Metal organic framework chiral separation membrane as well as preparation method and application thereof

Abstract

The invention belongs to the field of RS-naproxen chiral resolution, and relates to a metal organic framework chiral separation membrane as well as a preparation method and application thereof. The preparation method of the metal organic framework chiral separation membrane comprises the steps that a chiral selection solution is evenly laid on a PVDF base membrane and then subjected to vacuum suction filtration, and the chiral selection solution is an aqueous solution containing hydroxypropyl-beta-cyclodextrin, sulfobutyl-beta-cyclodextrin, N-ethylaniline, diphenyl sulfoxide and alkali metal hydroxide; and heating the obtained membrane in a methanol steam environment, and washing with water to obtain the metal organic framework chiral separation membrane. The metal organic framework chiral separation membrane obtained by the method has good separation performance and stability when being used for chiral resolution of RS-naproxen.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of chiral resolution of RS-naproxen, and relates to a metal-organic framework chiral separation membrane and a preparation method and application thereof. BACKGROUND

[0002] Chiral molecules of single enantiomers are essential for molecular recognition and replication processes. The production of pure enantiomers has attracted great interest in the food, pesticide, and especially pharmaceutical industries. Generally, in the field of chemistry, enantiomers refer to compounds whose molecular structures are mirror images of each other but cannot be superimposed, and the differences in spatial structure of these compounds lead to their possibly completely different behaviors and effects in biological systems. Specifically, one enantiomer can have the expected biological or pharmacological effect, such as being able to effectively bind to a specific biological target and exert a therapeutic effect. However, its mirror image enantiomer, although chemically identical, can exhibit different biological or pharmacological effects, which can include different affinities, metabolic pathways, toxicological properties, and can even be completely inactive. This phenomenon is very important in drug development and pharmacological research, as it emphasizes the need to consider stereochemical properties in drug design and clinical applications.

[0003] With the increasing demand for high-purity enantiomeric compounds, the importance of enantiomeric separation of drugs has become increasingly prominent. More than half of the drugs are racemic compounds, and these enantiomers exhibit completely different interactions in the human body, producing different pharmacological effects through their respective metabolic pathways. Generally, only one enantiomer exhibits strong biological activity, rapid metabolic speed, and ideal pharmacological properties, while its enantiomer can have lower activity and sometimes even toxic side effects, so it is extremely important to develop a chiral separation technology suitable for large-scale commercialization.

[0004] The asymmetry of molecular structure endows it with chiral characteristics, resulting in different effects of enantiomers when interacting with biological systems. Although many chiral drugs are used in the form of racemic mixtures for treatment, in the stereoselective biological environment of the human body, significant differences are often observed in their pharmacological properties, pharmacokinetic distribution, and metabolic rates. This further emphasizes the importance of chiral separation in multiple scientific and industrial fields, particularly in chemistry, pharmacy, biochemistry, and medicine, where the impact is particularly significant. Therefore, accurate determination of the purity of enantiomers is of great significance for optimizing drug design, in-depth understanding of the metabolic dynamics and mechanisms of drugs, and evaluation of potential side effects. The application of chiral separation technology makes it possible to manufacture enantiomeric pure substances, which not only has great practical application value but also brings significant economic benefits.

[0005] 2-(6-methoxy-2-naphthyl)-propionic acid, commonly known as naproxen, belongs to a class of 2-arylpropionic acids, which are widely used for their anti-inflammatory, antipyretic and analgesic properties. Naproxen usually presents a white or nearly white crystalline powder and has no or almost no taste. This drug is well soluble in ethanol, methanol or chloroform, has a lower solubility in diethyl ether, and is almost insoluble in water, and has the therapeutic effects of antipyretic, analgesic and anti-inflammatory and anti-rheumatic. By 1994, naproxen was identified as an over-the-counter drug, and was one of the four pillars of antipyretic analgesics together with aspirin, paracetamol and ibuprofen. Naproxen has a chiral center, and there are two enantiomers of R and S types. Among them, S-naproxen is the enantiomer with pharmacological activity, while R-naproxen has lower or no activity, and may even cause adverse reactions. Therefore, the chiral separation of naproxen is of great significance in drug research and development and production.

[0006] At present, the methods for chiral separation of naproxen mainly include high performance liquid chromatography, supercritical fluid chromatography, capillary electrophoresis, crystallization method, enzyme catalytic resolution method and membrane separation method. Among them, the membrane separation method mainly uses membrane materials with chiral recognition ability to realize chiral separation through selective permeation. Although the membrane separation method has potential advantages such as simple operation and low energy consumption in the chiral separation of naproxen, it still has the defect of poor stability. The chiral membrane is easily polluted, aged or structurally damaged during long-term use, resulting in a decrease in separation performance. SUMMARY

[0007] The first object of the present application is to overcome the defect of poor stability of the prior art in chiral resolution of naproxen by using membrane separation method, and to provide a new preparation method of metal organic framework chiral separation membrane. The metal organic framework chiral separation membrane prepared by the method has good separation performance and stability in chiral resolution of RS-naproxen.

[0008] The second object of the present application is to provide a metal organic framework chiral separation membrane prepared by the above method.

[0009] The third object of the present application is to provide the application of the above metal organic framework chiral separation membrane in chiral resolution of RS-naproxen.

[0010] The preparation method of the metal organic framework chiral separation membrane provided by the present application comprises uniformly laying a chiral selection solution on a PVDF base film and then vacuum filtering, wherein the chiral selection solution is an aqueous solution containing hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, N-ethylaniline, diphenyl sulfoxide and alkali metal hydroxide. Then the obtained membrane is heated and treated in a methanol vapor environment and washed with water, and the metal organic framework chiral separation membrane is obtained.

[0011] The key of the present application is to use hydroxypropyl-beta-cyclodextrin and sulfobutyl-beta-cyclodextrin complex as a chiral selector, and N-ethylaniline and diphenyl sulfoxide and alkali metal hydroxide as modifying substances, so that the metal organic framework chiral separation membrane has good separation performance and stability. It is speculated that the reason is that: on the one hand, cyclodextrin is naproxen chiral resolution agent, and the hydrophobic cavity formed by the combined modification of hydroxypropyl and sulfobutyl of cyclodextrin is highly matched with the molecular configuration of S-naproxen, which can form inclusion compound with chiral molecules, and preferentially form host-guest inclusion compound and be adsorbed on the membrane, R-naproxen is preferentially permeated due to the weak interaction force, and the combined introduction of hydroxypropyl and sulfobutyl can provide more reaction sites for cyclodextrin, so that it can interact with other molecules more complexly, and realize more efficient and precise selective recognition of target molecules, and the pore structure formed by the combined modification of hydroxypropyl and sulfobutyl of cyclodextrin has strong interaction with naproxen molecules, which can effectively avoid the gradual penetration of chiral drug molecules through the membrane pore in the long-term separation process, thereby reducing the separation efficiency; on the other hand, since the alkali metal hydroxide can form metal organic framework (MOFs) structure of cyclodextrin in the presence of methanol atmosphere, this structure has high specific surface area and excellent chiral control ability, avoids the formation of defect channels in the separation layer, ensures the integrity of the separation layer structure, and can improve the chiral separation performance; in addition, the SO group in diphenyl sulfoxide forms a hydrogen bond with the hydroxyl group outside the cyclodextrin ring, the benzene ring in diphenyl sulfoxide and N-ethylaniline is easy to insert into the cavity structure of cyclodextrin, and N-ethylaniline can be bonded to cyclodextrin, and the phosphorus-containing group is introduced into the cyclodextrin molecule by chemical reaction to form a moderate cross-linking structure, which may give the membrane higher stability. BRIEF DESCRIPTION OF DRAWINGS

[0012] Figure 1 The structure diagram of the chiral resolution device for RS-naproxen enantiomers adopted in the present application. DETAILED DESCRIPTION

[0013] The preparation method of the metal organic framework chiral separation membrane provided by the present application comprises uniformly laying the chiral selection liquid on the PVDF base film, then vacuum filtering, and then placing the obtained membrane piece in a closed container containing methanol for heating treatment, and then washing with water to obtain the metal organic framework chiral separation membrane.

[0014] In the present application, the chiral selection liquid is an aqueous solution containing hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, N-ethylaniline, diphenyl sulfoxide and alkali metal hydroxide. Among them, the mass ratio of hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, N-ethylaniline and diphenyl sulfoxide in the chiral selection liquid is preferably 1:(0.1-0.5):(0.01-0.1):(0.01-0.1), at which point the components can achieve the best combination, thereby imparting better separation performance and stability to the metal organic framework chiral separation membrane. Specifically, the mass ratio of hydroxypropyl-β-cyclodextrin to sulfobutyl-β-cyclodextrin can be, for example, 1:0.1, 1:0.15, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5 or any value therebetween. The mass ratio of hydroxypropyl-β-cyclodextrin to N-ethylaniline can be, for example, 1:0.01, 1:0.02, 1:0.03, 1:0.04, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.1 or any value therebetween. The mass ratio of hydroxypropyl-β-cyclodextrin to diphenyl sulfoxide can be, for example, 1:0.01, 1:0.02, 1:0.03, 1:0.04, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.1 or any value therebetween. The mass ratio of the metal hydroxide to hydroxypropyl-β-cyclodextrin is preferably (0.01-0.1):1, and can be, for example, 0.01:1, 0.02:1, 0.03:1, 0.04:1, 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1, 0.1:1 or any value therebetween.

[0015] In the present application, the alkali metal hydroxide can be any of the existing strong alkaline compounds formed by the combination of alkali metal elements and hydroxyl groups, and can be, for example, at least one of lithium hydroxide, sodium hydroxide and potassium hydroxide.

[0016] In the present application, the solid content of the chiral selection liquid is preferably 1-10 wt%, at which point the separation performance and stability of the metal organic framework chiral separation membrane are further improved. It is speculated that the reason for this is that if the solid content of the chiral selection liquid is less than 1 wt%, the order of the molecular chain arrangement of the separation layer will be affected, and as the concentration increases, the molecular chain arrangement of the separation layer tends to be ordered and the crosslinking degree increases, and the interface bonding between the separation layer and the base membrane is enhanced, but if the concentration is higher than 10 wt%, local densification and micro-cracks will appear on the surface of the separation layer, affecting the separation performance and stability of the membrane. The solid content of the chiral selection liquid can be, for example, 1 wt%, 2 wt%, 4 wt%, 6 wt%, 8 wt%, 10 wt% or any value therebetween.

[0017] In the present application, the heating treatment conditions preferably include a temperature of 45-55℃ and a time of 10-30min. Specifically, the temperature of the heating treatment can be 45℃, 48℃, 50℃, 52℃, 55℃ or any value therebetween. The time of the heating treatment can be 10min, 15min, 20min, 25min, 30min or any value therebetween.

[0018] The present application also provides a metal organic framework chiral separation membrane prepared by the above method.

[0019] The present application also provides the use of the above metal organic framework chiral separation membrane in the chiral resolution of RS-naproxen.

[0020] The present application will be described in detail below through examples.

[0021] In the following examples and comparative examples, hydroxypropyl-β-cyclodextrin was purchased from Aldrich Group Co., Ltd., with CAS No. 128446-35-5; sulfobutyl-β-cyclodextrin was purchased from Aldrich Group Co., Ltd., with CAS No. 182410-00-0.

[0022] Example 1

[0023] S1. PVDF polymer (number average molecular weight of 400,000, same below) was added to a certain amount of N,N-dimethylacetamide (DMAc), and the obtained suspension was mechanically stirred at a temperature of 70℃ for 4 hours until complete dissolution, to obtain a PVDF solution with a concentration of 12wt%. After the PVDF solution was degassed at 50℃ for 24h and then lowered to room temperature, it was coated on a glass plate with a 0.5mm doctor blade and then quickly immersed in a pure water coagulation bath to form a film, after which the film was washed with deionized water to remove the solvent, to obtain a PVDF-based film.

[0024] S2. Hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, N-ethylaniline, diphenyl sulfoxide and sodium hydroxide were dissolved in water according to a mass ratio of 1:0.1:0.1:0.1:0.01 to obtain a chiral selection solution with a solid content of 2wt%. The chiral selection solution was uniformly laid on the PVDF-based film with a thickness of 1mm, and then vacuum filtered, and the obtained film was suspended in a closed container containing methanol, and then the container was placed in an oven at 50℃ for heating for 10min, so that the methanol vapor diffused, and the film was placed in the methanol vapor environment, and then the obtained film was washed with deionized water, to obtain a metal organic framework chiral separation membrane, denoted as SSM-1.

[0025] The scanning electron microscope is used to observe the morphology of the metal-organic framework chiral separation membrane. The test results show that the metal-organic framework chiral separation membrane includes a base film and a separation layer attached to the surface of the base film, and the separation layer includes a finger-shaped pore layer and a loose porous layer.

[0026] Example 2

[0027] S1. PVDF polymer was added to a certain amount of N,N-dimethylacetamide (DMAc), and the obtained suspension was mechanically stirred at a temperature of 70°C for 4 hours until completely dissolved to obtain a PVDF solution with a concentration of 13wt%. After the PVDF solution was degassed at 50°C for 24h and then reduced to room temperature, it was coated on a glass plate with a 0.5mm doctor blade and then quickly immersed in a pure water coagulation bath to form a film. After that, the film was washed with deionized water to remove the solvent, and a PVDF base film was obtained.

[0028] S2. Hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, N-ethylaniline, diphenyl sulfoxide and lithium hydroxide were dissolved in water according to a mass ratio of 1:0.5:0.01:0.01:0.1 to obtain a chiral selection solution with a solid content of 5wt%. The chiral selection solution was uniformly laid on the PVDF base film with a thickness of 1mm, and then vacuum filtration was performed. The obtained film was then placed in a closed container containing methanol, and then the container was placed in an oven at 50°C for heating for 10min to make the methanol vapor diffuse, so that the film was placed in a methanol vapor environment. After that, the obtained film was washed with deionized water to obtain a metal-organic framework chiral separation membrane, which is denoted as SSM-2.

[0029] The scanning electron microscope is used to observe the morphology of the metal-organic framework chiral separation membrane. The test results show that the metal-organic framework chiral separation membrane includes a base film and a separation layer attached to the surface of the base film, and the separation layer includes a finger-shaped pore layer and a loose porous layer.

[0030] Example 3

[0031] S1. PVDF polymer was added to a certain amount of N,N-dimethylacetamide (DMAc), and the obtained suspension was mechanically stirred at a temperature of 70°C for 4 hours until completely dissolved to obtain a PVDF solution with a concentration of 13wt%. After the PVDF solution was degassed at 50°C for 24h and then reduced to room temperature, it was coated on a glass plate with a 0.5mm doctor blade and then quickly immersed in a pure water coagulation bath to form a film. After that, the film was washed with deionized water to remove the solvent, and a PVDF base film was obtained.

[0032] S2. Hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, N-ethylaniline, diphenyl sulfoxide and potassium hydroxide were dissolved in water according to the mass ratio of 1:0.3:0.05:0.05:0.05 to obtain a chiral selection solution with a solid content of 3wt%. After the chiral selection solution was uniformly laid on the PVDF base film with a thickness of 1mm and vacuum filtration, the obtained film was placed in a closed container containing methanol, and then the container was placed in an oven at 50°C for 10min to diffuse methanol vapor, so that the film was placed in a methanol vapor environment. Then the obtained film was washed with deionized water to obtain a metal organic framework chiral separation membrane, denoted as SSM-3.

[0033] The scanning electron microscope was used to observe the morphology. From the test results, it can be seen that the metal organic framework chiral separation membrane includes a base film and a separation layer attached to the surface of the base film, and the separation layer includes a finger-shaped pore layer and a loose porous layer.

[0034] Example 4

[0035] The metal organic framework chiral separation membrane was prepared according to the method of Example 1, except that the amount of water added was adjusted to control the solid content of the chiral selection solution to 0.5wt%, and the other conditions were the same as those of Example 1, to obtain a metal organic framework chiral separation membrane, denoted as SSM-4.

[0036] Example 5

[0037] The metal organic framework chiral separation membrane was prepared according to the method of Example 1, except that the amount of water added was adjusted to control the solid content of the chiral selection solution to 20wt%, and the other conditions were the same as those of Example 1, to obtain a metal organic framework chiral separation membrane, denoted as SSM-5.

[0038] Comparative Example 1

[0039] The metal organic framework chiral separation membrane was prepared according to the method of Example 1, except that sulfobutyl-β-cyclodextrin was replaced by the same weight of hydroxypropyl-β-cyclodextrin, and the other conditions were the same as those of Example 1, to obtain a metal organic framework chiral separation membrane, denoted as DSSM-1.

[0040] Comparative Example 2

[0041] The metal organic framework chiral separation membrane was prepared according to the method of Example 1, except that hydroxypropyl-β-cyclodextrin was replaced by the same weight of sulfobutyl-β-cyclodextrin, and the other conditions were the same as those of Example 1, to obtain a metal organic framework chiral separation membrane, denoted as DSSM-2.

[0042] Comparative Example 3

[0043] A chiral metal-organic framework separation membrane was prepared according to the method of Example 1, except that hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin were replaced with the same amount of α-cyclodextrin by weight. The other conditions were the same as in Example 1. The resulting chiral metal-organic framework separation membrane was designated as DSSM-3.

[0044] Comparative Example 4

[0045] A chiral metal-organic framework separation membrane was prepared according to the method of Example 1, except that N-ethylaniline was replaced with the same amount of diphenyl sulfoxide by weight, and the other conditions were the same as in Example 1. The resulting chiral metal-organic framework separation membrane was designated as DSSM-4.

[0046] Comparative Example 5

[0047] A chiral metal-organic framework separation membrane was prepared according to the method of Example 1, except that diphenyl sulfoxide was replaced with the same amount of N-ethylaniline by weight, and the other conditions were the same as in Example 1. The resulting chiral metal-organic framework separation membrane was designated as DSSM-5.

[0048] Test case like Figure 1 As shown, the chiral separation device for RS-naproxen enantiomers includes two chambers: a feed side and a permeate side. A chiral separation membrane is disposed 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 was loaded into the feed side, while an equal volume of 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 area of ​​R-naproxen and the peak area of ​​S-naproxen in the sample were obtained by high performance liquid chromatography. 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.

[0049]

[0050] In equation (1), ee is the separation efficiency (%);

[0051] A R is the concentration of R-naproxen on the permeate side (g / L);

[0052] A S is the concentration of S-naproxen on the permeate side (g / L).

[0053] Table 1

[0054]

[0055] As can be seen from the results of Table 1, the metal organic framework chiral separation membranes obtained in Examples 1-3 have both good separation performance and stability, and the ee values can reach 100% within 4h. The metal organic framework chiral separation membranes obtained in Examples 4-7 have ee values reaching 100% within 3h, but the ee values slightly decrease at 10h. The metal organic framework chiral separation membranes obtained in Comparative Examples 1-5 have ee values reaching 100% within 2h, but the ee values obviously decrease with the increase of running time, and the ee values decrease to below 93.5% at 3h and to below 36% at 4h.

[0056] Although the embodiments of the present application have been shown and described above, it should be understood by those skilled in the art that the above embodiments are exemplary and should not be construed as limiting the present application, and those skilled in the art can make changes, modifications, replacements and variations to the above embodiments without departing from the principles and purposes of the present application within the scope of the present application.

Claims

1. A method for preparing a chiral metal-organic framework separation membrane, characterized in that, The method involves uniformly spreading a chiral selective liquid onto a PVDF base membrane and then vacuum filtering it. The chiral selective liquid is an aqueous solution containing hydroxypropyl-β-cyclodextrin, sulfonyl-β-cyclodextrin, N-ethylaniline, diphenyl sulfoxide, and alkali metal hydroxide. The resulting membrane is then heated in a methanol vapor environment and washed with water to obtain a metal-organic framework chiral separation membrane.

2. The method for preparing a chiral metal-organic framework separation membrane according to claim 1, characterized in that, The mass ratio of hydroxypropyl-β-cyclodextrin to sulfobutyl-β-cyclodextrin in the chiral selection solution is 1:(0.1-0.5).

3. The method for preparing the chiral metal-organic framework separation membrane according to claim 1, characterized in that, The mass ratio of hydroxypropyl-β-cyclodextrin to N-ethylaniline in the chiral selection solution is 1:(0.01~0.1).

4. The method for preparing a chiral metal-organic framework separation membrane according to claim 1, characterized in that, The mass ratio of hydroxypropyl-β-cyclodextrin to diphenyl sulfoxide in the chiral selection solution is 1:(0.01~0.1).

5. The method for preparing a chiral metal-organic framework separation membrane according to claim 1, characterized in that, The mass ratio of metal hydroxide to hydroxypropyl-β-cyclodextrin in the chiral selection solution is (0.01–0.1):

1.

6. The method for preparing a chiral metal-organic framework separation membrane according to claim 1, characterized in that, The alkali metal hydroxide is selected from at least one of lithium hydroxide, sodium hydroxide, and potassium hydroxide.

7. The method for preparing a chiral metal-organic framework separation membrane according to any one of claims 1 to 6, characterized in that, The solid content of the chiral selection liquid is 1-10 wt%.

8. The method for preparing a chiral metal-organic framework separation membrane according to any one of claims 1 to 6, characterized in that, The heat treatment conditions include a temperature of 45℃ to 55℃ and a time of 10 min to 30 min.

9. A chiral metal-organic framework separation membrane prepared by the method according to any one of claims 1 to 8.

10. The application of the metal-organic framework chiral separation membrane of claim 9 in the chiral separation of RS-naproxen.

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