CN114057817B - Method for preparing arylboronic acid from On-DNA aryl halide - Google Patents

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

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CN114057817B
CN114057817B CN202010776536.8A CN202010776536A CN114057817B CN 114057817 B CN114057817 B CN 114057817B CN 202010776536 A CN202010776536 A CN 202010776536A CN 114057817 B CN114057817 B CN 114057817B
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CN114057817A (en
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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 On-DNA aryl halide, which takes tetrahydroxy diboron or bisboronic acid pinacol ester as a boration reagent and can realize the conversion from On-DNA aryl halide to aryl boric acid only under the heating condition. The method provided by the invention can be used for constructing the boric acid library structure, and simultaneously, the arylboronic acid can be used as a synthetic building block for constructing various structures through chemical reaction, and the method has the advantages of wide substrate universality, high yield, mild condition and convenient operation, and is suitable for synthesizing the DNA coding compound library by a porous plate.

Description

Method for preparing arylboronic 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 arylboronic acid in the construction of a DNA coding compound library.
Background
In drug development, especially new drug development, high throughput screening against biological targets is one of the main means to rapidly obtain lead compounds. However, conventional high throughput screening based on single molecules requires long time, huge equipment investment, limited numbers of library compounds (millions), and the build-up of compound libraries requires decades of accumulation, limiting the efficiency and possibilities of discovery of lead compounds. The recent advent of DNA-encoded compound library technology (WO 2005058479, WO2018166532, CN 103882532), combining combinatorial chemistry and molecular biology techniques, tagged each compound with a DNA tag at the molecular level, and capable of synthesizing up to hundred million classes of compound libraries in extremely short time, has become a trend for the next generation of compound library screening technology, and began to be widely used in the pharmaceutical industry, producing a number of positive effects (Accounts of Chemical Research,2014,47,1247-1255).
The DNA encoding compound library rapidly generates a huge compound library by combinatorial chemistry, and can screen the lead compound with high flux, so that the screening of the lead compound becomes unprecedented rapid and efficient. One of the challenges in constructing libraries of DNA-encoding compounds is the need to synthesize small molecules with chemical diversity on DNA in high yields. Since DNA needs to be stable under certain conditions (solvent, pH, temperature, ion concentration), higher yields are also required for the On-DNA reaction constructed from DNA encoding compound libraries. Therefore, the kind of the reagent, the kind of the reaction and the reaction condition of the chemical reaction (called On-DNA reaction for short) performed On the DNA directly influence the richness and the selectivity of the DNA coding compound library. Thus, the development of chemical reactions compatible with DNA is also a long-term research and study direction of the current DNA coding compound library technology, and directly influences the application and commercial value of the DNA coding compound library.
The arylboronic acid compound has unique pharmaceutical effect in the pharmaceutical 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 adding compounds such as aldehyde, ketone, imine, unsaturated ketone and the like. At present, no relevant literature report exists On the construction of an On-DNA arylboronic acid structure. Therefore, a construction method of On-DNA arylboronic 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, which takes tetrahydroxy diboron or bisboronic acid pinacol ester as a boration reagent and can realize the conversion from the On-DNA aryl halide into the aryl boric acid 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 producing DNA coding compound libraries, and can remarkably improve the diversity of molecules in the compound libraries.
In order to solve the technical problems, the invention adopts the following technical scheme:
a process for preparing arylboronic acids from On-DNA aryl halidesThe reaction is to take an On-DNA aryl halogenated compound as a raw material, and react in the presence of a boration 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) 2 The boration reagent is tetrahydroxydiboron or bisboronic acid pinacol ester.
Wherein the DNA in the formula comprises a single-stranded or double-stranded nucleotide chain polymerized from artificially modified and/or unmodified nucleotide monomers, the nucleotide chain being linked to Ar by one or more chemical bonds or groups; the length of the single-stranded or double-stranded nucleotide chain is 5-200 bp; -X of said On-DNA aryl halide is attached to the ring of Ar, X being selected from chlorine, bromine or iodine; the size of the DNA is 10 to 200 bases.
Wherein Ar in the structural formula is selected from a substituted aromatic ring or an aromatic heterocyclic ring.
Ar is selected from the following groups:
wherein Ar has one OR more substituents selected from the group consisting of hydrogen, halogen, carboxyl, cyano, hydroxyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy, heterocyclyl, substituted heterocyclyl, aromatic heterocyclyl, alkylthio, -C (O) OR 1 、-OC(O)R 1 、-C(O)R 2 、-OR 3 Random combinations of any one or more of said R 1 Selected from C 1 ～C 20 Alkyl, said R 2 Selected from hydrogen or C 1 ～C 20 An alkyl group; said R is 3 Selected from aryl or aromatic heterocyclic groups;
the alkyl group being C 1 -C 20 Straight or branched alkyl of (a); the alkoxy is C 1 -C 20 Straight or branched alkoxy 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 of halogen, cyano, carboxyl and cycloalkyl which are independent of each other;
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 selected from halogen, cyano and carboxyl independently;
the number of the substituent groups of the substituent heterocyclic group is one or more, and the substituent groups of the substituent heterocyclic group are one or more selected from halogen, cyano, carboxyl and oxygen atoms independently.
Preferably, ar isAr has one or more substituents, which are substituted heterocyclic groups, alkyl groups, substituted alkyl groups, halogen and C 1 -C 6 Alkoxy, substituted C 1 -C 6 Alkoxy, C 1 -C 6 Alkylmercapto, aromatic heterocyclic, -OR 3 Random combinations of any one or more of said R 3 Phenyl or pyridyl; the heterocyclic group is a five-membered saturated heterocyclic group containing nitrogen; the aromatic heterocyclic group is a five-membered aromatic heterocyclic group containing nitrogen;
the alkyl group being C 1 -C 6 Straight or branched alkyl of (a); the C is 1 ～C 6 The alkyl is specifically selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexane;
the C is 1 ～C 6 Alkoxy is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy;
the number of the substituent groups of the substituent heterocyclic group is one or more, and the substituent groups of the substituent heterocyclic group are one or more selected from halogen, carboxyl and oxygen atoms independently;
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 of halogen, carboxyl and saturated 3-6 membered cycloalkyl which are independent of each other;
said substitution C 1 -C 6 The number of substituents of the alkoxy group isOne or more, substituted C 1 -C 6 The substituent of the alkoxy is one or more selected from halogen and carboxyl independently.
Preferably, ar isThe Ar has one or more substituents, wherein the substituents are substituted heterocyclic groups, halogen and C 1 ～C 6 Alkyl, substituted C 1 ～C 6 Random combinations of any one or more of alkyl groups, the heterocyclic group being a nitrogen-containing six-membered saturated heterocyclic group, the C 1 ～C 6 The alkyl is specifically selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexane;
the number of the substituent groups of the substituent heterocyclic group is one or more, and the substituent groups of the substituent heterocyclic group are one or more selected from halogen, cyano, carboxyl and oxygen atoms independently.
Said substitution C 1 ～C 6 The number of substituents of the alkyl group being one or more, substituted C 1 ～C 6 The substituent of the alkyl is one or more of halogen, carboxyl and saturated 3-6 membered cycloalkyl independently.
Preferably, ar isThe Ar has one or more substituents, wherein the substituents are halogen, carboxyl and C 1 ～C 6 Alkyl, carboxyl substituted C 1 ～C 6 A random combination of any one or more of alkyl groups; the C is 1 ～C 6 The alkyl group is specifically selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl.
Preferably, the On-DNA aryl halide is specifically selected from the following structures:
a method for preparing arylboronic acids from On-DNA aryl halides comprising the steps of: adding a boration reagent into an aryl halide solution with molar equivalent of 1 and molar concentration of 0.5-5 mM, and reacting for 0.5-48 hours at 0-100 ℃.
The chemical reaction equation for the above reaction is as follows:
further, the borating agent is tetrahydroxydiboron or bisboronic acid pinacol ester; preferably, the borating agent is tetrahydroxydiboron.
Further, the reaction is carried out in a solvent, and the solvent is any one or a plurality of water-containing mixed solvents 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 to 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 halide compound is 1, and the molar equivalent of the boration agent is 10-800. Preferably, the molar equivalent of the borating agent is 400.
Further, the reaction is carried out by adding On-DNA aryl halogenated compound and then adding solution of boration reagent.
Further, the above method is used for batch multi-well plate operations.
Further, the above method is used for the synthesis of DNA encoding compound libraries in multiwell plates.
The method can realize the conversion of the On-DNA aryl halogenated compound to the arylboronic 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 water phase of an organic solvent/water phase, is simple to operate, and is suitable for synthesizing the DNA coding compound library by using a porous plate.
In a preferred embodiment of the invention, the reaction yield is improved by controlling the ratio of the reaction raw materials to the reagents, and the accuracy of the method applied to library construction of the DNA coding compound is improved.
Definition of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on 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 represented by prefixes, for example, prefixes (Ca to C b ) Alkyl indicates any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C 1 ～C 20 Alkyl refers to straight or branched chain alkyl groups containing 1 to 20 carbon atoms.
Alkyl refers to a straight or branched hydrocarbon radical containing at least one hydrogen atom in the alkane molecule, e.g. methyl-CH 3 ethyl-CH 2 CH 3 The method comprises the steps of carrying out a first treatment on the surface of the The alkyl group may also be part of other groups such as C1-C6 alkoxy.
Cycloalkyl: 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.
An alkoxy group: refers to alkyl groups bound to oxygen atoms to form substituents, e.g. methoxy groups of-OCH 3 。
Alkylthio: refers to alkyl groups bound to sulfur atoms to form substituents, e.g. methyl mercapto-SCH 3 。
A heterocyclic group: is a saturated or unsaturated, monocyclic or polycyclic hydrocarbon group of 3 to 8 atoms which carries at least one atom selected from O, S, N.
Aryl: refers to an aromatic single cyclic or multiple cyclic groups composed of C atoms without heteroatoms.
The aromatic heterocyclic group means that 5 to 12 atoms such as C, O, S, N and the like form a single ring or a plurality of ring groups having aromaticity.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
Fig. 1: LC-Ms and Ms spectra of compound 2 in example 1. The arylboronic acid has a peak on MS of M-n (H) 2 0),n＝1 or 2。
Fig. 2: LC-Ms and Ms spectra for compound 4 in example 2.
Fig. 3: LC-Ms and Ms spectra of compound 6 in example 3.
Fig. 4: LC-Ms and Ms spectra for compound 8 in example 4.
Fig. 5: LC-Ms and Ms spectra of compound 10 in example 5.
Fig. 6: LC-Ms and Ms spectra for compound 12 in example 6.
Fig. 7: LC-Ms and Ms spectra for compound 14 in example 7.
Fig. 8: LC-Ms and Ms spectra for compound 16 in example 8.
Fig. 9: LC-Ms and Ms spectra for compound 18 in example 9.
Fig. 10: LC-Ms and Ms spectra of compound 20 in example 10.
Fig. 11: LC-Ms and Ms spectra for compound 22 in example 11.
Fig. 12: LC-Ms and Ms spectra for compound 24 in example 12.
Fig. 13: LC-Ms and Ms spectra for compound 26 in example 13.
Fig. 14: LC-Ms and Ms spectra for compound 28 in example 14.
Fig. 15: LC-Ms and Ms spectra of compound 30 in example 15.
Fig. 16: LC-Ms and Ms spectra for compound 32 in example 16.
Fig. 17: LC-Ms and Ms spectra for compound 34 in example 17.
Fig. 18: LC-Ms and Ms spectra for compound 36 in example 18.
Fig. 19: LC-Ms and Ms spectra for compound 38 in example 19.
Fig. 20: LC-Ms and Ms spectra of compound 40 in example 20.
Fig. 21: LC-Ms and Ms spectra for compound 42 in example 21.
Fig. 22: LC-Ms and Ms spectra for compound 44 in example 22.
Fig. 23: LC-Ms and Ms spectra for compound 46 in example 23.
Fig. 24: LC-Ms and Ms spectra for compound 48 in example 24.
Fig. 25: LC-Ms and Ms spectra of compound 50 in example 25.
Fig. 26: LC-Ms and Ms spectra for compound 52 in example 26.
Detailed Description
The technical scheme of the invention is fully and clearly described below with reference to specific embodiments. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.
DNA-NH in the present invention 2 with-NH-formed by single-or double-stranded DNA and linker groups 2 DNA structure of the linker, e.g. "comp" in WO2005058479DNA-NH of bond 1' 2 Structure is as follows. Also for example the following DNA structure:
wherein A is adenine, T is thymine, C is cytosine, and G is guanine.
In the present invention, "rt" means 20 to 25 ℃.
EXAMPLE 1 Synthesis of On-DNA boronic acid Compound 2
On-DNA aryl bromide compound 1 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, pouring out 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
On-DNA aryl bromide 3 was dissolved in deionized water to prepare a 1mM concentration solution, tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, pouring out 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
The On-DNA aryl bromide compound 5 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, pouring out 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
On-DNA aryl bromide compound 7 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, pouring out 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
The On-DNA aryl bromide compound 9 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, pouring out the supernatant, and dissolving the rest precipitate with deionized water to obtain the On-DNA boric acid compound 10 with the conversion rate of 67.01%.
EXAMPLE 6 Synthesis of On-DNA boronic acid Compound 12
The On-DNA aryl bromide compound 11 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, pouring out the 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
The On-DNA aryl bromide compound 13 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, pouring out the supernatant, and dissolving the rest precipitate with deionized water to obtain the On-DNA boric acid compound 14 with the conversion rate of 61.42%.
EXAMPLE 8 Synthesis of On-DNA boronic acid Compound 16
The On-DNA aryl iodide-bromide compound 15 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, 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
On-DNA aryl bromide compound 17 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, pouring out 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
The On-DNA aryl bromide compound 19 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, pouring out the 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
The On-DNA aryl bromide compound 21 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, pouring out 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
On-DNA aryl bromide compound 23 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, pouring out 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
The On-DNA aryl bromide compound 25 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, 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
The On-DNA aryl bromide compound 27 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, pouring out 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 boronic acid Compound 30
The On-DNA aryl bromide compound 29 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, pouring out the 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
The On-DNA aryl bromide compound 31 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, pouring out 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
The On-DNA aryl bromide compound 33 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, 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
The On-DNA aryl iodide 35 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, pouring out supernatant, and dissolving the rest precipitate with deionized water to obtain the On-DNA boric acid compound 36 with the conversion rate of 87.08%.
EXAMPLE 19 Synthesis of On-DNA boronic acid Compound 38
The On-DNA aryl iodide 37 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, 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
The On-DNA aryl iodide 39 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, pouring out the supernatant, and dissolving the rest precipitate with deionized water to obtain the On-DNA boric acid compound 40 with the conversion rate of 81.11%.
EXAMPLE 21 Synthesis of On-DNA boronic acid Compound 42
The On-DNA aryl chloride compound 41 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, pouring out supernatant, and dissolving the rest precipitate with deionized water to obtain the On-DNA boric acid compound 42 with the conversion rate of 80.85%.
EXAMPLE 22 Synthesis of On-DNA boronic acid Compound 44
The On-DNA aryl bromide compound 43 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, pouring out supernatant, and dissolving the rest precipitate with deionized water to obtain the On-DNA boric acid compound 44 with the conversion rate of 67.2%.
EXAMPLE 23 Synthesis of On-DNA boronic acid Compound 46
The On-DNA aryl bromide compound 45 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, pouring out 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
The On-DNA aryl bromide compound 47 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, pouring out supernatant, and dissolving the rest precipitate with deionized water to obtain the On-DNA boric acid compound 48 with the conversion rate of 55.6%.
EXAMPLE 25 Synthesis of On-DNA boronic acid Compound 50
The On-DNA aryl bromide compound 49 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, then continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, pouring out supernatant, and dissolving the rest precipitate with deionized water to obtain the On-DNA boric acid compound 50 with the conversion rate of 50.9%.
EXAMPLE 26 Synthesis of On-DNA boronic acid Compound 52
The On-DNA aryl bromide compound 51 was dissolved in deionized water to prepare a 1mM concentration solution, and tetrahydroxydiboron (400 equivalents, 400mM aqueous solution) was added to the solution, and the mixture was uniformly mixed and reacted at 50℃for 6 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, pouring out 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 such as solvent, temperature, time and the like during the reaction. The On-DNA aryl halogenated compound is used as a raw material, and the conversion from the aryl halogenated compound to the aryl boric acid is realized under the action of a boration reagent. The method has high yield and single product, can be carried out in water phase, is simple to operate, and is suitable for synthesizing the DNA coding compound library by using a porous plate.

Claims (8)

1. A method for preparing arylboronic acid from On-DNA aryl halide, characterized in that: the method is that an On-DNA aryl halogenated compound is taken as a raw material, and the On-DNA aryl boric acid compound is obtained by reaction in the presence of a boration 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 formula comprises a single-stranded or double-stranded nucleotide chain polymerized from artificially modified and/or unmodified nucleotide monomers, the nucleotide chain being linked to Ar by one or more chemical bonds or groups; the length of the single-stranded or double-stranded nucleotide chain is 5-200 bp; -X of the On-DNA aryl halogenated compound is connected to a ring of Ar, and X is chlorine, bromine or iodine;
ar is selected from the following groups:
wherein Ar has one or more substituents, and the substituents are hydrogen, fluorine, methyl, methylthio and methoxy;
the method comprises the following steps: adding a boration reagent into an aryl halogenated compound solution with molar equivalent of 1 and molar concentration of 0.5-5 mM, and reacting for 0.5-48 hours at 0-100 ℃.
2. The method according to claim 1, characterized in that: the boration agent is selected from tetrahydroxydiboron or bisboronic acid pinacol ester.
3. The method according to claim 1, characterized in that: the reaction is carried out in a solvent, and the solvent is any one or a plurality of water-containing mixed solvents of water, methanol, acetonitrile, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone.
4. The method according to claim 1, characterized in that: the reaction temperature is 40 ℃,50 ℃, 60 ℃, 70 ℃ or 80 ℃.
5. The method according to claim 1, characterized in that: the reaction time was 1 hour, 2 hours, 4 hours or 16 hours.
6. The method according to claim 1, characterized in that: in the method, the molar equivalent of the On-DNA aryl halogenated compound is 1, and the molar equivalent of the boration reagent is 10-800.
7. The method according to any one of claims 1-6, wherein: the method is used for batch multi-well plate operation.
8. The method according to any one of claims 1 to 6, wherein the method is used for the synthesis of a library of DNA encoding compounds of a multiwell plate.
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Citations (2)

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US6075126A (en) * 1996-08-05 2000-06-13 Prolinx, Inc. Phenyldiboronic acid reagents and complexes
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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

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Xiaochuan Yang，et al..Boronic acid-modified DNA that changes fluorescent properties upon carbohydrate binding.《Chem. Commun.》.2010,第46卷1073–1075. *

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