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Synthesizing method of 1,2,3-triazole compound of On-DNA in DNA coded compound storehouse

A technology for compound libraries and synthesis methods, which is applied in chemical instruments and methods, sugar derivatives, sugar derivatives, etc., can solve the problems of unstable azide reagents, few commercially available types, and limited applications, and achieves universal substrate availability. The effect of high adaptability, easy availability of reaction raw materials and high yield

Active Publication Date: 2019-07-23
上海药明康德新药开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The above literature has not verified whether the obtained product is 1, 4 substitution or 1, 5 substitution, and because azide reagents are unstable, explosive, and there are few commercially available types, which limits the synthesis of related reactions in DNA-encoded compound libraries. application in

Method used

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  • Synthesizing method of 1,2,3-triazole compound of On-DNA in DNA coded compound storehouse
  • Synthesizing method of 1,2,3-triazole compound of On-DNA in DNA coded compound storehouse
  • Synthesizing method of 1,2,3-triazole compound of On-DNA in DNA coded compound storehouse

Examples

Experimental program
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Effect test

Embodiment 1

[0046] Example 1, On-DNA alkyne compound reacts with boronic acid or boric acid ester in the presence of copper catalyst and azide reagent to obtain On-DNA 1,4-disubstituted 1,2,3-triazole compound

[0047] 1) Synthesis of On-DNA alkyne compounds

[0048] DNA-NH 2 (For example, the initial head fragment mentioned in patent CN108070009A) was dissolved in 250mM, pH=9.5 boric acid buffer solution, prepared into a 1mM concentration solution, and reacted with p-acetylenebenzoic acid using EDCI as a condensation agent and s-NHS condensation activator to obtain the corresponding On-DNA alkyne compounds (references: Nat.Chem., 2015,7,3,241, see figure 1 ), after the reaction is completed, ethanol precipitation treatment, concentration and drying are directly used for the next On-DNA cycloaddition reaction.

[0049]

[0050] The purity of the On-DNA alkyne compound after ethanol precipitation treatment was 95%.

[0051] 2) Synthesis of On-DNA 1,4-disubstituted 1,2,3-triazole comp...

Embodiment 2

[0059] Example 2, On-DNA azide compound is prepared in the presence of bis(cyclopentadiene) nickel and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene 1, 5-disubstituted 1,2,3-triazole compounds

[0060] 1) Synthesis of On-DNA azide compounds

[0061] DNA-NH 2 (For example, the starting head fragment mentioned in patent CN108070009A) was dissolved in 250mM, pH=9.5 boric acid buffer solution, prepared into a 1mM concentration solution, and reacted with p-azidobenzoic acid using EDCI as a condensation agent and s-NHS condensation activator Obtain the corresponding On-DNA azide compound (references: Nat.Chem., 2015,7,3,241, see Figure 4 ), after the reaction is completed, ethanol precipitation treatment, concentration and drying are directly used for the next On-DNA cycloaddition reaction.

[0062]

[0063] The purity of the On-DNA azide compound after ethanol precipitation treatment was 93%.

[0064] 2) Synthesis of On-DNA 1,5-disubstituted 1,2,3-triazole compounds

[006...

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Abstract

The invention discloses a synthesizing method of a 1,2,3-triazole compound of On-DNA during construction of a DNA coded compound storehouse. The method is divided into two types, wherein in one type of the method, an On-DNA alkyne compound is used as a substrate, in the presence of a Cu catalyst and an azide type reagent, the On-DNA alkyne compound reacts with micromolecule boric acid or a boric acid ester reagent to obtain a 1,4-disubstituted-1,2,3-triazole compound of the On-DNA; and in the other type of the method, an On-DNA azide compound is used as a substrate, in the presence of a metalNi catalyst or a metal Ru catalyst and a phosphine reagent, the On-DNA azide compound reacts with a micromolecule alkyne reagent to obtain a 1,5-disubstituted-1,2,3-triazole compound of On-DNA. According to the preparation method of the 1,2,3-triazole compound of the On-DNA, provided by the invention, the raw materials are easy to obtain, the reaction condition is mild, the production rate is high, the universality of the substrate is high, the selectivity of products is good, and the synthesizing method is suitable for synthesizing of a DNA coded compound storehouse using a porous plate.

Description

technical field [0001] The invention belongs to the technical field of DNA-encoded compound libraries, in particular to a method for synthesizing On-DNA 1,2,3-triazole compounds in DNA-encoded compound libraries and the obtained On-DNA 1,4 or 1,5- Disubstituted 1,2,3-triazole compounds. Background technique [0002] Sydney Brenner and Professor Richard Lerner of the Scripps Research Institute in the United States proposed the concept of DNA Encoded Library (DNA Encoded Library, referred to as DEL) in 1992 (reference: Proc.Natl.Acad.Sci., 1992,89,5381, patent : US5573905), the method connects an organic small molecule reagent with a unique sequence of DNA at the molecular level (i.e. DNA labeling the small molecule reagent), and utilizes the "combination-splitting" strategy of combinatorial chemistry to pass two at most A large number of compound libraries can be quickly constructed in one cycle, each compound in the compound library is composed of different organic small mo...

Claims

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Application Information

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IPC IPC(8): C07H21/04C07H1/00
CPCC07H21/04C07H1/00
Inventor 吴阿亮张朝欣曲毅徐艳芬裴增飞陈雯婷李科蒯乐天杨洪芳彭宣嘉
Owner 上海药明康德新药开发有限公司
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