Fractionated-pore chiral MOFs for chiral drug resolution and preparation method thereof

Abstract

The application discloses a preparation method of hierarchical-pore chiral MOFs for chiral drug resolution, and the method comprises the following steps: dissolving 2-amino-1,1'-biphenyl-4,4'-dicarboxylic acid in DMF to obtain an initial solution; increasing the temperature to 110-130 DEG C, adding aluminum chloride hexahydrate, and stirring for 24 h or more; after cooling, performing solid-liquid separation, washing, drying, and vacuum drying to obtain DUT-5-NH2; dissolving chiral molecules in MES buffer, adding a coupling agent to activate for 1-2 h, adding DUT-5-NH2, immediately adding acetonitrile to stop the hydrolysis process of DUT-5-NH2 after ultrasonic treatment for 1-2 min; again performing ultrasonic treatment for 1-2 min, and stirring for 5 d or more; performing solid-liquid separation, washing, and drying to obtain hierarchical-pore chiral MOFs materials; four kinds of hierarchical-pore chiral MOFs are successfully prepared by using the post-synthesis modification method, are used for selective adsorption and separation of macromolecular chiral drugs, and have good separation effects on various macromolecular chiral drugs, and therefore, the synthesis method is simple, the performance is excellent, the stability is good, the cost is low, and therefore, the method has a wide prospect in the separation of macromolecular chiral drugs.

Description

Technical Field

[0001] This invention belongs to the field of materials technology, specifically relating to a hierarchical porous chiral MOF and its preparation method. Background Technology

[0002] The efficient separation of chiral drugs is a widely concerned issue in the modern pharmaceutical field. Currently, commonly used separation methods include crystallization, chemical, biological, extraction, chromatographic, and membrane separation. Each method has its advantages and limitations: for example, while crystallization has been industrialized, it typically requires large quantities of resolving agents or seed crystals, generating waste liquid that is environmentally harmful; enzymatic separation has excellent enantiomeric recognition capabilities, but enzyme screening and preservation are difficult and costly; chemical separation is suitable for industrial production, but the selection of resolving agents and solvents remains limited; liquid chromatography is sensitive and effective, but chiral stationary and mobile phases are expensive, making it unsuitable for large-scale production. However, regardless of the method used, obtaining materials with a single chirality is a crucial step in subsequent chiral separation.

[0003] In recent years, metal-organic frameworks (MOFs), as novel three-dimensional porous crystalline materials, are constructed from metal nodes and organic linkers through coordination interactions. They possess advantages such as strong designability of pore structures, large specific surface area, and structural stability. Their pore structures can be modified by introducing different functional groups or small molecules to achieve functionalized designs that provide specific chiral environments. Therefore, MOFs are considered excellent precursor materials for chiral modification. However, traditional MOFs are mostly microporous structures with limited pore size. Current research on chiral MOFs mainly focuses on the resolution of small-molecule chiral compounds, and research on the effective resolution of large-molecule chiral drugs remains scarce. This has led to hierarchical porous MOFs becoming an emerging direction in chiral drug resolution research, providing a new material platform for the selective recognition of large-molecule chiral drugs.

[0004] Therefore, developing a novel method for preparing hierarchical chiral MOFs materials is of great significance to overcome the current limitations in chiral drug resolution, especially for applications in resolving large chiral drugs. Summary of the Invention

[0005] Chiral drug resolution methods suffer from problems such as low efficiency, high cost, and difficulty in scaling up, especially for large-molecule chiral drugs (molecular weight ≥300 Dalton, such as amlodipine, cetirizine hydrochloride, omeprazole, and diclazuril). There is a lack of chiral resolution materials that are both highly efficient, easy to synthesize, low in raw material cost, and have good stability.

[0006] This invention provides a novel method for preparing hierarchical pore chiral MOFs (HMOFs), which exhibits high stability and effectiveness in resolving large-molecule chiral drugs (molecular weight ≥300 Dalton, such as amlodipine, cetirizine hydrochloride, omeprazole, diclazuril, etc.). Furthermore, the synthesis method is simple and the raw materials are inexpensive, making it a promising candidate for large-scale application in the resolution of large-molecule chiral drugs.

[0007] To achieve the above objectives, the following technical solution is adopted: A method for preparing hierarchical chiral MOFs for chiral drug resolution includes the following steps: (1) Dissolve 2-amino-1,1''-biphenyl-4,4''-dicarboxylic acid in DMF to obtain an initial solution; (2) Heat to 110-130 ℃, add aluminum chloride hexahydrate, and stir for more than 24 h; (3) After cooling, solid-liquid separation, washing, drying, and vacuum drying are performed to obtain DUT-5-NH2; (4) Dissolve the chiral molecules in MES buffer, add a coupling agent to activate for 1-2 h, add DUT-5-NH2, sonicate for 1-2 min and immediately add acetonitrile to stop the hydrolysis of DUT-5-NH2; sonicate again for 1-2 min and stir for more than 5 days; separate solid and liquid, wash and dry to obtain hierarchical pore chiral MOFs material.

[0008] According to the above scheme, the concentration of 2-amino-1,1''-biphenyl-4,4''-dicarboxylic acid in the initial solution of step 1 is 1.5-2.5 mmol / 50mL.

[0009] According to the above scheme, the molar ratio of aluminum chloride hexahydrate to 2-amino-1,1''-biphenyl-4,4''-dicarboxylic acid in step 2 is 1:(0.7-1.3).

[0010] According to the above scheme, the washing process in step 3 includes soaking in fresh DMF for 12 hours each time and washing with methanol three times; the drying process includes drying at 80 ℃ overnight.

[0011] According to the above scheme, the vacuum drying temperature in step 3 is 130 ℃ and the time is 18-24 h.

[0012] According to the above scheme, the molar ratio of coupling agent, chiral molecule, and DUT-5-NH2 in step 4 is 1:1:0.33.

[0013] According to the above scheme, the coupling agent in step 4 is a mixture of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxythiosuccinimide sodium salt in a molar ratio of 1:0.2.

[0014] According to the above scheme, the intensity of ultrasonic treatment in step 4 is 400-2000 W / cm. 2 .

[0015] According to the above scheme, the chiral molecule mentioned in step 4 is L-His, L-Glu, L-Trp or CM-β-CD, and the corresponding products are DUT-5-NH-L-His, DUT-5-NH-L-Glu, DUT-5-NH-L-Trp and DUT-5-NH-CM-β-CD, respectively.

[0016] The present invention also provides a hierarchical chiral MOF for chiral drug resolution, which is prepared using the above-described method.

[0017] Compared with the prior art, the beneficial effects of the present invention are as follows: Aluminum chloride hexahydrate with a metal center and the organic ligand 2-amino-1,1'-biphenyl-4,4'-dicarboxylic acid self-assembled in DMF to synthesize DUT-5-NH2 via simple solvothermal processing. Immersion and washing in DMF and methanol effectively removed solvent molecules from the pores. Further high-temperature activation enhanced the exposure of functional groups (amino groups) in the pores, improving the subsequent chiral molecule grafting rate. Chiral post-modification of DUT-5-NH2 was performed using controlled water treatment (CWT). The coupling agent and chiral molecule were dissolved in MES buffer, and the terminal carboxyl groups of the chiral molecule were activated for approximately 1 hour. Utilizing the hydrolytic properties of DUT-5-NH2, it was dispersed in this solution. After sonication for 1-2 minutes, acetonitrile was immediately added to stop the hydrolysis of DUT-5-NH2. After reacting at room temperature for 5 days, hierarchical chiral MOFs were obtained. Washing with acetonitrile aqueous solution (v:v=1:1) and methanol yielded a pale yellow powder, which was then dried at room temperature to obtain HMOFs.

[0018] This invention prepares DUT-5-NH2 via a self-assembly solvothermal method and, for the first time, uses a controlled water treatment method to prepare hierarchical pore MOFs. Four types of hierarchical pore chiral MOFs were successfully prepared using a post-synthetic modification method for the selective adsorption and separation of macromolecular chiral drugs, demonstrating good separation effects for a variety of macromolecular chiral drugs. The synthesis method is simple, the performance is excellent, the stability is good, and the cost is low, thus showing broad prospects for the separation of macromolecular chiral drugs. Attached Figure Description

[0019] Figure 1Schematic diagram of the synthesis of DUT-5-NH-X (X=L-Glu, L-His, L-Trp and CM-β-CD).

[0020] Figure 2 Scanning electron microscope images of DUT-5-NH2, DUT-5-NH-L-Glu, DUT-5-NH-L-His, DUT-5-NH-L-Trp and DUT-5-NH-CM-β-CD.

[0021] Figure 3 Infrared spectra of DUT-5-NH2, DUT-5-NH-L-Glu, DUT-5-NH-L-His, DUT-5-NH-L-Trp and DUT-5-NH-CM-β-CD.

[0022] Figure 4 XRD patterns of DUT-5-NH2, DUT-5-NH-L-Glu, DUT-5-NH-L-His, DUT-5-NH-L-Trp and DUT-5-NH-CM-β-CD.

[0023] Figure 5 Nitrogen adsorption and desorption of DUT-5-NH2, DUT-5-NH-L-Glu, DUT-5-NH-L-His, DUT-5-NH-L-Trp and DUT-5-NH-CM-β-CD are shown in the attached diagram and pore size distribution diagram.

[0024] Figure 6 Thermogravimetric analysis diagrams of DUT-5-NH2, DUT-5-NH-L-Glu, DUT-5-NH-L-His, DUT-5-NH-L-Trp and DUT-5-NH-CM-β-CD.

[0025] Figure 7 Graph showing the change in adsorption amount of DUT-5-NH2 on the chiral drug amlodipine over time, and the change in ee value of the chiral drug amlodipine over time.

[0026] Figure 8 Graph showing the change in adsorption amount of DUT-5-NH-L-Glu for the chiral drug amlodipine over time, and the change in ee value of the chiral drug amlodipine over time.

[0027] Figure 9 : The adsorption amount of DUT-5-NH-L-His on the chiral drug amlodipine changes over time, and the ee value of the chiral drug amlodipine changes over time.

[0028] Figure 10: The adsorption amount of DUT-5-NH-L-Trp on the chiral drug amlodipine changes over time, and the ee value of the chiral drug amlodipine changes over time.

[0029] Figure 11 Graph showing the change in adsorption amount of DUT-5-NH-CM-β-CD for the chiral drug amlodipine over time, and the change in ee value of the chiral drug amlodipine over time.

[0030] Figure 12 Chromatographic separation of large chiral drugs using HMOF solid-phase extraction column. Detailed Implementation

[0031] The following embodiments further illustrate the technical solution of the present invention, but are not intended to limit the scope of protection of the present invention.

[0032] Example 1 An HMOFs material is prepared as follows: (1) Dissolve BPDC-NH2 in DMF to obtain an initial solution with a concentration of 1.08 mmol / 50 mL; (2) Keep at 120 °C, add aluminum chloride hexahydrate, and continue stirring for 24 h; the molar ratio of aluminum chloride hexahydrate to BPDC-NH2 is 1:0.77; (3) After cooling, solid-liquid separation was performed. Fresh DMF was used for soaking for 12 h / time, followed by washing with methanol three times and vacuum drying at 130 ℃ for 20 h to obtain DUT-5-NH2. (4) Dissolve the chiral molecule L-His in MES buffer, add a coupling agent to activate for 1-2 h, add activated DUT-5-NH2, and use a cell disruptor at 800 W / cm 2 After ultrasonic treatment for 1-2 min, acetonitrile was immediately added to stop the hydrolysis of DUT-5-NH2, and then the hydrolysis was stopped again at 800 W / cm. 2 After ultrasonic treatment for 1-2 min, the mixture was stirred at room temperature for 5 days. Solid-liquid separation, washing, and drying were performed to obtain the hierarchical porous chiral MOF material DUT-5-NH-L-His. The molar ratio of coupling agent, chiral molecule, and DUT-5-NH2 was 1:1:0.33. The coupling agent was a mixture of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxythiosuccinimide sodium salt in a molar ratio of 1:0.2.

[0033] Example 2 Repeat Example 1, replacing the chiral molecule L-His with L-Glu to obtain the product DUT-5-NH-L-Glu.

[0034] Example 3 Repeat Example 1, replacing the chiral molecule L-His with L-Trp to obtain the product DUT-5-NH-L-Trp.

[0035] Example 4 Repeat Example 1, replacing the chiral molecule L-His with CM-β-CD to obtain the product DUT-5-NH-CM-β-CD.

[0036] The morphologies of DUT-5-NH2, DUT-5-NH-L-His, DUT-5-NH-L-Glu, DUT-5-NH-L-Trp, and DUT-5-NH-CM-β-CD were observed using scanning electron microscopy, and the results are as follows: Figure 2 As shown, the overall structure of HMOFs and MOFs remained unchanged, exhibiting a coral-like stacked structure, indicating that the crystal structure of MOFs was not destroyed during the post-modification process. However, there were slight differences in the surface morphology of the particles. Compared to the slightly shriveled, dispersed, and short coral-like surface of MOFs, the surfaces of HMOFs showed full, stacked, and slender coral-like structures, respectively. These subtle differences in particle surface caused by the modification of MOFs by chiral molecules are due to these chiral molecules. The surface of DUT-5-NH2 before modification exhibited a relatively regular polyhedral shape, while the overall shape of the modified material particles did not change significantly from the unmodified particles, remaining relatively uniform spherical granules, but the surface morphology of the entire material changed significantly.

[0037] DUT-5-NH2, DUT-5-NH-L-His, DUT-5-NH-L-Glu, DUT-5-NH-L-Trp, and DUT-5-NH-CM-β-CD were characterized using infrared spectroscopy, and the results are as follows: Figure 3 As shown. Comparing the two infrared spectra below, it was found that MOFs lacked the region located at 3300-2500 cm⁻¹. -1 The stretching vibration peak of the hydroxyl group, and the fingerprint region at 911 cm⁻¹ -1 The bending vibration peak of the hydroxyl group and 1689 cm⁻¹ -1 The stretching vibration peak of the carbonyl group is observed, but at 3400 cm⁻¹ -1 The retention of the stretching vibration peak of the primary amine indicates that the carboxyl group in the ligand has coordinated with the metal center, demonstrating the successful synthesis of our MOFs. Comparison of the five infrared spectra above reveals that the 3400 cm⁻¹ peak in HMOFs... -1 The primary amine disappears at 3500-3100 cm. -1 The stretching vibration peak of secondary amines appears, as does the 1689 cm⁻¹ peak in HMOFs. -1 The appearance of the stretching vibration peak of the carbonyl group indicates that the carboxyl group of the chiral molecule has been successfully amidated with the amino group on the pore surface of MOFs.

[0038] The crystal types of DUT-5-NH2, DUT-5-NH-L-His, DUT-5-NH-L-Glu, DUT-5-NH-L-Trp, and DUT-5-NH-CM-β-CD were characterized using powder X-ray diffraction, and the results are as follows: Figure 4 As shown, strong diffraction peaks are observed at diffraction angles of 2θ of 6°, 12°, 18°, and 24°, which are in good agreement with the simulated XRD results and consistent with the diffraction positions reported in previous literature, indicating the successful synthesis of DUT-5-NH2. The remaining four XRD patterns are the XRD patterns of HMOFs modified with chiral molecules after MOFs were modified. Compared with the unmodified HMOFs, the diffraction positions of the modified HMOFs did not change, but the diffraction intensities were reduced to some extent. This is because the chiral molecules were successfully grafted onto the surface of the MOFs, and the crystal structure of the MOFs was not destroyed during the grafting process.

[0039] DUT-5-NH2, DUT-5-NH-L-His, DUT-5-NH-L-Glu, DUT-5-NH-L-Trp, and DUT-5-NH-CM-β-CD were characterized using a nitrogen adsorption analyzer, and the results are as follows: Figure 5 As shown in Table 1, the specific surface area of ​​DUT-5-NH2 is as high as 1575 m². 2 The result of / g is consistent with the literature, further demonstrating the successful synthesis of MOFs. Furthermore, the unmodified DUT-5-NH2-CWT, treated only with controlled water, exhibits an H4-type hysteresis loop, indicating that controlled water treatment transforms the microporous material into a microporous-mesoporous material containing numerous mesopores. This exposes more sites and increases the pore size, reducing mass transfer resistance during molecular movement within the pores, which is beneficial for post-modification and subsequent enantiomeric recognition of large chiral drug molecules. The specific surface area of ​​DUT-5-NH-L-Glu is 1347 m² / g. 2 The specific surface area of ​​DUT-5-NH-L-His is 1252 m² / g. 2 / g, the specific surface area of ​​DUT-5-NH-L-His-Trp is 1037 m². 2 / g, the specific surface area of ​​DUT-5-NH-CM-β-CD is 890 m². 2 / g. After controlled water treatment, the mesoporous area, total porosity, mesopore size, and average pore size all decreased, indicating that the chiral molecules were successfully grafted into the pores.

[0040] Table 1 Pore structure parameters of HMOFs

[0041] Thermogravimetric analysis was used to characterize the thermal stability of DUT-5-NH2, DUT-5-NH-L-His, DUT-5-NH-L-Glu, DUT-5-NH-L-Trp, and DUT-5-NH-CM-β-CD, respectively. The results are as follows: Figure 6 As shown, the large-scale collapse of the framework structures of MOFs and HMOFs begins around 370 °C, with the collapse rate reaching its maximum at 500 °C, indicating good thermal stability. The temperatures at which large-scale collapse begins are consistent with literature reports. Due to the successful grafting of chiral molecules, the chiral molecules in HMOFs decompose before the framework collapses with increasing temperature, thus HMOFs begin to collapse earlier than MOFs. The frameworks of DUT-5-NH-L-Glu and DUT-5-NH-CM-β-CD begin to collapse around 220 °C, while those of DUT-5-NH-L-His and DUT-5-NH-L-Trp begin to collapse around 250 °C.

[0042] Using amlodipine as a model molecule, selective adsorption experiments were conducted on the HMOFs material prepared in Example 1 at different time points to preliminarily explore the enantiomeric separation ability and adsorption capacity of the HMOFs material for amlodipine. Figure 7 As shown, the saturated adsorption capacity of DUT-5-NH2 for amlodipine enantiomers is 7.5 mg / g, indicating almost no enantiomer separation ability; Figure 8 As shown, DUT-5-NH-L-Glu preferentially adsorbs S-amlodipine, with a saturation adsorption capacity of 5.1 mg / g and a maximum ee value of 3.8%; Figure 9 As shown, DUT-5-NH-L-His preferentially adsorbs S-amlodipine, with a saturation adsorption capacity of 7.8 mg / g and a maximum ee value of 5.5%; Figure 10 As shown, DUT-5-NH-L-Trp preferentially adsorbs S-amlodipine, with a saturation adsorption capacity of 5.5 mg / g and a maximum ee value of 5.5%; Figure 11 As shown, DUT-5-NH-CM-β-CD preferentially adsorbs R-amlodipine, with a saturation adsorption capacity of 26.3 mg / g and a maximum ee value of 21.1%.

[0043] The prepared HMOFs material was packed into a solid-phase extraction column, and solid-phase extraction experiments were performed on the racemic mixture of amlodipine. The racemic solutions and eluents of the drug before and after extraction were detected by high-performance liquid chromatography (HPLC). Figure 12As shown, the enantiomeric separation capabilities of HMOF materials for amlodipine racemic solutions, from strongest to weakest, are DUT-5-NH-CM-β-CD, DUT-5-NH-L-His, DUT-5-NH-L-Trp, and DUT-5-NH-L-Glu, with ee values ​​of 36.2%, 18.6%, 12.3%, and 8.3%, respectively. It can be seen that DUT-5-NH-CM-β-CD material exhibits the best enantiomeric separation capability. To investigate the broad applicability of this material, the enantiomeric separation capabilities of solid-phase extraction columns packed with DUT-5-NH-CM-β-CD material for other large-molecule chiral drugs were studied, such as... Figure 12 As shown, the ee value calculated for separating omeprazole was 29.8%, for diclazuril was 26.2%, and for cetirizine hydrochloride was 32.1%. This indicates that the hierarchical chiral MOFs—DUT-5-NH-CM-β-CD material prepared by a controlled water treatment method—have good enantiomeric resolution capabilities and exhibit good resolution effects for most large-molecule chiral drugs.

[0044] The testing conditions are as follows: 1. Amlodipine: Column: EnantioPak SCDP column (5 µm, 4.6 × 250 mm2); Mobile phase: n-hexane:ethanol = 80:20 (v:v) (0.1% trifluoroacetic acid); Injection volume: 20 µL; Detection wavelength: 237 nm; Column temperature: 30 ℃; Flow rate: 1 mL / min.

[0045] 2. Omeprazole: Mobile phase: n-hexane:ethanol = 70:30 (v:v) (0.1% trifluoroacetic acid); Detection wavelength: 220nm; Other conditions are the same as those for amlodipine.

[0046] 3. Diclazuril: Detection wavelength: 275 nm; other conditions are the same as those for omeprazole.

[0047] 4. Cetirizine hydrochloride: Column: CHIRALPAK AD-H column (5 µm, 4.6 × 250 mm2); Mobile phase: n-hexane:isopropanol = 80:20 (v:v) (0.1% trifluoroacetic acid and 0.1% diethylamine); Injection volume: 20 µL; Detection wavelength: 230 nm; Column temperature: 30 ℃; Flow rate: 1 mL / min.

[0048] Controlled water treatment successfully transformed microporous DUT-5-NH2 into a microporous-mesoporous hierarchical material. Nitrogen adsorption-desorption experiments showed that the treated material exhibited a significant H4-type hysteresis loop, with a significant increase in mesopore volume and average pore size (see Table 1), proving the successful introduction of mesopores. Thermogravimetric analysis showed that the obtained hierarchical chiral MOFs material only began to undergo large-scale framework collapse at around 370℃. Powder X-ray diffraction indicated that the post-modification process did not destroy the crystal structure of the MOFs, demonstrating that the material has good thermal and structural stability. The hierarchical chiral MOFs prepared in this invention, especially DUT-5-NH-CM-β-CD, exhibited excellent resolution capabilities for large-molecule chiral drugs with molecular weights exceeding 300 Daltons (such as amlodipine, omeprazole, diclazuril, and cetirizine hydrochloride). Solid-phase extraction column experiments showed that the enantiomeric excess (ee) values ​​for amlodipine, cetirizine hydrochloride, omeprazole, and diclazuril reached 36.2%, 32.1%, 29.8%, and 26.2%, respectively, which are significantly higher than those for unmodified DUT-5-NH2 (which has almost no resolving ability). The raw materials used in this invention (such as 2-amino-1,1'-biphenyl-4,4'-dicarboxylic acid and aluminum chloride hexahydrate) are inexpensive, and the synthesis and post-modification processes do not require expensive equipment and reagents. The operation steps are relatively simple, and it has the potential for large-scale production.

Claims

1. A method for preparing hierarchical chiral MOFs for chiral drug resolution, characterized in that... Includes the following steps: (1) Dissolve 2-amino-1,1''-biphenyl-4,4''-dicarboxylic acid in DMF to obtain an initial solution; (2) Heat to 110-130 ℃, add aluminum chloride hexahydrate, and stir for more than 24 h; (3) After cooling, solid-liquid separation, washing, drying, and vacuum drying are performed to obtain DUT-5-NH2; (4) Dissolve the chiral molecules in MES buffer, add a coupling agent to activate for 1-2 h, add DUT-5-NH2, sonicate for 1-2 min and immediately add acetonitrile to stop the hydrolysis of DUT-5-NH2; sonicate again for 1-2 min and stir for more than 5 days; separate solid and liquid, wash and dry to obtain hierarchical pore chiral MOFs material.

2. The method for preparing hierarchical chiral MOFs for chiral drug resolution as described in claim 1, characterized in that... In step 1, the concentration of 2-amino-1,1''-biphenyl-4,4''-dicarboxylic acid in the initial solution was 1.5-2.5 mmol / 50mL.

3. The method for preparing hierarchical chiral MOFs for chiral drug resolution as described in claim 1, characterized in that... In step 2, the molar ratio of aluminum chloride hexahydrate to 2-amino-1,1''-biphenyl-4,4''-dicarboxylic acid is 1:(0.7-1.3).

4. The method for preparing hierarchical chiral MOFs for chiral drug resolution as described in claim 1, characterized in that... Step 3 includes washing with fresh DMF for 12 hours each time and washing with methanol three times; the drying process includes drying at 80 °C overnight.

5. The method for preparing hierarchical chiral MOFs for chiral drug resolution as described in claim 1, characterized in that... In step 3, the vacuum drying temperature is 130 ℃ and the time is 18-24 h.

6. The method for preparing hierarchical chiral MOFs for chiral drug resolution as described in claim 1, characterized in that... In step 4, the molar ratio of coupling agent, chiral molecule, and DUT-5-NH2 is 1:1:0.

33.

7. The method for preparing hierarchical chiral MOFs for chiral drug resolution as described in claim 1, characterized in that... The coupling agent in step 4 is a mixture of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxythiosuccinimide sodium salt in a molar ratio of 1:0.

2.

8. The method for preparing hierarchical chiral MOFs for chiral drug resolution as described in claim 1, characterized in that... The intensity of the ultrasonic treatment in step 4 is 400-2000 W / cm. 2 .

9. The method for preparing hierarchical chiral MOFs for chiral drug resolution as described in claim 1, characterized in that... The chiral molecule mentioned in step 4 is L-His, L-Glu, L-Trp or CM-β-CD, and the corresponding products are DUT-5-NH-L-His, DUT-5-NH-L-Glu, DUT-5-NH-L-Trp and DUT-5-NH-CM-β-CD, respectively.

10. A hierarchical chiral MOF for chiral drug resolution, characterized in that... It is prepared by the preparation method described in any one of claims 1-9.

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