A chiral three-dimensional covalent organic framework material, a preparation method thereof and application in chiral separation

Abstract

The application provides a chiral three-dimensional covalent organic framework material, a preparation method of the chiral three-dimensional covalent organic framework material and application of the chiral three-dimensional covalent organic framework material in chiral separation, and the structural general formula of the covalent organic framework material is shown as formula (I). The covalent organic framework material has high crystallinity, good porosity and strong chemical stability.

Description

Technical Field

[0001] The present invention belongs to the technical field of porous material preparation and chiral separation, and specifically relates to a chiral three-dimensional covalent organic framework material, a preparation method thereof and an application in chiral separation. Background Art

[0002] The separation of chiral compounds is crucial in the biopharmaceutical and pesticide industries because enantiomers with different absolute configurations can exhibit significant differences in biological activity, pharmacology, and toxicity. Among various chiral separation techniques, chiral stationary phase chromatography (CSP) is the most efficient, economical, and convenient method for separating and obtaining pure enantiomers.

[0003] Currently, a large number of new materials have been used as CSPs to separate drug molecules, but most of them currently suffer from problems such as poor separation efficiency, stringent mobile phase requirements, and short service life. Covalent organic frameworks (COFs) are a class of crystalline organic porous polymers that generally have good porosity, high stability, and functional designability, showing various potential applications in many fields. However, to date, only a few chiral COFs have been used as CSPs for enantiomer separation, and the application of three-dimensional chiral COFs in this regard is extremely scarce. This is because it is difficult to ensure a balance between crystallinity, stability, and chiral structure when constructing three-dimensional chiral COFs. Summary of the Invention

[0004] The present invention aims to at least partially address one of the technical problems in the related art. To this end, the inventors of the present invention, considering that the three-dimensional COF has a through-pore structure that is more conducive to sufficient contact between the chiral sites and the analyte, and is expected to obtain a CSP with efficient separation, explored the construction of a series of qtz topological COFs using tetrahedral chiral molecular building blocks with the same absolute configuration. These COFs have high crystallinity, good porosity, strong chemical stability, and both molecular chirality and topological chirality. The inventors also studied the application of these COFs in enantiomeric resolution.

[0005] According to an embodiment of the present invention, the main purpose of the present invention is at least one of the following:

[0006] 1) Provides a universal strategy for constructing qtz topological COFs;

[0007] 2) A series of highly crystalline chiral three-dimensional COFs were prepared;

[0008] 3) The chiral chromatographic column assembled with qtz topological chiral three-dimensional COF can separate multiple enantiomers with good selectivity and durability, and has great potential as a new type of chiral chromatographic column.

[0009] According to an embodiment of the present invention, the main method of the qtz topological chiral covalent organic framework material and the preparation method thereof of the present invention includes: adding the COF powder obtained under solvent thermal conditions to ethanol and fully dispersing it by ultrasonication; then adding amino silica gel and ultrasonically mixing it; then using a mechanical stirring paddle to repeat the ultrasonic stirring process 3 times, and after completing the process, the obtained suspension is allowed to settle; removing the upper turbid liquid, and taking the bottom precipitate to obtain COF@SiO2, namely CSP.

[0010] According to embodiments of the present invention, the present invention breaks through the limitations of three-dimensional COF applications and provides chiral three-dimensional covalent organic framework materials, preparation methods, and applications thereof. According to embodiments of the present invention, a novel three-dimensional chiral COF is prepared using binaphthol as a chiral group. According to embodiments of the present invention, the use of a binaphthol-based three-dimensional chiral COF with a qtz topology as a CSP in the present invention has at least one of the following advantages in the resolution of racemic compounds:

[0011] 1) The material according to the embodiment of the present invention is a three-dimensional ordered porous material, whose special pore morphology and pore size are conducive to the diffusion of analytes;

[0012] 2) The COFs according to embodiments of the present invention have a unique qtz topology, and their inherent topological chirality, including DNA-like chiral double-helical channels and single-helical triangular channels, facilitate different degrees of interaction with chiral substances of different stereo configurations;

[0013] 3) The COF according to the embodiments of the present invention is a fully chiral skeleton with abundant molecular chiral sites, which is conducive to interaction with the analyte;

[0014] 4) The COF according to the embodiments of the present invention has excellent thermal stability and chemical stability (resistant to strong acids and bases) and has low requirements for the mobile phase;

[0015] 5) The CSP of the present invention is simple to prepare and can be loaded into a column by simply combining silica gel and chiral COF;

[0016] 6) The chiral columns prepared using this type of material according to the embodiments of the present invention have a long lifespan and maintain good separation performance after repeated use for at least one month;

[0017] 7) The application of the chiral COF in chiral separation includes but is not limited to high performance liquid chromatography separation as a chiral stationary phase. The chiral separation method using the chiral COF as the active material is within the scope of protection of this patent.

[0018] In the first aspect of the present invention, the present invention provides a covalent organic framework material. According to an embodiment of the present invention, the structural formula of the covalent organic framework material is shown in formula (I):

[0019]

[0020]

[0021] Where X is CR 1 R 2 or PO2R 3 ;

[0022] Y is CR 4 or N;

[0023] R 1 、R 2 、R 3 、R 4 are each independently selected from H, alkyl, alkynyl, alkenyl, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the alkyl, alkynyl, alkenyl, aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 halogen, OH, cyano, alkyl, alkynyl, alkenyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0024] The wavy lines represent periodic extended structures. This invention uses the well-known axially chiral binaphthol as a chiral backbone to prepare a three-dimensional chiral COF with high crystallinity, excellent porosity, and strong chemical stability. Thanks to the abundant chiral binaphthol recognition sites and the confinement effect of the pores, HPLC columns filled with this COF can highly selectively separate various racemates.

[0025] According to an embodiment of the present invention, the above-mentioned covalent organic framework material may further include at least one of the following additional technical features:

[0026] According to an embodiment of the present invention, X is CH2 or PO2H.

[0027] According to an embodiment of the present invention, Y is CH or N.

[0028] According to an embodiment of the present invention, the structure is as shown in one of the following:

[0029]

[0030] In another aspect of the present invention, a method for preparing a covalent organic framework material is also provided. According to an embodiment of the present invention, the method comprises condensing a compound represented by formula (II) with a compound represented by formula (III) to obtain a covalent organic framework material, wherein the covalent organic framework material has a structural formula represented by formula (I).

[0031]

[0032] Where X is CR 1 R 2or PO2R 3 ;

[0033] Y is CR 4 or N;

[0034] R 1 、R 2 、R 3 、R 4 are each independently selected from H, alkyl, alkynyl, alkenyl, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the alkyl, alkynyl, alkenyl, aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 halogen, OH, cyano, alkyl, alkynyl, alkenyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0035] The wavy lines represent periodic extended structures.

[0036] According to an embodiment of the present invention, the above application may further include at least one of the following additional technical features: According to an embodiment of the present invention, X is CH2 or PO2H.

[0037] According to an embodiment of the present invention, Y is CH or N.

[0038] According to an embodiment of the present invention, the structure of the material represented by formula (I) is shown as one of the following:

[0039] According to an embodiment of the present invention, the compound represented by formula (II) is as follows:

[0040]

[0041] According to an embodiment of the present invention, the compound represented by formula (III) is as follows:

[0042]

[0043] According to an embodiment of the present invention, the compound represented by formula (II) and the compound represented by formula (III) have the same configuration.

[0044] According to an embodiment of the present invention, the molar ratio of the compound represented by formula (II) to the compound represented by formula (III) is 1:1.

[0045] According to an embodiment of the present invention, the condensation reaction is carried out in the following manner:

[0046] S1: Place the compound represented by formula (II) and the compound represented by formula (III) in a 10 mL ampoule tube, add a certain proportion of organic solvent, and sonicate the mixture for 10 minutes to completely dissolve or evenly disperse the solids;

[0047] S2: Add acetic acid aqueous solution to the reaction vessel, then evacuate and ventilate with nitrogen using liquid nitrogen, repeat this step three times, and then seal the ampoule tube under vacuum conditions;

[0048] S3: After returning to room temperature, place it in a 120°C oven for 168 hours;

[0049] S4: After the reaction is completed, the mixture is cooled to room temperature, the powder is collected by filtration, washed with ethanol and acetone, and then placed in a Soxhlet extractor. It is extracted with tetrahydrofuran, methanol, dichloromethane, and acetone in sequence for 24 hours, and vacuum dried to obtain the material represented by formula (I).

[0050] In yet another aspect of the present invention, the present invention further proposes the use of the aforementioned covalent organic framework material or the covalent organic framework material prepared according to the aforementioned method in chiral separation.

[0051] According to an embodiment of the present invention, the above application may further include at least one of the following additional technical features:

[0052] According to an embodiment of the present invention, the chiral separation is performed using a chiral chromatography column.

[0053] According to an embodiment of the present invention, the covalent organic framework material and the amino silica gel are mixed and loaded into a column.

[0054] According to an embodiment of the present invention, the structure of the amino silica gel is:

[0055]

[0056] The particle size of the amino silica gel is 5 μm and the pore size is

[0057] Silica stands for silica gel.

[0058] According to an embodiment of the present invention, the mass ratio of the covalent organic framework material to the amino silica gel is 1:7.

[0059] According to an embodiment of the present invention, the displacement pressure in the column packing process is 38 MPa.

[0060] In another aspect of the present invention, the present invention also proposes a quartz (qtz) topological chiral three-dimensional covalent organic framework material. According to an embodiment of the present invention, the general structural formula of the qtz topological chiral three-dimensional covalent organic framework material is:

[0061]

[0062] The wavy lines in the structural formula represent periodic extended structures.

[0063] According to an embodiment of the present application, the qtz topology chiral three-dimensional covalent organic framework material comprises the following structure:

[0064]

[0065] According to an embodiment of the present application, the qtz topology chiral three-dimensional covalent organic framework material comprises the above-mentioned 18 chiral COFs, but is not limited to the chiral COFs prepared by aldehyde and amine three components and above multi-component building blocks.

[0066] According to an embodiment of the present application, the chiral three-dimensional covalent organic framework material has a quartz (qtz) topology.

[0067]

[0068] The polyhedron represents a chiral amine or a chiral aldehyde of a stereotetra-connected node.

[0069] According to an embodiment of the present application, the chiral three-dimensional covalent organic framework material is a covalent organic framework material prepared by imine condensation of optically pure chiral amine and chiral aldehyde.

[0070] The structural general formula of the chiral amine is:

[0071]

[0072] The chiral amine comprises the following amino compounds:

[0073]

[0074] The structural general formula of the chiral aldehyde is:

[0075]

[0076] The chiral aldehyde comprises the following aldehyde compounds:

[0077]

[0078] In another aspect of the present application, a preparation method of the qtz topology chiral three-dimensional covalent organic framework material is also provided. According to an embodiment of the present application, the chiral three-dimensional covalent organic framework material is prepared by imine condensation of chiral amine and chiral aldehyde with the same absolute configuration, i.e., the aldehyde and the amine are both in R configuration or both in S configuration.

[0079] According to an embodiment of the present application, the chiral three-dimensional covalent organic framework material can be prepared by one aldehyde and one amine, or three components including two amines and one aldehyde or two aldehydes and one amine, and the proportion of the three components can be adjusted.

[0080] According to an embodiment of the present application, the method comprises the following steps:

[0081] (1): Chiral amine and chiral aldehyde are placed in a 10 mL ampoule tube, followed by a certain proportion of organic solvent, and the mixture is ultrasonicated for 10 minutes to completely dissolve the solid;

[0082] (2): Add acetic acid aqueous solution of a certain concentration and volume to the reaction vessel, then freeze with liquid nitrogen, evacuate and pass nitrogen, repeat this step three times, and then seal the ampoule tube under vacuum conditions;

[0083] (3): After returning to room temperature, place it in an oven at 120°C for 7 days;

[0084] (4): After the reaction is complete, the mixture is cooled to room temperature. The powder is collected by filtration, washed with ethanol and acetone, and then placed in a Soxhlet extractor. Extracted with tetrahydrofuran, methanol, dichloromethane, and acetone for 24 hours in sequence, and dried in vacuo to obtain a light yellow powder.

[0085] According to an embodiment of the present invention, the molar ratio of the chiral amine to the chiral aldehyde is 1:1.

[0086] According to an embodiment of the present invention, in step (3), the reaction time is 168 hours.

[0087] In yet another aspect of the present invention, the present invention also provides a covalent organic framework material prepared by the above-mentioned preparation method.

[0088] In another aspect of the present invention, the present invention further provides a method for preparing the aforementioned three-dimensional covalent organic framework material for a chiral chromatographic column, characterized in that the method comprises the following steps:

[0089] (1) The COF powder obtained under solvothermal conditions was added to ethanol, fully dispersed by ultrasonication, and then ultrasonically mixed with amino silica gel;

[0090] (2) Using a mechanical stirring paddle, homogenize the slurry and let it stand, then take the bottom precipitate and add ethanol for ultrasonic dispersion;

[0091] (3) The suspension was loaded into a 3.0*150 mm stainless steel column tube, and the replacement solvent was methanol.

[0092] (4) After the chromatographic column is filled, use ethanol as the mobile phase and rinse it for later use.

[0093] According to an embodiment of the present invention, the structure of the amino silica gel is:

[0094]

[0095] Its particle size is 5μm and pore size

[0096] According to an embodiment of the present invention, the amount of the chiral three-dimensional covalent organic framework material is 1 part by mass, and the amount of the amino silica gel is 7 parts by mass.

[0097] According to an embodiment of the present invention, the displacement pressure of the column is 38 MPa.

[0098] Definitions and General Terms

[0099] Unless otherwise specified, the terms and definitions used in this application, including the specification and claims, are as follows.

[0100] Those skilled in the art will understand that, according to the conventions used in the art, in the structural formula of this application, Used to depict chemical bonds, which are the points where a moiety or substituent is attached to a core or backbone structure.

[0101] The present invention will list the literature corresponding to the specific content of the invention in detail, and the examples are accompanied by diagrams of structural formulas and chemical formulas. The present invention is intended to cover all options, variations and equivalents that may be included in the existing invention field as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which can be applied to the practice of the present invention. The present invention is in no way limited to the description of methods and materials. There are many documents and similar materials that differ or conflict with the present application, including but not limited to the definition of terms, the usage of terms, the technology described, or the scope controlled by the present application.

[0102] The following definitions apply to the present invention unless otherwise indicated. For purposes of the present invention, the chemical elements are defined according to the Periodic Table of the Elements, CAS version, and the Chemical Handbook, 75th Ed, 1994. In addition, general principles of organic chemistry are described in "Organic Chemistry," by Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, all of which are incorporated herein by reference.

[0103] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0104] Compounds as described herein may optionally be substituted with one or more substituents, as described in the general formulae of the present invention, or as described in the specific examples, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." In general, the term "optionally," whether preceded by the term "substituted," indicates that one or more hydrogen atoms in a given structure are replaced with the specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from the specified group, the substituents may be the same or different at each position.The substituents may be, but are not limited to, hydrogen, F, Cl, Br, I, nitro, cyano, oxo (=O), hydroxy, alkyl, hydroxyalkyl, alkylamino, aminoalkyl, haloalkoxy, cycloalkyl, amino, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, cycloalkyloxy, alkoxy, alkoxyalkyl, haloalkyl, -COOH, -alkylene-C (=O) O-alkyl, -alkylene-S (=O) 2 -alkyl, -alkylene-S (=O) 2 -amino, -S (=O) 2 -alkyl, -S (=O) 2 -amino, -S (=O) 2 OH, -O-alkylene-C (=O) O-alkyl, -O-alkylene-S (=O) 2 -alkyl, -O-alkylene -S(=O)2-amino, -O-alkylene-S(=O)2OH, -C(=O)NH2, -C(=O)NH-alkyl, -C(=O)N(alkyl)-alkyl, -C(=O)NHS(=O)2-alkyl, -C(=O)NHS(=O)2-amino, -C(=O)NHS(=O)2OH, -N(haloalkyl)-alkyl, -N(alkyl)-S(=O)2-alkyl, -NHS(=O)2-alkyl, -NHS(=O)2-haloalkyl, -N(alkyl)S(=O)2-haloalkyl, -N(alkyl)S(=O)2-alkylamino, -NHC(=O)-alkyl, -NHC(=O)-haloalkyl, - N(alkyl)C(=O)-haloalkyl, -N(alkyl)C(=O)-alkylamino, -N(alkyl)C(=O)O-alkyl, -NHC(=O)O-alkyl, -NHC(=O)O-haloalkyl, -N(alkyl)C(=O)O-haloalkyl, -N(alkyl)C(=O)O-aminoalkyl, -NHC(=O)-NH2, -NHC(=O)NH-(alkyl), -NHC(=O)NH(haloalkyl), -NHC(=O)N(alkyl)-alkyl, -OC(=O)-alkyl, -OC(=O)-amino, -OC(=O)-alkylamino, -OC(=O)-aminoalkyl, -OC(=O)-alkoxy, -C (=O)N(alkyl)S(=O)2-alkyl, -C(=O)N(alkyl)S(=O)2-amino, -C(=O)NH-S(=O)2OH, -C(=NH)NH2, -C(=NH)NH-alkyl, -C(=NH)N(alkyl)-alkyl, -C(=N-alkyl)-NH2, -C(=O)NH-alkylene-S(=O)2OH, -C(=O)NHC(=O)OH, -C(=O)NHC(=O)O-alkyl, -C(=O)N(alkyl)C(=O)O-alkyl, -C(=O)NH-alkylene-C(=O)OH and -C(=O)NH-alkylene-C(=O)O-alkyl, and the like.

[0105] As used herein, the term "alkyl" includes saturated linear or branched monovalent hydrocarbon groups of 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms, wherein the alkyl group may be independently optionally substituted with one or more substituents described herein. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t- -Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl -1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2C H3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl and n-octyl, etc. The term "alkyl" and its prefix "alkane" as used herein include straight and branched saturated carbon chains. The term "alkylene" or "alkylene" as used herein refers to a saturated divalent hydrocarbon radical derived from a straight or branched saturated hydrocarbon by eliminating two hydrogen atoms. Examples of such radicals include, but are not limited to, methylene, ethylene, and isopropylene, etc.

[0106] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position is unsaturated, i.e., one CC is sp 2double bond, wherein the alkenyl group can be independently and optionally substituted with one or more substituents described herein, including groups with "trans", "cis" or "E", "Z" orientations, wherein specific examples of alkenyl include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0107] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is unsaturated, i.e., one C—C is an sp triple bond, wherein the alkynyl group may be independently and optionally substituted with one or more substituents described herein. Specific examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), and the like.

[0108] The term "halogen" refers to F, Cl, Br or I.

[0109] As used herein, the term "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0110] The term "cycloalkyl" or "cycloalkane" refers to a monovalent or polyvalent saturated monocyclic, bicyclic, or tricyclic carbon ring system containing 3-12 carbon atoms, which may be saturated or contain one or more unsaturated bonds, but never aromatic. In one embodiment, a cycloalkyl group contains 3-10 carbon atoms; in another embodiment, a cycloalkyl group contains 3-8 carbon atoms; and in yet another embodiment, a cycloalkyl group contains 3-6 carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.

[0111] The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring containing 3 to 12 ring atoms, never including aromatic rings, wherein at least one ring atom is a heteroatom. In one embodiment, "heterocyclyl" or "heterocycle" contains 3 to 10 ring atoms; in one embodiment, "heterocyclyl" or "heterocycle" contains 3 to 8 ring atoms; in another embodiment, "heterocyclyl" or "heterocycle" contains 5 to 8 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 3 to 6 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 5 to 6 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 4 to 6 ring atoms; unless otherwise specified, a heterocyclyl group may be a carbon group or a nitrogen group, and heteroatoms have the meanings as described herein. Examples of heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine Base, diazepine thiazolinone Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidonyl, 3,5-dioxopiperidinyl, and pyrimidinedione. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl. The heterocyclic groups may be optionally substituted with one or more substituents described herein.

[0112] The term "aryl" refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic, wherein each ring comprises 3-7 ring atoms, and has one or more points of attachment to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring." Examples of aryl groups include phenyl, naphthyl, and anthracene. The aryl groups may be independently and optionally substituted with one or more substituents described herein.

[0113] The term "heteroaryl" denotes a monocyclic, bicyclic and tricyclic ring system containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring contains 5-7 atoms in the ring and has one or more points of attachment to the remainder of the molecule. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, a 5-10 atom containing heteroaryl group contains 1, 2, 3, or 4 heteroatoms independently selected from O, S and N, wherein the nitrogen atom can be further oxidized.

[0114] Examples of heteroaryl groups include, but are not limited to: furanyl, imidazolyl (such as N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl, oxazolyl (such as 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (such as N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl, pyrimidinyl (such as 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl, thiazolyl (such as 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (such as 5-tetrazolyl), triazolyl, thiophenyl (such as 2-thiophenyl, 3-thiophenyl), pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl; also included are bicyclic rings, but are by no means limited to these: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxolanyl, indolinyl, isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl and [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

[0115] Additionally, it should be noted that, unless otherwise expressly stated, the term "independently" used in the present invention should be broadly construed to mean that the individual entities described are independent of one another and may independently represent the same or different specific groups. More specifically, the term "independently" can mean that specific options expressed by identical symbols in different groups do not affect each other, or that specific options expressed by identical symbols in the same group do not affect each other. BRIEF DESCRIPTION OF THE DRAWINGS

[0116] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the following description of the embodiments with reference to the accompanying drawings, in which:

[0117] Figure 1 is the molecular structure of (R,R)-BINOL(C1)-COF and its powder X-ray diffraction pattern;

[0118] Figure 2 is the solid circular dichroism spectrum of (R,R)-BINOL(C1)-COF;

[0119] Figure 3 N2 adsorption-desorption curve (a) and pore size distribution diagram (b) of (R,R)-BINOL(C1)-COF;

[0120] Figure 4 is the powder X-ray diffraction pattern of (R,R)-BINOL(C1)-COF after immersion in different solvents for 7 days;

[0121] Figure 5 It is based on the separation performance of the chiral column (R,R)-BINOL(C1)-COF for a variety of racemic compounds;

[0122] Figure 6 The figure shows the comparison of the separation performance of the (R,R)-BINOL(C1)-COF chiral chromatographic column after initial use and one month of use. DETAILED DESCRIPTION

[0123] The embodiments described below with reference to the accompanying drawings are exemplary and are intended to explain the present invention, but should not be construed as limiting the present invention.

[0124] The abbreviation of the present invention is as follows:

[0125] Example 1

[0126] Preparation of (R)-BINOL(C1)-TBA:

[0127]

[0128] The raw material (R)-BINOL-DBDI used in this embodiment is a known compound and can be synthesized by methods known in the art.

[0129] (1) (R)-BINOL-DBDI (5 g, 7.2 mmol), bromochloromethane (0.98 mL, 14.4 mol), and cesium carbonate (9.4 g, 28.8 mmol) were added to a 150 mL round-bottom flask. 30 mL of acetone was then added, and the reaction solution was refluxed for 36 h until the reaction was complete as monitored by a plate. After cooling to room temperature, the precipitate was filtered and washed with acetone. The solvent in the resulting solution was removed by rotary evaporation. Purification by column chromatography (petroleum ether: dichloromethane = 5:1, v:v) gave a light yellow solid (3.35 g, yield: 66%).

[0130] (2) (R)-BINOL(C1)-DBDI (5.0 g, 7.09 mmol), 4-formylphenylboronic acid (6.39 g, 42.54 mmol), cesium fluoride (12.9 g, 85.08 mmol) and tetrakis(triphenylphosphine)palladium (0.41 g, 0.35 mmol) were added to a 500 mL single-necked flask, followed by addition of ethylene glycol dimethyl ether (350 mL) and degassing for 10 min. The reaction was heated and stirred at 110 °C for 2 days under nitrogen protection. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth and washed with dichloromethane until no UV absorption was observed on the diatomaceous earth plate. After evaporation of the solvent, the residue was purified by silica gel column chromatography using a gradient eluent of dichloromethane → dichloromethane / ethyl acetate (v / v = 5:1) to obtain (R)-BINOL(C1)-TBA as a white powder (3.0 g, yield: 60%).

[0131] Example 2

[0132] Preparation of (R)-BINOL(C1)-TPA:

[0133]

[0134] A solution of (R)-BINOL(C1)-DBDI (5.0 g, 7.09 mmol) and 4-aminophenylboronic acid pinacol ester (9.3 g, 42.54 mmol) in ethylene glycol dimethyl ether (350 mL) was degassed for 10 min, followed by the addition of cesium fluoride (12.7 g, 83.6 mmol) and tetrakis(triphenylphosphine palladium) (0.41 g, 0.35 mmol). The reaction mixture was stirred under nitrogen at 110°C for 2 days. After cooling to room temperature, the mixture was filtered through celite, and the filtrate was washed with dichloromethane and ethyl acetate. After removal of the solvent, the residue was purified by silica gel column chromatography using dichloromethane → dichloromethane / ethyl acetate (v / v = 5:1) as the eluent to afford (R)-BINOL(C1)-TPA as a white powder (2.8 g, 60% yield).

[0135] Example 3

[0136] Preparation of (R)-BINOL(PA)-TPA:

[0137]

[0138] The raw material (R)-BINOL(Me)-TPA used in this example can be synthesized using the method of Example 1 above.

[0139] (1) (R)-BINOL(Me)-TPA (1.8 g, 2.65 mmol) was weighed and placed in a 250 mL round-bottom flask. 30 mL of dichloromethane was added to dissolve the mixture. 30 mL of a 1 M boron tribromide / dichloromethane solution was then slowly added dropwise to the reaction mixture using a constant pressure dropping funnel. The mixture was stirred at room temperature overnight. The reaction was quenched with dilute ammonia water and the pH was adjusted to 7. An off-white solid precipitated, which was filtered under normal pressure, washed with distilled water several times, and dried under vacuum to obtain solid (R)-BINOL-TPA (1.48 g, yield: 86%).

[0140] (2) (R)-BINOL-TPA (500 mg, 0.77 mmol) was weighed into a 10 mL round-bottom flask. 5 mL of pyridine and 500 μL of phosphorus oxychloride were added to the reaction flask and reacted at 90°C for 24 h. After cooling to room temperature, 5 mL of water was added and the temperature was raised to 60°C and reacted for 4 h. 6 mL of 6 M aqueous hydrochloric acid was added to the reaction system, followed by the addition of dilute ammonia to neutralize the acid in the system. The off-white flocculent precipitate was collected by filtration, washed with water, and dried to obtain a gray solid (R)-BINOL(PA)-TPA (465 mg, yield: 85%).

[0141] Example 4

[0142] Preparation of (R)-BINOL(PA)-TBA:

[0143]

[0144] The raw material (R)-BINOL(MOM)-TBA(Pro) used in this example can be synthesized using the method in Example 1 above.

[0145] (1) (R)-BINOL(MOM)-TBA(Pro) (6 g, 5.2 mol) was weighed into a 250 mL round-bottom flask. 100 mL of dichloromethane and 25 mL of trifluoroacetic acid were added to the reaction flask and stirred at room temperature overnight. The pH was adjusted to 5 with sodium bicarbonate to precipitate a pale yellow solid. Filter under normal pressure to obtain a beige solid (3.5 g, yield: 96%).

[0146] (2) Weigh (R)-BINOL-TBA (300 mg, 0.4274 mmol) into a 25 mL round-bottom flask, connect the flask to a double-row tube, evacuate the air and backfill with nitrogen to form a nitrogen atmosphere. Add 5 mL of pyridine and 78 μL of phosphorus oxychloride to the reaction flask and react at 60°C for 12 h. Cool to room temperature and add 6 mL of water. A white solid precipitates. React at 60°C for 4 h. Add 6 mL of 6 M aqueous hydrochloric acid to the reaction system. A large amount of precipitated solid is filtered and washed with a large amount of water to obtain a beige solid (R)-BINOL(PA)-TBA (300 mg, yield: 92%).

[0147] Example 5

[0148] Preparation of (R)-BINOL(C1)-TPyA:

[0149]

[0150] (1) (R)-BINOL(C1)-DBDI (3 g, 4.3 mmol), 2-aminopyridine-5-boronic acid pinacol ester (5.6 g, 25 mmol), potassium carbonate (5.5 g, 40 mmol) and tetrakis(triphenylphosphine)palladium (400 mg, 0.35 mmol) were weighed into a 500 mL round-bottom flask. 150 mL of a mixed solvent of toluene / ethanol / water (v:v:v = 1 / 1 / 1) was added under nitrogen protection. After reacting at 90°C for 2 days, the reaction solution was cooled to room temperature and extracted with ethyl acetate. The solvent was then distilled off under reduced pressure. The collected solid was purified by column chromatography (dichloromethane / methanol = 10:1, v:v) to obtain a white solid (R)-BINOL(C1)-TPyA (1.7 g, yield: 60%).

[0151] Example 6

[0152] Preparation of (R)-BINOL(C1)-TPyAl:

[0153]

[0154] (1) (R)-BINOL(C1)-DBDI (6 g, 8.5 mmol), 2-(5,5-dimethyl-1,3-dioxan-2-yl)-pyridine-5-boronic acid pinacol ester (12 g, 37.6 mmol), cesium fluoride (15.6 g, 0.1027 mol) and tetrakis(triphenylphosphine)palladium (660 mg, 0.5719 mmol) were weighed and placed in a 500 mL round-bottom flask. 250 mL of ethylene glycol dimethyl ether was added to the reaction mixture. The mixture was heated and stirred at 90°C for 2 days under nitrogen protection. The reaction solution was cooled to room temperature, the solution phase was collected by filtration through celite, and then distilled under reduced pressure. The solid was collected and purified by column chromatography (dichloromethane / ethyl acetate = 5:1, v:v) to obtain a white solid (R)-BINOL(C1)-TPyAl(Pro) (6.2 g, yield: 69%).

[0155] (2) (R)-BINOL(C1)-TPyAl(Pro) (3 g, 2.8 mmol) was weighed into a 250 mL round-bottom flask, and 50 mL of tetrahydrofuran was added. Under nitrogen protection, 100 mL of 1 M aqueous hydrochloric acid solution was added dropwise to the reaction using a constant pressure dropping funnel. The mixture was stirred and heated to 70°C. The reaction progress was monitored by thin-layer chromatography until the raw materials were completely reacted. The pH was adjusted to 7 with saturated sodium bicarbonate, and the solid was collected by vacuum filtration. The solid was separated and purified by column chromatography (dichloromethane / ethyl acetate = 8:1, v:v) to obtain a white solid (R)-BINOL(C1)-TPyAl (1.8 g, yield: 89%).

[0156] Example 7

[0157] Preparation of (R,R)-BINOL(C1)-COF:

[0158] (1) (R)-BINOL(C1)-TBA (10.7 mg, 0.015 mmol) and (R)-BINOL(C1)-TPA (9.9 mg, 0.015 mmol) were placed in a 10 mL ampoule. 1 mL of chloroform and 1 mL of nitrobenzene were added, and the mixture was sonicated for 10 min to completely dissolve the solids.

[0159] (2) Add 0.15 mL of 10 M acetic acid aqueous solution to the reaction vessel, then evacuate the liquid nitrogen and ventilate with nitrogen. Repeat this step three times, and then seal the ampoule tube under vacuum conditions.

[0160] (3) After returning to room temperature, place the mixture in an oven at 120°C for 7 days. After the reaction is complete, cool the mixture to room temperature. Collect the powder by filtration, wash with ethanol and acetone, place the mixture in a Soxhlet extractor, and extract with tetrahydrofuran, methanol, dichloromethane, and acetone for 24 hours in sequence. Dry the mixture in a vacuum to obtain a light yellow powder.

[0161] Example 8

[0162] Preparation of (R,R)-BINOL(C1)-COF chiral stationary phase:

[0163]

[0164] (1) Add 100 mg of the obtained (R,R)-BINOL(C1)-COF powder to 50 mL of ethanol and disperse it thoroughly by ultrasonication; then add 700 mg of amino silica gel and mix it by ultrasonication; then use a mechanical stirring paddle to stir for 30 minutes, repeat the process of ultrasonication for 30 minutes and stirring for 30 minutes three times, and after completing the process, pour the obtained suspension into a 50 mL graduated cylinder and let it settle for 12 hours; then remove the upper turbid suspension and take the bottom precipitate (R,R)-BINOL(C1)-COF@SiO2 for use.

[0165] (2) (R,R)-BINOL(C1)-COF@SiO2 solid was ultrasonically dispersed in 40 mL of ethanol. The suspension was then loaded into a 3.0 x 150 mm stainless steel column. The displacement solvent was methanol, the displacement pressure was 38 MPa, and the displacement volume was 60 mL. The loaded column was flushed for 8 h using ethanol as the mobile phase at 0.1 mL / min.

[0166] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0167] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A covalent organic framework material, characterized in that Its general structural formula is shown in formula (I): The structural formula shown in formula (I) is Where X is CR 1 R 2 or PO2R 3 ; Y is CR 4 or N; R 1 、R 2 、R 3 、R 4 are each independently selected from H, alkyl, alkynyl, alkenyl, aryl, cycloalkyl or heterocyclyl, wherein the alkyl, alkynyl, alkenyl, aryl, cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 halogen, OH, cyano, alkyl, alkynyl, alkenyl, aryl, cycloalkyl or heterocyclyl; The wavy lines represent periodic extended structures.

2. The covalent organic framework material according to claim 1, characterized in that The heterocyclic group is a heteroaryl group.

3. The covalent organic framework material according to claim 1, characterized in that X is CH2 or PO2H.

4. The covalent organic framework material according to claim 1, characterized in that Y is CH or N.

5. The covalent organic framework material according to claim 1, characterized in that Its structure is one of the following: 。 6. A method for preparing a covalent organic framework material, characterized in that: The method comprises condensing a compound represented by formula (II) with a compound represented by formula (III) to obtain a covalent organic framework material, wherein the covalent organic framework material has a structural formula represented by formula (I). The structural formula shown in formula (I) is The compound represented by formula (II), The compound represented by formula (III), Where X is CR 1 R 2 or PO2R 3 ; Y is CR 4 or N; R 1 、R 2 、R 3 、R 4 are each independently selected from H, alkyl, alkynyl, alkenyl, aryl, cycloalkyl or heterocyclyl, wherein the alkyl, alkynyl, alkenyl, aryl, cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 halogen, OH, cyano, alkyl, alkynyl, alkenyl, aryl, cycloalkyl or heterocyclyl; The wavy lines represent periodic extended structures.

7. The method according to claim 6, characterized in that The heterocyclic group is a heteroaryl group.

8. The method according to claim 6, characterized in that X is CH2 or PO2H.

9. The method according to claim 6, characterized in that Y is CH or N.

10. The method according to claim 6, characterized in that The structure of the material represented by formula (I) is shown as one of the following: 。 11. The method according to claim 6, characterized in that The compound represented by formula (II) is shown as one of the following: 。 12. The method according to claim 6, characterized in that The compound represented by formula (III) is shown as one of the following: 。 13. The method according to claim 6, characterized in that The molar ratio of the compound represented by formula (II) to the compound represented by formula (III) is 1:

1.

14. The method according to claim 6, characterized in that The condensation reaction is carried out in the following manner: S1: Place the compound represented by formula (II) and the compound represented by formula (III) in a 10 mL ampoule, then add a certain proportion of organic solvent, and sonicate the mixture for 10 minutes to completely dissolve or evenly disperse the solids; S2: Add acetic acid aqueous solution to the reaction vessel, then evacuate and ventilate with nitrogen using liquid nitrogen, repeat this step three times, and then seal the ampoule tube under vacuum conditions; S3: After returning to room temperature, place it in a 120°C oven for 168 hours; S4: After the reaction is completed, the mixture is cooled to room temperature, the powder is collected by filtration, washed with ethanol and acetone, and then placed in a Soxhlet extractor. It is extracted with tetrahydrofuran, methanol, dichloromethane, and acetone in sequence for 24 hours, and dried in vacuo to obtain the compound represented by formula (I).

15. Use of the covalent organic framework material according to any one of claims 1 to 5 or the covalent organic framework material prepared according to the method according to any one of claims 6 to 14 in chiral separation.

16. The use according to claim 15, characterized in that The chiral separation is performed using a chiral chromatographic column.

17. The use according to claim 15, characterized in that The covalent organic framework material and amino silica gel are mixed and loaded into a column.

18. The use according to claim 17, characterized in that The structure of the amino silica gel is: The amino silica gel has a particle size of 5 μm and a pore size of 1000 Å; Silica stands for silica gel.

19. The use according to claim 17, characterized in that The mass ratio of the covalent organic framework material to the amino silica gel is 1:7.

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