Method for preparation of novel 12-crown-4-ether covalent organic framework material and use thereof in chiral separation

Abstract

The present invention provides a method for synthesis of a novel covalent organic framework material having a 12-crown-4-ether group based on chiral separation. The novel covalent organic framework material having a 12-crown-4-ether group is prepared in the present invention, and CCOF-HTOD-1 can be used as a fluorescent probe for achieving chiral separation of different chiral drugs (L-PGL, D-PGL, L-PAL, D-TPL, L-TPL and D-TPL). The CCOF-HTOD-1 prepared in the present invention not only has advantages such as a simple preparation method, suitability for large-scale production, a uniform structure for the prepared novel 12-crown-4-ether covalent organic framework material, ease of dispersion, and excellent CD optical activity, but also exhibits excellent performance in detection of various chiral drugs, including high detection efficiency, high selectivity, and recycling. As a result, common problems in chiral drugs, such as difficult separation and low detection efficiency, can be solved thereby.

Description

A novel method for preparing a twelve-crown tetraether covalent organic framework material and its application in chiral sieving. (I) Technical Field

[0001] This invention relates to a method for preparing a novel twelve-crown tetraether covalent organic framework material with simple preparation and mild synthesis conditions, and its application in chiral sieving, belonging to the field of fluorescence detection. (II) Background Technology

[0002] Chirality is a fundamental characteristic of life, playing a crucial role in various chemical and biological processes. Due to its numerous potential applications, testing the chirality of various drugs is essential. Commonly used testing and separation methods, such as asymmetric catalysis, chiral separation, and magnetic techniques, are costly and complex. Fluorescence sensing offers a more efficient and effective strategy for chiral sieving. This requires the preparation of chiral fluorescent materials. Currently, a common strategy for preparing chiral fluorescent materials is to utilize chiral modules to create chiral framework structures. The principle involves using optically active chiral monomers to compose chiral materials, and then converting the inherent chirality of the monomers into the chirality of the material through a chirality conservation process. Based on this principle, and according to the physicochemical properties of the target chiral drug, a feasible strategy is to chemically bond functional ligands (such as crown ethers) that can interact with the target chiral drug to a porous material to prepare a fluorescent probe.

[0003] Covalent organic frameworks (COFs) are a new class of crystalline polymers with tunable molecular composition, structure, and function, similar to metal-organic frameworks (MOFs). Compared to MOFs, fewer COFs have been developed, particularly crown ether-functionalized vinyl COFs for chiral sieving. Currently reported vinyl COFs not only exhibit high fluorescence properties but also demonstrate stability suitable for most chiral sieving scenarios. Therefore, preparing ligands with functionalized crown ether chemical bonds and their derived vinyl CCOFs for chiral sieving is both innovative and reasonable. Thus, we prepared a novel twelve-crown tetraether covalent organic framework for the chiral sieving of common chiral drugs, anticipating its high efficiency, selectivity, and recyclability in the detection of these drugs. (III) Summary of the Invention

[0004] With the goal of chiral screening of different chiral drugs, and based on the methods and strategies described above, the present invention aims to provide a novel method for synthesizing a twelve-crown tetraether covalent organic framework material, wherein the chiral drug is selected from L-phenylglycine (L-PGL), D-phenylglycine (D-PGL), L-phenylalanine (L-PAL), D-phenylalanine (D-PAL), L-tryptophanol (L-TPL), and D-tryptophanol (D-TPL). The material developed in this invention has the advantages of high efficiency, high selectivity, and recyclability in the detection of chiral drugs, effectively solving the shortcomings of traditional chiral screening materials such as instability and low efficiency.

[0005] The technical solution of the present invention is as follows:

[0006] A novel CCOF-HTOD-1 material with a twelve-crown tetraether group was prepared according to the following method:

[0007] In a 10 ml Schlenk reaction tube, 2,3,5,6-tetramethylpyrazine (TMP), 2,3,5,6,8,9-hexahydrobenzo[B][1,4,7,10]tetraoxetine-11,14-p-dibenzaldehyde (HTOD), benzoic anhydride, and benzoic acid were placed into the Schlenk reaction tube, thoroughly mixed, and subjected to nitrogen protection three times. The reaction system was then heated in an oven for a period of time. After the reaction was completed, it was cooled, washed several times with a mixture of NaOH solution and methanol, then several times with DMF, and then several times with ethanol. It was then dried under vacuum at 100 °C to obtain yellow CCOF-HTOD-1.

[0008] The molar ratio of TMP to HTOD is 1:0.1-5;

[0009] The molar ratio of HTOD to benzoic anhydride is 1:0.1-10;

[0010] The molar ratio of benzoic anhydride to benzoic acid is 1:0.01-50;

[0011] The reaction temperature is 100℃-220℃;

[0012] The reaction time is 0.1-7 days.

[0013] The substantial advantages of this invention compared to existing technologies are:

[0014] (1) The preparation method is simple and can be carried out on a large scale;

[0015] (2) The novel twelve-crown tetraether covalent organic framework material obtained has a uniform structure, which is conducive to dispersion;

[0016] (3) CCOF-HTOD-1 has excellent CD optical activity and is suitable for chiral screening of chiral drugs.

[0017] (4) CCOF-HTOD-1 has the advantages of high detection efficiency, high selectivity and recyclability for hand-like drugs. (iv) Description of the attached drawings

[0018] Figure 1 is a schematic diagram of the structure of CCOF-HTOD-1 in Embodiment 1 of the present invention;

[0019] Figure 2 is a schematic diagram of BET for CCOF-HTOD-1 in Embodiment 1 of the present invention;

[0020] Figure 3 is an XRD diagram of CCOF-HTOD-1 in Embodiment 1 of the present invention;

[0021] Figure 4 is a schematic diagram of the chiral drug molecule structure detected by CCOF-HTOD-1 in Example 1 of the present invention;

[0022] Figure 5 is a schematic diagram of the chiral drug detection performance of CCOF-HTOD-1 in Example 1 of the present invention;

[0023] Figure 6 is a schematic diagram of the selectivity of CCOF-HTOD-1 for chiral drugs in Comparative Example 1 of the present invention;

[0024] Figure 7 is a schematic diagram of the detection of chiral drug circulation using CCOF-HTOD-1 in Comparative Example 1 of the present invention; (V) Detailed Implementation

[0025] The present invention will be described in detail below with reference to specific embodiments. However, the present invention is not limited to the following embodiments. Any variations or implementations that do not depart from the content and scope of the present invention should be included within the technical scope of the present invention.

[0026] Example 1: Preparation of CCOF-HTOD-1

[0027] In a 10 ml Schlenk reaction tube, 2,3,5,6-tetramethylpyrazine (TMP) (0.5 mmol, 68.1 mg), 2,3,5,6,8,9-hexahydrobenzo[B][1,4,7,10]tetraoxetine-11,14-p-dibenzaldehyde (HTOD) (0.5 mmol, 140.1 mg), benzoic anhydride (2 mmol, 452 mg), and benzoic acid (0.2 mmol, 24.6 mg) were added, thoroughly mixed, and subjected to nitrogen protection three times. The reaction system was then reacted in an oven at 180 °C for 4 days. After the reaction was completed, the mixture was cooled, washed three times with a mixture of NaOH and methanol, three times with DMF, and three times with ethanol. The mixture was then dried under vacuum at 100 °C to obtain yellow CCOF-HTOD-1.

[0028] Example 2: Preparation of CCOF-HTOD-1

[0029] In a 10 ml Schlenk reaction tube, 2,3,5,6-tetramethylpyrazine (TMP) (1 mmol, 136.2 mg), 2,3,5,6,8,9-hexahydrobenzo[B][1,4,7,10]tetraoxetine-11,14-p-dibenzaldehyde (HTOD) (0.5 mmol, 140.1 mg), benzoic anhydride (2 mmol, 452 mg), and benzoic acid (0.2 mmol, 24.6 mg) were added, thoroughly mixed, and subjected to nitrogen protection three times. The reaction system was then reacted in an oven at 180 °C for 4 days. After the reaction was completed, the mixture was cooled, washed three times with a mixture of NaOH and methanol, three times with DMF, and three times with ethanol. The mixture was then dried under vacuum at 100 °C to obtain yellow CCOF-HTOD-1.

[0030] Example 3: Preparation of CCOF-HTOD-1

[0031] In a 10 ml Schlenk reaction tube, 2,3,5,6-tetramethylpyrazine (TMP) (0.5 mmol, 68.1 mg), 2,3,5,6,8,9-hexahydrobenzo[B][1,4,7,10]tetraoxetine-11,14-p-dibenzaldehyde (HTOD) (0.5 mmol, 140.1 mg), benzoic anhydride (4 mmol, 904 mg), and benzoic acid (0.2 mmol, 24.6 mg) were added, thoroughly mixed, and subjected to nitrogen protection three times. The reaction system was then reacted in an oven at 180 °C for 4 days. After the reaction was completed, the mixture was cooled, washed three times with a mixture of NaOH and methanol, three times with DMF, and three times with ethanol. The mixture was then dried under vacuum at 100 °C to obtain yellow CCOF-HTOD-1.

[0032] Example 4: Preparation of CCOF-HTOD-1

[0033] In a 10 ml Schlenk reaction tube, 2,3,5,6-tetramethylpyrazine (TMP) (0.5 mmol, 68.1 mg), 2,3,5,6,8,9-hexahydrobenzo[B][1,4,7,10]tetraoxetine-11,14-p-dibenzaldehyde (HTOD) (0.5 mmol, 140.1 mg), benzoic anhydride (2 mmol, 452 mg), and benzoic acid (0.4 mmol, 49.2 mg) were added, thoroughly mixed, and subjected to nitrogen protection three times. The reaction system was then reacted in an oven at 180 °C for 4 days. After the reaction was completed, the mixture was cooled, washed three times with a mixture of NaOH and methanol, three times with DMF, and three times with ethanol. The mixture was then dried under vacuum at 100 °C to obtain yellow CCOF-HTOD-1.

[0034] Example 5: Preparation of CCOF-HTOD-1

[0035] In a 10 ml Schlenk reaction tube, 2,3,5,6-tetramethylpyrazine (TMP) (0.5 mmol, 68.1 mg), 2,3,5,6,8,9-hexahydrobenzo[B][1,4,7,10]tetraoxetine-11,14-p-dibenzaldehyde (HTOD) (0.5 mmol, 140.1 mg), benzoic anhydride (2 mmol, 452 mg), and benzoic acid (0.2 mmol, 24.6 mg) were added, thoroughly mixed, and subjected to nitrogen protection three times. The reaction system was then reacted in an oven at 150 °C for 4 days. After the reaction was completed, the mixture was cooled, washed three times with a mixture of NaOH and methanol, three times with DMF, and three times with ethanol. The mixture was then dried under vacuum at 100 °C to obtain yellow CCOF-HTOD-1.

[0036] Example 6: Preparation of CCOF-HTOD-1

[0037] In a 10 ml Schlenk reaction tube, 2,3,5,6-tetramethylpyrazine (TMP) (0.5 mmol, 68.1 mg), 2,3,5,6,8,9-hexahydrobenzo[B][1,4,7,10]tetraoxetine-11,14-p-dibenzaldehyde (HTOD) (0.5 mmol, 140.1 mg), benzoic anhydride (2 mmol, 452 mg), and benzoic acid (0.2 mmol, 24.6 mg) were added, thoroughly mixed, and subjected to nitrogen protection three times. The reaction system was then reacted in an oven at 180 °C for 2 days. After the reaction was completed, the mixture was cooled, washed three times with a mixture of NaOH and methanol, three times with DMF, and three times with ethanol. The mixture was then dried under vacuum at 100 °C to obtain yellow CCOF-HTOD-1.

[0038] Example 7: Performance Test of CCOF-HTOD-1 for Chiral Drug Detection

[0039] Weigh 10 mg of CCOF-HTOD-1 from Example 1, grind it, and add it to a vial containing 20 ml of water. After thorough stirring and sonication, take out 2 ml of the CCOF-HTOD-1 suspension and place it in a cuvette for fluorescence detection. Add chiral drug solutions (L-PGL, D-PGL, L-PAL, D-TPL, L-TPL, D-TPL) (1 mM, 20 μL each time) to the CCOF-HTOD-1 suspension sequentially. Measure the fluorescence intensity of the CCOF-HTOD-1 suspension (2 ml) immediately after each addition of chiral drug solution, for a total of 10 times. Throughout the fluorescence detection experiment, the mixed solution was stirred at a constant rate to maintain its homogeneity. Fluorescence detection experiments showed that the quenching efficiencies of CCOF-HTOD-1 for L-type chiral drugs (L-PGL, L-PAL, L-TPL) reached 93%, 98%, and 95%, respectively, which far exceeded the detection performance of other traditional fluorescent materials for chiral drugs.

[0040] Example 8: CCOF-HTOD-1 test for selectivity of chiral drugs

[0041] The CCOF-HTOD-1 sample from Example 1 was subjected to K-type reactions with L-chiral drugs (L-PGL, L-PAL, L-TPL). sv Values ​​and K values ​​for D-type chiral drugs (D-PGL, D-PAL, D-TPL) sv The value is used as a ratio; taking PGL as an example, the calculation method is K. QR =K sv[L-PGL] / K sv[D-PGL] A higher value indicates better selectivity. The Ki values ​​obtained from the CCOF-HTOD-1 sample in Example 1 were used to measure the selectivity of PGL, PAL, and TPL. QR The values ​​were 3.56, 6.22 and 4.85, respectively, indicating that the CCOF-HTOD-1 sample has significant selectivity for the detection of PGL, PAL and TPL.

[0042] Example 9: Cyclic performance test of regenerated CCOF-HTOD-1 for chiral drugs

[0043] After conducting chiral drug detection experiments using CCOF-HTOD-1 from Example 1, the CCOF-HTOD-1 that had been tested for chiral drugs was taken, stirred with ethanol at room temperature for 12 hours, washed three times, and filtered. It was then vacuum-dried at 100°C, and the weight change of CCOF-HTOD-1 before and after chiral drug elution was measured. The eluted material was reused for chiral drug detection experiments, with at least 5 cycles.

[0044] After five cycles of testing, CCOF-HTOD-1 still maintains over 99% of its original maximum detection performance for L-type chiral drugs.

[0045] Of course, the above specific embodiments are merely detailed explanations of the corresponding technical solutions of the present invention, and are not limited to the above implementation methods. For those skilled in the art, various changes or modifications can still be made based on the above embodiments. Not all implementation methods are listed here; any changes or modifications derived from the above principles or mechanisms are within the protection scope of the present invention.

Claims

1. A novel CCOF-HTOD-1 material of dodecakis crown tetraether group characterized by: The novel COF material with a twelve-crown tetraether group was prepared according to the following method: In a 10 ml Schlenk reaction tube, 2,3,5,6-tetramethylpyrazine (TMP), 2,3,5,6,8,9-hexahydrobenzo[B][1,4,7,10]tetraoxetine-11,14-p-dibenzaldehyde (HTOD), benzoic anhydride, and benzoic acid were placed into the Schlenk reaction tube, thoroughly mixed, and subjected to nitrogen protection three times. The reaction system was then heated in an oven for a period of time. After the reaction was completed, it was cooled, washed several times with a mixture of NaOH solution and methanol, then several times with DMF, and then several times with ethanol. It was then dried under vacuum at 100 °C to obtain yellow CCOF-HTOD-1.

2. The novel CCOF-HTOD-1 material of dodecacrown tetraether group as claimed in claim 1, wherein: The molar ratio of TMP to HTOD is 1:0.1-5.

3. The novel CCOF-HTOD-1 material of dodecacrown tetraether group as claimed in claim 1, wherein: The molar ratio of HTOD to benzoic anhydride is 1:0.1-10.

4. The novel CCOF-HTOD-1 material of dodecacrown tetraether group as claimed in claim 1, wherein: The molar ratio of benzoic anhydride to benzoic acid is 1:0.01-50.

5. The novel CCOF-HTOD-1 material of dodecacrown tetraether group as claimed in claim 1, wherein: The reaction temperature is 100℃-220℃.

6. The novel CCOF-HTOD-1 material of dodecacrown tetraether group as claimed in claim 1, wherein: The reaction time is 0.1-7 days.

7. The novel CCOF-HTOD-1 material of dodecacrown tetraether group as claimed in claim 1, wherein: The quenching efficiencies of CCOF-HTOD-1 against L-type chiral drugs (L-PGL, L-PAL, and L-TPL) reached 93%, 98%, and 95%, respectively.

8. The novel CCOF-HTOD-1 material of dodecacrown tetraether group as claimed in claim 1, wherein: The CCOF-HTOD-1 sample had K QR values of 3.56, 6.22 and 4.85, respectively.

9. The novel CCOF-HTOD-1 material of dodecacrown tetraether group as claimed in claim 1, wherein: The CCOF-HTOD-1 can maintain more than 99% of its original maximum detection performance for L-type chiral drugs after 5 cycles of testing.

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