano-resolving agent is added. After addition, the system is ultrasonically dispersed to make the magnetic nano-resolving agent uniformly dispersed in the crystallization solution.

[0061] (4) The solution containing the magnetic nano-resolving agent was placed in a 25°C water bath and slowly cooled to the crystallization temperature. A small amount of threonine seed crystals were added to induce threonine crystallization. The solution was then allowed to stand for 24 hours to crystallize.

[0062] (5) After crystallization, the supernatant mother liquor is poured off and the resulting crystal mixture is collected. The crystals are washed with an ethanol / water mixed solvent to remove residual mother liquor and free magnetic nano-resolving agent from the crystal surface. The washed crystals are dried under vacuum to obtain a crystal mixture containing magnetic and non-magnetic crystals.

[0063] (6) Place the dried crystal mixture obtained in step (5) near an external magnetic field, and separate the magnetic crystal components by adsorption with a magnet; collect the crystals that are not adsorbed by the magnet as non-magnetic crystal components. Collect the magnetic crystal components and non-magnetic crystal components separately, and perform weighing and chiral analysis.

[0064] The crystal composition obtained in this embodiment was characterized for yield and enantiomeric excess. The results showed that the nonmagnetic crystal composition was... L -Threonine, with a yield of 17.7% and an ee value of 91.7%; the magnetic crystal composition is as follows: D -Threonine, with a yield of 19.9% ​​and an ee value of 82.2%.

[0065] Example 7: Magnetic nano-resolving agent for the crystallization and resolution of hydrogenated benzoin In this embodiment, the organic chiral small molecule complex obtained in Example 2 is used. R- Mandelic acid-modified magnetic nano-resolving agent (Fe3O4@PS) 91 -P4VP 58 / R -MA) is used for the crystallization and separation of the ethanol phase of racemic hydrogenated benzoin.

[0066] The specific operating method is as follows: (1) Add ( ) to a 20 mL vial S,S )-Hydrogenated benzoin 0.25 g, ( R,R 0.25 g of hydroxybenzoin and 1.7 mL of ethanol were added. The resulting mixture was heated and stirred at 60 °C until the solid was completely dissolved, yielding a clear solution.

[0067] (2) Filter the solution obtained in step (1) while it is still hot to remove insoluble impurities or undissolved solids, and obtain the racemic hydrogenated benzoin ethanol solution to be separated.

[0068] (3) Add the solution prepared in Example 2 to the filtrate obtained in step (2). R- Mandelic acid composite magnetic nano-resolving agent (10 mg, corresponding to 2 wt% of the total mass of racemic hydrogenated benzoin). After addition, the system is ultrasonically dispersed to ensure that the magnetic nano-resolving agent is uniformly dispersed in the crystallization solution.

[0069] (4) Place the above-mentioned crystallized solution containing the magnetic nano-resolving agent in a water bath and slowly cool it to 15°C. After cooling, add a small amount of ( S,S Seed crystals of hydroxybenzoin were used to induce the crystallization of hydroxybenzoin. The crystals were then allowed to stand at 15°C for 12 h to crystallize.

[0070] (5) After crystallization, the upper mother liquor was poured off and the resulting crystal mixture was collected. The crystals were washed with an ethanol / water mixed solvent to remove residual mother liquor and free magnetic nano-resolving agent from the crystal surface. The washed crystals were dried under vacuum to obtain a mixture of hydrogenated benzoin crystals containing magnetic and non-magnetic crystals.

[0071] (6) Place the dried crystal mixture obtained in step (5) near an external magnetic field, and separate the magnetic crystal components by adsorption with a magnet; collect the crystals that are not adsorbed by the magnet as non-magnetic crystal components. Collect the magnetic crystal components and non-magnetic crystal components separately, and perform weighing and chiral high-performance liquid chromatography analysis.

[0072] (7) After dissolving the obtained crystalline sample, chiral HPLC testing was performed using an OD-H chiral column. The results showed that the non-magnetic crystalline component was ( S,S )-Hydrogenated benzoin, with a yield of 14.1% and an ee value of 75%; the magnetic crystal composition is ( R,R)-Hydrogenated benzoin, with a yield of 15.9% and an ee value of 51%.

[0073] The present invention has been described in detail above. Those skilled in the art will recognize that the invention can be practiced in a wide range of ways with equivalent parameters, concentrations, and conditions without departing from its spirit and scope, and without requiring unnecessary experiments. While specific embodiments have been provided, it should be understood that further modifications can be made to the invention. In summary, according to the principles of the invention, this application is intended to include any changes, uses, or improvements to the invention, including changes made using conventional techniques known in the art that depart from the scope disclosed herein.

Claims

1. A magnetic nano-resolving agent platform having a core-shell structure, with magnetic nanoparticles as the core and a polymer assembly layer as the shell; that is, the magnetic nano-resolving agent platform includes magnetic nanoparticles and a polymer assembly layer coating or composited on the outside of the magnetic nanoparticles.

2. The magnetic nano-resolving agent platform according to claim 1, characterized in that, The magnetic nanoparticles are Fe, Co, FePt, CoPt, Fe3O4, γ- Fe2O3, MFe2O4, wherein M is at least one of Zn, Mn, Ni or Co, and its particle size is 5-100 nm; The polymer assembly layer is formed from block copolymers containing coordination or ion-binding sites.

3. The magnetic nano-resolving agent platform according to claim 2, characterized in that, The block copolymer is a block copolymer containing poly(4-vinylpyridine) segments; Specifically, the block copolymer is poly(4-vinylpyridine)-block-polystyrene or polystyrene-block-poly(4-vinylpyridine).

4. A magnetic nano-resolving agent, formed by non-covalently combining the magnetic nano-resolving agent according to any one of claims 1-3 with a chiral small molecule; in, The chiral small molecule can non-covalently recombine with poly(4-vinylpyridine) segments and provide a chiral recognition interface.

5. The magnetic nano-resolving agent according to claim 4, characterized in that, The chiral small molecule is a chiral sulfonic acid, a chiral carboxylic acid, or a salt thereof; Specifically, the chiral small molecule is L -Sulfoalanine, R - Mandelic acid, L - Camphor sulfonic acid, R - Naproxen or its salts.

6. A method for preparing the magnetic nano-resolving agent according to claim 4 or 5, comprising the following steps: (1) Dissolve the block copolymer containing poly(4-vinylpyridine) segments in a good solvent to obtain a polymer solution; (2) Add a hydrophobic ligand-stabilized magnetic nanoparticle dispersion to the polymer solution and mix thoroughly; (3) Under stirring conditions, a selective solvent or precipitation-inducing solvent is slowly added to the mixed solution to cause the magnetic nanoparticles and block copolymers to co-assemble and form magnetic polymer composite micelles. (4) Remove unassembled components and organic solvents, and transfer the system to the aqueous or alcohol phase; (5) Add chiral small molecules to the obtained magnetic polymer composite micelles and construct a chiral interface layer on the outer layer of the micelles through non-covalent composite; (6) Remove the uncomposite chiral small molecules to obtain magnetic nano-resolving agent.

7. The method according to claim 6, characterized in that, In step (1), the good solvent is chloroform, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, dioxane, or a combination thereof; In step (3), the selective solvent or precipitation-inducing solvent is ethanol, methanol, isopropanol, water, acidic water, or a combination thereof; The mass ratio of the magnetic nanoparticles to the block copolymer is 0.25-5:1; The chiral small molecule is used in an amount of 0.1-5.0 equivalents relative to the poly(4-vinylpyridine) repeating unit.

8. The application of the magnetic nano-resolving agent platform according to any one of claims 1-3 or the magnetic nano-resolving agent according to claim 4 or 5 in the crystallization resolution of chiral compounds.

9. The application according to claim 8, characterized in that, The chiral compounds include any one of chiral amino acids and their hydrates, chiral amino acid derivatives, chiral alcohols, chiral acids, and chiral esters that are crystallized in the form of racemic mixtures.

10. A method for crystallizing and resolving chiral compounds, comprising: Prepare a supersaturated solution or a solution to be crystallized from the chiral compound to be separated. Add the magnetic nano-resolving agent as described in claim 4 or 5 and disperse it evenly; Crystals are precipitated by isothermal crystallization, cooling crystallization, seed crystallization, or solvent evaporation crystallization; after crystallization, an external magnetic field is used to separate the magnetically responsive crystals from the non-magnetic or weakly magnetic crystals; the magnetic and non-magnetic crystals are collected separately, thus realizing the crystallization separation of chiral compounds.

Images