CN114411267B - Method for constructing beta-aliphatic substituted ketone compound by On-DNA reaction - Google Patents

Method for constructing beta-aliphatic substituted ketone compound by On-DNA reaction Download PDF

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CN114411267B
CN114411267B CN202011161395.5A CN202011161395A CN114411267B CN 114411267 B CN114411267 B CN 114411267B CN 202011161395 A CN202011161395 A CN 202011161395A CN 114411267 B CN114411267 B CN 114411267B
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CN114411267A (en
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李进
蔡坤良
高森
刘观赛
万金桥
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Hitgen Inc
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    • C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B30/00—Methods of screening libraries
    • C40B30/04—Methods of screening libraries by measuring the ability to specifically bind a target molecule, e.g. antibody-antigen binding, receptor-ligand binding

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Abstract

The invention relates to a method for constructing beta-aliphatic substituted ketone compound by On-DNA reaction, which takes On-DNA alpha, beta-unsaturated carbonyl compound as raw material, and reacts with aliphatic boric acid/boric acid ester or trifluoroborate to obtain the beta-aliphatic substituted ketone compound in the presence of photosensitizer and alkali. The method can be carried out in a mixed water phase of an organic solvent/water phase, has simple post-treatment and mild conditions, can obtain a DNA coding compound library with high diversity in a short time and high yield, and is suitable for synthesizing the DNA coding compound by a porous plate.

Description

Method for constructing beta-aliphatic substituted ketone compound by On-DNA reaction
Technical Field
The invention belongs to the technical field of coding compound libraries, and particularly relates to a method for constructing On-DNA beta-aliphatic substituted ketone compounds in 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.
Alpha, beta unsaturated carbonyl compounds and fatty boric acid/boric acid esters form sp at beta position of carbonyl by photocatalytic addition 3 The hybridized carbon atom connecting site can enrich the topological structure of the drug compound, and the introduction of the beta-aliphatic substituted ketone compound into the DNA coding compound library can further expand the diversity of the compound library, thereby being beneficial to improving the probability of screening effective compounds. However, no method for synthesizing On-DNA beta-aliphatic substituted ketone compounds by On-DNA alpha, beta-unsaturated carbonyl compounds has been reported. Therefore, it is hoped to develop a new synthesis method of On-DNA beta-aliphatic substituted ketone compounds suitable for large-scale porous plate operation, so as to increase the diversity of DNA coding compound library and further improve the application value of DNA coding compound library technology.
Disclosure of Invention
In order to solve the problems, the invention develops a synthetic method of a DNA coding compound library, which has the advantages of stable storage of raw materials, mild reaction conditions, good substrate universality, small damage to DNA, and suitability for batch operation by using porous plates, and can quickly convert On-DNA alpha, beta-unsaturated carbonyl compounds into On-DNA beta-aliphatic substituted ketone compounds through one-step reaction.
The technical scheme adopted by the invention is as follows:
a method for constructing beta-aliphatic substituted ketone compound by On-DNA reaction, which takes On-DNA alpha, beta-unsaturated carbonyl compound as raw material, reacts with aliphatic boric acid/boric acid ester or trifluoroborate in the presence of photosensitizer and alkali to obtain On-DNA beta-aliphatic substituted ketone compound; wherein the structural formula of the On-DNA alpha, beta-unsaturated carbonyl compound isThe structural formula of the fatty boric acid/boric acid ester is +.>The structural formula of the On-DNA beta-aliphatic substituted ketone compound is +.>
Wherein the DNA in the formula comprises a single-or double-stranded nucleotide chain polymerized from artificially modified and/or unmodified nucleotide monomers, the nucleotide chain being linked to a nitrogen atom by one or more chemical bonds or groups; the length of the DNA is 10-200 bp.
Wherein the DNA in the structural formula is connected with the nitrogen atom through one chemical bond or a plurality of chemical bonds. When a chemical bond is formed, the DNA in the structural formula is directly connected with a nitrogen atom; in the case of multiple chemical bonds, the DNA of the formula is bonded to the nitrogen atom via multiple chemical bonds, e.g., a methylene group (-CH) 2 (-) are connected, namely through two chemical bonds; or the amino group of the DNA is connected with the nitrogen atom through a carbonyl (-CO-) and also connected through two chemical bonds; or DNA and nitrogen atom through a methylenecarbonyl group (-CH) 2 CO-) is linked to the amino group of the DNA, also via three consecutive chemical bonds.
R 1 A group selected from hydrogen or a group having a molecular weight of 1000 or less which is directly bonded to a carbon atom at the α position of the α, β -unsaturated carbonyl group;
R 2 a group selected from the group having a molecular weight of 1000 or less and directly bonded to a boron atom in the aliphatic boric acid/boric acid ester;
R 3 、R 4 independently selected from hydrogen or groups with molecular weight below 1000 which are directly connected with oxygen atoms in the borate; or R is 3 、R 4 Are connected into a ring.
As preferable: the R is 1 Selected from alkyl, substituted alkyl, aryl or substituted aryl; wherein the alkyl group is C 1 ～C 20 Alkyl or C 3 ～C 8 Cycloalkyl; the number of substituents for the substituted alkyl group is one or more; the substituent of the substituted alkyl is one or more of halogen, nitro, alkoxy, halogenated phenyl, alkylphenyl and heterocyclic independently; the aryl is selected from pyridyl, quinolyl, thiazolyl, thienyl or phenyl; the number of substituents of the substituted aryl is one or more, and the substituents of the substituted aryl are independently selected from halogen, cyano, nitro, alkoxy and C 1 ～C 20 One or more of alkyl groups;
the R is 2 Selected from alkyl, substituted alkyl; wherein the alkyl group is C 1 ～C 20 Alkyl or C 3 ～C 8 Cycloalkyl; the number of substituents for the substituted alkyl group is one or more; the substituent of the substituted alkyl is one or more of halogen, nitro, alkoxy, halogenated phenyl, alkylphenyl and heterocyclic independently;
the R is 3 、R 4 Selected from C 1 ～C 20 An alkyl group; or R is 3 、R 4 Are connected into a ring.
Further; said R is 1 Selected from C 1 ～C 6 Alkyl, substituted C 1 ～C 6 Alkyl, phenyl, said C 1 ～C 6 The alkyl is specifically selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexane; substitution C 1 ～C 6 The substituent of the alkyl is selected from phenyl and 5-6 membered saturated heterocyclic groups; the 5-to 6-membered saturated heterocyclic group is a saturated monocyclic hydrocarbon group having 3 to 6 atoms selected from at least one of O, N.
Said R is 2 Selected from C 1 ～C 6 Alkyl, substituted C 1 ～C 6 Alkyl, saturated C 3 ～C 8 Cycloalkyl 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 saturated C 3 ～C 8 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexylA base; substitution C 1 ～C 6 The substituent of the alkyl is selected from phenyl and amino.
The R is 3 、R 4 Selected from C 1 ～C 6 Alkyl, or R 3 、R 4 Are connected in a ring, the C 1 ～C 6 The alkyl group is specifically selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl.
As preferable: the On-DNA alpha, beta-unsaturated carbonyl compound is specifically selected from the following components:
as preferable: the boric acid/borate is specifically selected from:
as preferable: the trifluoroborate isFurther, the trifluoroborate is
A method for constructing beta-aliphatic substituted ketone compounds by On-DNA reaction, which comprises the following steps: adding 10-1000 times of mole equivalent of fatty boric acid/boric acid ester or trifluoro borate and 10-1000 times of mole equivalent of alkali into an On-DNA alpha, beta-unsaturated carbonyl compound solution with the mole equivalent of 1 and the mole concentration of 0.5-5mM, adding 0.1-1000 times of mole equivalent of photosensitizer and reacting for 0.1-24 hours at the temperature of 10-100 ℃.
Further; the base is selected from sodium borate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, N-methylmorpholine, triethylamine, diisopropylethylamine, DBU (1, 8-diazabicyclo undec-7-ene), 4-dimethylaminopyridine, 2, 6-dimethylpyridine or N-methylimidazole; preferably, the base is dipotassium hydrogen phosphate.
Further; the photosensitizer is selected from 2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile and Ir [ p-F (Me) ppy ]] 2 (dtbbpy)PF 6 、[Ir(dtbbpy)(ppy) 2 ][PF 6 ]、(Ir[dF(CF 3 )ppy] 2 (dtbpy))PF 6 、Ir[dF(Me)ppy] 2 (dtbbpy)PF 6 、[Ir{dFCF 3 ppy} 2 (bpy)]PF 6 (2, 2' -bipyridine) bis (2-phenylpyridine) iridium (III) hexafluorophosphate; preferably, the photosensitizer is (Ir [ dF (CF) 3 )ppy] 2 (dtbpy))PF 6 。
Further; the reaction is carried out in a solvent, wherein the solvent is any one or a plurality of aqueous mixed solvents of water, methanol, ethanol, acetonitrile, dimethyl sulfoxide, inorganic salt buffer solution, organic acid buffer solution and organic alkali buffer solution; preferably, the reaction solvent comprises water, dimethylsulfoxide. More preferably, the organic phase volume ratio in the solvent is 60-80%. Even more preferably, the organic phase volume fraction in the solvent is 70%.
Further; the reaction temperature of the reaction is 10-100 ℃; preferably, the reaction temperature is 20 ℃, 30 ℃, 40 ℃,50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃,100 ℃.
Further; the reaction time of the reaction is 0.1 to 24 hours; preferably, the reaction time is 0.1 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 10 hours, 16 hours, 18 hours, 20 hours, 24 hours.
Further; in the method, the molar equivalent of the On-DNA alpha, beta-unsaturated carbonyl compound is 1, and the molar equivalent of the fatty boric acid/boric acid ester or the trifluoroborate is 50 equivalents, 100 equivalents, 200 equivalents, 300 equivalents, 400 equivalents, 500 equivalents, 600 equivalents, 800 equivalents and 1000 equivalents; the equivalents of base are 50 equivalents, 100 equivalents, 120 equivalents, 150 equivalents, 200 equivalents, 300 equivalents, 400 equivalents, 500 equivalents, 600 equivalents, 800 equivalents, 1000 equivalents; the molar equivalent of the photosensitizer is 0.1 equivalent, 0.5 equivalent, 1 equivalent, 5 equivalent, 10 equivalent, 20 equivalent, 50 equivalent, 80 equivalent; most preferably, the molar equivalent of fatty boric acid/borate or trifluoroborate is 100, the molar equivalent of base is 120, and the molar equivalent of photosensitizer is 1.
Further, the reaction is carried out under nitrogen.
Further, the reaction is carried out under the irradiation of blue light, wherein the wavelength of the blue light is 420-460 nm; preferably, the blue wavelength is 440nm.
Further; the method is used for batch multi-well plate operation.
Further; the method is used for the synthesis of DNA encoding compound libraries in multiwell plates.
The method can obtain the On-DNA beta-aliphatic substituted ketone compound from the On-DNA alpha, beta-unsaturated carbonyl compound in the DNA coding compound library, can be widely applied to various On-DNA alpha, beta-unsaturated carbonyl substrates, and can introduce various substituted aliphatic boric acid/boric acid ester compounds On a large scale as a synthesis module. The method has single product, can be carried out in a mixed water phase of an organic solvent/water phase, is simple to operate, is environment-friendly, and is suitable for synthesizing the DNA coding compound library by using a porous plate.
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. Because ofThis is, for example, C 1 ～C 20 Alkyl refers to straight or branched chain alkyl groups containing 1 to 20 carbon atoms.
Alkyl refers to straight or branched hydrocarbon groups substituted by H in the alkane molecule, e.g. methyl CH 3 -, ethyl CH 3 CH 2 -, methylene-CH 2 -。
Cycloalkyl: refers to saturated or unsaturated cycloalkyl groups in which H is substituted; the halogen is fluorine, chlorine, bromine or iodine.
Aromatic group: refers to a group in which part H on the aromatic ring is substituted, such as pyridyl, quinolyl, thiazolyl or phenyl.
An alkoxy group: refers to alkyl groups bound to oxygen atoms to form substituents, e.g. methoxy groups of-OCH 3 。
Halogenated phenyl: refers to a group formed by substituting H on phenyl with halogen.
Alkylphenyl: refers to a group formed by substituting H on phenyl with alkyl.
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.
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 by way of the following embodiments, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
Fig. 1-2: the corresponding conversion profiles of 30 On-DNA beta-aliphatic substituted ketones prepared in example 2.
Detailed Description
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.
In the present invention, "room temperature" means 20 to 25 ℃.
DMA: dimethylacetamide (Dimethylacetamide); DMF: dimethylformamide.
HATU:2- (7-azabenzotriazol) -N, N' -tetramethylurea hexafluorophosphate;
DIPEA: n, N-diisopropylethylamine;
DMSO: dimethyl sulfoxide; THF: tetrahydrofuran.
DNA-NH in the present invention 2 Is formed by single-stranded or double-stranded DNA and a linker group and carries-NH 2 DNA structure of linker, e.g. DNA-NH of "component 1" in WO2005058479 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.
EXAMPLE 1 Synthesis of On-DNA beta-aliphatic substituted ketones
Step 1, synthesis of On-DNA alpha, beta-unsaturated carbonyl Compound
DNA-NH 2 (A) Dissolving in 250mM boric acid buffer solution (pH=9.4) to prepare 1mM concentration solution (20. Mu.L, 20 nmol); 2-methacrylic acid (25 eq, 500nmol,0.2M DMA solution) and DIPEA (25 eq, 500nmol,0.2M DMA solution) were mixed well, then HATU (25 eq, 500nmol,0.2M DMA solution) was added, mixed well and activated at 0deg.C for 5 minutes; the activated solution was added to the DNA solution in 2 portions, reacted at 0℃for 5 minutes, and then reacted at 25℃for 30 minutes.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the reacted solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice, freezing for 0.5 hour, centrifuging at low temperature (4 ℃) at the rotation speed of 12000rpm for half an hour, pouring out supernatant, dissolving the rest precipitate by deionized water to obtain the solution of the On-DNA alpha, beta-unsaturated carbonyl compound (1), quantifying by an enzyme-labeled instrument OD, and then sending the solution to LC-MS to confirm that the conversion rate of the compound1 is 97% respectively.
Step 2, synthesis of On-DNA beta-aliphatic substituted ketone compound
The On-DNA alpha, beta-unsaturated carbonyl compound (1) was prepared into a 1mM concentration solution (20. Mu.L, 20 nmol) with deionized water, and isopropylboric acid (2000 nmol,100 equivalents, 0.5M DMSO solution) and K were sequentially added to the solution 2 HPO 4 (2400nmol, 120 eq, 0.3M DMSO solution), (Ir [ dF (CF) 3 )ppy] 2 (dtbpy))PF 6 (20 nmol,1 eq, 0.01M DMSO solution), then 59. Mu.L DMSO was added to make the organic phase volume ratio of the reaction system 70%, mixed well, purged with nitrogen for 2 hours, oxygen was removed, and then irradiated with an LED blue light (λ=440 nm) lamp for 1 hour.
After the reaction is finished, adding 5M sodium chloride solution with the total volume of 10% into the solution after the reaction, then continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice for freezing for 0.5 hour, centrifuging at low temperature (4 ℃) for half an hour at the rotating speed of 12000rpm, pouring out the supernatant, dissolving the rest precipitate by deionized water, thus obtaining the solution of the On-DNA beta-fat substituted ketone compound (1 a), quantifying by an enzyme-labeled instrument OD, and then sending LC-MS to confirm that the conversion rate of the compound 1a is 81% respectively.
EXAMPLE 2 Synthesis of On-DNA beta-aliphatic substituted ketones
Following the procedure of example 1, with other conditions unchanged, 5 α, β -unsaturated carbonyl compounds (1-5) were reacted with 6 fatty boric acid/borate or trifluoroborate salts (a-f), respectively, with specific reaction product yields shown in the accompanying figures.
In summary, the On-DNA beta-aliphatic substituted ketone compound can be obtained by the reaction of the On-DNA alpha, beta-unsaturated carbonyl compound and the aliphatic boric acid/boric acid ester or the trifluoroborate under the existence of alkali by controlling the conditions of solvent, temperature, pH and the like during the reaction. The method has wide substrate application range, can be carried out in a mixed water phase of an organic solvent/water phase, is simple to operate, is environment-friendly, and is suitable for synthesizing the DNA coding compound library by using a porous plate.

Claims (6)

1. A method for constructing beta-aliphatic substituted ketone compound by On-DNA reaction is characterized in that: the method uses On-DNA alpha, beta-unsaturated carbonyl compound as raw material, and uses the On-DNA alpha, beta-unsaturated carbonyl compound as raw material and uses the On-DNA alpha, beta-unsaturated carbonyl compound as photosensitive agent (Ir dF (CF) 3 )ppy] 2 (dtbpy))PF 6 Alkali K 2 HPO 4 Reacting with fatty boric acid/borate or trifluoroborate in the presence of the compound to obtain an On-DNA beta-fatty substituted ketone compound; wherein the structural formula of the On-DNA alpha, beta-unsaturated carbonyl compound isThe structural formula of the fatty boric acid/boric acid ester is +.>The structural formula of the On-DNA beta-aliphatic substituted ketone compound is +.>
Wherein the DNA in the formula comprises a single-or double-stranded nucleotide chain polymerized from artificially modified and/or unmodified nucleotide monomers, the nucleotide chain being linked to a nitrogen atom by one or more chemical bonds or groups;
said R is 1 Selected from hydrogen, C 1 ～C 6 Alkyl, substituted C 1 ～C 6 Alkyl, phenyl, said C 1 ～C 6 The alkyl is specifically selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexane; substitution C 1 ～C 6 The substituent of the alkyl is selected from phenyl and 5-6 membered saturated heterocyclic groupsThe method comprises the steps of carrying out a first treatment on the surface of the The 5-to 6-membered saturated heterocyclic group is a saturated monocyclic hydrocarbon group of 3 to 6 atoms carrying at least one atom selected from O, N;
said R is 2 Selected from C 1 ～C 6 Alkyl, substituted C 1 ～C 6 Alkyl, saturated C 3 ～C 8 Cycloalkyl 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 saturated C 3 ～C 8 Cycloalkyl is specifically selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; substitution C 1 ～C 6 The substituent of the alkyl is selected from phenyl and amino;
the R is 3 、R 4 Selected from hydrogen, C 1 ～C 6 Alkyl, or R 3 、R 4 Are connected in a ring, 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 method comprises the following steps: to an On-DNA alpha, beta-unsaturated carbonyl compound solution with a molar equivalent of 1 and a molar concentration of 0.5-5mM, 10-1000 times of molar equivalent of fatty boric acid/boric acid ester or trifluoroborate and 10-1000 times of molar equivalent of alkali K are added 2 HPO 4 Then 0.1 to 100 times molar equivalent of photosensitizer (Ir [ dF (CF) 3 )ppy] 2 (dtbpy))PF 6 Then adding DMSO to make the volume ratio of the organic phase of the reaction system be 70%, uniformly mixing, introducing nitrogen for 2 hours, removing oxygen, then irradiating for 1 hour by using an LED blue light (lambda=440 nm) lamp, and reacting for 0.1-24 hours at 10-100 ℃.
2. The method according to claim 1, characterized in that: the reaction temperature of the reaction was 20 ℃, 30 ℃, 40 ℃,50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃,100 ℃.
3. The method according to claim 1, characterized in that: the reaction time of the reaction is 0.1 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours, 10 hours, 16 hours, 18 hours, 20 hours.
4. The method according to claim 1, characterized in that: when the molar equivalent of the On-DNA α, β -unsaturated carbonyl compound is 1, the molar equivalent of the fatty boric acid/borate or trifluoroborate is 50 equivalents, 100 equivalents, 200 equivalents, 300 equivalents, 400 equivalents, 500 equivalents, 600 equivalents, 800 equivalents, 1000 equivalents; the molar equivalents of the base are 50 equivalents, 100 equivalents, 120 equivalents, 150 equivalents, 200 equivalents, 300 equivalents, 400 equivalents, 500 equivalents, 600 equivalents, 800 equivalents, 1000 equivalents; the molar equivalent of the photosensitizer is 0.1 equivalent, 0.5 equivalent, 1 equivalent, 5 equivalent, 10 equivalent, 20 equivalent, 50 equivalent, 80 equivalent.
5. The method according to any one of claims 1-4, wherein the method is used for batch multi-well plate operations.
6. The method according to any one of claims 1 to 4, wherein the method is used for the synthesis of a library of DNA encoding compounds of a multiwell plate.
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CN109680342A (en) * 2018-12-18 2019-04-26 上海药明康德新药开发有限公司 The method that On-DNA virtue nitro compound is reduced into On-DNA aromatic amine compound in DNA encoding compound library
CN110359097A (en) * 2019-07-08 2019-10-22 上海药明康德新药开发有限公司 The method that On-DNA aromatic compound is obtained by Suzuki coupling reaction in the building of DNA encoding compound library

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