CN114057817A - Method for preparing aryl boric acid from On-DNA aryl halide - Google Patents

Method for preparing aryl boric acid from On-DNA aryl halide Download PDF

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CN114057817A
CN114057817A CN202010776536.8A CN202010776536A CN114057817A CN 114057817 A CN114057817 A CN 114057817A CN 202010776536 A CN202010776536 A CN 202010776536A CN 114057817 A CN114057817 A CN 114057817A
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李进
纪跃
戴东良
罗华东
刘观赛
万金桥
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Hitgen Inc
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Abstract

The invention relates to a method for preparing aryl boric acid from an On-DNA aryl halide, which uses tetrahydroxy diboron or pinacol bisboronate as a boronizing reagent and can realize the conversion from the On-DNA aryl halide to the aryl boric acid only under the heating condition. The method provided by the invention can be used for constructing the structure of the boric acid library, simultaneously, the arylboronic acid can be used for constructing various structures through chemical reaction as a synthetic building block, and the method has the advantages of wide substrate universality, high yield, mild conditions and convenient operation, and is suitable for synthesizing the DNA coding compound library by using a porous plate.

Description

Method for preparing aryl boric acid from On-DNA aryl halide
Technical Field
The invention belongs to the technical field of coding compound libraries, and particularly relates to a method for converting On-DNA aryl halide into aryl boric acid in the construction of a DNA coding compound library.
Background
In drug development, especially new drug development, high-throughput screening for biological targets is one of the main means for rapidly obtaining lead compounds. However, traditional high throughput screening based on single molecules requires long time, large equipment investment, limited number of library compounds (millions), and the building of compound libraries requires decades of accumulation, limiting the efficiency and possibility of discovery of lead compounds. The recent DNA-encoded compound library technologies (WO2005058479, WO2018166532, CN103882532) combine the technologies of combinatorial chemistry and molecular biology, add a DNA tag to each compound on the molecular level, and synthesize up to hundred million levels of compound libraries in a very short time, which is a trend of the next generation compound library screening technology, and begin to be widely applied in the pharmaceutical industry, resulting in many positive effects (Accounts of Chemical Research,2014,47, 1247-.
The DNA coding compound library can rapidly generate a giant compound library through combinatorial chemistry, and can screen out a lead compound with high flux, so that the screening of the lead compound becomes unprecedented rapidness and high efficiency. One of the challenges in constructing libraries of DNA-encoding compounds is the need to synthesize chemically diverse small molecules on DNA in high yields. Because DNA can be kept stable under certain conditions (solvent, pH, temperature and ion concentration), the On-DNA reaction applied to the construction of the DNA coding compound library also needs higher yield. Therefore, the reagent type, reaction type and reaction condition of the chemical reaction (On-DNA reaction for short) carried out On DNA directly influence the richness and selectivity of the DNA coding compound library. Therefore, the development of chemical reactions compatible with DNA is also a long-term research and research direction of the current DNA coding compound library technology, and the application and commercial value of the DNA coding compound library are directly influenced.
The arylboronic acid compound has unique pharmacological action in a drug structure, can be used as a synthetic building block for constructing C-C, C-N, C-S and C-O bonds, and can be used as a nucleophilic reagent for performing addition reaction on compounds such as aldehyde, ketone, imine, unsaturated ketone and the like. At present, no relevant literature report exists On the construction of the On-DNA arylboronic acid structure. Therefore, a construction method of the On-DNA aryl boric acid needs to be developed, and the application value of the DNA coding compound library technology is further improved.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for converting an On-DNA aryl halide into aryl boric acid, wherein tetrahydroxy diboron or pinacol diborate is used as a boronizing reagent, and the conversion of the On-DNA aryl halide into the aryl boric acid can be realized only under the heating condition. The method has the advantages of mild reaction conditions, high selectivity, high yield and simple post-treatment, is suitable for the production of the DNA coding compound library, and can obviously improve the diversity of molecules of the compound library.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a method for preparing aryl boric acid from an On-DNA aryl halide is characterized in that an On-DNA aryl halide compound is used as a raw material in the reaction, and the reaction is carried out in the presence of a boronizing reagent to obtain an On-DNA aryl boric acid compound; the structural formula of the On-DNA aryl halogenated compound is DNA-Ar-X, and the structural formula of the On-DNA aryl boric acid compound is DNA-Ar-B (OH)2The boronizing agent is tetrahydroxy diboron or pinacol diboron diborate.
Wherein, the DNA in the structural formula comprises a single-stranded or double-stranded nucleotide chain obtained by polymerizing artificially modified and/or unmodified nucleotide monomers, and the nucleotide chain is connected with Ar through one or more chemical bonds or groups; the length of the single-stranded or double-stranded nucleotide chain is 5-200 bp; the-X of the On-DNA aryl halide is connected to the ring of Ar, and X is selected from chlorine, bromine or iodine; the size of the DNA is 10-200 basic groups.
Wherein Ar in the structural formula is selected from substituted aromatic rings or aromatic heterocycles.
Ar is selected from the following groups:
Figure BDA0002618132210000021
wherein Ar has one OR more substituents selected from the group consisting of hydrogen, halogen, carboxyl, cyano, hydroxyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy, heterocyclic, substituted heterocyclic, aromatic heterocyclic, alkylmercapto, -C (O) OR1、-OC(O)R1、-C(O)R2、-OR3Any one or more of the random combinations of R1Is selected from C1～C20Alkyl, said R2Selected from hydrogen or C1～C20An alkyl group; said R3Selected from aryl or aromatic heterocyclic radical;
the alkyl group is C1-C20Linear or branched alkyl of (a); the alkoxy is C1-C20A straight or branched alkoxy group of (a);
the number of the substituent groups of the substituted alkyl is one or more, and the substituent groups of the substituted alkyl are one or more independently selected from halogen, cyano, carboxyl and cycloalkyl;
the number of the substituent groups of the substituted alkoxy is one or more, and the substituent groups of the substituted alkoxy are one or more independently selected from halogen, cyano and carboxyl;
the number of the substituent of the substituted heterocyclic group is one or more, and the substituent of the substituted heterocyclic group is one or more independently selected from halogen, cyano, carboxyl and oxygen atom.
Preferably, Ar is
Figure BDA0002618132210000031
One or more substituents are arranged on Ar, and the substituents are substituted heterocyclic group, alkyl, substituted alkyl, halogen and C1-C6Alkoxy, substituted C1-C6Alkoxy radical, C1-C6Alkanethiol, arylheterocyclyl, -OR3Any one or more of the random combinations of R3Is phenyl or pyridyl; the heterocyclic group is a nitrogen-containing five-membered saturated heterocyclic group; the aromatic heterocyclic group is a five-membered aromatic heterocyclic group containing nitrogen;
the alkyl group is C1-C6Linear or branched alkyl of (a); said C is1～C6The alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl;
said C is1～C6Alkoxy is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy;
the number of the substituent of the substituted heterocyclic group is one or more, and the substituent of the substituted heterocyclic group is one or more independently selected from halogen, carboxyl and oxygen atoms;
the number of the substituent groups of the substituted alkyl is one or more, and the substituent groups of the substituted alkyl are one or more independent from each other and selected from halogen, carboxyl and saturated 3-6-membered cycloalkyl;
said substitution C1-C6The number of substituents of the alkoxy group being one or more, substituted C1-C6The substituent of the alkoxy is one or more independently selected from halogen and carboxyl.
Preferably, Ar is
Figure BDA0002618132210000032
One or more substituents are arranged on Ar, and the substituents are substituted heterocyclic radical, halogen and C1～C6Alkyl, substituted C1～C6Any one or more of alkyl in random combination, wherein the heterocyclic group is a nitrogen-containing six-membered saturated heterocyclic group, and C is1～C6The alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl;
the number of the substituent of the substituted heterocyclic group is one or more, and the substituent of the substituted heterocyclic group is one or more independently selected from halogen, cyano, carboxyl and oxygen atoms.
Said substitution C1～C6The number of substituents of the alkyl group being one or more, substituted C1～C6The substituent of the alkyl is one or more of halogen, carboxyl and saturated 3-6 membered cycloalkyl which are mutually independent.
Preferably, Ar is
Figure BDA0002618132210000033
One or more substituents are arranged on Ar, and the substituents are halogen, carboxyl and C1～C6Alkyl, carboxy substituted C1～C6A random combination of any one or more of alkyl groups; said C is1～C6The alkyl group is specifically selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl.
Preferably, the On-DNA aryl halide is specifically selected from the following structures:
Figure BDA0002618132210000041
a method of preparing arylboronic acids from On-DNA aryl halides comprising the steps of: adding a boronizing reagent into an aryl halide solution with the molar equivalent of 1 and the molar concentration of 0.5-5 mM, and reacting for 0.5-48 hours at 0-100 ℃.
The chemical reaction equation of the above reaction is as follows:
Figure BDA0002618132210000051
further, the boronizing agent tetrahydroxydiboron or pinacol diboron; preferably, the boronating agent is tetrahydroxydiboron.
Further, the reaction is carried out in a solvent, wherein the solvent is an aqueous mixed solvent of any one or more of water, methanol, acetonitrile, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone. Preferably, the solvent is water.
Further, the reaction temperature of the reaction is 0-100 ℃; preferably, the reaction temperature is 40 ℃, 50 ℃, 60 ℃, 70 ℃ or 80 ℃.
Further, the reaction time of the reaction is 0.5-48 hours; preferably, the reaction time is 1 hour, 2 hours, 4 hours or 16 hours.
Further, in the method, the molar equivalent of the On-DNA aryl halogenated compound is 1, and the molar equivalent of the boronizing reagent is 10-800. Preferably, the boronating agent has a molar equivalent of 400.
Furthermore, the feeding sequence of the reaction is that the On-DNA aryl halogenated compound is firstly added, and then the solution of the boronizing reagent is added.
Further, the above method is used for batch multi-well plate operations.
Further, the above method is used for the synthesis of libraries of DNA-encoding compounds for multi-well plates.
The method can realize the conversion of the On-DNA aryl halogenated compound to the aryl boric acid in the construction of the DNA coding compound library. The method has high yield and single product, can be carried out in a mixed aqueous phase of an organic solvent and an aqueous phase, is simple to operate, and is suitable for synthesizing a DNA coding compound library by using a multi-well plate.
In the preferred embodiment of the invention, the reaction yield is improved and the accuracy of applying the method to library construction of the DNA coding compound is improved by controlling the proportion of the reaction raw materials and the reagents.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
The minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, e.g. prefix (Ca-C)b) Alkyl means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C1～C20The alkyl group is a straight-chain or branched alkyl group having 1 to 20 carbon atoms.
Alkyl is a straight or branched chain hydrocarbon radical derived from an alkane molecule by the removal of one hydrogen atom, e.g. methyl-CH3ethyl-CH2CH3(ii) a The alkyl group may also be part of other groups, such asSuch as C1-C6 alkoxy.
Cycloalkyl groups: refers to saturated or partially saturated cyclic groups having multiple carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged, and spiro ring systems).
The halogen is fluorine, chlorine, bromine or iodine.
Alkoxy groups: means that the alkyl radical is bound to an oxygen atom to form a substituent, e.g. methoxy is-OCH3。
Alkanethiol: means that an alkyl group is bound to a sulfur atom to form a substituent, e.g. methylmercapto-SCH3。
Heterocyclic group: is a saturated or unsaturated monocyclic or polycyclic hydrocarbon group carrying at least one atom of 3 to 8 selected from O, S, N.
Aryl: refers to an aromatic single cyclic or multiple cyclic group composed of C atoms and containing no hetero atom.
The aromatic heterocyclic group is a single ring or a plurality of ring groups having aromaticity composed of 5 to 12 atoms such as C, O, S, N.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1: LC-Ms spectrum and Ms spectrum of compound 2 in example 1. Due to the structural characteristics of the arylboronic acid, the peak of the arylboronic acid on MS is M-n (H)20),n＝1 or 2。
FIG. 2: LC-Ms spectrum and Ms spectrum of compound 4 in example 2.
FIG. 3: LC-Ms spectrum and Ms spectrum of compound 6 in example 3.
FIG. 4: LC-Ms spectrum and Ms spectrum of compound 8 in example 4.
FIG. 5: LC-Ms spectrum and Ms spectrum of compound 10 in example 5.
FIG. 6: LC-Ms spectrum and Ms spectrum of compound 12 in example 6.
FIG. 7: LC-Ms spectrum and Ms spectrum of compound 14 in example 7.
FIG. 8: LC-Ms spectrum and Ms spectrum of compound 16 in example 8.
FIG. 9: LC-Ms spectrum and Ms spectrum of compound 18 in example 9.
FIG. 10: LC-Ms spectrum and Ms spectrum of compound 20 in example 10.
FIG. 11: LC-Ms spectrum and Ms spectrum of compound 22 in example 11.
FIG. 12: LC-Ms spectrum and Ms spectrum of compound 24 in example 12.
FIG. 13: LC-Ms spectrum and Ms spectrum of compound 26 in example 13.
FIG. 14: LC-Ms spectrum and Ms spectrum of compound 28 in example 14.
FIG. 15: LC-Ms spectrum and Ms spectrum of compound 30 in example 15.
FIG. 16: LC-Ms spectrum and Ms spectrum of compound 32 in example 16.
FIG. 17: LC-Ms spectrum and Ms spectrum of compound 34 in example 17.
FIG. 18: LC-Ms spectrum and Ms spectrum of compound 36 in example 18.
FIG. 19: LC-Ms spectrum and Ms spectrum of compound 38 in example 19.
FIG. 20: LC-Ms spectrum and Ms spectrum of compound 40 in example 20.
FIG. 21: LC-Ms spectrum and Ms spectrum of compound 42 in example 21.
FIG. 22: LC-Ms spectrum and Ms spectrum of compound 44 in example 22.
FIG. 23: LC-Ms spectrum and Ms spectrum of compound 46 in example 23.
FIG. 24: LC-Ms spectrum and Ms spectrum of compound 48 in example 24.
FIG. 25: LC-Ms spectrum and Ms spectrum of compound 50 in example 25.
FIG. 26: LC-Ms spectrum and Ms spectrum of compound 52 in example 26.
Detailed Description
The technical solution of the present invention is fully and clearly described below with reference to specific examples. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. The raw materials and equipment used in the invention are known products and are obtained by purchasing commercial products.
DNA-NH in the present invention2with-NH formed by single-or double-stranded DNA and linker groups2DNA constructs for linkers, e.g. DNA-NH of "compound 1" in WO20050584792And (5) structure. Also for example the following DNA structure:
Figure BDA0002618132210000071
wherein A is adenine, T is thymine, C is cytosine, and G is guanine.
In the invention, "rt" means 20-25 ℃.
Example 1 Synthesis of On-DNA boronic acid Compound 2
Figure BDA0002618132210000081
The On-DNA aryl bromide compound1 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equiv., 400mM aqueous solution) was added to the solution, mixed well, and reacted at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethyl alcohol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out the supernatant, and dissolving the rest precipitate with deionized water to obtain the On-DNA boric acid compound 2 with the conversion rate of 71.8%.
Example 2 Synthesis of On-DNA boronic acid Compound 4
Figure BDA0002618132210000082
The On-DNA aryl bromide compound 3 was dissolved in deionized water to prepare a 1mM solution, and tetrahydroxydiboron (400 equiv., 400mM aqueous solution) was added to the solution, mixed well, and reacted at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethyl alcohol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out a supernatant, and dissolving the rest precipitate with deionized water to obtain an On-DNA boric acid compound 4 with the conversion rate of 69.23%.
Example 3 Synthesis of On-DNA boronic acid Compound 6
Figure BDA0002618132210000083
Dissolving the On-DNA aryl bromide compound 5 into deionized water to prepare a 1mM concentration solution, adding tetrahydroxydiboron (400 equiv., 400mM aqueous solution) into the solution, mixing uniformly, and reacting at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding anhydrous ethanol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out the supernatant, and dissolving the rest precipitate with deionized water to obtain the On-DNA boric acid compound 6 with the conversion rate of 75.73%.
Example 4 Synthesis of On-DNA boronic acid Compound 8
Figure BDA0002618132210000091
The On-DNA aryl bromide compound 7 was dissolved in deionized water to prepare a 1mM solution, and tetrahydroxydiboron (400 equiv., 400mM aqueous solution) was added to the solution, mixed well, and reacted at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethyl alcohol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out a supernatant, and dissolving the rest precipitate with deionized water to obtain an On-DNA boric acid compound 8 with the conversion rate of 74.67%.
Example 5 Synthesis of On-DNA boronic acid Compound 10
Figure BDA0002618132210000092
Dissolving the On-DNA aryl bromide compound 9 into deionized water to prepare a 1mM concentration solution, adding tetrahydroxydiboron (400 equiv., 400mM aqueous solution) into the solution, mixing uniformly, and reacting at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethyl alcohol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out a supernatant, and dissolving the rest precipitate with deionized water to obtain an On-DNA boric acid compound 10 with the conversion rate of 67.01%.
Example 6 Synthesis of On-DNA boronic acid Compound 12
Figure BDA0002618132210000093
Dissolving the On-DNA aryl bromide compound 11 in deionized water to prepare a 1mM concentration solution, adding tetrahydroxydiboron (400 equiv., 400mM aqueous solution) to the solution, mixing uniformly, and reacting at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethyl alcohol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out a supernatant, and dissolving the rest precipitate with deionized water to obtain the On-DNA boric acid compound 12 with the conversion rate of 75.88%.
Example 7 Synthesis of On-DNA boronic acid Compound 14
Figure BDA0002618132210000101
The On-DNA aryl bromide compound 13 was dissolved in deionized water to prepare a 1mM solution, and tetrahydroxydiboron (400 equiv., 400mM aqueous solution) was added to the solution, mixed well, and reacted at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding anhydrous ethanol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out a supernatant, and dissolving the rest precipitate with deionized water to obtain an On-DNA boric acid compound 14 with the conversion rate of 61.42%.
Example 8 Synthesis of On-DNA boronic acid Compound 16
Figure BDA0002618132210000102
Dissolving the On-DNA aryl iodobromide compound 15 into deionized water to prepare a 1mM solution, adding tetrahydroxy diboron (400 equiv., 400mM aqueous solution) into the solution, uniformly mixing, and reacting at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding anhydrous ethanol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out the supernatant, and dissolving the rest precipitate with deionized water to obtain the On-DNA boric acid compound 16 with the conversion rate of 72.85%.
Example 9 Synthesis of On-DNA boronic acid Compound 18
Figure BDA0002618132210000111
The On-DNA aryl bromide compound 17 was dissolved in deionized water to prepare a 1mM solution, and tetrahydroxydiboron (400 equiv., 400mM aqueous solution) was added to the solution, mixed well, and reacted at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethyl alcohol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out a supernatant, and dissolving the rest precipitate with deionized water to obtain the On-DNA boric acid compound 18 with the conversion rate of 77.22%.
Example 10 Synthesis of On-DNA boronic acid Compound 20
Figure BDA0002618132210000112
The On-DNA aryl bromide compound 19 was dissolved in deionized water to prepare a 1mM solution, and tetrahydroxydiboron (400 equiv., 400mM aqueous solution) was added to the solution, mixed well, and reacted at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethyl alcohol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out a supernatant, and dissolving the rest precipitate with deionized water to obtain the On-DNA boric acid compound 20 with the conversion rate of 60.07%.
Example 11 Synthesis of On-DNA boronic acid Compound 22
Figure BDA0002618132210000113
Dissolving the On-DNA aryl bromide compound 21 in deionized water to prepare a 1mM concentration solution, adding tetrahydroxydiboron (400 equiv., 400mM aqueous solution) to the solution, mixing uniformly, and reacting at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethyl alcohol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out the supernatant, and dissolving the rest precipitate with deionized water to obtain the On-DNA boric acid compound 22 with the conversion rate of 64.94%.
Example 12 Synthesis of On-DNA boronic acid Compound 24
Figure BDA0002618132210000121
The On-DNA aryl bromide compound 23 was dissolved in deionized water to prepare a 1mM solution, and tetrahydroxydiboron (400 equiv., 400mM aqueous solution) was added to the solution, mixed well, and reacted at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding anhydrous ethanol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out the supernatant, and dissolving the rest precipitate with deionized water to obtain the On-DNA boric acid compound 24 with the conversion rate of 77.02%.
Example 13 Synthesis of On-DNA boronic acid Compound 26
Figure BDA0002618132210000122
The On-DNA aryl bromide compound 25 was dissolved in deionized water to prepare a 1mM solution, and tetrahydroxydiboron (400 equiv., 400mM aqueous solution) was added to the solution, mixed well, and reacted at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding anhydrous ethanol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out the supernatant, and dissolving the rest precipitate with deionized water to obtain the On-DNA boric acid compound 26 with the conversion rate of 88.87%.
Example 14 Synthesis of On-DNA boronic acid Compound 28
Figure BDA0002618132210000123
The On-DNA aryl bromide compound 27 was dissolved in deionized water to prepare a 1mM solution, and tetrahydroxydiboron (400 equiv., 400mM aqueous solution) was added to the solution, mixed well, and reacted at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethyl alcohol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out the supernatant, and dissolving the rest precipitate with deionized water to obtain the On-DNA boric acid compound 28 with the conversion rate of 64.00%.
Example 15 Synthesis of On-DNA Borate Compound 30
Figure BDA0002618132210000131
The On-DNA aryl bromide compound 29 was dissolved in deionized water to prepare a 1mM solution, and tetrahydroxydiboron (400 equiv., 400mM aqueous solution) was added to the solution, mixed well, and reacted at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethyl alcohol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out a supernatant, and dissolving the rest precipitate with deionized water to obtain the On-DNA boric acid compound 30 with the conversion rate of 62.97%.
Example 16 Synthesis of On-DNA boronic acid Compound 32
Figure BDA0002618132210000132
The On-DNA aryl bromide compound 31 was dissolved in deionized water to prepare a 1mM solution, and tetrahydroxydiboron (400 equiv., 400mM aqueous solution) was added to the solution, mixed well, and reacted at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethyl alcohol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out a supernatant, and dissolving the rest precipitate with deionized water to obtain the On-DNA boric acid compound 32 with the conversion rate of 63.85%.
Example 17 Synthesis of On-DNA boronic acid Compound 34
Figure BDA0002618132210000141
The On-DNA aryl bromide compound 33 was dissolved in deionized water to prepare a 1mM solution, and tetrahydroxydiboron (400 equiv., 400mM aqueous solution) was added to the solution, mixed well, and reacted at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding anhydrous ethanol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out the supernatant, and dissolving the rest precipitate with deionized water to obtain the On-DNA boric acid compound 34 with the conversion rate of 69.05%.
Example 18 Synthesis of On-DNA boronic acid Compound 36
Figure BDA0002618132210000142
Dissolving the On-DNA aryl iodide compound 35 in deionized water to prepare a 1mM concentration solution, adding tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) to the solution, mixing uniformly, and reacting at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethyl alcohol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out a supernatant, and dissolving the rest precipitate with deionized water to obtain an On-DNA boric acid compound 36 with the conversion rate of 87.08%.
Example 19 Synthesis of On-DNA Borate Compound 38
Figure BDA0002618132210000143
The On-DNA aryl iodide 37 was dissolved in deionized water to prepare a 1mM solution, and tetrahydroxydiboron (400 equiv., 400mM aqueous solution) was added to the solution, mixed well, and reacted at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding anhydrous ethanol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out the supernatant, and dissolving the rest precipitate with deionized water to obtain the On-DNA boric acid compound 38 with the conversion rate of 67.53%.
Example 20 Synthesis of On-DNA boronic acid Compound 40
Figure BDA0002618132210000151
The On-DNA aryl iodide 39 was dissolved in deionized water to prepare a 1mM solution, and tetrahydroxydiboron (400 equiv., 400mM aqueous solution) was added to the solution, mixed well, and reacted at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding anhydrous ethanol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out a supernatant, and dissolving the rest precipitate with deionized water to obtain an On-DNA boric acid compound 40 with the conversion rate of 81.11%.
Example 21 Synthesis of On-DNA boronic acid Compound 42
Figure BDA0002618132210000152
The On-DNA aryl chloride compound 41 was dissolved in deionized water to prepare a 1mM solution, and tetrahydroxydiboron (400 equiv., 400mM aqueous solution) was added to the solution, mixed well, and reacted at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding anhydrous ethanol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out a supernatant, and dissolving the rest precipitate with deionized water to obtain an On-DNA boric acid compound 42 with the conversion rate of 80.85%.
Example 22 Synthesis of On-DNA boronic acid Compound 44
Figure BDA0002618132210000153
The On-DNA aryl bromide compound 43 was dissolved in deionized water to prepare a 1mM solution, and tetrahydroxydiboron (400 equiv., 400mM aqueous solution) was added to the solution, mixed well, and reacted at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethyl alcohol with the total volume of 3 times of the solution, after uniform oscillation, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out the supernatant, and dissolving the rest precipitate with deionized water to obtain an On-DNA boric acid compound 44 with the conversion rate of 67.2%.
Example 23 Synthesis of On-DNA boronic acid Compound 46
Figure BDA0002618132210000161
The On-DNA aryl bromide compound 45 was dissolved in deionized water to prepare a 1mM solution, and tetrahydroxydiboron (400 equiv., 400mM aqueous solution) was added to the solution, mixed well, and reacted at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethyl alcohol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out a supernatant, and dissolving the rest precipitate with deionized water to obtain an On-DNA boric acid compound 46 with the conversion rate of 61.4%.
Example 24 Synthesis of On-DNA boronic acid Compound 48
Figure BDA0002618132210000162
The On-DNA aryl bromide compound 47 was dissolved in deionized water to prepare a 1mM solution, and tetrahydroxydiboron (400 equiv., 400mM aqueous solution) was added to the solution, mixed well, and reacted at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethyl alcohol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out a supernatant, and dissolving the rest precipitate with deionized water to obtain an On-DNA boric acid compound 48 with the conversion rate of 55.6%.
EXAMPLE 25 Synthesis of On-DNA boronic acid Compound 50
Figure BDA0002618132210000163
The On-DNA aryl bromide compound 49 was dissolved in deionized water to prepare a 1mM solution, and tetrahydroxydiboron (400 equiv., 400mM aqueous solution) was added to the solution, mixed well, and reacted at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding anhydrous ethanol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out a supernatant, and dissolving the rest precipitate with deionized water to obtain an On-DNA boric acid compound 50 with the conversion rate of 50.9%.
Example 26 Synthesis of On-DNA boronic acid Compound 52
Figure BDA0002618132210000171
The On-DNA aryl bromide compound 51 was dissolved in deionized water to prepare a 1mM solution, and tetrahydroxydiboron (400 equiv., 400mM aqueous solution) was added to the solution, mixed well, and reacted at 50 ℃ for 6 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethyl alcohol with the total volume of 3 times of the solution, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out the supernatant, and dissolving the rest precipitate with deionized water to obtain the On-DNA boric acid compound 52 with the conversion rate of 45.4%.
In summary, the present invention controls the conditions of solvent, temperature, time, etc. during the reaction. The conversion from aryl halogenated compound to aryl boric acid is realized by taking On-DNA aryl halogenated compound as raw material under the action of boronizing reagent. The method has high yield, single product, simple operation, and suitability for synthesis of DNA coding compound library with multi-well plate.

Claims (10)

1. A method for preparing aryl boric acid from an On-DNA aryl halide is characterized in that: the reaction takes an On-DNA aryl halogenated compound as a raw material, and the On-DNA aryl boric acid compound is obtained by reaction in the presence of a boronizing reagent; the structural formula of the On-DNA aryl halogenated compound is DNA-Ar-X, and the structural formula of the On-DNA aryl boric acid compound is DNA-Ar-B (OH)2；
Wherein, the DNA in the structural formula comprises a single-stranded or double-stranded nucleotide chain obtained by polymerizing artificially modified and/or unmodified nucleotide monomers, and the nucleotide chain is connected with Ar through one or more chemical bonds or groups; the length of the single-stranded or double-stranded nucleotide chain is 5-200 bp; the-X of the On-DNA aryl halogenated compound is connected to the ring of Ar, and X is chlorine, bromine or iodine;
wherein Ar in the structural formula is selected from substituted aromatic rings or aromatic heterocycles.
2. The method of claim 1, wherein: ar is selected from the following groups:
Figure FDA0002618132200000011
wherein Ar has one OR more substituents selected from the group consisting of hydrogen, halogen, carboxyl, cyano, hydroxyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy, heterocyclic, substituted heterocyclic, aromatic heterocyclic, alkylmercapto, -C (O) OR1、-OC(O)R1、-C(O)R2、-OR3Any one or more of the random combinations of R1Is selected from C1～C20Alkyl, said R2Selected from hydrogen or C1～C20An alkyl group; said R3Selected from aryl or aromatic heterocyclic radical;
the alkyl is C1-C20Linear or branched alkyl of (a); the alkoxy is C1-C20Straight or branched chain ofAn alkoxy group;
the number of the substituent groups of the substituted alkyl is one or more, and the substituent groups of the substituted alkyl are one or more independently selected from halogen, cyano, carboxyl and cycloalkyl;
the number of the substituent groups of the substituted alkoxy is one or more, and the substituent groups of the substituted alkoxy are one or more independently selected from halogen, cyano and carboxyl;
the number of the substituent of the substituted heterocyclic group is one or more, and the substituent of the substituted heterocyclic group is one or more independently selected from halogen, cyano, carboxyl and oxygen atom.
3. The method of claim 1, wherein: the reaction steps are as follows: adding a boronizing reagent into an aryl halogenated compound solution with the molar equivalent of 1 and the molar concentration of 0.5-5 mM, and reacting for 0.5-48 hours at 0-100 ℃.
4. The method of claim 3, wherein: the boronizing agent is selected from tetrahydroxydiboron or pinacol diboron.
5. The method of claim 3, wherein: the reaction is carried out in a solvent, and the solvent is one or a mixture of water, methanol, acetonitrile, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone.
6. The method of claim 3, wherein: the reaction temperature is 40 ℃, 50 ℃, 60 ℃, 70 ℃ or 80 ℃.
7. The method of claim 3, wherein: the reaction time is 1 hour, 2 hours, 4 hours, or 16 hours.
8. The method of claim 3, wherein: in the method, the molar equivalent of the On-DNA aryl halogenated compound is 1, and the molar equivalent of the boronizing reagent is 10-800.
9. The method according to any one of claims 1-8, wherein: the method is used for batch multi-well plate operations.
10. The method of any one of claims 1 to 8, wherein the method is used for the synthesis of libraries of DNA-encoding compounds for multi-well plates.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6075126A (en) * 1996-08-05 2000-06-13 Prolinx, Inc. Phenyldiboronic acid reagents and complexes
WO2010019847A2 (en) * 2008-08-15 2010-02-18 Georgia State University Research Foundation, Inc. Aptamer inhibition of thrombus formation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6075126A (en) * 1996-08-05 2000-06-13 Prolinx, Inc. Phenyldiboronic acid reagents and complexes
WO2010019847A2 (en) * 2008-08-15 2010-02-18 Georgia State University Research Foundation, Inc. Aptamer inhibition of thrombus formation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MARCO HEBEL，ET AL.: "Sequence Programming with Dynamic Boronic Acid/Catechol Binary Codes" *
XIAOCHUAN YANG，ET AL.: "Boronic acid-modified DNA that changes fluorescent properties upon carbohydrate binding" *

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