Quinoxaline molecular cup macrocyclic host compound derived from resorcinol calix [4] arene as well as preparation method and application of quinoxaline molecular cup macrocyclic host compound

Abstract

The invention relates to a resorcinol calix [4] arene derivatized quinoxaline molecular calix-macrocyclic host compound and a preparation method and application thereof, resorcinol calix [4] arene is used as a skeleton, and through deepening of four aromatic walls, introduction of an upper edge quinoxaline structure and introduction of a lower edge nitrogen methylimidazolium salt, the quinoxaline molecular calix-macrocyclic host compound is obtained. A tetracyclic quinoxaline molecular cup main body H1 or an octaethyl quinoxaline molecular cup main body H2 is prepared, a cavity main body part of the tetracyclic quinoxaline molecular cup main body is alkyl quinoxaline, and compared with the prior art, the nitrogen methylimidazolium salt water-soluble foot at the lower edge of H1 or H2 endows the molecular cup main body with water solubility; eight nitrogen atoms in the quinoxaline structure on the upper edge can provide hydrogen bond sites for recognition of polar guest molecules, so that the ibuprofen drug molecule can be recognized in an aqueous solution, in addition, in the reduction reaction step of the chloro-octanitro molecular cup, the dosage of required stannous chloride is small, the reaction condition is mild, and the preparation method is suitable for industrial production. The green chemical purpose is met.

Description

Technical Field

[0001] The present invention relates to the technical field of macrocyclic host design in supramolecular chemistry, and in particular to a quinoxaline molecular calix macrocyclic host compound derived from resorcinol calix[4]arene, and a preparation method and application thereof. Background Art

[0002] Resorcinol calix[4]arene is a type of cyclic tetramer formed by the condensation reaction of resorcinol monomers and aldehyde compounds, connected by methylene groups. Resorcinol calix[4]arene has a hydrophobic cavity that can accommodate guest molecules. Water-soluble molecular calix is ​​an important component of resorcinol calix[4]arene. As a synthetic molecular container, it is widely used in molecular recognition and other fields. In recent years, supramolecular chemists have conducted extensive research on the synthesis and application of water-soluble molecular calix, which shows that the application of water-soluble molecular calix in aqueous media has unique advantages. On the one hand, water is an ideal green solvent. In recent years, the concept of green chemistry has gradually been valued by more and more scientists. However, due to the solubility of reactants, catalysts, etc. in aqueous environments and the existence of many problems such as stability in water, many chemical reactions that successfully occur in organic phases cannot be successfully carried out in water. The unique ability of water-soluble molecular calix to enclose small guest molecules in hydrophobic cavities determines that it can be used as a good medium tool to solve many practical problems that arise when conducting organic chemical reactions in aqueous environments.

[0003] Although water-soluble supramolecular calixes developed from resorcinol have different compositions, they share a consistent cup-shaped cavity structure when recognizing objects in water. Therefore, the structure of the four aromatic walls of a molecular calix, composed of different aromatic walls, determines their different cavity volumes and shapes, further determining their differential recognition of different molecules. Because the cavity volume of a molecular calix determines the size of the guest molecules it can recognize, developing molecular calixes with different aromatic wall structures is crucial. Two main strategies are lateral and longitudinal cavity expansion. For example, Chinese patent CN113461701A discloses a supramolecular macrocyclic host compound derived from calixarene. This patent uses a resorcinol derivative as a starting material, introduces a sodium carboxylate salt at the lower edge to achieve overall water solubility, and introduces different pyridine groups at the upper edge. This increases the depth of the cavity while also reducing the cavity diameter and slowing guest exchange. Chinese patent CN115504988A discloses a molecular calix macrocyclic main body compound based on resorcinol calix[4]arene derivatization. Resorcinol calix[4]arene is used as the skeleton. By deepening the aromatic wall, introducing 2-hydroxymethylimidazolyl groups on the upper edge and water-soluble groups on the lower edge, the synthesis of new functionalized water-soluble 2-hydroxymethylimidazolyl molecular calix main bodies H1 and H2 is achieved, which can recognize choline molecules.

[0004] However, the existing technology often uses difluorodinitrobenzene to deepen the cavity depth during longitudinal cavity expansion, and subsequently often uses stannous chloride to reduce the nitro group. However, this method generally uses a large amount of stannous chloride and requires oxygen-free and high-temperature reaction conditions. Therefore, it is of great significance to improve the existing method of reducing the nitro group. Summary of the Invention

[0005] The purpose of the present invention is to provide a quinoxaline molecular calix macrocyclic main compound derived from resorcinol calix [4] arene and its preparation method and application. The prepared quinoxaline molecular calix macrocyclic main compound has a deepened hydrophobic cavity and can recognize the drug molecule ibuprofen in aqueous solution. The amount of stannous chloride required in the reduction step of the chloro-octanonitro molecular calix in its preparation method is small and the reaction conditions are mild.

[0006] The purpose of the present invention can be achieved by the following technical solutions:

[0007] One of the purposes of the present invention is to provide a resorcinol calix[4]arene-derived quinoxaline molecular calix macrocyclic main body compound, wherein the cavity main body portion is an alkylquinoxaline, and the structure thereof includes a tetracyclic quinoxaline molecular calix main body H1 or an octaethylquinoxaline molecular calix main body H2, and the structural formula is as follows:

[0008]

[0009] Preferably, the quinoxaline molecular calix macrocyclic main compound has two conformations in water: a "vase" conformation and a "kite" conformation. In aqueous solution, there is a dynamic equilibrium between the two conformations.

[0010] Preferably, the quinoxaline molecular calix macrocyclic main compound has a deepened hydrophobic cavity. When a guest molecule is present, the guest molecule can induce the quinoxaline molecular calix macrocyclic main compound to transform from a "kite" conformation to a "vase" conformation, and the guest molecule is encapsulated in the hydrophobic cavity of the "vase" conformation; when the guest molecule is not present, in order to reduce the hydrophobic area of ​​its aromatic wall, it mainly exists in a "kite" conformation stacked on top of each other.

[0011] The second object of the present invention is to provide a method for preparing the resorcinol calix [4] arene-derived quinoxaline molecular calix macrocyclic main compound, which uses resorcinol calix [4] arene as the skeleton and sequentially deepens the aromatic walls on all four sides, introduces the quinoxaline structure on the upper edge, and introduces the nitrogen-methyl imidazole salt on the lower edge to prepare the quinoxaline molecular calix macrocyclic main compound.

[0012] Preferably, using resorcinol calix[4]arene as the skeleton, different alkyl groups were introduced into the upper edge by deepening the four aromatic walls and using 1,2-cyclohexanedione and 3,4-hexanedione respectively, to achieve the synthesis of functionalized water-soluble quinoxaline molecular cup bodies H1 and H2.

[0013] Preferably, the method for preparing the resorcinolcalix[4]arene-derived quinoxaline molecular calix macrocyclic main compound comprises the following steps:

[0014] a. Under nitrogen protection, dissolve chloro-foot resorcinol calix[4]arene S1 and 1,2-difluoro-4,5-dinitrobenzene in DMF; add triethylamine dropwise at room temperature, and heat to react for 7 hours after the addition is complete; after the reaction, the solid product chloro-foot octanonitro molecular calix S2 is obtained by rotary evaporation, ultrasonication, filtration, washing, and drying.

[0015] b. Using 1-butyl-3-methylimidazolium tetrafluoroborate ion solvent as the reaction solvent, the chloro-foot octanitro molecular cup S2 was mixed with SnCl2·2H2O, and then ultrasonically reacted at room temperature; after the reaction, the solid product chloro-foot octanitro molecular cup S3 was obtained by centrifugation;

[0016] c. Dissolve the chloro-foot octaamino molecular calix S3 in acetonitrile, add triethylamine at room temperature, then add 1,2-cyclohexanedione or 3,4-hexanedione, and reflux under nitrogen protection; after the reaction, cool, filter, and wash, and purify the collected solid by column chromatography to obtain the corresponding chloro-foot tetracyclic quinoxaline molecular calix S4 or chloro-foot octaethylquinoxaline molecular calix S5;

[0017] d. At room temperature, the chloro-based tetracyclic quinoxaline molecular cup S4 or the chloro-based octaethylquinoxaline molecular cup S5 and nitrogen-based methylimidazole are ultrasonically dispersed until uniformly dispersed, and then heated to react under nitrogen protection; after the reaction is completed, the solid is cooled to room temperature, acetone is added, the solid is precipitated, and the crude product is obtained by filtration; the obtained crude product is refluxed in acetone, cooled, centrifuged, washed, and dried to obtain the tetracyclic quinoxaline molecular cup body H1 or the octaethylquinoxaline molecular cup body H2 accordingly.

[0018] Preferably, the synthetic route for the preparation of the resorcinolcalix[4]arene-derived quinoxaline molecular calix macrocyclic main compound is as follows:

[0019]

[0020] Preferably, in step a, the molar ratio of the chlororesorcinol calix[4]arene S1, 1,2-difluoro-4,5-dinitrobenzene, and triethylamine is 1:3-5:7-9.

[0021] Further preferably, in step a, the molar ratio of the chlororesorcinol calix[4]arene S1, 1,2-difluoro-4,5-dinitrobenzene and triethylamine is 1:4:8.

[0022] Preferably, in step a, the concentration of the chlororesorcinol calix[4]arene S1 in DMF is 0.1-0.2 mol / L, more preferably 0.126 mol / L.

[0023] Preferably, in step a, the heating reaction refers to reacting in an oil bath preheated to 55-75° C. for 6-8 hours. Too long a reaction time will reduce the yield.

[0024] Further preferably, in step a, the heating reaction refers to reacting in an oil bath preheated to 65° C. for 7 hours.

[0025] Preferably, in step a, after the reaction is completed, a rotary ring evaporator is used to remove residual triethylamine and DMF solvent, 0.8-1.2 mol / L hydrochloric acid is added to the residue to remove excess triethylamine, and the product is fully precipitated in the hydrochloric acid solution, placed in an ultrasonic bath and ultrasonicated for 1.5-2.5 hours, and filtered using a Buchner funnel to obtain a yellow solid product, and the solid is washed with methanol and ether, and vacuum dried to obtain a chloro-foot octanonitro molecular cup S2, which can be directly used in subsequent reactions without further purification.

[0026] Further preferably, in step a, the ultrasonication time is 2 hours.

[0027] Further preferably, in step a, the DMF is super-dry DMF, and the triethylamine is super-dry triethylamine.

[0028] Preferably, in step b, the molar ratio between the chloro-octanitro molecular cup S2 and SnCl2·2H2O is 1:15-25, more preferably 1:20, and SnCl2·2H2O is used as an excess reducing agent to fully reduce the nitro group in the chloro-octanitro molecular cup S2.

[0029] Preferably, in step b, the concentration of the chloro-octanonitro molecular cup S2 in the 1-butyl-3-methylimidazolium tetrafluoroborate ion solvent ([BMIM]BF4) is 0.012-0.022 mol / L.

[0030] Preferably, in step b, the amount of [BMIM]BF4 used is sufficient to slightly cover the solid raw materials (chloro-octanonitro molecular cup S2 and SnCl2·2H2O), and the two raw materials can be fully stirred before ultrasonication to fully mix.

[0031] Preferably, in step b, the ultrasonic reaction is carried out under a nitrogen environment.

[0032] Preferably, in step b, the ultrasonic reaction time is 0.5-1.5 hours, and the ultrasonic power is 80kHz-100kHz.

[0033] Further preferably, in step b, the ultrasonic reaction time is 1 hour and the ultrasonic power is 100 kHz.

[0034] Preferably, in step c, the molar ratio of the chloro-octaamino molecular cup S3, triethylamine, 1,2-cyclohexanedione or 3,4-hexanedione is 1:7-9:7-9, and more preferably 1:8:8.

[0035] Preferably, in step b, the liquid obtained by centrifugation is neutralized by adding sodium bicarbonate, and then extracted with dichloromethane, and can be reused for the next reduction without further treatment.

[0036] Preferably, in step c, the concentration of the chloro-octaamino molecular cup S3 in acetonitrile is 0.003-0.004 mol / L.

[0037] Preferably, in step c, the reflux reaction time is 40-56 hours, and the reaction temperature is 90°C-100°C.

[0038] Preferably, in step c, the washing refers to washing with acetonitrile or diethyl ether to remove excess 1,2-cyclohexanedione or 3,4-hexanedione and triethylamine.

[0039] Further preferably, in step c, the triethylamine is super dry triethylamine.

[0040] Further preferably, in step c, the acetonitrile is anhydrous acetonitrile.

[0041] Preferably, in step c, the chloro-tetracyclic quinoxaline molecular cup S4 is obtained by using 1,2-cyclohexanedione, and the chloro-octaethylquinoxaline molecular cup S5 is obtained by using 3,4-hexanedione.

[0042] Preferably, in step d, the concentration of the chloro-tetracyclic quinoxaline molecular calix S4 or the chloro-octaethylquinoxaline molecular calix S5 in nitrogen-methylimidazole is 0.01-0.02 mol / L, and the heating reaction refers to an 80-95° C. oil bath reaction for 20-28 hours.

[0043] Preferably, in step d, nitrogen-methylimidazole is in excess, which not only serves as a solvent for the reaction but also serves as a starting material for the reaction.

[0044] Further preferably, in step d, the heating reaction refers to a 90° C. oil bath reaction for 24 hours.

[0045] Preferably, in step d, the reaction is completed, cooled to room temperature, acetone is added, a white solid is precipitated, and the crude product is obtained by filtration through a Buchner funnel. The obtained crude product is refluxed with acetone for 20-28 hours, cooled to room temperature, and then centrifuged to collect the solid. The obtained solid is washed with acetone 6-10 times to remove residual nitrogen-methylimidazole, and the solid is collected and dried under vacuum to obtain a tetracyclic quinoxaline molecular cup body H1 or an octaethylquinoxaline molecular cup body H2.

[0046] Further preferably, in step d, the tetracyclic quinoxaline molecular cup S4 is reacted to produce a tetracyclic quinoxaline molecular cup body H1, and the octaethylquinoxaline molecular cup S5 is reacted to produce an octaethylquinoxaline molecular cup body H2.

[0047] Preferably, the method for preparing the resorcinolcalix[4]arene-derived quinoxaline molecular calix macrocyclic main compound comprises the following steps:

[0048] a. Take one equivalent of chloro-1-difluoro-1-difluoro-4,5-dinitrobenzene as raw materials, add ultra-dry DMF solvent, and stir under nitrogen protection until the solid is completely dissolved. At room temperature, use a syringe to add 8 equivalents of ultra-dry triethylamine dropwise. After the addition is completed, react in an oil bath preheated to 65°C for 7 hours. After the reaction is completed, use a rotary ring evaporator to remove the residual triethylamine and DMF solvent. Add 1 mol / L hydrochloric acid to the residual mixture, place it in an ultrasonic bath for 2 hours, and use a Buchner funnel to filter to obtain a yellow solid product. Wash the solid with a small amount of methanol and ether. After vacuum drying, obtain chloro-1-difluoro ...

[0049] b. Weigh the product S2 obtained in the previous step and place it in a 10 mL sealed tube. Add 20 equivalents of SnCl2·2H2O and an appropriate amount of 1-butyl-3-methylimidazolium tetrafluoroborate ion solvent ([BMIM]BF4) as the reaction solvent, replace nitrogen, and sonicate at room temperature for 1 hour. After the reaction, centrifuge to obtain a white solid S3. The white solid can be used directly in the subsequent reaction without further purification. The liquid obtained by centrifugation is neutralized by adding sodium bicarbonate and then extracted with dichloromethane, which can be reused.

[0050] c. The prepared chloro-foot octaamino molecular cup S3 obtained in the previous step was added to a round-bottom flask, anhydrous acetonitrile was added as a solvent, and then 8 equivalents of ultra-dry triethylamine were added at room temperature, and then 8 equivalents of diketone (1,2-cyclohexanedione was used to synthesize S4, 3,4-hexanedione was used to synthesize S5) were added, and refluxed under nitrogen for 48 hours; after the reaction was completed, it was cooled to room temperature, and the solid was collected by filtration, washed with acetonitrile and diethyl ether 3 times, and the solid was collected and purified by column chromatography to obtain chloro-foot tetracyclic quinoxaline molecular cup S4 and chloro-foot octaethylquinoxaline molecular cup S5;

[0051] d. The purified product in the previous step was added to a round-bottom flask, and an excess of nitrogen-methylimidazole (as a reaction solvent and reaction raw material) was added at room temperature. The mixture was ultrasonically dispersed until the solid was evenly dispersed, and the reaction was carried out in an oil bath at 90°C under nitrogen protection for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, and acetone was added thereto. A white solid precipitated, which was filtered through a Buchner funnel to obtain a crude product. The crude product was refluxed with acetone for 24 hours, cooled to room temperature, and then centrifuged to collect the solid. The obtained solid was washed with acetone 8 times, the solid was collected, and dried under vacuum to obtain water-soluble molecular cups H1 and H2.

[0052] The third object of the present invention is to provide an application of the resorcinol calix [4] arene-derived quinoxaline molecular calix macrocyclic main body compound, wherein the tetracyclic quinoxaline molecular calix main body H1 or the octaethylquinoxaline molecular calix main body H2 can recognize ibuprofen drug molecules having a carboxyl hydrophilic group by relying on hydrophobic interaction and hydrogen bonding.

[0053] The present invention first uses chloro-1,2-dihydroquinoxaline cup [4] arene S1 as the starting reaction raw material, and deepens the aromatic walls on all four sides thereof, thereby making the molecular cup body of the present invention have a deepened hydrophobic cavity; secondly, nitrogen methyl imidazole salt is introduced at the lower edge to give the body water solubility; finally, quinoxaline structure is introduced at the upper edge by condensing 1,2-cyclohexanedione and 3,4-hexanedione with the o-phenylenediamine structure in the chloro-1,2-dihydroquinoxaline molecular cup S3, so that the upper edge part becomes tetracyclohexylquinoxaline or octaethylquinoxaline, thereby preparing water-soluble tetracycloquinoxaline molecular cup body H1 and water-soluble octaethylquinoxaline molecular cup H2. Both the tetracycloquinoxaline molecular cup body H1 and the octaethylquinoxaline molecular cup H2 have quinoxaline structure, and the eight nitrogen atoms therein can provide hydrogen bonding sites for the recognition of polar guest molecules, thereby enabling the present invention to recognize the drug molecule ibuprofen in aqueous solution.

[0054] In addition, in the prior art, in the nitro reduction of the chloro-octanonitro molecular cup, the amount of SnCl2·2H2O used often reaches 120-240 equivalents, a large amount of strong acid (37% HCl) needs to be added to the reaction, and a high-temperature reflux of 110°C is required during the reaction. However, in the present invention, only 20 equivalents of SnCl2·2H2O are used in the process, and the reaction only requires [BMIM]BF4 as a solvent for ultrasonication. The synthetic route is simple, the raw materials are easily available and reusable, the reaction conditions are mild, and it conforms to the purpose of green chemistry.

[0055] Compared with the prior art, the present invention has the following beneficial effects:

[0056] (1) The present invention provides a quinoxaline molecular calix macrocyclic main body compound derived from resorcinol calix [4] arene, wherein the structure of the quinoxaline molecular calix macrocyclic main body compound includes two water-soluble quinoxaline molecular calix main bodies H1 and H2, and the main body has a deepened hydrophobic cavity, which can be used to recognize the drug molecule ibuprofen in aqueous solution, and solves the problem of the existing technology that a large amount of stannous chloride is used and harsh reaction conditions such as oxygen-free high temperature are required.

[0057] (2) The tetracyclic quinoxaline molecular cup body H1 or the octaethyl quinoxaline molecular cup body H2 prepared by the present invention is a functionalized water-soluble quinoxaline molecular cup body with a novel structure. The body has a deepened hydrophobic cavity and exists in two conformations in water: a "vase" conformation and a "kite" conformation. When a guest molecule is present, the guest molecule can induce the quinoxaline molecular cup macrocyclic body to transform from the "kite" conformation to the "vase" conformation, so that the guest molecule is encapsulated in the hydrophobic cavity of the "vase" conformation, which can be used in the field of molecular recognition.

[0058] (3) The lower edge of the present invention is a nitrogen-methylimidazole salt-soluble foot, which gives the molecular cup body water solubility, and the upper edge is a quinoxaline structure. The eight nitrogen atoms in the quinoxaline structure can provide hydrogen bonding sites for the recognition of polar guest molecules, thereby enabling the present invention to recognize the drug molecule ibuprofen in aqueous solution.

[0059] (4) In the reaction step of nitro reduction of the chloro-octanonitro molecular cup of the present invention, the reaction only requires [BMIM]BF4 as a solvent. The chloro-octanonitro molecular cup S2 and SnCl2·2H2O are mixed and then ultrasonically reacted at room temperature. Only 15-25 equivalents of SnCl2·2H2O are needed during the reaction, and the subsequent [BMIM]BF4 can be reused, which is in line with the purpose of green chemistry.

[0060] (5) The synthetic route of the present invention is simple, the raw materials are readily available and can be reused, the reaction conditions are mild, and the reproducibility is good. BRIEF DESCRIPTION OF THE DRAWINGS

[0061] Figure 1This is the H NMR spectrum (600 MHz, DMSO-d6, 298 K) of the molecular cup H1 in Example 1 of the present invention.

[0062] Figure 2 This is the H NMR spectrum (600 MHz, DMSO-d6, 298 K) of the molecular cup H2 in Example 1 of the present invention.

[0063] Figure 3 This is the C NMR spectrum (151 MHz, DMSO-d6, 298 K) of the molecular cup H1 in Example 1 of the present invention.

[0064] Figure 4 This is the C NMR spectrum (151 MHz, DMSO-d6, 298 K) of the molecular cup H2 in Example 1 of the present invention.

[0065] Figure 5 This is a high-resolution mass spectrum of the molecular cup H1 in Example 1 of the present invention.

[0066] Figure 6 This is a high-resolution mass spectrum of the molecular cup H2 in Example 1 of the present invention.

[0067] Figure 7 This is the H NMR spectrum of the “kite” conformation of the molecular cups H1 and H2 in heavy water in Example 1 of the present invention.

[0068] Figure 8 This is the NMR spectrum (600 MHz, D2O, 298 K) of the host-guest complex of molecular cups H1 and H2 (1 mmol / L, 500 μL) recognizing ibuprofen in Example 1 of the present invention.

[0069] Figure 9 Schematic diagram of the structure of the water-soluble tetracyclic quinoxaline molecular calix H1 and the octaethylquinoxaline molecular calix H2 of the present invention. DETAILED DESCRIPTION

[0070] The present invention is described in detail below with reference to the accompanying drawings and specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and specific operation process, but the protection scope of the present invention is not limited to the following embodiments.

[0071] Unless otherwise specified, the reagents, methods, instruments and equipment used in the present invention are conventional reagents, methods, instruments and equipment in the art. Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0072] In the following examples, chloro-resorcinol-1-ol cup[4]arene S1 was prepared in the laboratory. The preparation process was referred to the paper Org.Chem.Front., 2019, 6, 1236-1243. The preparation process was as follows: resorcinol was dissolved in methanol solvent, concentrated hydrochloric acid was added in an ice bath, 4-chlorobutyraldehyde dimethyl acetal was slowly added dropwise, and after stirring in an ice bath for half an hour, the temperature was raised to 60°C and stirred, and the reaction was carried out for four days. After the reaction was completed, the temperature was cooled to room temperature, and the solid was filtered to obtain the solid. The solid was washed with deionized water 3 times, and the solid was collected and dried under vacuum to obtain the product chloro-resorcinol-1-ol cup[4]arene S1; the molar volume ratio of resorcinol to methanol was 1.5 mol / L; the molar volume of resorcinol to concentrated hydrochloric acid was 6 mol / L; the molar ratio of resorcinol to 4-chlorobutyraldehyde dimethyl acetal was 1:1.05.

[0073] A resorcinol calix[4]arene-derived quinoxaline molecular calix macrocyclic main body compound, wherein the cavity main body portion is an alkyl quinoxaline, and the structure thereof includes a tetracyclic quinoxaline molecular calix main body H1 or an octaethyl quinoxaline molecular calix main body H2, and the structural formula is as follows:

[0074]

[0075] The tetracyclic quinoxaline molecular cup main body H1 or the octaethylquinoxaline molecular cup main body H2 is prepared by using resorcinol calix[4]arene as the skeleton, deepening the four aromatic walls, introducing the quinoxaline structure at the upper edge, and introducing the nitrogen-methyl imidazole salt at the lower edge.

[0076] Example 1

[0077] A resorcinolcalix[4]arene-derived quinoxaline molecular calix macrocyclic main compound, the preparation method of which comprises the following synthetic steps:

[0078] a. Weigh 1 g, 1.26 mmol, 1 eq of chloro-1,2-difluoro-4,5-dinitrobenzene (1.03 g, 5.04 mmol, 4 eq) and place them in a 100 mL two-necked flask. Add 10 mL of ultra-dry DMF under N2 protection and stir until the solid is completely dissolved. Add triethylamine (1.4 mL, 10.1 mmol, 8 eq) dropwise using a syringe at room temperature and place the mixture in an oil bath preheated to 65°C for 7 hours. After the reaction is completed, use a rotary ring evaporator to remove the residual triethylamine and DMF solvent. Add 100 mL of 1N hydrochloric acid to the residual mixture and place it in an ultrasonic bath for 2 hours. Use a Buchner funnel to filter and obtain a yellow solid product. Wash the solid with a small amount of methanol and ether. After vacuum drying, obtain 1.98 g of chloro-1,2-difluoro-1,2-dinitrobenzene S2 with a yield of 86%. It can be used directly in subsequent reactions without further purification.

[0079] b. Weigh S2 (500 mg, 0.34 mmol, 1 eq) obtained in the previous step and place it in a 10 mL sealed tube. Add SnCl2·H2O (1.5 g, 6.8 mmol, 20 eq) and 2 mL of 1-butyl-3-methylimidazolium tetrafluoroborate ion solvent ([BMIM]BF4). Replace nitrogen and place in an ultrasonic bath for sonication at room temperature for 1 h. After the reaction, centrifuge to obtain a white solid product S3, 375 mg, with a yield of 91%. The product can be used directly in the subsequent reaction without further purification. Add 2 mL of saturated sodium bicarbonate to the liquid and extract it with dichloromethane (3×5 mL). It can be reused for the next reduction without further treatment.

[0080] c. The prepared chloro-foot octaamino molecular cup S3 (81 mg, 0.067 mmol, 1 eq) obtained in the previous step was added to a round-bottom flask, and 20 mL of anhydrous acetonitrile was added as a solvent. Subsequently, 74 μL of ultra-dry triethylamine was added at room temperature, and then 8 equivalents of diketone (1,2-cyclohexanedione was used to synthesize S4, and 3,4-hexanedione was used to synthesize S5) was added. The mixture was refluxed under nitrogen for 48 hours. After the reaction was completed, the mixture was cooled to room temperature, and the solid was collected by filtration. The solid was washed with acetonitrile (3×10 mL) and diethyl ether (3×10 mL) respectively, and the solid was collected and purified by column chromatography to obtain chloro-foot tetracyclic quinoxaline molecular cup S4 and chloro-foot octaethylquinoxaline molecular cup S5.

[0081] d. The purified product in the previous step was added to a round-bottom flask, and an excess of nitrogen-methylimidazole (as a reaction solvent and reaction raw material) was added at room temperature. The mixture was ultrasonically dispersed until the solid was evenly dispersed, and the reaction was carried out in an oil bath at 100°C under nitrogen protection for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, and acetone was added thereto. A white solid precipitated, which was filtered through a Buchner funnel to obtain a crude product. The crude product was refluxed with acetone for 24 hours, cooled to room temperature, and then centrifuged to collect the solid. The obtained solid was washed with acetone 8 times, the solid was collected, and dried under vacuum to obtain water-soluble molecular cups H1 and H2.

[0082] In this embodiment, see Figure 1 、 Figure 3 、 Figure 5 The molecular cup H1 was characterized by nuclear magnetic resonance and mass spectrometry. 1HNMR (600MHz, DMSO-d6, 298K, δppm) δ9.49(s,4H),8.53(s,8H),8.24(s,4H),8.09(t,J=1.8Hz,4H),8.02(s,4H),7.78(t,J=2.0Hz,4H) ,5.60(t,J=8.4Hz,4H),4.35(t,J=6.7Hz,8H),3.90(s,12H),3.01-2.94(m,8H),2.90-2.78(m,16H),2.08(s,8H),1.86-1.77(m,24H). 13 CNMR(151MHz,DMSO-d6,298K,δppm)154.51,153.79,152.94,139.12,136.98,135.69,126.32,123.66, 122.65,122.29,116.22,49.28,35.98,33.78,32.25,30.80,28.62,28.07,22.00.ESI-HRMS:Calcd.for chemical formula C 104 H 100 C l4 N 16 O8:1843.85,found924.8760.[M+2H] 2+ .

[0083] In this embodiment, see Figure 2 、 Figure 4 、 Figure 6 The molecular cup H2 was characterized by nuclear magnetic resonance and mass spectrometry. 1 HNMR(600MHz,DMSO-d6,298K,δppm)δ9.52(s,4H),8.47(s,8H),8.21(s,4H),8.12-8.07(m,8H),7.79(t,1.8Hz,4H),5.59(t,8.4Hz, 4H),4.36(t,6.6Hz,8H),3.91(s,12H),2.94-2.85(m,8H),2.83-2.74(m,16H),2.08(s,8H),1.85-1.78(m,8H),1.22(t,7.3Hz,24H). 13C NMR (151MHz, DMSO-d6, 298K, δppm)156.68,154.35,152.79,138.66,136.87,135.37,126.01,123.53,1 22.54,122.31,116.39,49.28,35.97,33.76,30.78,28.57,28.05,27.22,11.58.ESI-HRMS:Calcd.for chemical formula C 104 H 100 C l4 N 16 O8:1851.91,found 928.9095[M+2H] 2+ .

[0084] Host-guest NMR data analysis:

[0085] Accurately weigh H1 (18.44 mg, 10.00 μmol) and add it to a 25 mL sample bottle. Use a pipette to transfer 10 mL of D2O and sonicate to fully dissolve it to obtain a clear and transparent light yellow solution with a concentration of 1 mM.

[0086] Accurately weigh H2 (18.52 mg, 10.00 μmol) and add it to a 25 mL sample bottle. Use a pipette to transfer 10 mL of D2O and sonicate to fully dissolve it to obtain a clear, transparent, colorless solution with a concentration of 1 mM.

[0087] 500 μL of 1 mM solution of H1 or H2 was transferred to a sample vial with a pipette, and 2.5 μL of ibuprofen was added to the sample vial. The sample was ultrasonicated at room temperature for 1 hour and transferred to a Bruker AVANCEⅢHD 600M nuclear magnetic resonance tube. The nuclear magnetic hydrogen spectrum test temperature was set to 298 K, the spectrum center was 5 ppm, the spectrum width was 25 ppm, and the number of scans was 64.

[0088] Analysis of the two conformations of the molecular cup H1 and H2 by nuclear magnetic proton spectrum: The main body of the molecular cup H1 and H2 exists in two conformations in water: the "vase" conformation and the "kite" conformation. In aqueous solution, there is a dynamic equilibrium between the two conformations. When there is a suitable guest molecule, the guest molecule can induce the transformation from the "kite" conformation to the "vase" conformation. The guest molecule can exist in the hydrophobic cavity of the "vase" conformation; however, when there is no suitable guest in the solution, in order to reduce the hydrophobic area of ​​its aromatic wall, it mainly exists in the "kite" conformation stacked on top of each other ( Figure 7 ).

[0089] The host-guest complex core of molecular cups H1 and H2 with ibuprofen 1H NMR analysis: Both molecular cups H1 and H2 can well identify the ibuprofen drug molecule. The carboxyl group of the ibuprofen molecule faces the upper end of the molecular cup, while the alkyl part is inserted into the molecular cup. Due to the shielding effect of the molecular cup, the peak of the guest can be seen in the high field region. Because of the better shielding effect of the molecular cup H1, the two hydrogen peaks on the ibuprofen methylene molecule can be seen in the nuclear magnetic spectrum. The nuclear magnetic results show that molecular cups H1 and H2 form a 1:1 host-guest complex with the guest molecule. Figure 8 、 9 These experimental results indicate that the molecular cups H1 and H2 have excellent host-guest recognition performance.

[0090] The above description of the embodiments is intended to facilitate understanding and use of the invention by those skilled in the art. It will be apparent that those skilled in the art can readily make various modifications to these embodiments and apply the general principles described herein to other embodiments without requiring inventive effort. Therefore, the present invention is not limited to the above-described embodiments. Improvements and modifications made by those skilled in the art based on the disclosure of the present invention, without departing from the scope of the present invention, should be within the scope of protection of the present invention.

Claims

1. A resorcinol calix[4]arene-derived quinoxaline molecular calix macrocyclic main compound, characterized in that: The main part of the cavity is alkylquinoxaline, and its structure includes a tetracyclic quinoxaline molecular cup main body H1 or an octaethylquinoxaline molecular cup main body H2, and the structural formula is as follows:

2. A method for preparing the resorcinol calix[4]arene-derived quinoxaline molecular calix macrocyclic main compound as claimed in claim 1, characterized in that: With resorcinol calix[4]arene as the skeleton, the quinoxaline molecular calix macrocyclic main compound is prepared by deepening the four aromatic walls, introducing the quinoxaline structure at the upper edge, and introducing the nitrogen-methyl imidazole salt at the lower edge.

3. The method for preparing the resorcinolcalix[4]arene-derived quinoxaline molecular calix macrocyclic main compound according to claim 2, characterized in that: The following steps are involved: a. Under nitrogen protection, dissolve chloro-foot resorcinol calix[4]arene S1 and 1,2-difluoro-4,5-dinitrobenzene in DMF; add triethylamine dropwise at room temperature, and heat to react for 7 hours after the addition is complete; after the reaction, the solid product chloro-foot octanonitro molecular calix S2 is obtained by rotary evaporation, ultrasonication, filtration, washing, and drying. b. Using 1-butyl-3-methylimidazolium tetrafluoroborate ion solvent as the reaction solvent, the chloro-foot octanitro molecular cup S2 was mixed with SnCl2·2H2O, and then ultrasonically reacted at room temperature; after the reaction, the solid product chloro-foot octanitro molecular cup S3 was obtained by centrifugation; c. Dissolve the chloro-foot octaamino molecular calix S3 in acetonitrile, add triethylamine at room temperature, then add 1,2-cyclohexanedione or 3,4-hexanedione, and reflux under nitrogen protection; after the reaction, cool, filter, and wash, and purify the collected solid by column chromatography to obtain the corresponding chloro-foot tetracyclic quinoxaline molecular calix S4 or chloro-foot octaethylquinoxaline molecular calix S5; d. At room temperature, the chloro-based tetracyclic quinoxaline molecular cup S4 or the chloro-based octaethylquinoxaline molecular cup S5 and nitrogen-based methylimidazole are ultrasonically dispersed until uniformly dispersed, and then heated to react under nitrogen protection; after the reaction is completed, the solid is cooled to room temperature, acetone is added, the solid is precipitated, and the crude product is obtained by filtration; the obtained crude product is refluxed in acetone, cooled, centrifuged, washed, and dried to obtain the tetracyclic quinoxaline molecular cup body H1 or the octaethylquinoxaline molecular cup body H2 accordingly.

4. The method for preparing the resorcinol calix[4]arene-derived quinoxaline molecular calix macrocyclic main compound according to claim 3, characterized in that: In step a, the molar ratio of the chlororesorcinol calix[4]arene S1, 1,2-difluoro-4,5-dinitrobenzene, and triethylamine is 1:3-5:7-9; the concentration of the chlororesorcinol calix[4]arene S1 in DMF is 0.1-0.2 mol / L, and the heating reaction refers to reacting in an oil bath preheated to 55-75°C for 6-8 hours.

5. The method for preparing the resorcinolcalix[4]arene-derived quinoxaline molecular calix macrocyclic main compound according to claim 3, characterized in that: In step a, after the reaction is completed, the residual triethylamine and DMF solvent are removed using a rotary ring evaporator, 0.8-1.2 mol / L hydrochloric acid is added to the residue, and the mixture is placed in an ultrasonic bath for 1.5-2.5 hours. A yellow solid product is obtained by filtration using a Buchner funnel, and the solid is washed with methanol and ether, and vacuum dried to obtain the chloro-foot octanonitro molecular cup S2.

6. The method for preparing the resorcinolcalix[4]arene-derived quinoxaline molecular calix macrocyclic main compound according to claim 3, characterized in that: In step b, the molar ratio between the chloro-octanonitro molecular cup S2 and SnCl2·2H2O is 1:15-25, the concentration of the chloro-octanonitro molecular cup S2 in the 1-butyl-3-methylimidazolium tetrafluoroborate ion solvent is 0.012-0.022 mol / L, the ultrasonic reaction is carried out under a nitrogen environment, the ultrasonic reaction time is 0.5-1.5 hours, and the ultrasonic power is 80kHz-120kHz.

7. The method for preparing the resorcinolcalix[4]arene-derived quinoxaline molecular calix macrocyclic main compound according to claim 3, characterized in that: In step c, the molar ratio of the chloro-octaamino molecular cup S3, triethylamine, and 1,2-cyclohexanedione or 3,4-hexanedione is 1:7-9:7-9, the concentration of the chloro-octaamino molecular cup S3 in acetonitrile is 0.003-0.004 mol / L, the reflux reaction time is 40-56 hours, and the reaction temperature is 90°C-100°C; the washing refers to washing with acetonitrile and ether to remove excess 1,2-cyclohexanedione or 3,4-hexanedione and triethylamine.

8. The method for preparing the resorcinolcalix[4]arene-derived quinoxaline molecular calix macrocyclic main compound according to claim 3, characterized in that: In step d, the concentration of the chloro-tetracyclic quinoxaline molecular calix S4 or the chloro-octaethylquinoxaline molecular calix S5 in nitrogen-methylimidazole is 0.01-0.02 mol / L, and the heating reaction refers to an oil bath reaction at 80-95° C. for 20-28 hours.

9. The method for preparing the resorcinolcalix[4]arene-derived quinoxaline molecular calix macrocyclic main compound according to claim 3, characterized in that: In step d, the reaction is completed, cooled to room temperature, acetone is added, a white solid is precipitated, and the crude product is obtained by filtration through a Buchner funnel. The obtained crude product is refluxed with acetone for 20-28 hours, cooled to room temperature, and then centrifuged to collect the solid. The obtained solid is washed with acetone 6-10 times to remove residual nitrogen-methylimidazole. The solid is collected and dried under vacuum to obtain a tetracyclic quinoxaline molecular cup body H1 or an octaethylquinoxaline molecular cup body H2.

10. An application of the resorcinolcalix[4]arene-derived quinoxaline molecular calix macrocyclic main compound as claimed in claim 1, characterized in that: The tetracyclic quinoxaline molecular calix body H1 or the octaethylquinoxaline molecular calix body H2 is used to identify ibuprofen drug molecules having a carboxyl hydrophilic group.

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