A method for preparing a chiral porous organic cage membrane and its application in enantiomer separation

Abstract

The present invention provides a method for preparing a chiral porous organic cage membrane, and the application of a chiral separation membrane based on a chiral porous organic cage in enantiomer separation. The preparation method comprises the following steps: dispersing chiral porous organic cage crystals in a polymer solution to obtain a casting solution; the chiral porous organic cage crystals are formed by a condensation reaction of a chiral diamine monomer and an aldehyde monomer; and the casting solution is subjected to a phase transformation to form a chiral porous organic cage membrane. The present invention prepares a chiral porous organic cage membrane for enantiomer separation based on the chiral characteristics of POCs and the processability of the solution. The prepared chiral separation membrane based on chiral POCs can achieve highly selective separation of racemic mixtures of different concentrations in different solvent systems, and in particular can achieve efficient enantioselective separation of racemic mixtures of key intermediates of chiral drugs of different concentrations.

Description

Technical Field

[0001] The invention belongs to the technical field of chiral separation membranes, and relates to a method for preparing a chiral porous organic cage membrane, and application of a chiral separation membrane based on the chiral porous organic cage in enantiomer separation. Background Art

[0002] Chirality is a fundamental property of nature, used to describe the non-superimposability of a substance and its mirror image. Chiral compounds are widely used in the production of medicines, foods, pesticides and other fine chemical products, especially in the pharmaceutical industry. A large proportion of chemical drugs used for treatment are chiral drugs, and the enantiomers of chiral drugs usually exhibit different or even opposite pharmacological activities and toxicities. Therefore, rapid and efficient separation of enantiomers is crucial to ensure the safety and effectiveness of chiral drugs.

[0003] Traditional chiral separation technologies such as crystallization, enzyme catalysis, chromatography, etc. belong to chemical separation methods, which usually have the disadvantages of complex operation process and high cost. With the development of chiral separation technology, membrane separation has the potential advantages of low cost, easy operation and easy scalability, and has received extensive attention and research in the field of chiral separation. As an emerging chiral separation technology, chiral membrane separation has the characteristics of high efficiency, simplicity, low energy consumption, and continuous operation, and has great potential in the field of chiral separation. Currently, most commercial membrane materials are prepared from organic polymers. Although the current chiral separation membranes have proved the feasibility of achieving enantioselective separation, the existing membrane materials have the disadvantages of poor selectivity, low permeation flux, poor stability, and difficulty in breaking the restrictive relationship between selectivity and permeation flux, which greatly limits further application. In recent years, the manufacture of high-performance chiral separation membrane materials is still scarce. Therefore, it is urgent to develop new chiral separation membrane materials, such as new materials with richer chiral sites, stronger stability, and more molecular channels, and to construct a new generation of chiral separation membranes with high selectivity and high flux through simple and easy-to-control preparation methods.

[0004] Chiral porous materials such as chiral metal organic frameworks (chiral MOFs) and chiral covalent organic frameworks (chiral COFs) have the characteristics of high surface area, adjustable pore size and diverse structure, and are considered to be a promising class of chiral separation membrane materials. They have good separation effects in some chiral separation technologies. At present, most chiral MOFs and COFs are prepared by post-synthetic modification strategy of chiral functional groups, but this method has problems such as uneven distribution of chiral sites and uncontrollable loading of chiral functional groups. Summary of the invention

[0005] In view of this, the present invention provides a method for preparing a chiral porous organic cage membrane and its application in enantiomer separation. The present invention can construct a chiral separation membrane based on a chiral porous organic cage through a simple and easily controllable membrane preparation method, which has good application prospects in the separation of racemic mixtures of key intermediates of chiral drugs.

[0006] The present invention provides a method for preparing a chiral porous organic cage membrane, comprising the following steps:

[0007] S1, dispersing chiral porous organic cage crystals in a polymer solution to obtain a casting solution; the chiral porous organic cage crystals are formed by a condensation reaction of a chiral diamine monomer and an aldehyde monomer;

[0008] S2, forming a chiral porous organic cage membrane by phase inversion of the casting solution.

[0009] In an embodiment of the present invention, in step S1, the chiral porous cage is any one of CC3, CC4, CC9, CC10 and CC19.

[0010] In an embodiment of the present invention, in the step S1, the polymer in the polymer solution is protonated polyalkylbiphenylpyridine.

[0011] In an embodiment of the present invention, in the step S1, the dispersing is performed under stirring and ultrasonic conditions to obtain a transparent casting solution.

[0012] In an embodiment of the present invention, in the step S2, the phase conversion is performed at room temperature.

[0013] The present invention provides the use of the chiral porous organic cage membrane obtained by the above-mentioned preparation method in the separation of enantiomers.

[0014] In an embodiment of the present invention, the application is the selective separation of racemic mixtures of different concentrations in different solvent systems.

[0015] In an embodiment of the present invention, the solvent is one or more of water, methanol, ethanol, isopropanol and n-hexane.

[0016] In an embodiment of the present invention, the concentration of the racemic mixture is 0.0001 mol / L to 1 mol / L, further 0.001 mol / L to 0.1 mol / L.

[0017] In an embodiment of the present invention, the racemic mixture is a R / S-2-phenylpropionic acid racemic mixture or a R / S-mandelic acid racemic mixture.

[0018] The chiral porous organic cage described in the present invention is referred to as chiral POCs, which is a porous material with permanent pores formed by the polycondensation reaction of chiral diamine monomers and aldehyde monomers, and has uniformly distributed chiral recognition sites, which can specifically recognize and separate enantiomers. At the same time, compared with the lack of solution processability of chiral MOFs and chiral COFs, the chiral POCs can be dissolved in common organic solvents and have good solution processability. It is expected to construct high-performance chiral separation membranes through simple membrane preparation methods, and has great potential in the field of chiral separation.

[0019] Based on the chiral characteristics and good solution processability of chiral POCs, the present invention prepares a chiral porous organic cage membrane for enantiomer separation, which is mainly prepared by casting liquid phase transformation, and the membrane preparation method is simple and easy to control. The prepared chiral separation membrane based on chiral POCs can achieve high selective separation of racemic mixtures of different concentrations in different solvent systems, especially can achieve efficient enantioselective separation of racemic mixtures of key intermediates of chiral drugs of different concentrations, for example, the enantiomeric excess (ee) of R / S-2-phenylpropionic acid and R / S-mandelic acid can reach 100%. The present invention can improve the problems of uneven mixing, poor film forming, many defects and poor mechanical properties that are prone to occur in the synthesis process of existing chiral mixed matrix membranes, and has broad development prospects in the separation and application of chiral drug intermediates. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying creative work.

[0021] Figure 1 Circular dichroism spectra of chiral POCs materials CC3 and CC4 used in the examples of the present invention;

[0022] Figure 2 IR spectra of chiral separation membranes CC3-MMM and CC4-MMM based on chiral POCs prepared in the examples of the present invention;

[0023] Figure 3 This is a scanning electron microscope image of the chiral separation membrane CC3-MMM based on chiral POCs prepared in an example of the present invention;

[0024] Figure 4 This is a scanning electron microscope image of the chiral separation membrane CC4-MMM based on chiral POCs prepared in an example of the present invention;

[0025] Figure 5 This is a standard liquid chromatogram of the racemic mixture of 2-phenylpropionic acid, a key intermediate of the chiral drug used in Example 3 of the present invention;

[0026] Figure 6 This is a liquid chromatogram of the separation of the racemic mixture of 2-phenylpropionic acid, a key intermediate of chiral drugs, by the chiral separation membrane CC3-MMM based on chiral POCs in Example 3 of the present invention;

[0027] Figure 7 This is a standard liquid chromatogram of the racemic mixture of mandelic acid, a key intermediate of the chiral drug used in Example 7 of the present invention;

[0028] Figure 8 This is a liquid chromatogram of the separation of the racemic mixture of mandelic acid, a key intermediate of chiral drugs, by the chiral separation membrane CC3-MMM based on chiral POCs in Example 7 of the present invention. DETAILED DESCRIPTION

[0029] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0030] The present invention provides a method for preparing a chiral porous organic cage membrane, comprising the following steps:

[0031] S1, dispersing chiral porous organic cage crystals in a polymer solution to obtain a casting solution; the chiral porous organic cage crystals are formed by a condensation reaction of a chiral diamine monomer and an aldehyde monomer;

[0032] S2, forming a chiral porous organic cage membrane by phase inversion of the casting solution.

[0033] The present invention can construct a chiral separation membrane based on a chiral porous organic cage through a simple and easily controllable membrane preparation method, and has good application prospects in the separation of racemic mixtures of key intermediates of chiral drugs.

[0034] Porous organic cages (POCs) have a three-dimensional cage structure, which is composed of discrete building blocks such as imine (C=N bond) and borate (BO bond) molecular cages connected by weak interactions (such as weak van der Waals forces or hydrogen bonds). Among them, imine-type POCs (such as [4+6] tetrahedral cages and [2+3] triangular prismatic cages) are synthesized by imine condensation / reaction of various amines and aldehydes.

[0035] The chiral porous organic cage crystal described in the embodiment of the present invention is an imine type, which is formed by a condensation reaction of a chiral diamine monomer and an aldehyde monomer, specifically, by condensation of chiral 1,2-diaminocyclohexane and 1,3,5-triformylbenzene to form a chiral imine cage CC3 (covalent cage 3, the number is its naming sequence number) with an octahedral spatial configuration. In the embodiment of the present invention, the chiral porous cage includes but is not limited to any one of the chiral POCs such as CC3, CC4, CC9, CC10 and CC19, preferably CC3 or CC4; it can be obtained by commercially available or self-synthesis.

[0036] Specifically, the aldehyde monomers of CC3, CC4, CC9 and CC10 are all 1,3,5-triformylbenzene, among which the diamine monomer of CC3 is chiral 1,2-diaminocyclohexane; the diamine monomer of CC4 is chiral 1,2-diaminocyclopentane; the diamine monomer of CC9 is chiral 1,2-diphenylethylenediamine; the diamine monomer of CC10 is chiral 1,2-di(4-fluorophenyl)ethane-1,2-diamine. The aldehyde monomer of CC19 is 2-hydroxy-1,3,5-triformylbenzene, and the diamine monomer of CC19 is chiral 1,2-diaminocyclohexane. The molecular formula of CC3 is C 72 H 48 N 12 , CC4 molecular formula is C 66 H 72 N 12 The chiral porous organic cage is a porous molecular cage with a specific surface area of ​​about 300-1000 m 2 / g, and the pore size distribution is 0.5-1.2nm.

[0037] In the embodiment of the present invention, the chiral POCs crystals are used as chiral selectors and are uniformly dispersed in a polymer solution to obtain a transparent casting solution. Then, the casting solution is prepared into the chiral separation membrane based on the chiral POCs by phase inversion.

[0038] In an embodiment of the present invention, the polymer in the polymer solution is the main film-forming substance, preferably protonated polyalkyl biphenyl pyridine. In addition to protonated polyalkyl biphenyl pyridine (HPABP), the polymer also includes any one of polyethylene, polystyrene, polymethyl methacrylate, polyvinyl chloride, polycarbonate, polyurethane, polyethylene terephthalate, polylactic acid, etc.; there is no special requirement for the molecular weight of the polymer, as long as it can form a stable film. In addition, the solvent is mainly a mixture of dichlorohexane and methanol. In addition to the mixed solvent of dichloromethane and methanol, it also includes a mixed solvent formed by organic solvents such as chloroform, methanol, ethanol, N,N-dimethylformamide, dimethyl sulfoxide, acetone, tetrahydrofuran, etc. in a certain proportion. In some embodiments, the mass ratio of the chiral POCs crystal to the polymer can be 0.1~0.5:1.5~2.0, preferably 0.3:1.7. The dispersion is preferably carried out under stirring and ultrasonic conditions to obtain a uniform and stable casting solution. The mass fraction of POC crystals relative to polymer is 0-30%, preferably 15%. The mass ratio of dichloromethane to methanol can be 4:0.6-3, preferably 4:1.

[0039] Under room temperature conditions, the casting liquid obtained in the preferred embodiment of the present invention undergoes phase inversion. Specifically, the casting liquid can be scraped on a substrate such as a glass plate to remove the solvent, thereby obtaining the chiral porous organic cage membrane. The room temperature is well known to those skilled in the art, such as 10-30°C. Preferred specific process parameters for phase inversion: the film-making temperature is controlled in the range of 5-35°C, and the evaporation and drying time is 12-24 hours. The embodiment of the present invention uses a chiral porous organic cage material, and a defect-free chiral separation membrane can be prepared through simple steps such as mixing solvents. The thickness of the prepared chiral separation membrane can be 40-80 microns.

[0040] The present invention provides the use of the chiral porous organic cage membrane obtained by the preparation method as described above in the separation of enantiomers, and specifically preferably the use of the chiral separation membrane based on chiral POCs in separating racemic mixtures of key chiral drug intermediates of different concentrations in different solvent systems.

[0041] In an embodiment of the present invention, the different solvent systems include but are not limited to one or more of water, methanol, ethanol, isopropanol and n-hexane, and specifically water, ethanol or n-hexane. In addition, the different concentrations of the racemic mixture include but are not limited to a concentration range of 0.001 mol / L to 0.1 mol / L, such as 0.001 mol / L, 0.005 mol / L, 0.01 mol / L, 0.03 mol / L, 0.08 mol / L, 0.1 mol / L, etc.

[0042] The separation application process of the embodiment of the present invention specifically includes: fixing the chiral porous organic cage membrane in the middle of a detachable U-shaped diffusion tank, sealing and connecting with a rubber gasket, adding a racemic mixture solution to the feed chamber, adding an equal amount of solvent to the permeation chamber, continuously stirring the feed chamber and the permeation chamber with a magnetic stirring device, collecting the permeate from the permeation chamber after diffusion, slowly emitting nitrogen from the collected sample to evaporate the solvent, increasing the solution concentration, and facilitating high performance liquid chromatography (HPLC) identification and analysis. The feed amount depends on the size of the U-shaped tank used, and is 15 mL in the examples of the present invention, and the diffusion time can be 0-12 hours.

[0043] In some specific embodiments, the chiral porous organic cage membrane is used for the selective separation of the racemic mixture of R / S-2-phenylpropionic acid, a key intermediate of chiral drugs, and in other embodiments, the chiral porous organic cage membrane is used for the selective separation of the racemic mixture of R / S-mandelic acid, a key intermediate of chiral drugs. HPLC results show that the chiral separation membrane based on chiral POCs in the embodiment of the present invention can achieve an enantiomeric excess (ee) of 100% for R / S-2-phenylpropionic acid and R / S-mandelic acid, thereby achieving a highly selective separation of the racemic mixture.

[0044] In order to further understand the present invention, the present invention is described in detail below in conjunction with the examples, and the protection scope of the present invention is not limited by the following examples. In the examples, all raw reagents and materials are commercially available, and the experimental methods without specifying specific experimental conditions are conventional methods and conditions well known in the art.

[0045] It should be noted that the chiral POCs and polymers used in the examples are all synthesized in the laboratory, and the chromatographic column used for high performance liquid chromatography (HPLC) is Daicel CHIRALPAK® AD-H (250×4.6 mm, 5 µm). The synthesized POCs are CC3 and CC4 cages, CC3 is formed by the dehydration condensation of trimesic acid and R,R-cyclohexanediamine, and CC4 is formed by the dehydration condensation of trimesic acid and R,R-cyclopentanediamine. The polymer is protonated polyalkyl biphenyl pyridine (HPABP), which is synthesized by the polymerization reaction of 4-acetylpyridine and biphenyl catalyzed by superacid.

[0046] Embodiment 1-2:

[0047] The preparation method of the chiral separation membrane based on chiral POCs comprises the following steps:

[0048] 0.3 g of chiral POCs (CC3, CC4) crystals were used as chiral selectors, mixed evenly with solvent (methylene chloride and methanol in a mass ratio of 4:1) and 1.7 g of polymer (protonated polyalkyl biphenyl pyridine), stirred repeatedly and ultrasonicated to completely disperse and dissolve, and a transparent casting solution was obtained. The casting solution was phase-inverted at room temperature, specifically, the casting solution was evenly scraped on a glass plate, and after the solvent was completely evaporated, the membrane was soaked in cold water and taken out to prepare the chiral separation membrane based on chiral POCs. The separation membranes of Example 1 and Example 2 were recorded as CC3-MMM membrane and CC4-MMM membrane, respectively.

[0049] Figure 1 Circular dichroism spectra of chiral POCs materials CC3 and CC4 used in the examples of the present invention; Figure 2 Infrared spectra of the prepared chiral separation membranes CC3-MMM and CC4-MMM based on chiral POCs. Figure 3 and Figure 4 Scanning electron micrographs of the prepared chiral separation membranes CC3-MMM and CC4-MMM based on chiral POCs, respectively, including photos of different scales.

[0050] Figure 1 The circular dichroism spectra of CC3 and CC4 crystals are described respectively, as Figure 1 As shown, the optical rotation curves of CC3 and CC4 crystals both have peaks at 270 nm, indicating that both crystals have chiral characteristics.

[0051] Figure 2 The infrared absorption spectra of the prepared chiral separation membranes CC3-MMM and CC4-MMM are shown in Figure 2. Figure 2 As shown, CC3-MMM and CC4-MMM films have a peak at 1699 cm -1 There are infrared absorption peaks everywhere, which are the C=N characteristic absorption peaks of POC crystals (CC3, CC4), indicating the successful introduction of POC crystals into the polymer and the successful synthesis of the mixed matrix membrane.

[0052] Figure 3 and Figure 4 The following are scanning electron microscope images of the prepared chiral separation membranes CC3-MMM and CC4-MMM based on chiral POCs. It can be seen from the electron microscope images that the prepared CC3-MMM and CC4-MMM have a dense and defect-free morphology with a thickness of about 65 microns.

[0053] Embodiment 3:

[0054] The experiment of using CC3-MMM membrane to separate the racemic mixture of 2-phenylpropionic acid, a key intermediate of chiral drugs, in an ethanol system was carried out as follows:

[0055] Preparation of 0.001 mol·L -1 2-phenylpropionic acid racemic (R-2-phenylpropionic acid: S-2-phenylpropionic acid = 1:1, the structural formulas are as follows) ethanol solution.

[0056] Fix the CC3-MMM membrane in the middle of a detachable U-shaped diffusion trough and seal the connection with a rubber gasket. Add 15 ml of the above-mentioned 2-phenylpropionic acid racemic ethanol solution into the feed chamber and add an equal amount of pure ethanol into the permeation chamber. Use a magnetic stirring device to continuously stir the feed chamber and the permeation chamber. Collect the permeate from the permeation chamber after diffusion for 2 h. Slowly discharge nitrogen from the collected samples to evaporate ethanol and increase the solution concentration for easy identification and analysis by high performance liquid chromatography (HPLC).

[0057] , .

[0058] Figure 5 The standard liquid chromatogram of the racemic mixture of 2-phenylpropionic acid, a key intermediate of the chiral drug used; Figure 6 This is the liquid chromatogram of the separation of the racemic mixture of 2-phenylpropionic acid, a key intermediate of chiral drugs, using the chiral separation membrane CC3-MMM based on chiral POCs.

[0059] HPLC results show that CC3-MMM membrane exhibits good enantioselectivity for racemic 2-phenylpropionic acid ethanol solution. When the diffusion time is 2 h, only R-2-phenylpropionic acid is detected in the permeate, and no peak of S-2-phenylpropionic acid is detected. This indicates that CC3-MMM membrane only allows R-2-phenylpropionic acid molecules to pass through, and the ee value of R-2-phenylpropionic acid is as high as 100%, indicating that CC3-MMM membrane exhibits efficient chiral separation effect on 2-phenylpropionic acid racemic mixture.

[0060] Embodiment 4:

[0061] The experiment of using CC3-MMM membrane to separate the racemic mixture of 2-phenylpropionic acid, a key intermediate of chiral drugs, in an ethanol system was carried out as follows:

[0062] 1) Preparation of 0.01 mol L -1The CC3-MMM membrane was fixed in the middle of a detachable U-shaped diffusion tank, and the connection was sealed with a rubber gasket. 15 ml of the above-mentioned 2-phenylpropionic acid racemic ethanol solution was added to the feed chamber, and an equal amount of pure ethanol was added to the permeation chamber. The feed chamber and the permeation chamber were continuously stirred with a magnetic stirring device. After diffusion for 30 minutes, the permeate was collected from the permeation chamber. The collected samples were slowly discharged with nitrogen to evaporate the ethanol and increase the solution concentration, which was convenient for high performance liquid chromatography (HPLC) identification and analysis.

[0063] 2) HPLC results show that CC3-MMM membrane exhibits good enantioselectivity for racemic 2-phenylpropionic acid ethanol solution. When the diffusion time is 30 min, only R-2-phenylpropionic acid is detected in the permeate, and no peak of S-2-phenylpropionic acid is detected. This indicates that CC3-MMM membrane only allows R-2-phenylpropionic acid molecules to pass through, and the ee value of R-2-phenylpropionic acid is as high as 100%, indicating that CC3-MMM membrane exhibits efficient chiral separation effect on 2-phenylpropionic acid racemic mixture.

[0064] Embodiment 5:

[0065] The experiment of using CC3-MMM membrane to separate the racemic mixture of 2-phenylpropionic acid, a key intermediate of chiral drugs, in an ethanol system was carried out as follows:

[0066] 1) Preparation of 0.1 mol L -1 The CC3-MMM membrane was fixed in the middle of a detachable U-shaped diffusion tank, and the connection was sealed with a rubber gasket. 15 ml of the above-mentioned 2-phenylpropionic acid racemic ethanol solution was added to the feed chamber, and an equal amount of pure ethanol was added to the permeation chamber. The feed chamber and the permeation chamber were continuously stirred with a magnetic stirring device. After 15 minutes of diffusion, the permeate was collected from the permeation chamber. The collected samples were slowly discharged with nitrogen to evaporate the ethanol and increase the solution concentration, which was convenient for high performance liquid chromatography (HPLC) identification and analysis.

[0067] 2) HPLC results show that CC3-MMM membrane exhibits good enantioselectivity for racemic 2-phenylpropionic acid ethanol solution. When the diffusion time is 15 min, only R-2-phenylpropionic acid is detected in the permeate, and no peak of S-2-phenylpropionic acid is detected. This indicates that CC3-MMM membrane only allows R-2-phenylpropionic acid molecules to pass through, and the ee value of R-2-phenylpropionic acid is as high as 100%, indicating that CC3-MMM membrane exhibits efficient chiral separation effect on 2-phenylpropionic acid racemic mixture.

[0068] Embodiment 6:

[0069] The experiment of using CC4-MMM membrane to separate the racemic mixture of 2-phenylpropionic acid, a key intermediate of chiral drugs, in an ethanol system was carried out as follows:

[0070] 1) Preparation of 0.001 mol L -1 The CC4-MMM membrane was fixed in the middle of a detachable U-shaped diffusion tank, and the connection was sealed with a rubber gasket. 15 ml of the above-mentioned 2-phenylpropionic acid racemic ethanol solution was added to the feed chamber, and an equal amount of pure ethanol was added to the permeation chamber. The feed chamber and the permeation chamber were continuously stirred with a magnetic stirring device. After 2 h of diffusion, the permeate was collected from the permeation chamber. The collected samples were slowly discharged with nitrogen to evaporate the ethanol and increase the solution concentration, which was convenient for high performance liquid chromatography (HPLC) identification and analysis.

[0071] 2) HPLC results show that CC4-MMM membrane exhibits good enantioselectivity for racemic 2-phenylpropionic acid ethanol solution. When the diffusion time is 2 h, only R-2-phenylpropionic acid is detected in the permeate, and no peak of S-2-phenylpropionic acid is detected. This indicates that CC4-MMM membrane only allows R-2-phenylpropionic acid molecules to pass through, and the ee value of R-2-phenylpropionic acid is as high as 100%, indicating that CC4-MMM membrane exhibits efficient chiral separation effect on 2-phenylpropionic acid racemic mixture.

[0072] Embodiment 7:

[0073] The experiment of using CC3-MMM membrane to separate the racemic mixture of mandelic acid, a key intermediate of chiral drugs, in water system was carried out as follows:

[0074] Preparation of 0.01 mol L -1 An aqueous solution of racemic mandelic acid (R-mandelic acid: S-mandelic acid = 1:1, the structural formulas are as follows).

[0075] , .

[0076] The CC3-MMM membrane was fixed in the middle of a detachable U-shaped diffusion trough and sealed with a rubber gasket. 15 ml of the above-mentioned racemic mandelic acid aqueous solution was added to the feed chamber, and an equal amount of pure water was added to the permeation chamber. The feed chamber and the permeation chamber were continuously stirred with a magnetic stirring device. After diffusion for 2 h, the permeate was collected from the permeation chamber. The collected samples were heated to evaporate the water, and then quantitative ethanol was added to dissolve them, and they were analyzed by high performance liquid chromatography (HPLC).

[0077] Figure 7 The standard liquid chromatogram of the racemic mixture of mandelic acid, a key intermediate of the chiral drug used; Figure 8 This is the liquid chromatogram of the separation of the racemic mixture of mandelic acid, a key intermediate of chiral drugs, using the chiral separation membrane CC3-MMM based on chiral POCs.

[0078] HPLC results show that CC3-MMM membrane exhibits good enantioselectivity for racemic mandelic acid aqueous solution. When the diffusion time is 2 h, only R-mandelic acid is detected in the permeate, and no peak of S-mandelic acid is detected. This indicates that CC3-MMM membrane only allows R-mandelic acid molecules to pass through, and the ee value of R-mandelic acid is as high as 100%, indicating that CC3-MMM membrane exhibits efficient chiral separation effect on mandelic acid racemic mixture.

[0079] Embodiment 8:

[0080] The experiment of using CC4-MMM membrane to separate the racemic mixture of mandelic acid, a key intermediate of chiral drugs, in water system was carried out. The specific implementation method is as follows:

[0081] 1) Preparation of 0.01 mol L -1 Aqueous solution of racemic mandelic acid (R-mandelic acid: S-mandelic acid = 1:1) was prepared. The CC4-MMM membrane was fixed in the middle of a detachable U-shaped diffusion tank and sealed with a rubber gasket. 15 ml of the racemic mandelic acid aqueous solution was added to the feed chamber, and an equal amount of pure water was added to the permeation chamber. The feed chamber and the permeation chamber were continuously stirred with a magnetic stirring device. After diffusion for 2 h, the permeate was collected from the permeation chamber. The collected samples were heated to evaporate the water, and then quantitative ethanol was added to dissolve them, and they were analyzed by high performance liquid chromatography (HPLC).

[0082] 2) HPLC results show that CC4-MMM membrane exhibits good enantioselectivity for racemic mandelic acid aqueous solution. When the diffusion time is 2 h, only R-mandelic acid is detected in the permeate, and no peak of S-mandelic acid is detected. This indicates that CC4-MMM membrane only allows R-mandelic acid molecules to pass through, and the ee value of R-mandelic acid is as high as 100%, indicating that CC4-MMM membrane exhibits efficient chiral separation effect on mandelic acid racemic mixture.

[0083] The separation performance of existing MOF and COF separation membranes cannot achieve an enantiomeric excess (ee) of 100%, and is generally distributed between 30-90%, and single enantioselective chiral molecules cannot be obtained. However, the chiral porous organic cage membrane for enantiomeric separation prepared in the embodiment of the present invention can achieve efficient enantiomeric selective separation of racemic mixtures of key intermediates of chiral drugs of different concentrations, for example, the enantiomeric excess (ee) of R / S-2-phenylpropionic acid and R / S-mandelic acid can reach 100%.

[0084] As can be seen from the above examples, the chiral porous organic cage membrane for enantiomer separation is prepared in the present invention, which is mainly prepared by liquid phase transformation of film casting, and the membrane preparation method is simple and easy to control. The prepared chiral separation membrane based on chiral POCs can achieve high selective separation of racemic mixtures of different concentrations in different solvent systems, especially can achieve efficient enantioselective separation of racemic mixtures of key intermediates of chiral drugs of different concentrations, for example, the enantiomeric excess (ee) of R / S-2-phenylpropionic acid and R / S-mandelic acid can reach 100%. The present invention can improve the problems of uneven mixing, poor film forming, many defects and poor mechanical properties that are prone to occur in the synthesis process of existing chiral mixed matrix membranes, and has broad development prospects in the separation and application of chiral drug intermediates.

[0085] The specific embodiments described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above description is only a specific embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. Application of a chiral porous organic cage membrane in enantiomer separation; wherein: The preparation method of the chiral porous organic cage membrane comprises the following steps: S1, dispersing chiral porous organic cage crystals in a polymer solution to obtain a casting solution; the chiral porous organic cage crystals are formed by a condensation reaction of a chiral diamine monomer and an aldehyde monomer; S2, the casting solution is subjected to phase inversion, wherein the phase inversion is performed at room temperature to form a chiral porous organic cage membrane; In the step S1, the chiral porous cage is any one of CC3, CC4, CC9, CC10 and CC19; the polymer in the polymer solution is protonated polyalkyl biphenyl pyridine; the dispersion is carried out under stirring and ultrasonic conditions to obtain a transparent casting solution; The enantiomers are a racemic mixture, which is a R / S-2-phenylpropionic acid racemic mixture or a R / S-mandelic acid racemic mixture.

2. The use according to claim 1, characterized in that: The application is the selective separation of racemic mixtures of different concentrations in different solvent systems.

3. The use according to claim 2, characterized in that: The solvent is one or more of water, methanol, ethanol, isopropanol and n-hexane.

4. The use according to claim 2, characterized in that: The concentration of the racemic mixture is 0.0001 mol / L to 1 mol / L.

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