Method for chiral resolution of RS-naproxen by using carbon-based chiral separation membrane

Abstract

The invention belongs to the field of chiral resolution of RS-naproxen, and relates to a chiral resolution method of RS-naproxen, which comprises the following steps: separating an RS-naproxen enantiomer solution to be separated by using a carbon-based chiral separation membrane; the chiral separation membrane is a separation membrane prepared by taking a PVDF (Polyvinylidene Fluoride) base membrane as a bottom membrane and taking composite beta-cyclodextrin and multi-element acyl chloride as two-phase monomers to carry out interfacial polymerization reaction; the compound beta-cyclodextrin contains hydroxypropyl-beta-cyclodextrin and sulfobutyl-beta-cyclodextrin, and the compound beta-cyclodextrin contains hydroxypropyl-beta-cyclodextrin and sulfobutyl-beta-cyclodextrin; the multi-element acyl chloride contains trimesoyl chloride and 5-isocyanate isophthaloyl chloride, and the method has good separation performance and stability.

Description

Technical Field

[0001] This invention belongs to the field of chiral separation of RS-naproxen and relates to a method for chiral separation of RS-naproxen using a carbon-based chiral separation membrane. Background Technology

[0002] Chirality is a fundamental structural characteristic found in nature, prevalent in the molecules of chemical substances. Although these molecules may share the same chemical formula, differences in the three-dimensional structures of carbon atoms, sulfur atoms, or phosphorus atoms result in structural asymmetry, preventing them from perfectly matching their mirror images, much like how our left hand cannot perfectly match our right. This asymmetry is ubiquitous in chemistry, biology, and indeed in nature itself, forming a crucial foundation for the complexity, diversity, and functionality of the natural world. Enantiomers of chiral compounds, due to their unique physical and chemical properties, typically exhibit drastically different metabolic rates, toxicities, and pharmacological responses in a chiral environment.

[0003] Single enantiomers of chiral molecules are crucial for molecular recognition and replication. The production of pure enantiomers has attracted significant interest from the food, pesticide, and especially pharmaceutical industries. Generally, in chemistry, enantiomers are compounds whose molecular structures are mirror images of each other but cannot be superimposed. These differences in spatial structure can lead to drastically different behaviors and effects in living organisms. Specifically, an enantiomer may have a desired biological or pharmacological effect, such as effectively binding to a specific biological target to exert a therapeutic effect. However, its mirror-image enantiomers, despite having the same chemical properties, may exhibit different biological or pharmacological effects, which may include different affinities, metabolic pathways, toxicological properties, or even complete inactivity. This phenomenon is crucial in drug development and pharmacological research because it underscores the necessity of considering stereochemical properties in drug design and clinical applications.

[0004] 2-(6-Methoxy-2-naphthyl)-propionic acid, commonly known as naproxen, belongs to the 2-arylpropionic acid class of drugs. This drug is widely used due to its anti-inflammatory, antipyretic, and analgesic properties. Naproxen typically appears as a white or nearly white crystalline powder, and is tasteless or almost odorless. It is well soluble in ethanol, methanol, or chloroform, has low solubility in ether, and is almost insoluble in water. It possesses antipyretic, analgesic, anti-inflammatory, and antirheumatic therapeutic effects. By 1994, naproxen was recognized as an over-the-counter drug, ranking alongside aspirin, acetaminophen, and ibuprofen as one of the four pillars of antipyretic analgesics. Naproxen has a chiral center and exists as two enantiomers, R- and S-. S-naproxen is the pharmacologically active enantiomer, while R-naproxen has low or no activity and may even cause adverse reactions. Therefore, the chiral separation of naproxen is of great significance in drug development and production.

[0005] Currently, methods for chiral separation of naproxen mainly include high-performance liquid chromatography (HPLC), supercritical fluid chromatography (SFC), capillary electrophoresis, crystallization, enzyme-catalyzed resolution, and membrane separation. Among these, for example... Figure 1 As shown, membrane separation mainly uses membrane materials with chiral recognition capabilities to achieve chiral separation through selective permeation. Although membrane separation has potential advantages such as simple operation and low energy consumption in the chiral separation of naproxen, it still suffers from poor stability. Chiral membranes are prone to fouling, aging, or structural damage during long-term use, leading to a decline in separation performance. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of existing technologies that use membrane separation methods for chiral separation of naproxen, which suffer from poor stability, and to provide a new chiral separation method for RS-naproxen that combines good separation performance and stability.

[0007] The chiral separation method for RS-naproxen provided by this invention includes separating the enantiomer solutions of RS-naproxen to be separated using a chiral separation membrane; the chiral separation membrane is a separation membrane made by interfacial polymerization of a PVDF-based membrane as the base membrane and a composite β-cyclodextrin and a polyacrylamide chloride as two-phase monomers; the PVDF-based membrane is a composite of PVDF and graphene oxide; the composite β-cyclodextrin contains hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin; the polyacrylamide chloride contains trimesoyl chloride and 5-isocyanate isophthaloyl chloride.

[0008] The key to this invention lies in using a composite of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin as the aqueous phase and a composite of trimesoyl chloride and 5-isocyanate isophthaloyl chloride as the oil phase. The resulting chiral separation membrane exhibits both excellent separation performance and stability. This is presumably due to the following: Firstly, cyclodextrin is a chiral resolving agent for naproxen. The hydrophobic cavity formed by the combined modification of cyclodextrin with hydroxypropyl and sulfobutyl groups highly matches the molecular configuration of S-naproxen, enabling it to form inclusion complexes with chiral molecules. R-naproxen preferentially permeates due to its weaker interaction. Furthermore, the combined introduction of hydroxypropyl and sulfobutyl groups provides cyclodextrin with more reaction sites, allowing for more complex interactions with other molecules and achieving more efficient and precise selective recognition of target molecules. Simultaneously, the pore structure formed by the combined modification of cyclodextrin with hydroxypropyl and sulfobutyl groups has a strong interaction with naproxen molecules, effectively preventing long-term separation. During the separation process over time, chiral drug molecules gradually permeate through the membrane pores, reducing separation efficiency. On the other hand, the chlorine atom in pyromellitic chloroformyl chloride has a strong electron-withdrawing effect, which enhances the positive charge of the carbonyl carbon, making it more susceptible to attack by hydroxyl groups. At the same time, the chlorine atom, as a leaving group, is more stable and easier to leave, thus giving it very high reactivity. However, excessive reactivity can lead to a rough separation layer structure or the formation of defective channels, or even damage to the integrity of the separation layer. These defects and damage to the integrity of the separation layer can affect its stability. The introduction of 5-isocyanate isophthaloyl chloride can moderately reduce the reactivity without reducing the crosslinking density of the separation layer, thereby avoiding the formation of defective channels and ensuring the integrity of the separation layer structure.

[0009] In a preferred embodiment, the total concentration of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin in the aqueous phase containing the complex β-cyclodextrin is 1 wt% to 8 wt%, which is more conducive to improving the separation performance and stability of the chiral separation membrane. The reason for this is presumably that if the total concentration of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin in the aqueous phase containing the complex β-cyclodextrin is less than 1 wt%, it will affect the orderliness of the molecular chain arrangement of the separation layer. As the concentration increases, the molecular chain arrangement of the separation layer tends to be more ordered and the degree of cross-linking increases, strengthening the interfacial bonding between the separation layer and the substrate. However, if the concentration is higher than 8 wt%, local densification and microcracks will appear on the surface of the separation layer, affecting the separation performance and stability of the membrane.

[0010] In a preferred embodiment, during the preparation of the chiral separation membrane, the number of repetitions of the contact and heat treatment steps is controlled to be 3 to 5 times. It is ensured that the concentration difference between the aqueous phase containing the complex β-cyclodextrin and the oil phase containing the polyacrylamide chloride is greater than 0.5 wt% in adjacent contact steps. This is more conducive to the long-term stable chiral separation of RS-naproxen. The reason for this is presumably that controlling the number of layers to 3 to 5 allows the cross-linking network of the complex β-cyclodextrin and polyacrylamide chloride to accumulate layer by layer, evolving the cross-sectional layered structure from a simple layered structure to a complex stack. Controlling the concentration difference between the aqueous phase containing the complex β-cyclodextrin and the oil phase containing the polyacrylamide chloride in adjacent contact steps within the aforementioned range allows for a synergistic effect between the multilayer cross-linking networks. Each polymer layer introduces new cross-linking points to enhance the chemical connection between layers, while simultaneously promoting the directional growth of voids, ultimately forming a layered internal structure that enhances the chiral recognition sites of the membrane and improves separation selectivity. Attached Figure Description

[0011] Figure 1 This is a schematic diagram of the chiral separation of naproxen using a membrane method. Detailed Implementation

[0012] The chiral separation method for RS-naproxen provided by this invention includes separating the enantiomer solutions of RS-naproxen to be separated using a chiral separation membrane. The chiral separation membrane is a separation membrane prepared by interfacial polymerization of a PVDF-based membrane as the base membrane and a composite β-cyclodextrin and a polyacrylamide chloride as two-phase monomers. The PVDF-based membrane is a composite of PVDF and graphene oxide. The composite β-cyclodextrin contains hydroxypropyl-β-cyclodextrin and sulfonyl-β-cyclodextrin; the polyacrylamide chloride contains trimesoyl chloride and 5-isocyanate isophthaloyl chloride.

[0013] In the preparation process of the chiral separation membrane described above, the mass ratio of PVDF to graphene oxide in the PVDF base membrane is preferably 100:(1-5), such as 100:1, 100:2, 100:3, 100:4, 100:5 or any value between them.

[0014] In the preparation of the chiral separation membrane described above, the molar ratio of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin is preferably 1:(0.1 to 0.3), such as 1:0.1, 1:0.12, 1:0.15, 1:0.18, 1:0.2, 1:0.22, 1:0.25, 1:0.28, 1:0.3 or any value between them.

[0015] In the preparation of the chiral separation membrane described above, the molar ratio of trimesoyl chloride and 5-isocyanate isophthaloyl chloride is preferably 1:(0.5-1), such as 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1, or any value between them. The 5-isocyanate isophthaloyl chloride has the following structure:

[0016]

[0017] In a preferred embodiment, the method of the interfacial polymerization reaction includes:

[0018] S1. Hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, and triethylamine are dissolved in water to obtain an aqueous phase containing complex β-cyclodextrin; pyromellitic methyl methacrylate chloride and 5-isocyanate isophthaloyl chloride are dissolved in n-hexane to obtain an oil phase containing polyacrylamide chlorides;

[0019] S2. The bottom membrane is sequentially contacted with an aqueous phase containing complex β-cyclodextrin and an oil phase containing polyacryl chloride, followed by heat treatment to polymerize at the interface of the bottom membrane surface. The above contact and heat treatment steps are optionally repeated sequentially to obtain a chiral separation membrane.

[0020] In the preparation process of the chiral separation membrane described above, the preferred contact time between the bottom membrane and the aqueous phase containing complex β-cyclodextrin is 1 to 10 min, such as 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, or any value between them. The preferred contact time between the bottom membrane and the oil phase containing polyacrylamide chloride is 1 to 10 min, such as 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, or any value between them.

[0021] In the preparation process of the chiral separation membrane described above, the heat treatment conditions preferably include a temperature of 50 to 100°C, such as 50°C, 60°C, 70°C, 80°C, 90°C, 100°C or any value between them; and a time of 0.5 to 10 min, such as 0.5 min, 1 min, 2 min, 4 min, 6 min, 8 min, 10 min or any value between them.

[0022] In the preparation of the chiral separation membrane described above, the total concentration of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin in the aqueous phase containing the complex β-cyclodextrin is preferably 1 wt% to 8 wt%, such as 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, 3 wt%, 3.5 wt%, 4 wt%, 4.5 wt%, 5 wt%, 5.5 wt%, 6 wt%, 6.5 wt%, 7 wt%, 7.5 wt%, 8 wt%, or any value between them. The total concentration of trimesoyl chloride and 5-isocyanate isophthaloyl chloride in the oil phase containing polyacrylamide chloride is preferably 1 wt% to 8 wt%, such as 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, 3 wt%, 3.5 wt%, 4 wt%, 4.5 wt%, 5 wt%, 5.5 wt%, 6 wt%, 6.5 wt%, 7 wt%, 7.5 wt%, 8 wt%, or any value between them.

[0023] In the preparation process of the chiral separation membrane, the contact and heat treatment steps are preferably repeated 3 to 5 times.

[0024] In the preparation process of the chiral separation membrane described above, in two adjacent contact steps, the concentration difference of the aqueous phase containing complex β-cyclodextrin is preferably 0.5 wt% or more, more preferably 0.5 wt% to 2 wt%, such as 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1 wt%, 1.2 wt%, 1.4 wt%, 1.6 wt%, 1.8 wt%, 2 wt%, or any value between them. The concentration difference of the oil phase containing polyacrylamide chloride is preferably 0.5 wt% or more, more preferably 0.5 wt% to 2 wt%, such as 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1 wt%, 1.2 wt%, 1.4 wt%, 1.6 wt%, 1.8 wt%, 2 wt%, or any value between them.

[0025] The present invention will be described in detail below through embodiments.

[0026] In the following examples and comparative examples, hydroxypropyl-β-cyclodextrin was purchased from Aladdin Holdings Group Limited, CAS No. 128446-35-5; sulfobutyl-β-cyclodextrin was purchased from Aladdin Holdings Group Limited, CAS No. 182410-00-0.

[0027] Example 1

[0028] This embodiment illustrates the chiral separation membrane and its preparation method provided by the present invention.

[0029] S1. PVDF polymer (number average molecular weight of 400,000, the same below) and graphene oxide were added to a certain amount of N,N-dimethylacetamide (DMAc) at a mass ratio of 100:1. The resulting suspension was mechanically stirred at 70℃ for 4 hours until completely dissolved, yielding a PVDF solution with a concentration of 13wt%. The PVDF solution was then degassed at 80℃ for 24 hours and then cooled to 50℃. It was then coated onto a glass plate using a 0.5mm doctor blade and quickly immersed in a pure water coagulation bath to form a membrane. The membrane was then washed with deionized water to remove the solvent, yielding a PVDF base membrane.

[0030] S2ˋ. Hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin were dissolved in water with triethylamine at a molar ratio of 1:0.3:0.01 to prepare an aqueous phase containing complex β-cyclodextrin; pyromellitic methyl methacrylate chloride and 5-isocyanate isophthaloyl chloride were dissolved in n-hexane at a molar ratio of 1:1 to obtain an oil phase containing polyacrylamide chloride;

[0031] S3ˋ. Apply an aqueous phase containing complex β-cyclodextrin (total concentration of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin is 1 wt%) to the surface of the PVDF base membrane and allow it to soak for 10 min to promote the adsorption of aqueous monomers onto the PVDF base membrane. Then, use a spin coater to rotate for 1 min to remove excess aqueous phase from the membrane surface. Add an oil phase containing polyacrylamide chloride (total concentration of pyromellitic acid trimethylolpropionate chloride and 5-isocyanate isophthaloyl chloride is 1 wt%) to the surface of the aqueous phase-treated membrane. The aqueous and oil phase monomers polymerize at the interface to form a polyamide separation layer. Then, spin coat the membrane surface using a spin coater and allow the membrane to stand in air for 1 min to obtain the first separation membrane.

[0032] S4ˋ Apply an aqueous phase containing complex β-cyclodextrin (total concentration of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin is 2wt%) to the separation layer surface of the first separation membrane and allow it to soak for 10 min to promote the adsorption of aqueous monomers onto the PVDF base membrane. Then, use a spin coater to rotate for 1 min to remove excess aqueous phase from the membrane surface. Add an oil phase containing polyacrylamide chloride (total concentration of pyromellitic acid chloride and 5-isocyanate isophthaloyl chloride is 2wt%) to the surface of the membrane after aqueous phase treatment. The aqueous and oil phase monomers polymerize at the interface to form a polyamide separation layer. Then, spin coat the membrane surface using a spin coater and allow the membrane to stand in air for 1 min to obtain the second separation membrane.

[0033] S5ˋ Apply an aqueous phase containing complex β-cyclodextrin (total concentration of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin is 3wt%) to the separation layer surface of the second separation membrane and allow it to soak for 10 min to promote the adsorption of aqueous monomers onto the PVDF base membrane. Then, use a spin coater to rotate for 1 min to remove excess aqueous phase from the membrane surface. Add an oil phase containing polyacrylamide chloride (total concentration of pyromellitic acid chloride and 5-isocyanate isophthaloyl chloride is 3wt%) to the surface of the aqueous phase-treated membrane. The aqueous and oil phase monomers polymerize at the interface to form a polyamide separation layer. Then, spin coat the membrane surface using a spin coater and allow the membrane to stand in air for 1 min. Then, place the obtained sample in an oven preheated to 60°C for 10 min to cure. After cooling, wash with distilled water and soak in distilled water for 24 h to obtain a chiral separation membrane, denoted as CSM-1.

[0034] The morphology of the chiral separation membrane was observed using a scanning electron microscope. The results showed that the chiral separation membrane includes a base membrane and a separation layer attached to the surface of the base membrane. The separation layer includes a finger-like pore layer and a loose porous layer.

[0035] Example 2

[0036] This embodiment illustrates the chiral separation membrane and its preparation method provided by the present invention.

[0037] S1. PVDF polymer and graphene oxide were added to a certain amount of N,N-dimethylacetamide (DMAc) at a mass ratio of 100:5. The resulting suspension was mechanically stirred at 70°C for 4 hours until completely dissolved, yielding a PVDF solution with a concentration of 15 wt%. The PVDF solution was then degassed at 80°C for 24 hours, cooled to 50°C, and coated onto a glass plate using a 0.5 mm doctor blade. The plate was then quickly immersed in a pure water coagulation bath to form a membrane. The membrane was then washed with deionized water to remove the solvent, yielding a PVDF base membrane.

[0038] S2ˋ, Hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin were dissolved in water at a molar ratio of 1:0.1:0.01 to prepare an aqueous phase containing complex β-cyclodextrin; Tristylacetyl chloride and 5-isocyanate isophthaloyl chloride were dissolved in n-hexane at a molar ratio of 1:0.5 to obtain an oil phase containing polyacrylamide chloride;

[0039] S3ˋ. Apply an aqueous phase containing complex β-cyclodextrin (total concentration of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin is 1 wt%) to the surface of the PVDF base membrane and allow it to soak for 10 min to promote the adsorption of aqueous monomers onto the PVDF base membrane. Then, use a spin coater to rotate for 1 min to remove excess aqueous phase from the membrane surface. Add an oil phase containing polyacrylamide chloride (total concentration of pyromellitic acid trimethylolpropionate chloride and 5-isocyanate isophthaloyl chloride is 1 wt%) to the surface of the aqueous phase-treated membrane. The aqueous and oil phase monomers polymerize at the interface to form a polyamide separation layer. Then, spin coat the membrane surface using a spin coater and allow the membrane to stand in air for 1 min to obtain the first separation membrane.

[0040] S4ˋ Apply an aqueous phase containing complex β-cyclodextrin (total concentration of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin is 2wt%) to the separation layer surface of the first separation membrane and allow it to soak for 10 min to promote the adsorption of aqueous monomers onto the PVDF base membrane. Then, use a spin coater to rotate for 1 min to remove excess aqueous phase from the membrane surface. Add an oil phase containing polyacrylamide chloride (total concentration of pyromellitic acid chloride and 5-isocyanate isophthaloyl chloride is 2wt%) to the surface of the membrane after aqueous phase treatment. The aqueous and oil phase monomers polymerize at the interface to form a polyamide separation layer. Then, spin coat the membrane surface using a spin coater and allow the membrane to stand in air for 1 min to obtain the second separation membrane.

[0041] S5ˋ Apply an aqueous phase containing complex β-cyclodextrin (total concentration of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin is 3wt%) to the separation layer surface of the second separation membrane and allow it to soak for 10 min to promote the adsorption of aqueous monomers onto the PVDF base membrane. Then, use a spin coater to rotate for 1 min to remove excess aqueous phase from the membrane surface. Add an oil phase containing polyacrylamide chloride (total concentration of pyromellitic acid chloride and 5-isocyanate isophthaloyl chloride is 3wt%) to the surface of the membrane after aqueous phase treatment. The aqueous and oil phase monomers polymerize at the interface to form a polyamide separation layer. Then, spin coat the membrane surface using a spin coater and allow the membrane to stand in air for 1 min. Then, place the obtained sample in an oven preheated to 60°C for 10 min to cure. After cooling, wash with distilled water and soak in distilled water for 24 h to obtain the third separation membrane.

[0042] S6ˋ Apply an aqueous phase containing complex β-cyclodextrin (total concentration of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin is 4wt%) to the separation layer surface of the third separation membrane and allow it to soak for 10 min to promote the adsorption of aqueous monomers onto the PVDF base membrane. Then, use a spin coater to rotate for 1 min to remove excess aqueous phase from the membrane surface. Add an oil phase containing polyacrylamide chloride (total concentration of pyromellitic acid chloride and 5-isocyanate isophthaloyl chloride is 4wt%) to the surface of the membrane after aqueous phase treatment. The aqueous and oil phase monomers polymerize at the interface to form a polyamide separation layer. Then, spin coat the membrane surface using a spin coater and allow the membrane to stand in air for 1 min. Then, place the obtained sample in an oven preheated to 60°C for 10 min to cure. After cooling, wash with distilled water and soak in distilled water for 24 h to obtain the fourth separation membrane.

[0043] S7ˋ Apply an aqueous phase containing complex β-cyclodextrin (total concentration of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin is 5 wt%) to the separation layer surface of the fourth separation membrane and allow it to soak for 10 min to promote the adsorption of aqueous monomers onto the PVDF base membrane. Then, use a spin coater to rotate for 1 min to remove excess aqueous phase from the membrane surface. Add an oil phase containing polyacrylamide chloride (total concentration of pyromellitic acid chloride and 5-isocyanate isophthaloyl chloride is 5 wt%) to the surface of the aqueous phase-treated membrane. The aqueous and oil phase monomers polymerize at the interface to form a polyamide separation layer. Then, spin coat the membrane surface using a spin coater and allow the membrane to stand in air for 1 min. Then, place the obtained sample in an oven preheated to 60°C for 10 min to cure. After cooling, wash with distilled water and soak in distilled water for 24 h to obtain a chiral separation membrane, denoted as CSM-2.

[0044] The morphology of the chiral separation membrane was observed using a scanning electron microscope. The results showed that the chiral separation membrane includes a base membrane and a separation layer attached to the surface of the base membrane. The separation layer includes a finger-like pore layer and a loose porous layer.

[0045] Example 3

[0046] This embodiment illustrates the chiral separation membrane and its preparation method provided by the present invention.

[0047] S1. PVDF polymer and graphene oxide were added to a certain amount of N,N-dimethylacetamide (DMAc) at a mass ratio of 100:3. The resulting suspension was mechanically stirred at 70℃ for 8 hours until completely dissolved, yielding a PVDF solution with a concentration of 18wt%. The PVDF solution was then degassed at 70℃ for 24 hours and then cooled to 50℃. The solution was coated onto a glass plate using a 0.5mm doctor blade and then quickly immersed in a pure water coagulation bath to form a membrane. The membrane was then washed with deionized water to remove the solvent, yielding a PVDF base membrane.

[0048] S2ˋ, Hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin were dissolved in water with triethylamine at a molar ratio of 1:0.2:0.01 to prepare an aqueous phase containing complex β-cyclodextrin; Tristylacetyl chloride and 5-isocyanate isophthaloyl chloride were dissolved in n-hexane at a molar ratio of 1:0.8 to obtain an oil phase containing polyacrylamide chloride;

[0049] S3ˋ. Apply an aqueous phase containing complex β-cyclodextrin (total concentration of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin is 2wt%) to the surface of the PVDF base membrane and allow it to soak for 10 min to promote the adsorption of aqueous monomers onto the PVDF base membrane. Then, use a spin coater to rotate for 1 min to remove excess aqueous phase from the membrane surface. Add an oil phase containing polyacrylamide chloride (total concentration of pyromellitic acid trimethylolpropionate chloride and 5-isocyanate isophthaloyl chloride is 2wt%) to the surface of the aqueous phase-treated membrane. The aqueous and oil phase monomers polymerize at the interface to form a polyamide separation layer. Then, spin coat the membrane surface using a spin coater and allow the membrane to stand in air for 1 min to obtain the first separation membrane.

[0050] S4ˋ Apply an aqueous phase containing complex β-cyclodextrin (total concentration of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin is 4 wt%) to the separation layer surface of the first separation membrane and allow it to soak for 10 min to promote the adsorption of aqueous monomers onto the PVDF base membrane. Then, use a spin coater to rotate for 1 min to remove excess aqueous phase from the membrane surface. Add an oil phase containing polyacrylamide chloride (total concentration of pyromellitic acid trimethylolpropionate chloride and 5-isocyanate isophthaloyl chloride is 4 wt%) to the surface of the membrane after aqueous phase treatment. The aqueous and oil phase monomers polymerize at the interface to form a polyamide separation layer. Then, spin coat the membrane surface using a spin coater and allow the membrane to stand in air for 1 min to obtain the second separation membrane.

[0051] S5ˋ Apply an aqueous phase containing complex β-cyclodextrin (total concentration of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin is 6 wt%) to the separation layer surface of the second separation membrane and allow it to soak for 10 min to promote the adsorption of aqueous monomers onto the PVDF base membrane. Then, use a spin coater to rotate for 1 min to remove excess aqueous phase from the membrane surface. Add an oil phase containing polyacrylamide chloride (total concentration of pyromellitic acid chloride and 5-isocyanate isophthaloyl chloride is 6 wt%) to the surface of the membrane after aqueous phase treatment. The aqueous and oil phase monomers polymerize at the interface to form a polyamide separation layer. Then, spin coat the membrane surface using a spin coater and allow the membrane to stand in air for 1 min. Then, place the obtained sample in an oven preheated to 60°C for 10 min to cure. After cooling, wash with distilled water and soak in distilled water for 24 h to obtain the third separation membrane.

[0052] S6ˋ Apply an aqueous phase containing complex β-cyclodextrin (total concentration of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin is 8 wt%) to the separation layer surface of the third separation membrane and allow it to soak for 10 min to promote the adsorption of aqueous monomers onto the PVDF base membrane. Then, use a spin coater to rotate for 1 min to remove excess aqueous phase from the membrane surface. Add an oil phase containing polyacrylamide chloride (total concentration of pyromellitic acid trimethylolpropionate chloride and 5-isocyanate isophthaloyl chloride is 8 wt%) to the surface of the aqueous phase-treated membrane. The aqueous and oil phase monomers polymerize at the interface to form a polyamide separation layer. Then, spin coat the membrane surface using a spin coater and allow the membrane to stand in air for 1 min. Then, place the obtained sample in an oven preheated to 60°C for 10 min to cure. After cooling, wash with distilled water and soak in distilled water for 24 h to obtain a chiral separation membrane, denoted as CSM-3.

[0053] The morphology of the chiral separation membrane was observed using a scanning electron microscope. The results showed that the chiral separation membrane includes a base membrane and a separation layer attached to the surface of the base membrane. The separation layer includes a finger-like pore layer and a loose porous layer.

[0054] Example 4

[0055] A chiral separation membrane was prepared according to the method of Example 1, except that in step S5ˋ, the total concentration of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin in the aqueous phase containing complex β-cyclodextrin was controlled at 10 wt%, and the total concentration of trimesoyl chloride and 5-isocyanate isophthaloyl chloride in the oil phase containing polyacrylamide chloride was controlled at 10 wt%. The other conditions were the same as in Example 1, and a chiral separation membrane was obtained, which was denoted as CSM-4.

[0056] Example 5

[0057] A chiral separation membrane was prepared according to the method of Example 1, except that in steps S3ˋ, S4ˋ and S5ˋ, the total concentration of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin in the aqueous phase containing complex β-cyclodextrin was 2wt%, and the total concentration of trimesoyl chloride and 5-isocyanate isophthaloyl chloride in the oil phase containing polyacrylamide chloride was 2wt%. The other conditions were the same as in Example 1, and a chiral separation membrane was obtained, which was denoted as CSM-5.

[0058] Comparative Example 1

[0059] A chiral separation membrane was prepared according to the method of Example 1, except that the hydroxypropyl-β-cyclodextrin in the aqueous phase containing complex β-cyclodextrin was replaced with the same molar amount of sulfobutyl-β-cyclodextrin, and the other conditions were the same as in Example 1. The resulting chiral separation membrane was denoted as DCSM-1.

[0060] Comparative Example 2

[0061] A chiral separation membrane was prepared according to the method of Example 1, except that the sulfobutyl-β-cyclodextrin in the aqueous phase containing complex β-cyclodextrin was replaced with the same molar amount of hydroxypropyl-β-cyclodextrin. The other conditions were the same as in Example 1, and a chiral separation membrane was obtained, which was denoted as DCSM-2.

[0062] Comparative Example 3

[0063] A chiral separation membrane was prepared according to the method of Example 1, except that the 5-isocyanate isophthaloyl chloride in the oil phase containing polyacryl chloride was replaced with the same molar amount of trimesoyl pyromellitic chloride. The other conditions were the same as in Example 1, and a chiral separation membrane, denoted as DCSM-3, was obtained.

[0064] Test case

[0065] The chiral separation device for RS-naproxen enantiomers includes two chambers: a feed side and a permeate side. A chiral separation membrane is installed between the two chambers to separate the feed side and the permeate side. The connection between the chiral separation membrane and the side wall of the device is sealed with a fluororubber gasket. The feed solution must pass through the chiral separation membrane to diffuse from the feed side to the permeate side. 400 mL of 0.08 mol / L RS-naproxen enantiomer aqueous solution (racemic solution) was loaded into the feed side, while an equal volume of ethanol solution (Ethanol solution) was loaded into the permeate side. The concentration difference generated on both sides of the membrane was used to drive the permeate separation process. The feed side and the permeate side were continuously stirred with a magnetic stirrer to ensure uniform concentration. The permeate was sampled at fixed time intervals and sent to a high performance liquid chromatograph (HPLC) for determination. The peak areas of R-naproxen and S-naproxen in the sample were obtained by HPLC. Then, the concentrations of R-naproxen and S-naproxen in the sample were obtained by standard curves of R-naproxen and S-naproxen. The separation efficiency (ee) was calculated based on the concentration and by equation (1). The results are shown in Table 1.

[0066]

[0067] In equation (1), ee is the separation efficiency (%);

[0068] A R The concentration of R-naproxen on the osmotic side (g / L);

[0069] A S The concentration of S-naproxen on the osmotic side is given in g / L.

[0070] Table 1

[0071]

[0072] As can be seen from the results in Table 1, the chiral separation membranes obtained in Examples 1-3 exhibit both good separation performance and stability, with ee values ​​reaching 100% within 2 hours. The chiral separation membranes obtained in Examples 4-6 achieve ee values ​​of 100% within 1.5 hours, but the ee value decreases slightly after 2 hours. The chiral separation membranes obtained in Comparative Examples 1-3 achieve ee values ​​of 100% within 1 hour, but with the passage of time, the ee value decreases significantly, dropping below 94% after 1.5 hours and below 35% after 2 hours.

[0073] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention without departing from the principles and spirit of the present invention.

Claims

1. A chiral resolution method for RS-naproxen, characterized in that, The method includes separating the RS-naproxen enantiomer solution to be separated using a chiral separation membrane; the chiral separation membrane is a separation membrane made by interfacial polymerization of a PVDF-based membrane as the base membrane and a composite β-cyclodextrin and a polyacrylamide chloride as two-phase monomers; the PVDF-based membrane is a composite of PVDF and graphene oxide; the composite β-cyclodextrin contains hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin; the polyacrylamide chloride contains trimesoyl chloride and 5-isocyanate isophthaloyl chloride.

2. The chiral resolution method for RS-naproxen according to claim 1, characterized in that, The mass ratio of PVDF to graphene oxide in the PVDF-based film is 100:(1-5).

3. The chiral resolution method for RS-naproxen according to claim 1, characterized in that, The molar ratio of hydroxypropyl-β-cyclodextrin to sulfobutyl-β-cyclodextrin is 1:(0.1 to 0.3).

4. The chiral resolution method for RS-naproxen according to claim 1, characterized in that, The molar ratio of pyromellitic methyl chloride and 5-isocyanate isophthaloyl chloride is 1:(0.5-1).

5. The chiral resolution method for RS-naproxen according to any one of claims 1 to 4, characterized in that, The method for the interfacial polymerization reaction includes the following steps: S1. Hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, and triethylamine are dissolved in water to obtain an aqueous phase containing complex β-cyclodextrin; pyromellitic methyl methacrylate chloride and 5-isocyanate isophthaloyl chloride are dissolved in n-hexane to obtain an oil phase containing polyacrylamide chlorides; S2. The bottom membrane is sequentially contacted with an aqueous phase containing complex β-cyclodextrin and an oil phase containing polyacryl chloride, followed by heat treatment to polymerize at the interface of the bottom membrane surface. The contact and heat treatment steps are optionally repeated sequentially to obtain a chiral separation membrane.

6. The chiral resolution method for RS-naproxen according to claim 5, characterized in that, The contact time between the bottom film and the aqueous phase containing complex β-cyclodextrin is 1–10 min; the contact time between the bottom film and the oil phase containing polyacryl chloride is 1–10 min.

7. The chiral resolution method for RS-naproxen according to claim 5, characterized in that, The heat treatment conditions include a temperature of 50–100°C and a time of 0.5–10 min.

8. The chiral resolution method for RS-naproxen according to claim 5, characterized in that, The total concentration of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin in the aqueous phase containing the complex β-cyclodextrin is 1 wt% to 8 wt%; the total concentration of pyromellitic trimethylolpropionate chloride and 5-isocyanate isophthaloyl chloride in the oil phase containing polyacrylamide chloride is 1 wt% to 8 wt%.

9. The chiral resolution method for RS-naproxen according to claim 5, characterized in that, The above contact and heat treatment steps are repeated 3 to 5 times.

10. The chiral resolution method for RS-naproxen according to claim 8, characterized in that, In two adjacent contact steps, the concentration difference of the aqueous phase containing complex β-cyclodextrin is greater than 0.5 wt%, and the concentration difference of the oil phase containing polyacrylamide chloride is greater than 0.5 wt%.

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