CN114057658A - Polytriazole compound, preparation method and application thereof - Google Patents

Polytriazole compound, preparation method and application thereof Download PDF

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CN114057658A
CN114057658A CN202010758664.XA CN202010758664A CN114057658A CN 114057658 A CN114057658 A CN 114057658A CN 202010758664 A CN202010758664 A CN 202010758664A CN 114057658 A CN114057658 A CN 114057658A
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董佳家
王天宇
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Zhonghongxin Investment Holding Shenzhen Co ltd
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Abstract

The invention discloses a polytriazole compound, a preparation method and application thereof. The invention specifically discloses a polytriazole compound shown as a formula I or a salt thereof. The triazole compound disclosed by the invention is novel in structure, can be used for catalyzing copper-catalyzed azide-terminal alkyne cycloaddition reaction, and is improved in speed and yield. The polytriazole compounds are particularly effective in copper-catalyzed azide-alkyne cycloaddition reaction at low concentration, simple to prepare and easy to amplify.
Figure DDA0002612427040000011

Description

Polytriazole compound, preparation method and application thereof
Technical Field
The invention relates to a polytriazole compound, a preparation method and application thereof.
Background
The azide-terminal alkyne cycloaddition reaction catalyzed by cuprous is an organic chemical reaction which is widely applied to the fields of chemical biology, material science, pharmacy and the like at present, and has the advantages of rapidness, high selectivity and high biocompatibility. It has certain disadvantages including poor efficacy at lower concentrations (on the order of 1-10mM or less), toxicity of copper ions to cells at higher concentrations, and the like. In order to improve the copper-catalyzed azide-terminal alkyne cycloaddition reaction effect at low concentration and reduce the destructive effect of copper ions on living cells and other biological systems, ligands can be added into the system. The appropriate ligand can effectively improve the speed and the yield (especially under the condition of low concentration) of copper-catalyzed azide-terminal alkyne cycloaddition reaction, reduce the dosage of copper, reduce the interference of copper ions on a biological system and improve the biocompatibility.
In recent years, various polytriazole ligands suitable for use in the monovalent copper-catalyzed azide-terminal alkyne cycloaddition reaction have been reported, but all suffer from drawbacks. In 2009, m.g. finn et al reported a polytriazole ligand compound containing simple hydrocarbon groups such as benzyl, tert-butyl and adamantyl (world patent 2009/038685 a1), but in common application fields such as chemical biology, the polytriazole ligand compound has the disadvantages of poor water solubility, insufficient significant effect, large dosage and the like. P.wu et al reported a polytriazole ligand with an asymmetric (2+1) structure (world patent 2012/021390 a1) in 2012, and the use of tert-butyl azide causes great production risk, and the synthesis method is tedious, the raw materials are expensive, and the complex column chromatography operations are required, so that the preparation and amplification are very difficult. 2016 and 2017, Lilingjun et al reported a bis (1,2, 3-triazole) ligand (Chinese patent 105968116A, Chinese patent 107629013A), but the same problems of low catalytic efficiency, need of multi-step complicated column chromatography separation during preparation, and difficult preparation and amplification.
Disclosure of Invention
The invention aims to overcome the defects of low catalytic rate and low yield of the existing polytriazole compound in copper-catalyzed azide-terminal alkyne cycloaddition reaction, and provides the polytriazole compound, and a preparation method and application thereof. The triazole compound disclosed by the invention is novel in structure, can be used for catalyzing copper-catalyzed azide-terminal alkyne cycloaddition reaction, and is improved in speed and yield. The polytriazole compounds are particularly effective in copper-catalyzed azide-alkyne cycloaddition reaction at low concentration, simple to prepare and easy to amplify.
The invention solves the technical problems through the following technical scheme.
The invention provides a polytriazole compound shown as a formula I or a salt thereof,
Figure BDA0002612427020000021
wherein R is1is-C (═ O) OR1-1Substituted C1-C10Alkyl, unsubstituted or R1-2Substituted C1-C10Alkyl, hydroxy substituted C4-C10Alkyl, or, unsubstituted or R1-3Substituted C3-C14A cycloalkyl group;
when R is1is-C (═ O) OR1-1Substituted C1-C10Alkyl, wherein C1-C10Alkyl is optionally substituted by R1-4Substitution;
R1-1is hydrogen or C1-C6An alkyl group;
R1-2is unsubstituted or R1-2aSubstituted C3-C10Cycloalkyl radicals or
Figure BDA0002612427020000022
R1-3Is hydroxy, unsubstituted or R1-3aSubstituted C1-C6Alkyl OR-C (═ O) OR1-3b；
R1-4Is unsubstituted or R1-4aSubstituted C6-C10Aryl, or, unsubstituted or R1-4bSubstituted C3-C10A cycloalkyl group;
R1-2ais hydroxy or C1-C6An alkyl group;
R1-2b、R1-2cand R1-3bIndependently is hydrogen or C1-C6An alkyl group;
R1-3ais a hydroxyl group;
R1-4aand R1-4bIndependently is C1-C6An alkyl group;
the substituents are 1 or more, and when there are more, the same or different.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula I are defined as follows, and the substituents not referred to are defined as in any of the above schemes (hereinafter referred to simply as "in one scheme"):
when R is1is-C (═ O) OR1-1Substituted C1-C10When the alkyl is substituted, the radical-C (═ O) OR1-1The number of (a) may be 1,2 or 3.
In one aspect:
when R is1is-C (═ O) OR1-1Substituted C1-C10When alkyl, said C1-C10The alkyl group may be C1-C8The alkyl group may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group,
Figure BDA0002612427020000023
Figure BDA0002612427020000024
And can be
Figure BDA0002612427020000025
In one aspect:
when R is1Is unsubstituted or R1-2Substituted C1-C10When it is alkyl, said R1-2The number of (a) may be 1,2 or 3.
In one aspect:
when R is1Is unsubstituted or R1-2Substituted C1-C10When alkyl, said C1-C10The alkyl group may be C1-C6Alkyl, which may be methyl, ethyl, n-propyl,Isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl or n-pentyl, which in turn may be ethyl or n-pentyl.
In one aspect:
when R is1Is hydroxy-substituted C4-C10In the case of alkyl, the number of the hydroxyl groups may be 1,2 or 3.
In one aspect:
when R is1Is hydroxy-substituted C4-C10When alkyl, said C4-C10The alkyl group may be C4-C8Alkyl, which may be n-butyl, isobutyl, sec-butyl, tert-butyl or n-octyl, may also be
Figure BDA0002612427020000031
In one aspect:
when R is1Is unsubstituted or R1-3Substituted C3-C14When the cycloalkyl group is, said R1-3The number of (a) may be 1,2 or 3.
In one aspect:
when R is1Is unsubstituted or R1-3Substituted C3-C14When there is a cycloalkyl group, said C3-C14Cycloalkyl radicals may be C3-C14Monocyclic cycloalkyl, C3-C14Spirocyclic cycloalkyl radical, C3-C14Cycloalkyl having condensed rings or C3-C14Bridged cycloalkyl radicals, which may also be C3-C14Monocyclic cycloalkyl or C3-C14A bridged cycloalkyl group;
said C3-C14Monocyclic cycloalkyl can be C3-C6Monocyclic cycloalkyl which may be cyclobutyl, cyclopentyl or cyclohexyl, or cyclopentyl or cyclohexyl;
said C3-C14The bridged cycloalkyl radical can be C7-C10Bridged cycloalkyl, in turn, can be adamantyl.
In one aspect:
when R is1-1Is C1-C6When alkyl, said C1-C6The alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, and may also be methyl or ethyl.
In one aspect:
when R is1-2Is unsubstituted or R1-2aSubstituted C3-C10When the cycloalkyl group is, said R1-2aThe number of (a) may be 1,2 or 3.
In one aspect:
when R is1-2Is unsubstituted or R1-2aSubstituted C3-C10When there is a cycloalkyl group, said C3-C10Cycloalkyl radicals may be C3-C10Monocyclic cycloalkyl, C3-C10Spirocyclic cycloalkyl radical, C3-C10Cycloalkyl having condensed rings or C3-C10Bridged cycloalkyl radicals, which may also be C3-C10A monocyclic cycloalkyl group;
said C3-C10Monocyclic cycloalkyl can be C3-C6Monocyclic cycloalkyl, in turn, can be cyclohexyl.
In one aspect:
when R is1-3Is unsubstituted or R1-3aSubstituted C1-C6When it is alkyl, said R1-3aThe number of (a) may be 1,2 or 3.
In one aspect:
when R is1-3Is unsubstituted or R1-3aSubstituted C1-C6When alkyl, said C1-C6The alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, and may be methyl or isopropyl.
In one aspect:
when R is1-4Is unsubstituted or R1-4aSubstituted C6-C10When aryl is said to R1-4aThe number of (a) may be 1,2 or 3.
In one aspect:
when R is1-4Is unsubstituted or R1-4aSubstituted C6-C10When aryl, said C6-C10The aryl group can be phenyl.
In one aspect:
when R is1-4Is unsubstituted or R1-4bSubstituted C3-C10When the cycloalkyl group is, said R1-4bThe number of (a) may be 1,2 or 3.
In one aspect:
when R is1-4Is unsubstituted or R1-4bSubstituted C3-C10When there is a cycloalkyl group, said C3-C10Cycloalkyl radicals may be C3-C10Monocyclic cycloalkyl, C3-C10Spirocyclic cycloalkyl radical, C3-C10Cycloalkyl having condensed rings or C3-C10Bridged cycloalkyl radicals, which may also be C3-C10A monocyclic cycloalkyl group;
said C3-C10Monocyclic cycloalkyl can be C3-C6Monocyclic cycloalkyl, which in turn can be cyclopropyl.
In one aspect:
when R is1-2aIs C1-C6When alkyl, said C1-C6The alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.
In one aspect:
when R is1-2b、R1-2cAnd R1-3bIndependently is C1-C6When alkyl, said C1-C6Alkyl groups may independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, and may also be methyl.
In one aspect:
when R is1-4aAnd R1-4bIndependently is C1-C6When alkyl, said C1-C6Alkyl groups may independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, and may also be methyl.
In one aspect:
when R is1is-C (═ O) OR1-1Substituted C1-C10When the alkyl is substituted, the radical-C (═ O) OR1-1Substituted C1-C10The alkyl group can be
Figure BDA0002612427020000041
Figure BDA0002612427020000051
Figure BDA0002612427020000052
And can be
Figure BDA0002612427020000053
Figure BDA0002612427020000054
In one aspect:
when R is1Is unsubstituted or R1-2Substituted C1-C10When alkyl, said is unsubstituted or R1-2Substituted C1-C10The alkyl group can be
Figure BDA0002612427020000055
In one aspect:
when R is1Is hydroxy-substituted C4-C10When it is alkyl, said hydroxy-substituted C4-C10The alkyl group can be
Figure BDA0002612427020000056
And can be
Figure BDA0002612427020000057
In one aspect:
when R is1Is unsubstituted or R1-3Substituted C3-C14When a cycloalkyl group is present, theSaid unsubstituted or R1-3Substituted C3-C14The cycloalkyl group can be
Figure BDA0002612427020000058
Figure BDA0002612427020000059
Figure BDA00026124270200000510
And can be
Figure BDA00026124270200000511
Figure BDA0002612427020000061
In one aspect:
R1is-C (═ O) OR1-1Substituted C1-C10Alkyl radical, R1-2Substituted C1-C10Alkyl, hydroxy substituted C4-C10Alkyl, or, R1-3Substituted C3-C14A cycloalkyl group.
In one aspect:
when R is1is-C (═ O) OR1-1Substituted C1-C10Alkyl, wherein C1-C10Alkyl is optionally substituted by R1-4And (4) substitution.
In one aspect:
R1-1is H.
In one aspect:
R1-2is R1-2aSubstituted C3-C10Cycloalkyl radicals or
Figure BDA0002612427020000062
In one aspect:
R1-3is hydroxy, R1-3aSubstituted C1-C6Alkyl or-C (═ O) OH, which in turn may be-C (═ O) OH.
In one aspect:
R1-4is unsubstituted or R1-4aSubstituted C6-C10Aryl, or unsubstituted C3-C10Cycloalkyl radicals, which may in turn be unsubstituted C6-C10And (4) an aryl group.
In one aspect:
R1-2ais a hydroxyl group.
In one aspect:
R1-2band R1-2cIndependently is C1-C6An alkyl group.
In one aspect:
R1-3ais a hydroxyl group.
In one aspect:
R1is-C (═ O) OR1-1Substituted C1-C10Alkyl, e.g. C substituted by-C (═ O) OH1-C10An alkyl group.
In one aspect:
R1is hydroxy-substituted C4-C10An alkyl group.
In one aspect:
R1is unsubstituted or R1-3Substituted C3-C14A cycloalkyl group.
In one aspect:
R1is-C (═ O) OR1-1Substituted C1-C10Alkyl radical, R1-2Substituted C1-C10Alkyl, hydroxy substituted C4-C10Alkyl, or, R1-3Substituted C3-C14A cycloalkyl group;
when R is1is-C (═ O) OR1-1Substituted C1-C10Alkyl, wherein C1-C10Alkyl is optionally substituted by R1-4Substitution;
R1-1is hydrogen;
R1-2is R1-2aSubstituted C3-C10Cycloalkyl radicals or
Figure BDA0002612427020000071
R1-3Is hydroxy, R1-3aSubstituted C1-C6Alkyl or-C (═ O) OH;
R1-4is unsubstituted or R1-4aSubstituted C6-C10Aryl, or unsubstituted C3-C10A cycloalkyl group;
R1-2ais a hydroxyl group;
R1-2band R1-2cIndependently is C1-C6An alkyl group;
R1-3ais a hydroxyl group;
R1-4ais C1-C6An alkyl group.
In one aspect:
R1is-C (═ O) OR1-1Substituted C1-C10Alkyl, or, R1-3Substituted C3-C14A cycloalkyl group;
when R is1is-C (═ O) OR1-1Substituted C1-C10Alkyl, wherein C1-C10Alkyl is optionally substituted by R1-4Substitution;
R1-1is hydrogen;
R1-3is-C (═ O) OH;
R1-4is unsubstituted C6-C10And (4) an aryl group.
In one aspect:
R1is unsubstituted or R1-3Substituted C3-C14Cycloalkyl radical, said C3-C14Cycloalkyl is cyclopentyl or cyclohexyl.
In one aspect:
the compound shown in the formula I can be raceme.
In one aspect:
when the compound shown in the formula I contains a chiral carbon atom, the configuration of the chiral carbon atom can be S configuration or R configuration. In the invention, the configuration of the chiral carbon atom in the compound shown as the formula I has no obvious influence on the catalytic effect.
In one aspect:
when cis-trans isomers exist in the compound shown in the formula I, the configuration of the compound shown in the formula I can be cis or trans. In the invention, cis-trans isomerization of the compound shown as the formula I has no obvious influence on the catalytic effect.
In a certain embodiment, the salt of the polytriazole compound shown in formula I may be a salt or a base addition salt of an acid-protected amine commonly used in the art.
The acid may be an acid conventional in the art, for example an inorganic and/or organic acid, for example one or more of hydrochloric acid, sulphuric acid, phosphoric acid, methanesulphonic acid, p-toluenesulphonic acid, tartaric acid and oxalic acid, again for example hydrochloric acid.
The base addition salts may be those conventional in the art, for example salts of inorganic and/or organic bases, for example one or more of sodium, potassium, lithium, ammonium, diethylamine and triethylamine salts, again for example sodium salts.
In one aspect:
the compound shown in the formula I or the salt thereof can be selected from the following structures,
wherein the carbon atom with "-" or "-" is a chiral carbon atom, which is in S configuration, R configuration or a mixture of the two;
Figure BDA0002612427020000081
Figure BDA0002612427020000091
Figure BDA0002612427020000101
in one aspect:
the compound shown in the formula I or the salt thereof can be selected from the following structures,
Figure BDA0002612427020000111
Figure BDA0002612427020000121
the invention provides application of a compound shown as a formula I or a salt thereof in catalyzing azide-terminal alkyne cycloaddition reaction.
In a certain scheme, the azide-terminal alkyne cycloaddition reaction is a copper-catalyzed azide-terminal alkyne cycloaddition reaction.
In one aspect, the application comprises the steps of: in a solvent, in the presence of a reducing agent, copper salt and a ligand, carrying out cycloaddition reaction shown in the specification on an azide compound containing a fragment shown in a formula II and an alkyne-terminated compound containing a fragment shown in a formula III to obtain a compound containing a fragment IV; the ligand is a compound shown as a formula I or a salt thereof;
Figure BDA0002612427020000131
wherein R is1As defined in any of the previous schemes.
In one embodiment, in the application, the azide compound containing the fragment represented by formula II is of any one of the following structures:
Figure BDA0002612427020000132
in one embodiment, in the application, the terminal alkyne compound containing the fragment represented by formula III has the following structure:
Figure BDA0002612427020000133
in one embodiment, the solvent may be a solvent conventional in the art, and may be one or more of water, sulfoxide solvents (e.g., dimethylsulfoxide DMSO), amide solvents (e.g., N-dimethylformamide DMF), alcohol solvents (e.g., one or more of methanol, ethanol, and t-butanol), nitrile solvents (e.g., acetonitrile MeCN), ether solvents (e.g., one or more of methyl t-butyl ether MTBE, 1, 4-dioxane, diethyl ether, and tetrahydrofuran THF), and N-methylpyrrolidone, for example, tetrahydrofuran, N-dimethylformamide, a mixed solvent of water and dimethyl sulfoxide, a mixed solvent of water and N, N-dimethylformamide, a mixed solvent of water and t-butyl alcohol, a mixed solvent of water and N-methylpyrrolidone, and a mixed solvent of methyl t-butyl ether-water-dimethyl sulfoxide.
In one embodiment, the reducing agent used in the present invention may be any reducing agent that is conventional in the art, and may be ascorbic acid and/or a salt thereof, a trivalent phosphine compound, or a thiol-group-containing compound, such as sodium ascorbate, tris (2-carboxyethyl) phosphine, or glutathione.
In one embodiment, in the application, the copper salt may be a copper salt conventional in the art, and may be a monovalent copper salt and/or a divalent copper salt. The cuprous salt can be cuprous halide, cuprous acetate, cuprous trifluoromethanesulfonate, copper tetraacetonitrile hexafluorophosphate, etc. The cupric salt can be cupric chloride, cupric acetate, cupric sulfate, etc.
In one embodiment, the molar ratio of the terminal alkyne compound to the azide compound in the application can be a molar ratio conventional in the art, and can be from 0.5:1 to 2:1, such as 1: 1.
In one embodiment, the molar ratio of the reducing agent to the azide compound in the application may be a molar ratio conventional in the art, and may be from 0.5:1 to 30:1, such as 1:1, 5:1, or 25: 1.
In one embodiment, the molar ratio of the copper salt to the azide compound in the application may be a molar ratio conventional in the art, and may be 0.05:1 to 0.8:1, such as 0.01:1, 0.05:1, or 0.5: 1.
In one embodiment, the molar ratio of the ligand to the azide compound in the application may be a molar ratio conventional in the art, and may be from 0.05:1 to 0.8:1, such as 0.01:1, 0.05:1, or 0.5: 1.
In one embodiment, the molar ratio of the ligand to the copper salt in the application may be a molar ratio conventional in the art, and may be from 0.5:1 to 2:1, for example, 1: 1.
In one embodiment, the temperature of the cycloaddition reaction in the application may be a temperature conventional in the art, and may be 20-100 ℃, for example 30 ℃ or 40 ℃.
In one embodiment, the progress of the cycloaddition reaction in the application may be monitored by means conventional in the art (e.g. TLC, HPLC or LCMS), and the time for the cycloaddition reaction may be from 0.5 to 48 hours, such as 1 hour, 2.5 hours or 6 hours, based on the disappearance of the terminal alkyne compound.
In one embodiment, in the application, the cycloaddition reaction may be carried out in the presence of a buffer system. The buffer system may be a buffer system conventional in the art, and may be a citric acid-disodium hydrogen phosphate and/or disodium hydrogen phosphate-sodium dihydrogen phosphate buffer system. The pH of the buffer system may be between pH 4 and 8.
The invention provides a catalytic system which comprises a compound shown as a formula I, copper salt and a reducing agent. The compound shown as the formula I is described in any one of the previous schemes.
The reducing agent and the copper salt are defined as in any of the previous embodiments.
The invention also provides a preparation method of the compound shown in the formula I, which comprises the following steps: in a solvent, in the presence of a reducing agent and copper salt, performing cycloaddition reaction on a compound shown as a formula 1 and a compound shown as a formula 2 as shown in the specification;
Figure BDA0002612427020000151
wherein R is1As defined in any of the previous schemes.
In certain preferred embodiments of the present invention, in the preparation method, the solvent may be a solvent conventional in the art, and may be one or more of water, a sulfoxide solvent (e.g., dimethyl sulfoxide) and an amide solvent (e.g., N-dimethylformamide), such as a mixed solvent of water and dimethyl sulfoxide or a mixed solvent of water and N, N-dimethylformamide.
In certain preferred embodiments of the present invention, in the preparation method, the reducing agent may be ascorbic acid and/or a salt thereof, a trivalent phosphine compound or a mercapto group-containing compound, such as sodium ascorbate, tris (2-carboxyethyl) phosphine or glutathione.
In certain preferred embodiments of the present invention, in the preparation method, the copper salt may be a copper salt conventional in the art, and may be a monovalent copper salt and/or a divalent copper salt. The cuprous salt can be cuprous halide, cuprous acetate, cuprous trifluoromethanesulfonate, copper tetraacetonitrile hexafluorophosphate, etc. The cupric salt can be cupric chloride, cupric acetate, cupric sulfate, etc.
In certain preferred embodiments of the present invention, in the preparation method, the molar ratio of the compound represented by formula 2 to the compound represented by formula 1 may be a molar ratio which is conventional in the art, and may be 1:1 to 1:6, such as 1:1 or 1: 4.2.
In certain preferred embodiments of the present invention, in the preparation method, the molar ratio of the reducing agent to the compound represented by formula 1 may be a molar ratio which is conventional in the art, and may be 1:1 to 8:1, such as 2:1 or 4.8: 1.
In certain preferred embodiments of the present invention, in the preparation method, the molar ratio of the copper salt to the compound represented by formula 1 may be a molar ratio which is conventional in the art, and may be 0.1:1 to 0.5:1, such as 0.24:1 or 0.35: 1.
In certain preferred embodiments of the present invention, the temperature of the cycloaddition reaction in the preparation process may be a temperature conventional in the art, and may be from 20 to 80 ℃, for example 40 ℃.
In certain preferred embodiments of the present invention, the progress of the cycloaddition reaction in the preparation method can be monitored by means conventional in the art (e.g., TLC, HPLC or LCMS), and the time for the cycloaddition reaction can be 1-48h, such as 2h, 12h or 48h, based on the disappearance of the compound represented by formula 2.
Unless otherwise indicated, the following terms appearing in the specification and claims of the invention have the following meanings:
the term "salt" refers to a salt prepared from a compound of the present invention with an acid or base. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, and diethanolamine salt. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids including, but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The acids include organic acids including, but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e. 4,4' -methylene-bis (3-hydroxy-2-naphthoic acid)), amino acids (e.g. glutamic acid, arginine), and the like. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they may be converted to base addition salts or acid addition salts. See in particular Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19(1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P.Heinrich Stahl and Camile G.Wermuth, ed., Wiley-VCH, 2002).
The terms "compound" and "salt," if present as stereoisomers, may exist as single stereoisomers or as mixtures thereof (e.g., racemates). The term "stereoisomer" refers to either a cis-trans isomer or an optical isomer. The stereoisomers can be separated, purified and enriched by an asymmetric synthesis method or a chiral separation method (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography and the like), and can also be obtained by chiral resolution in a mode of forming bonds (chemical bonding and the like) or salifying (physical bonding and the like) with other chiral compounds and the like. The term "single stereoisomer" means that the mass content of one stereoisomer of the compound according to the invention is not less than 95% relative to all stereoisomers of the compound.
The term "alkyl" refers to a saturated straight or branched chain monovalent hydrocarbon radical having one to ten carbon atoms (e.g., C)1-C8Alkyl radicals, also e.g. C1-C6Alkyl radicals, also e.g. C1-C4Alkyl groups). Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-butyl, 2-butyl, t-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-1-pentyl, 2-methyl-2-pentyl, and the like, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, 1-heptyl and 1-octyl.
The term "cycloalkyl" refers to a saturated cyclic hydrocarbon radical having three to twenty carbon atoms (e.g., C)3-C6Cycloalkyl) including monocyclic cycloalkyl and polycyclic cycloalkyl. Cycloalkyl groups contain 3 to 20 carbon atoms, preferably 3 to 14 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 6 carbon atoms.
Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl.
Polycyclic cycloalkyl groups are polycyclic (e.g., bicyclic and tricyclic) cycloalkyl structures, including spiro, fused, and bridged cycloalkyl groups. Wherein spirocyclic cycloalkyl "refers to a polycyclic group having a 5 to 20 membered monocyclic ring sharing one carbon atom (called the spiro atom) between them, which may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Examples of spirocycloalkyl groups include, but are not limited to:
Figure BDA0002612427020000171
"fused-ring cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Examples of fused ring alkyl groups include, but are not limited to:
Figure BDA0002612427020000172
Figure BDA0002612427020000173
"bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. According to the number of constituent rings, they may be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridgesThe alkyl group is preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Examples of bridged cycloalkyl groups include, but are not limited to:
Figure BDA0002612427020000174
the term "aryl" refers to any stable monocyclic, bicyclic, or polycyclic carbocyclic ring of up to 10 atoms in each ring with aromatic character. Examples of the above aryl unit include phenyl, naphthyl, tetrahydronaphthyl, 2, 3-indanyl, biphenyl, phenanthryl, anthryl or acenaphthenyl (acenaphthyl).
The term "room temperature" means 10-40 ℃.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the triazole compound disclosed by the invention is novel in structure, can be used for catalyzing copper-catalyzed azide-terminal alkyne cycloaddition reaction, and is improved in speed and yield. The polytriazole compounds are particularly effective in copper-catalyzed azide-alkyne cycloaddition reaction at low concentration, simple to prepare and easy to amplify.
Drawings
FIG. 1 is a graph showing the reaction effect of (S) -TPBTA and three common ligands under the condition of a buffer solution.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
An experimental instrument:
1the H NMR spectrum was measured with an Agilent-400(400MHz) NMR spectrometer,1internal standard for H NMR was TMS (delta, 0.00) or CDCl3(δ,7.26)。
13The C NMR spectrum was measured with a nuclear magnetic resonance apparatus of the Bruker AM-400(100.7MHz) type,13internal standard of C NMR is CDCl3(δ,77.16)、DMSO-d6(δ,39.52)、CD3CN(δ,1.32)。
LC-MS (ESI) spectra were determined using a Waters ACQUITY UPLC H-Class system and an ACQUITY QDa mass spectrometer (eluent: 0.1% aqueous trifluoroacetic acid and acetonitrile). [ method: 7000psi, flow rate 0.6mL/min. t 0min, 95% H2O；t＝0.10min,95％H2O；t＝1.20min,5％H2O；t＝2.00min,5％H2O；t＝2.50min,95％H2O. total collection time 2.50min.]Stationary phase model ACQUITY
Figure BDA0002612427020000181
BEH C18 1.7μm)。
Tecan for fluorescence spectroscopy
Figure BDA0002612427020000182
And (3) measuring by using a multifunctional grating type microplate reader (a top reading method, wherein a carrying container is a Greiner flat-bottom black 96-hole plate, the excitation wavelength is 430nm, the emission wavelength is 490nm, and the width of a grating slit is 20 nm).
The reagents used were purchased from sigma aldrich (china) ltd (sigma aldrich), bailingwei technologies ltd (J & K), shanghai alading biochemistry technologies ltd (Aladdin), tai hei chemist ltd (shanghai), shanghai mclin biochemistry technologies ltd (Macklin), sahn chemistry technologies ltd (shanghai), Alfa Aesar (china) chemicals ltd (Alfa Aesar), shanghai tata technologies ltd (adamas), shanghai sub-medicine technologies ltd, shanghai Biao medicine ltd, shanghai Tianlian chemicals ltd, shanghai tianxia technologies ltd, shanghai Linkun chemist ltd or shanghai reagent ltd.
The solvent is purchased from national reagent company, Shanghai Michelin Biochemical technology company Limited (Macklin), Shanghai Tantake technology company Limited (adamas), Shanghai Tianlian chemical technology company Limited, Shanghai Dahe chemical company Limited, Shanghai Hebang pharmaceutical technology company Limited, and is directly used after being purchased without additional treatment.
Example 1: preparation of Azide Compounds 1-1 to 1-28
The azide compounds 1-1 to 1-28 are prepared from the corresponding primary amine compounds by the method described in example 2 of patent WO 2019/238057A1, and the products are used in the subsequent reaction without further isolation.
Figure BDA0002612427020000191
Example 2: preparation of polytriazole compounds I-1-I-28
Figure BDA0002612427020000192
The reaction solutions of the azide compounds 1-1 to 1-28 in example 1 were diluted to a concentration of 50mM with dimethyl sulfoxide, respectively, and used. Tripropargylamine was taken to prepare a 30mM dimethyl sulfoxide solution. Copper sulfate was prepared as an aqueous solution with a concentration of 60 mM. Sodium ascorbate was prepared as a 600mM aqueous solution. Tripropargylamine (30mM dimethyl sulfoxide solution, 20. mu.L, containing 0.6. mu. mol of tripropargylamine) and an azide compound R-N were precisely transferred to each well of a 96-well plate in this order using a pipette at room temperature (25 ℃ C.) in sequence3(Compounds 1-1 to 1-28 shown in the above figure, 50mM dimethyl sulfoxide-water mixed solution, 50. mu.L, containing 2.5. mu. mol of R-N3) Copper sulfate (60mM aqueous solution, 10. mu.L, containing 0.6. mu. mol of copper sulfate), sodium ascorbate (600mM aqueous solution, 20. mu.L, containing 12. mu. mol of sodium ascorbate). And (3) sealing the 96-pore plate by using a film, and oscillating at the rotating speed of 800rpm for 12 hours at the temperature of 40 ℃ to obtain the corresponding polytriazole ligand compound.
The product was characterized by hplc-ms, and the results are shown in table 1 below.
TABLE 1 Structure and characterization of polytriazole compounds I-1 to I-28
Figure BDA0002612427020000201
Figure BDA0002612427020000211
Figure BDA0002612427020000221
Example 3: preparation of ethyl (S) -2-azido-4-phenylbutyrate
Figure BDA0002612427020000222
8.53g (35mmol, 1.0 equivalent) of (S) -ethyl 2-amino-4-phenylbutyrate hydrochloride is placed in a glass eggplant-shaped bottle, 10.50g of potassium bicarbonate (105mmol, 3.0 equivalents) and 20mL of deionized water are added, and the mixture is stirred for 10 minutes at normal temperature by using a magnetic stirrer. After 10 minutes, 100mL of N, N-dimethylformamide was added under stirring, and after uniform mixing, 105mL of a t-butyl methyl ether solution of fluorosulfonyl azide (concentration: 0.36M, 36.75mmol of fluorosulfonyl azide, 1.05 equivalents) was quickly added, followed by reaction under stirring at room temperature for 20 minutes. After 20 minutes, the reaction of the raw material (S) -ethyl 2-amino-4-phenylbutyrate is determined to be finished by using ultra performance liquid chromatography-mass spectrometry or thin layer chromatography, and 150mL of ethyl acetate and 500mL of water are added into a bottle. After stirring was continued until all the solid was dissolved, 12M concentrated hydrochloric acid was added to the system until the pH of the aqueous phase of the system became 3 to 4, and then the whole liquid was transferred to a separatory funnel. The aqueous phase was discarded after the liquid phase had separated, and the organic phase was washed 3 times with 1M hydrochloric acid, 200mL each time, and 1 time with 150mL of a saturated sodium chloride solution. And drying the organic phase by using anhydrous sodium sulfate, filtering to remove the drying agent, and performing reduced pressure rotary evaporation on the residual organic phase to remove the solvent to obtain a crude product of the (S) -2-azido-4-phenylbutyric acid ethyl ester. The crude product was used directly in the next reaction without further purification.
Example 4: preparation of (2S,2 'S) -2,2' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (ethyl 4-phenylbutyrate)
Figure BDA0002612427020000231
All the crude ethyl (S) -2-azido-4-phenylbutyrate prepared in example 3 was placed in a glass eggplant-shaped bottle, 75mL of N, N-dimethylformamide was added thereto, and the mixture was stirred with a magnetic stirrer until the crude ethyl (S) -2-azido-4-phenylbutyrate was completely dissolved. 1.31g of propargylamine (10mmol, 1.0 eq) was weighed into the reactor and stirred well. 3.96g of sodium ascorbate (20mmol, 2.0 eq) was weighed into a beaker, dissolved by adding 30mL of deionized water, and adjusted to pH 5-6 by adding 1M hydrochloric acid, after which deionized water was added to dilute to a volume of 75 mL. To the sodium ascorbate solution was added 3.5mL of a copper sulfate solution (1M in concentration, containing 3.5mmol of copper sulfate, 0.35 equivalent), the mixture was shaken until the solution became a yellow suspension, and then the yellow suspension was quickly added to a reactor containing ethyl (S) -2-azido-4-phenylbutyrate and propargylamine, and the reaction was stirred at 40 ℃ for 2 hours. After the completion of the reaction is confirmed by using ultra performance liquid chromatography-mass spectrometry or thin layer chromatography, the reaction system is subjected to reduced pressure rotary evaporation to remove all the solvent. To the residue was added 200mL of ethyl acetate and 500mL of deionized water, and after stirring until all solids were dissolved, all liquids were transferred to a separatory funnel. The liquid was separated and the aqueous phase discarded, and the remaining organic phase was washed rapidly with 6M ammonia until the aqueous phase was colorless and transparent, and then washed 1 time with 200mL of a saturated sodium chloride solution acidified to pH 1 with hydrochloric acid. After washing, the organic phase is dried by anhydrous sodium sulfate, and the solvent is removed by reduced pressure rotary evaporation to obtain a crude product of (2S,2 'S) -2,2' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (4-phenylbutyric acid ethyl ester). Further purifying by silica gel column chromatography, wherein the mobile phase is a mixture of petroleum ether with a boiling range of 60-90 ℃ and ethyl acetate, and the mobile phase has a gradient of petroleum ether: ethyl acetate ═ 9: 1-1: 1. the product (2S,2 'S) -2,2' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (ethyl 4-phenylbutyrate) was obtained in a pure amount of 7.34g with a yield of 88% (based on the tripropargylamine) after purification. The compound is characterized by a high performance liquid chromatography-mass spectrometry combined method and a nuclear magnetic resonance method. Liquid chromatography retention time 1.85min, MS (ESI) [ M + H ]]+m/z＝831.42calc，831.52found。1H NMR(400MHz,CDCl3)δ7.98(s,3H),7.30–7.09(m,15H),5.29(td,J＝5.7,5.2,2.5Hz,3H),4.17(q,J＝7.1Hz,6H),3.82(s,6H),2.63–2.45(m,12H),1.22(t,J＝7.1Hz,9H).13C NMR(101MHz,CDCl3)δ168.86,144.25,139.47,128.77,128.67,126.64,123.72,62.39,62.12,47.21,34.08,31.88,14.15.
Example 5: preparation of (2S,2 'S) -2,2' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (4-phenylbutyric acid) hydrochloride (I-25)
Figure BDA0002612427020000241
7.30g (2S,2 'S) -2,2' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (4-phenylbutyric acid ethyl ester) (8.8mmol, 1.0 equivalent) obtained in example 4 was weighed out and placed in a glass eggplant-shaped bottle, and 75mL of tetrahydrofuran was added thereto, stirred and dissolved, and then placed in an ice-water bath at 0 ℃ to be cooled. 1.06g of lithium hydroxide (44.2mmol, 5.0 equiv.) was weighed out and dissolved in 75mL of deionized water, and the solid was cooled to 0 ℃ after complete dissolution. The lithium hydroxide solution obtained after cooling is rapidly added into a tetrahydrofuran solution of (2S,2 'S) -2,2' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (4-phenylbutyric acid ethyl ester), and stirred for reaction for 5 minutes in an ice bath. Immediately after complete conversion of the reaction as determined by hplc, a 12M hydrochloric acid acidification system was added dropwise to pH 1-2 while maintaining a stirred and ice bath environment. After the acidification was completed, the tetrahydrofuran was removed by rotary evaporation under reduced pressure, and the product gradually precipitated, followed by decantation to remove the aqueous phase. The solid product was washed three times with 1M hydrochloric acid and the aqueous phase was discarded altogether. To the residue was added 25mL of absolute ethanol, and after complete dissolution, 25mL of toluene was added, and after mixing well, all the solvent was removed by rotary evaporation under reduced pressure. 50mL of anhydrous ether was added to the remaining solid, sonicated for 15 minutes, rotary evaporated under reduced pressure to remove all solvent, finally heated to 60 ℃ and thoroughly removed using a vacuum pump to give the product (2S,2'S,2 "S) -2,2', 2" - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (4-phenylbutyric acid) hydrochloride in 6.50g pure form in 94% yield (as (2S,2'S,2 "S) -2,2', 2" - ((hypo-aminotris (methylene)) as hydrochlorideAminotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (ethyl 4-phenylbutyrate). The compound is characterized by a high performance liquid chromatography-mass spectrometry combined method and a nuclear magnetic resonance method. Liquid chromatography retention time 1.58min, MS (ESI) [ M-Cl ]]+m/z＝747.33calc，747.39found。1H NMR(400MHz,Methanol-d4)δ8.34(s,3H),7.30–7.09(m,15H),5.45–5.36(m,3H),4.49–4.35(m,6H),2.70–2.50(m,12H).13C NMR(101MHz,DMSO)δ170.55,140.60,129.37,128.90,128.87,128.67,126.63,62.26,47.05,33.26,31.79.
Example 6: preparation of ethyl 3-azido-3-methylbutyrate
Figure BDA0002612427020000242
1.82g (10mmol, 1.0 equivalent) of ethyl 3-amino-3-methylbutyrate hydrochloride is placed in a glass eggplant-shaped bottle, 3.00g of potassium bicarbonate (30mmol, 3.0 equivalents) and 5mL of deionized water are added immediately, and the mixture is stirred for 10 minutes at normal temperature by using a magnetic stirrer. After 10 minutes, 30mL of N, N-dimethylformamide was added under stirring, and after mixing uniformly, 30mL of a t-butyl methyl ether solution of fluorosulfonyl azide (concentration: 0.37M, 10.5mmol of fluorosulfonyl azide, 1.05 equivalent) was added rapidly, and the mixture was reacted for 20 minutes under stirring at room temperature. After 20 minutes, the reaction of the raw material ethyl 3-amino-3-methylbutyrate hydrochloride is determined to be finished by using ultra performance liquid chromatography-mass spectrometry or thin layer chromatography, and then 100mL of water is added into the bottle. After stirring was continued until all the solid was dissolved, 1M hydrochloric acid was added to the system to make the pH of the aqueous phase of the system 5 to 6, and then the whole liquid was transferred to a separatory funnel, and 100mL of dichloromethane and 500mL of water were added. The aqueous phase was discarded after the liquid had separated into layers, and the organic phase was washed 1 time with 300mL of 0.5M sodium carbonate solution, 2 times with 500mL of water, and 1 time with 200mL of saturated sodium chloride solution. And drying the organic phase by using anhydrous sodium sulfate, filtering to remove the drying agent, and performing reduced pressure rotary evaporation on the residual organic phase to remove the solvent to obtain a crude product of the 3-azido-3-methyl ethyl butyrate. The crude product was used directly in the next reaction without further purification.
Example 7: preparation of 3,3',3 "- ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (ethyl 3-methylbutyrate)
Figure BDA0002612427020000251
All the crude ethyl 3-azido-3-methylbutyrate product obtained in example 6 was placed in a glass eggplant-shaped bottle, 20mL of N, N-dimethylformamide was added thereto, and the mixture was stirred with a magnetic stirrer until it was completely dissolved. 375mg of tripropargylamine (2.85mmol, 1.0 eq) was weighed into the reactor and stirred well. 1.13g of sodium ascorbate (5.7mmol, 2.0 eq) was weighed into a beaker, dissolved by addition of 10mL of deionized water, and adjusted to pH 5-6 by addition of 1M hydrochloric acid, after which deionized water was added to dilute to a volume of 20 mL. 1.0mL of a copper sulfate solution (1M in concentration, containing 1.0mmol of copper sulfate, 0.35 equivalent) was added to the sodium ascorbate solution, the mixture was shaken until the solution became a yellow suspension, and then the yellow suspension was quickly added to a reactor containing ethyl 3-azido-3-methylbutyrate and propargylamine, and the mixture was stirred at 40 ℃ for 48 hours. After the completion of the reaction is confirmed by using ultra performance liquid chromatography-mass spectrometry or thin layer chromatography, the reaction system is subjected to reduced pressure rotary evaporation to remove all the solvent. To the residue were added 150mL of ethyl acetate and 500mL of deionized water, and after stirring until all solids were dissolved, all liquids were transferred to a separatory funnel. The liquid is separated, the water phase is discarded, the residual organic phase is quickly washed by 2M ammonia water until the water phase is colorless and transparent, then the organic phase is washed by 2 times, each time is 300mL, and finally the organic phase is washed by 1 time by 200mL of saturated sodium chloride solution. After washing, the organic phase is dried by anhydrous sodium sulfate, and the solvent is removed by reduced pressure rotary evaporation to obtain a crude product of 3,3' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (ethyl 3-methylbutyrate). Further purification was performed using silica gel column chromatography with a mobile phase of dichloromethane and methanol mixture and a mobile phase gradient of pure dichloromethane to dichloromethane: methanol 95: 5. The product, 3' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (ethyl 3-methylbutyrate) was obtained in a pure form of 1.27g with a yield of 69% (based on the tripropargylamine) after purification. The compound is characterized by a high performance liquid chromatography-mass spectrometry combined method and a nuclear magnetic resonance method. Liquid chromatography retention time1.53min，MS(ESI)[M+H]+m/z＝645.38calc，645.40found。1H NMR(400MHz,CDCl3)δ7.89(s,3H),4.01(q,J＝7.2Hz,6H),3.74(s,6H),2.98(s,6H),1.78(s,18H),1.17–1.09(m,9H).13C NMR(101MHz,CDCl3)δ185.35,169.52,143.08,123.80,122.01,60.89,60.68,59.75,47.03,46.54,45.93,28.09,14.16.
Example 8: preparation of 3,3',3 "- ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (3-methylbutyric acid) (I-20, TIVTA)
Figure BDA0002612427020000261
1.11g of 3,3',3 "- ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) ethyl tris (3-methylbutyrate) (1.7mmol, 1.0 equivalent) obtained in example 7 was weighed out and placed in a glass eggplant-shaped bottle, 10mL of tetrahydrofuran was added thereto, and the mixture was stirred and then placed in an ice-water bath at 0 ℃ to be cooled. 0.21g of lithium hydroxide (8.6mmol, 5.0 equivalents) was weighed out and dissolved in 10mL of deionized water, and the solid was cooled to 0 ℃ after complete dissolution. The lithium hydroxide solution obtained after cooling is rapidly added into a tetrahydrofuran solution of 3,3' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (ethyl 3-methylbutyrate), and stirred for reaction for 70 minutes in an ice bath. Immediately after complete conversion of the reaction as determined by hplc, a 12M hydrochloric acid acidification system was added dropwise to pH 5-6 while maintaining a stirred and ice bath environment. After the acidification was completed, all the solvent was removed by rotary evaporation under reduced pressure, and the residue was separated by preparative high performance liquid chromatography to give 0.20g of pure product 3,3',3 "- ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (3-methylbutyrate) hydrochloride in 20% yield (based on 3,3', 3" - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (ethyl 3-methylbutyrate). The compound is characterized by a high performance liquid chromatography-mass spectrometry combined method and a nuclear magnetic resonance method. Liquid chromatography retention time 1.22min, MS (ESI) [ M-Cl ]]+m/z＝561.29calc，561.35found。1H NMR(400MHz,D2O)δ8.36(s,3H),4.51(s,6H),3.09(s,6H),1.79(s,18H).13C NMR(101MHz,DMSO-d6)δ170.80,135.53,125.63,60.06,46.09,45.41,27.55.
Example 9: preparation of trans-4-azidocyclohexanecarboxylic acid methyl ester
Figure BDA0002612427020000271
7.75g (40mmol, 1.0 equivalent) of trans-4-aminocyclohexanecarboxylic acid methyl ester hydrochloride is put into a glass eggplant-shaped bottle, 10.44g of potassium bicarbonate (120mmol, 3.0 equivalents) and 20mL of deionized water are added, and the mixture is stirred for 10 minutes by a magnetic stirrer at normal temperature. After 10 minutes, 90mL of N, N-dimethylformamide was added under stirring, and after uniform mixing, 84mL of a t-butyl methyl ether solution of fluorosulfonyl azide (concentration: 0.50M, 42mmol of fluorosulfonyl azide, 1.05 equivalent) was rapidly added, and the mixture was reacted under stirring at room temperature for 30 minutes. After 30 minutes, using ultra performance liquid chromatography-mass spectrometry or thin layer chromatography to determine that the raw material trans-4-aminocyclohexanecarboxylic acid methyl ester hydrochloride is reacted, and then adding 200mL of water into the bottle. After stirring was continued until all the solid was dissolved, 1M hydrochloric acid was added to the system to make the pH of the aqueous phase of the system 2 to 3, and then the whole liquid was transferred to a separatory funnel, and 200mL of ethyl acetate and 400mL of water were added. The aqueous phase was discarded after the liquid had separated into layers, and the organic phase was washed 1 time with 300mL of 0.5M sodium carbonate solution, 2 times with 300mL of water, and 1 time with 300mL of saturated sodium chloride solution. And drying the organic phase by using anhydrous sodium sulfate, filtering to remove the drying agent, and performing reduced pressure rotary evaporation on the residual organic phase to remove the solvent to obtain a crude product of the trans-4-azido methyl cyclohexanecarboxylate. The crude product was used directly in the next reaction without further purification.
Example 10: preparation of (1r,1' r,4r,4' r) -4,4' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (cyclohexane-1-carboxylic acid methyl ester)
Figure BDA0002612427020000281
All the trans-4-azido cyclohexanecarboxylic acid methyl ester crude products obtained in example 6 were put in a glass eggplant-shaped bottle, and 20mL of N, N-dimethylformamide was addedAnd stirred using a magnetic stirrer until completely dissolved. 1.21g of tripropargylamine (9.2mmol, 1.0 eq) was weighed into the reactor and stirred well. 3.64g of sodium ascorbate (18.4mmol, 2.0 eq) was weighed into a beaker, dissolved by addition of 10mL of deionized water, and adjusted to pH 5-6 by addition of 1M hydrochloric acid, after which deionized water was added to dilute to a volume of 50 mL. 3.2mL of a copper sulfate solution (1M in concentration, containing 3.2mmol of copper sulfate, 0.35 equivalent) was added to the sodium ascorbate solution, the mixture was shaken until the solution became a yellow suspension, and then the yellow suspension was quickly added to a reactor containing trans-4-azidocyclohexanecarboxylate and tripropargylamine, and the reaction was stirred at 40 ℃ for 2 hours. After completion of the reaction was confirmed using ultra performance liquid chromatography-mass spectrometry or thin layer chromatography, 200mL of dichloromethane was added to the residue, all liquids were transferred to a separatory funnel after stirring until all solids were dissolved, and 500mL of sodium carbonate solution (concentration 0.1M) was added. The liquid is separated into layers and the water phase is discarded, the residual organic phase is quickly washed by 2M ammonia water until the water phase is colorless and transparent, then is washed by sodium carbonate solution (with the concentration of 0.1M) for 3 times, each time is 300mL, and finally is washed by 200mL of saturated sodium chloride solution for 1 time. After washing, the organic phase is dried by anhydrous sodium sulfate, and the solvent is removed by reduced pressure rotary evaporation to obtain a crude product (1r,1' r,4r,4' r) -4,4' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (cyclohexane-1-carboxylic acid methyl ester). Further purifying by recrystallization, wherein the recrystallization solvent is a mixed solvent of dichloromethane and ethyl acetate. The product (1r,1' r,4r,4' r) -4,4' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (cyclohexane-1-carboxylic acid methyl ester) was obtained in a pure amount of 5.20g with a yield of 83% (based on the tripropargylamine) by purification. The compound is characterized by a high performance liquid chromatography-mass spectrometry combined method and a nuclear magnetic resonance method. Liquid chromatography retention time 1.44min, MS (ESI) [ M + H ]]+m/z＝681.38calc，681.40found。1H NMR(400MHz,CDCl3)δ7.78(s,3H),4.41(tt,J＝12.2,4.1Hz,3H),3.72(s,6H),3.68(s,9H),2.39(tt,J＝12.1,3.8Hz,3H),2.34–2.24(m,6H),2.18(dd,J＝14.0,3.7Hz,6H),1.84(qd,J＝12.8,3.4Hz,6H),1.72–1.56(m,6H).13C NMR(101MHz,CDCl3)δ175.18,143.37,121.83,59.10,51.80,47.01,41.87,32.31,27.70.
Example 11: preparation of (1r,1' r,4r,4' r) -4,4' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (cyclohexane-1-carboxylic acid) (trans-TCCTA)
Figure BDA0002612427020000291
2.11g (1r,1' r,4r,4' r) -4,4' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (cyclohexane-1-carboxylic acid methyl ester) (3.1mmol, 1.0 equivalent) obtained in example 4 was weighed out and placed in a glass eggplant-shaped bottle, and 20mL of tetrahydrofuran was added thereto, stirred and then placed in an ice-water bath at 0 ℃ to be cooled. 0.37g of lithium hydroxide (15.5mmol, 5.0 equivalents) was weighed out and dissolved in 20mL of deionized water, and the solid was cooled to 0 ℃ after complete dissolution. The lithium hydroxide solution obtained after cooling is quickly added into a tetrahydrofuran suspension of (1r,1' r,4r,4' r) -4,4' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substitution)) tris (cyclohexane-1-carboxylic acid methyl ester), and the mixture is stirred and reacted for 15 minutes in an ice bath. Immediately after complete conversion of the reaction as determined by hplc, a 12M hydrochloric acid acidification system was added dropwise to pH 1-2 while maintaining a stirred and ice bath environment. After acidification is finished, tetrahydrofuran is removed by rotary evaporation under reduced pressure, products are gradually separated out, and then the filtrate is filtered and discarded. The filter cake was washed three times with 1M hydrochloric acid and the aqueous phase was discarded completely. The residue was thoroughly removed of all the solvent by means of a vacuum pump to obtain 1.98g of a pure product of (1r,1' r,4r,4' r) -4,4' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (cyclohexane-1-carboxylic acid) in a yield of 1.98g>99% (based on (1r,1' r,1 "r, 4r,4' r, 4" r) -4,4',4 "- ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (cyclohexane-1-carboxylic acid methyl ester). The compound is characterized by a high performance liquid chromatography-mass spectrometry combined method and a nuclear magnetic resonance method. Liquid chromatography retention time 1.17min, MS (ESI) [ M + H ]]+m/z＝639.34calc，639.38found。1H NMR(400MHz,D2O)δ7.90(s,3H),4.48(td,J＝12.8,12.0,6.0Hz,3H),3.82(s,6H),2.30–2.03(m,15H),1.79(tt,J＝12.2,7.4Hz,6H),1.67–1.47(m,6H).13C NMR(101MHz,CDCl3/CF3COOD)δ181.93,138.69,127.42,64.16,47.09,41.54,31.56,27.09.
Effect example 1: relative activity test of triazole ligand (compounds I-1-I-28)
Figure BDA0002612427020000292
The compounds I-1 to I-28 prepared in example 2 were mixed with an equimolar amount of copper sulfate and diluted with water to a 400. mu.M solution for use. 4.87g of anhydrous citric acid and 7.0g of anhydrous disodium hydrogen phosphate are dissolved in deionized water, and the volume is constant to 100mL, so that the pH value of the citric acid-disodium hydrogen phosphate buffer solution is 6. Preparing 3-azido-7-hydroxycoumarin into dimethyl sulfoxide solution with the concentration of 8mM, preparing 3-acetaminophenylacetylene into dimethyl sulfoxide solution with the concentration of 8mM, and preparing sodium ascorbate into citric acid-disodium hydrogen phosphate buffer solution with the pH value of 6 into 40mM aqueous solution containing buffer salt. 3-acetamidophenylacetylene (8mM dimethyl sulfoxide solution, 25. mu.L, containing 3-acetamidophenylacetylene 0.2. mu. mol), 3-azido-7-hydroxycoumarin (8mM dimethyl sulfoxide solution, 25. mu.L, containing 3-azido-7-hydroxycoumarin 0.2. mu. mol), 1:1 polytriazole-copper sulfate complex (aqueous solution of polytriazole and copper sulfate with concentration of 400 μ M, 25 μ L, copper sulfate 0.01 μmol, polytriazole ligand 0.01 μmol), and sodium ascorbate (aqueous solution of 40mM buffer system with pH 6, 25 μ L, containing sodium ascorbate 1 μmol, citric acid 6.35 μmol, and disodium hydrogen phosphate 12.43 μmol). After the 96-well plate was sealed with a film, it was immediately placed in a multifunctional microplate reader to measure the fluorescence intensity (excitation wavelength 430nm, emission wavelength 490nm) after shaking at 800rpm for 1 hour at 40 ℃.
The ligand of the fluorescent reference system is replaced by an equimolar amount of TBTA (tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine), the amounts and concentrations of other reactants and catalysts are kept unchanged, and the obtained fluorescence intensity values of other ligands are normalized with respect to the reference system. Neither the reactants nor the catalyst in this reaction are known to fluoresce at 490nm at an excitation wavelength of 430nm, so that at the low concentrations represented by current systems, the product concentration is directly proportional to the fluorescence intensity according to lambert-beer's law, and so the relative yield can be characterized relative to the fluorescence intensity. The results are shown in table 2 below.
TABLE 2 comparison of the effectiveness of Compounds I-1 to I-28 in catalyzing copper-catalyzed azide-terminal alkyne cycloaddition reactions
Figure BDA0002612427020000301
Figure BDA0002612427020000311
Figure BDA0002612427020000321
Effect example 2: comparison of the Activity of (2S,2 'S) -2,2' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (4-phenylbutyric acid) hydrochloride with three commonly used copper-catalyzed azido-terminal alkyne cycloaddition ligands
267mg of 3 '-azido-3' -deoxythymidine (0.5mmol) was weighed out and dissolved in a small amount of dimethyl sulfoxide, and the volume was adjusted to 50mL to obtain 20mM 3 '-azido-3' -deoxythymidine solution as a dimethyl sulfoxide solution for further use. 159mg of 3-acetaminophenylacetylene (0.5mmol) is weighed and dissolved in a small amount of dimethyl sulfoxide, and the volume is determined to 50mL to obtain 20mM 3-acetaminophenylacetylene and obtain dimethyl sulfoxide solution for later use. 250mg (1.0mmol) of copper sulfate pentahydrate is weighed and dissolved in a small amount of water, and the volume is determined to be 100mL to obtain 10mM copper sulfate solution for standby, and the solution is quantitatively diluted to 0.5mM concentration before use. 198mg sodium ascorbate (1.0mmol) was dissolved in a small amount of deionized water and made up to 50mL to obtain 20mM sodium ascorbate solution for further use. 783mg of (2S,2 'S) -2,2' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (4-phenylbutyric acid) hydrochloride (1.0mmol) and 160mg of sodium hydroxide (4.0mmol) were weighed out together in a beaker, and dissolved in 100mL of deionized water to give a 10mM (2S,2 'S) -2,2' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (4-phenylbutyric acid) trisodium salt solution (hereinafter referred to simply as (S) -TPBTA), which was diluted with deionized water to a concentration of 0.33mM in use. 639mg of (1r,1' r,4r,4' r) -4,4' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (cyclohexane-1-carboxylic acid) (1.0mmol) was weighed out together with 120mg of sodium hydroxide (3.0mmol) in a beaker, 100mL of deionized water was added to dissolve the mixture to obtain a solution of (1r,1' r,4r,4' r) -4,4' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (cyclohexane-1-carboxylic acid) trisodium salt (hereinafter referred to as trans-TCCTA), and the solution was diluted with deionized water to a concentration of 0.33mM for use. THPTA, BTTAA, BTTP, 3' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (3-methylbutyric acid) hydrochloride (TIVTA) (structural formula shown below) is dissolved in a proper amount of deionized water respectively to obtain a 0.33mM aqueous solution for later use.
Figure BDA0002612427020000331
3 '-azido-3' -deoxythymidine (20mM dimethyl sulfoxide solution, 25. mu.L, containing 0.5. mu. mol of 3 '-azido-3' -deoxythymidine), 3-acetamidophenylacetylene (20mM dimethyl sulfoxide solution, 25. mu.L, containing 0.5. mu. mol of 3-acetamidophenylacetylene), four ligand solutions to be tested or deionized water (0.33mM aqueous solution or deionized water, 15. mu.L, containing 0.005. mu. mol of ligand or not as a reference), copper sulfate or deionized water (0.5mM aqueous solution or deionized water, 10. mu.L, containing 0.005. mu. mol of copper sulfate or not), sodium ascorbate (20mM aqueous solution, 25. mu.L, containing 0.5. mu. mol of sodium ascorbate) were precisely transferred into each well of a 96-well plate in sequence at room temperature (25 ℃ C.) using a pipette gun. After the 96-pore plate is sealed by film pasting, the reaction product 3-acetaminophenylacetylene is respectively measured by a high performance liquid chromatography-mass spectrometry method after oscillation is carried out for 6 hours at the temperature of 30 ℃ and at the rotating speed of 800 rpm. The conversion was determined using the area of the ultraviolet absorption peak of the liquid chromatogram corresponding to 3-acetamidophenylacetylene in a reference system without any catalyst as a standard of 100%, at which time the conversion was 0%, and it was considered that the concentration of the reactant at this extremely dilute concentration was proportional to the area of the ultraviolet absorption peak thereof according to the Lambert-beer law. The results are shown in Table 3.
TABLE 3 comparison of the Effect of (S) -TPBTA on copper-catalyzed azide-terminal alkyne cycloaddition with three other commonly used ligands
Copper addition (equivalent weight)*) Ligand species and addition amount Conversion rate
0 Is free of 0
0.01 Is free of 2.2％
0.01 0.01 equivalent*THPTA 27.3％
0.01 0.01 equivalent*BTTAA 46.7％
0.01 0.01 equivalent*BTTP 49.6％
0.01 0.01 equivalent*(S)-TPBTA 76.2％
0.01 0.01 equivalent*TIVTA 93.5％
0.01 0.01 equivalent*trans-TCCTA 67.2％
*In this table, the equivalent weight is based on 1.0 equivalent of 3-acetamidophenylacetylene as a reactant
The catalytic effects of (S) -TPBTA, TIVTA and trans-TCCTA which are easily obtained from the data in the table 3 under the reaction condition are obviously higher than those of other three commonly used copper-catalyzed azide-terminal alkyne cycloaddition reaction ligands.
Effect example 3: comparison of the activity of (2S,2 'S) -2,2' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (4-phenylbutyric acid) hydrochloride with three commonly used copper-catalyzed azido-terminal alkyne cycloaddition ligands in a biomimetic environment
Figure BDA0002612427020000341
31.21g of sodium dihydrogen phosphate dihydrate (0.2mol) was weighed, dissolved in a small amount of deionized water, and then the volume was adjusted to 1L using deionized water to obtain 0.2M sodium dihydrogen phosphate solution for use. 71.64g of disodium hydrogen phosphate dodecahydrate (0.2mol) were weighed out, dissolved in a small amount of deionized water, and then made to volume of 1L using deionized water to obtain a 0.2M disodium hydrogen phosphate solution for use. 9.5mL of 0.2M sodium dihydrogen phosphate solution and 40.5mL of 0.2M disodium hydrogen phosphate solution are transferred, mixed uniformly and then the volume is determined to be 100mL by using deionized water, thus obtaining 0.1M disodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution with the pH value of 7.4. 250mg (1.0mmol) of copper sulfate pentahydrate is weighed and dissolved in a small amount of water, and the volume is determined to be 100mL to obtain 10mM copper sulfate solution for standby, and the solution is quantitatively diluted to 0.25mM before use. 99mg of sodium ascorbate (0.5mmol) was dissolved in a small amount of 0.1M disodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution with pH 7.4, and the buffer solution was used to a volume of 50mL to obtain a 10mM sodium ascorbate solution with pH 7.4 for further use. And preparing a proper amount of 3-azido-7-hydroxycoumarin into a dimethyl sulfoxide solution with the concentration of 2mM, and preparing a proper amount of propargyl alcohol into a water solution with the concentration of 0.2 mM. 783mg of (2S,2 'S) -2,2' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (4-phenylbutyric acid) hydrochloride (1.0mmol) and 160mg of sodium hydroxide (4.0mmol) were weighed out together in a beaker, and dissolved in 100mL of deionized water to give a 10mM (2S,2 'S) -2,2' - ((nitrilotris (methylene)) tris (1H-1,2, 3-triazole-4, 1-substituted)) tris (4-phenylbutyric acid) trisodium salt solution (hereinafter referred to simply as (S) -TPBTA), which was diluted with deionized water to a concentration of 0.2mM in use. Dissolving THPTA, BTTAA and BTTP in deionized water to obtain 0.2mM aqueous solution.
Propargyl alcohol (0.2mM aqueous solution, 25. mu.L containing 5nmol of propargyl alcohol), 3-azido-7-hydroxycoumarin (2mM dimethyl sulfoxide solution, 5. mu.L containing 10nmol of 3-azido-7-hydroxycoumarin), four ligand solutions to be tested or deionized water (0.2mM aqueous solution or deionized water, 25. mu.L containing 5nmol of ligand or no ligand as a reference), copper sulfate or deionized water (0.25mM aqueous solution or deionized water, 20. mu.L containing 5nmol of copper sulfate or no copper sulfate), sodium ascorbate (10mM aqueous buffer system with pH 7.4, 25. mu.L containing 0.25. mu. mol of sodium ascorbate, and 2.5. mu. mol of phosphate ion in each form) were precisely transferred into each well of a 96-well plate in sequence at room temperature (25 ℃ C.) using a pipette gun. Immediately after adding all the liquid, the 96-well plate was placed in a multifunctional microplate reader, shaken at 800rpm for 150 minutes at 40 ℃ and the fluorescence intensity (excitation wavelength 430nm, emission wavelength 490nm) was measured every 1 minute. Neither the reactants nor the catalyst in this reaction are known to fluoresce at 490nm at an excitation wavelength of 430nm, so that at the low concentrations represented by current systems, the product concentration is directly proportional to the fluorescence intensity according to lambert-beer's law, and so the relative yield can be characterized relative to the fluorescence intensity.
The above experimental operation was repeated 3 times, and the obtained data were averaged and plotted with time as the horizontal axis and the average relative fluorescence intensity as the vertical axis to obtain FIG. 1. Wherein the blank experimental group represents that no copper sulfate catalyst and ligand are added and equal volume of deionized water is used instead; the ligand-free group represents the addition of only copper sulfate catalyst without ligand, and the volume of ligand solution is replaced by equal volume of deionized water. Error bars represent standard deviations of the data from triplicate experiments.
As is readily apparent from FIG. 1, the reaction rate is very low without addition of a ligand, and the reaction is considered to be almost impossible, while (S) -TPBTA can still very effectively accelerate the copper-catalyzed azide-terminal alkyne cycloaddition reaction under the condition of a buffer solution with extremely low substrate concentration, and the effect is remarkably better than three currently-used ligands, namely THPTA, BTTAA and BTTP.

Claims (13)

1. A polytriazole compound shown as a formula I or a salt thereof,
Figure FDA0002612427010000011
wherein R is1is-C (═ O) OR1-1Substituted C1-C10Alkyl, unsubstituted or R1-2Substituted C1-C10Alkyl, hydroxy substituted C4-C10Alkyl, or, unsubstituted or R1-3Substituted C3-C14A cycloalkyl group;
when R is1is-C (═ O) OR1-1Substituted C1-C10Alkyl, wherein C1-C10Alkyl is optionally substituted by R1-4Substitution;
R1-1is hydrogen or C1-C6An alkyl group;
R1-2is unsubstituted or R1-2aSubstituted C3-C10Cycloalkyl radicals or
Figure FDA0002612427010000012
R1-3Is hydroxy, unsubstituted or R1-3aSubstituted C1-C6Alkyl OR-C (═ O) OR1-3b；
R1-4Is unsubstituted or R1-4aSubstituted C6-C10Aryl, or, unsubstituted or R1-4bSubstituted C3-C10A cycloalkyl group;
R1-2ais hydroxy or C1-C6An alkyl group;
R1-2b、R1-2cand R1-3bIndependently is hydrogen or C1-C6An alkyl group;
R1-3ais a hydroxyl group;
R1-4aand R1-4bIndependently is C1-C6An alkyl group;
the substituents are 1 or more, and when there are more, the same or different.
2. The polytriazole compound of formula I or a salt thereof, as defined in claim 1,
when R is1is-C (═ O) OR1-1Substituted C1-C10When the alkyl is substituted, the radical-C (═ O) OR1-1The number of (a) is 1,2 or 3;
and/or when R1is-C (═ O) OR1-1Substituted C1-C10When alkyl, said C1-C10Alkyl is C1-C8An alkyl group;
and/or when R1Is unsubstituted or R1-2Substituted C1-C10When it is alkyl, said R1-2The number of (a) is 1,2 or 3;
and/or when R1Is unsubstituted or R1-2Substituted C1-C10When alkyl, said C1-C10Alkyl is C1-C6An alkyl group;
and/or when R1Is hydroxy-substituted C4-C10When the alkyl is adopted, the number of the hydroxyl is 1,2 or 3;
and/or when R1Is hydroxy-substituted C4-C10When alkyl, said C4-C10Alkyl is C4-C8An alkyl group;
and/or when R1Is unsubstituted or R1-3Substituted C3-C14When the cycloalkyl group is, said R1-3The number of (a) is 1,2 or 3;
and/or when R1Is unsubstituted or R1-3Substituted C3-C14When there is a cycloalkyl group, said C3-C14Cycloalkyl being C3-C14Monocyclic cycloalkyl, C3-C14Spirocyclic cycloalkyl radical, C3-C14Cycloalkyl having condensed rings or C3-C14Bridged cycloalkyl radicals, which may also be C3-C14Monocyclic cycloalkyl or C3-C14A bridged cycloalkyl group;
and/or when R1-1Is C1-C6When alkyl, said C1-C6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;
and/or when R1-2Is unsubstituted or R1-2aSubstituted C3-C10When the cycloalkyl group is, said R1-2aThe number of (a) is 1,2 or 3;
and/or when R1-2Is unsubstituted or R1-2aSubstituted C3-C10When there is a cycloalkyl group, said C3-C10Cycloalkyl being C3-C10Monocyclic cycloalkyl, C3-C10Spirocyclic cycloalkyl radical, C3-C10Cycloalkyl having condensed rings or C3-C10Bridged cycloalkyl radicals, which may also be C3-C10A monocyclic cycloalkyl group;
and/or when R1-3Is unsubstituted or R1-3aSubstituted C1-C6When it is alkyl, said R1-3aThe number of (a) is 1,2 or 3;
and/or when R1-3Is unsubstituted or R1-3aSubstituted C1-C6When alkyl, said C1-C6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;
and/orWhen R is1-4Is unsubstituted or R1-4aSubstituted C6-C10When aryl is said to R1-4aThe number of (a) is 1,2 or 3;
and/or when R1-4Is unsubstituted or R1-4aSubstituted C6-C10When aryl, said C6-C10Aryl is phenyl;
and/or when R1-4Is unsubstituted or R1-4bSubstituted C3-C10When the cycloalkyl group is, said R1-4bThe number of (a) is 1,2 or 3;
and/or when R1-4Is unsubstituted or R1-4bSubstituted C3-C10When there is a cycloalkyl group, said C3-C10Cycloalkyl being C3-C10Monocyclic cycloalkyl, C3-C10Spirocyclic cycloalkyl radical, C3-C10Cycloalkyl having condensed rings or C3-C10Bridged cycloalkyl radicals, which may also be C3-C10A monocyclic cycloalkyl group;
and/or when R1-2aIs C1-C6When alkyl, said C1-C6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;
and/or when R1-2b、R1-2cAnd R1-3bIndependently is C1-C6When alkyl, said C1-C6Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl;
and/or when R1-4aAnd R1-4bIndependently is C1-C6When alkyl, said C1-C6Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl;
and/or the salt of the polytriazole compound shown in the formula I is an acid-protected amine salt or a base addition salt.
3. The polytriazole compound of formula I or a salt thereof, as defined in claim 2,
when R is1is-C (═ O) OR1-1Substituted C1-C10When alkyl, said C1-C10The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, or,
Figure FDA0002612427010000031
Figure FDA0002612427010000032
And can be
Figure FDA0002612427010000033
And/or when R1Is unsubstituted or R1-2Substituted C1-C10When alkyl, said C1-C10Alkyl is ethyl or n-pentyl;
and/or when R1Is hydroxy-substituted C4-C10When alkyl, said C4-C10The alkyl group is n-butyl, isobutyl, sec-butyl, tert-butyl or n-octyl, and may be
Figure FDA0002612427010000034
And/or when R1Is unsubstituted or R1-3Substituted C3-C14Cycloalkyl radical, said C3-C14Cycloalkyl being C3-C14When monocyclic cycloalkyl is present, said C3-C14Monocyclic cycloalkyl being C3-C6Monocyclic cycloalkyl which may be cyclobutyl, cyclopentyl or cyclohexyl, or cyclopentyl or cyclohexyl;
and/or when R1Is unsubstituted or R1-3Substituted C3-C14Cycloalkyl radical, said C3-C14Cycloalkyl being C3-C14When the bridged cycloalkyl is present, said C3-C14Bridged cycloalkyl radicals being C7-C10Bridged cycloalkyl, which may also be adamantyl;
and/or when R1-1Is C1-C6When alkyl, said C1-C6Alkyl is methyl or ethyl;
and/or when R1-2Is unsubstituted or R1-2aSubstituted C3-C10Cycloalkyl radical, said C3-C10Cycloalkyl being C3-C10When monocyclic cycloalkyl is present, said C3-C10Monocyclic cycloalkyl being C3-C6Monocyclic cycloalkyl, which in turn can be cyclohexyl;
and/or when R1-3Is unsubstituted or R1-3aSubstituted C1-C6When alkyl, said C1-C6Alkyl is methyl or isopropyl;
and/or when R1-4Is unsubstituted or R1-4bSubstituted C3-C10Cycloalkyl radical, said C3-C10Cycloalkyl being C3-C10When monocyclic cycloalkyl is present, said C3-C10Monocyclic cycloalkyl being C3-C6Monocyclic cycloalkyl, which in turn may be cyclopropyl;
and/or when R1-2b、R1-2cAnd R1-3bIndependently is C1-C6When alkyl, said C1-C6Alkyl is independently methyl;
and/or when R1-4aAnd R1-4bIndependently is C1-C6When alkyl, said C1-C6Alkyl is independently methyl;
and/or, when the salt of the polytriazole compound shown in the formula I is the salt of acid-protected amine, the acid is an inorganic acid and/or an organic acid;
and/or, when the salt of the polytriazole compound shown in the formula I is a base addition salt, the base addition salt is a salt of an inorganic base and/or a salt of an organic base.
4. The polytriazole compound of formula I or a salt thereof, according to claim 3,
when R is1is-C (═ O) OR1-1Substituted C1-C10When the alkyl is substituted, the radical-C (═ O) OR1-1Substituted C1-C10Alkyl is
Figure FDA0002612427010000041
Figure FDA0002612427010000042
And can be
Figure FDA0002612427010000043
Figure FDA0002612427010000044
And/or when R1Is unsubstituted or R1-2Substituted C1-C10When alkyl, said is unsubstituted or R1-2Substituted C1-C10Alkyl is
Figure FDA0002612427010000045
And/or when R1Is hydroxy-substituted C4-C10When it is alkyl, said hydroxy-substituted C4-C10Alkyl is
Figure FDA0002612427010000046
And can be
Figure FDA0002612427010000047
Figure FDA0002612427010000048
And/or when R1Is unsubstituted or R1-3Substituted C3-C14When cycloalkyl is said unsubstituted or R1-3Substituted C3-C14Cycloalkyl is
Figure FDA0002612427010000049
Figure FDA00026124270100000410
Figure FDA00026124270100000411
And can be
Figure FDA00026124270100000412
Figure FDA0002612427010000051
And/or, when the salt of the polytriazole compound shown in the formula I is a salt of acid-protected amine, the acid is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, tartaric acid and oxalic acid;
and/or, when the salt of the polytriazole compound shown in the formula I is a base addition salt, the base addition salt is one or more of a sodium salt, a potassium salt, a lithium salt, an ammonium salt, a diethylamine salt and a triethylamine salt.
5. Polytriazoles of formula I or their salts, as claimed in claim 1, wherein R is1、R2And R3Is defined as any one of the following schemes:
scheme 1:
R1is-C (═ O) OR1-1Substituted C1-C10An alkyl group;
scheme 2:
R1is hydroxy-substituted C4-C10An alkyl group;
scheme 3:
R1is unsubstituted or R1-3Substituted C3-C14A cycloalkyl group;
scheme 4:
R1is unsubstituted or R1-3Substituted C3-C14Cycloalkyl radical, said C3-C14Cycloalkyl is cyclopentyl or cyclohexyl;
scheme 5:
R1is-C (═ O) OR1-1Substituted C1-C10Alkyl radical, R1-2Substituted C1-C10Alkyl, hydroxy substituted C4-C10Alkyl, or, R1-3Substituted C3-C14A cycloalkyl group;
when R is1is-C (═ O) OR1-1Substituted C1-C10Alkyl, wherein C1-C10Alkyl is optionally substituted by R1-4Substitution;
R1-1is hydrogen;
R1-2is R1-2aSubstituted C3-C10Cycloalkyl radicals or
Figure FDA0002612427010000052
R1-3Is hydroxy, R1-3aSubstituted C1-C6Alkyl or-C (═ O) OH;
R1-4is unsubstituted or R1-4aSubstituted C6-C10Aryl, or unsubstituted C3-C10A cycloalkyl group;
R1-2ais a hydroxyl group;
R1-2band R1-2cIndependently is C1-C6An alkyl group;
R1-3ais a hydroxyl group;
R1-4ais C1-C6An alkyl group;
scheme 6:
R1is-C (═ O) OR1-1Substituted C1-C10Alkyl, or, R1-3Substituted C3-C14A cycloalkyl group;
when R is1is-C (═ O) OR1-1Substituted C1-C10Alkyl, wherein C1-C10Alkyl is optionally substituted by R1-4Substitution;
R1-1is hydrogen;
R1-3is-C (═ O) OH;
R1-4is unsubstituted C6-C10An aryl group;
scheme 7:
the compound shown in the formula I is raceme;
scheme 8:
when the compound shown in the formula I contains chiral carbon atoms, the configuration of the chiral carbon atoms is S configuration or R configuration;
scheme 9:
when cis-trans isomers exist in the compound shown in the formula I, the configuration of the compound shown in the formula I is cis or trans.
6. The polytriazole compound of formula I or a salt thereof, as defined in any one of claims 1-5, wherein the polytriazole compound of formula I or a salt thereof is selected from the group consisting of,
wherein the carbon atom with "-" or "-" is a chiral carbon atom, which is in S configuration, R configuration or a mixture of the two;
Figure FDA0002612427010000061
Figure FDA0002612427010000071
Figure FDA0002612427010000081
Figure FDA0002612427010000091
7. the polytriazole compound of formula I or a salt thereof, as defined in any one of claims 1-5, wherein the polytriazole compound of formula I or a salt thereof is selected from the group consisting of,
Figure FDA0002612427010000092
Figure FDA0002612427010000101
Figure FDA0002612427010000111
8. use of a polytriazole compound of formula I, or a salt thereof, as defined in any one of claims 1-7, in catalyzing an azide-terminal alkyne cycloaddition reaction, which may be a copper-catalyzed azide-terminal alkyne cycloaddition reaction.
9. The use according to claim 8, characterized in that said use comprises the steps of: in a solvent, in the presence of a reducing agent, copper salt and a ligand, carrying out cycloaddition reaction shown in the specification on an azide compound containing a fragment shown in a formula II and an alkyne-terminated compound containing a fragment shown in a formula III to obtain a compound containing a fragment IV; the ligand is a compound shown as a formula I or a salt thereof;
Figure FDA0002612427010000121
wherein R is1As defined in any one of claims 1 to 7.
10. The use according to claim 9,
the solvent is one or more of water, a sulfoxide solvent, an amide solvent, an alcohol solvent, a nitrile solvent, an ether solvent and N-methylpyrrolidone, and can also be tetrahydrofuran, N-dimethylformamide, a mixed solvent of water and dimethyl sulfoxide, a mixed solvent of water and N, N-dimethylformamide, a mixed solvent of water and tert-butyl alcohol, a mixed solvent of water and N-methylpyrrolidone and a mixed solvent of methyl tert-butyl ether-water-dimethyl sulfoxide;
and/or the reducing agent is one or more of ascorbic acid and/or salt thereof, a trivalent phosphine compound and a sulfhydryl-containing compound;
and/or the copper salt is a cuprous salt and/or a cupric salt;
and/or the mol ratio of the terminal alkyne compound to the azide compound is 0.5:1-2: 1;
and/or the molar ratio of the reducing agent to the azide compound is 0.5:1-30: 1;
and/or the molar ratio of the copper salt to the azide compound is 0.05:1-0.8: 1;
and/or the molar ratio of the ligand to the azide compound is 0.05:1-0.8: 1;
and/or the molar ratio of the ligand to the copper salt is 0.5:1-2: 1;
and/or the temperature of the cycloaddition reaction is 20-100 ℃;
and/or the time of the cycloaddition reaction is 0.5-48 h;
and/or the cycloaddition reaction is carried out in the presence of a buffer system.
11. The use according to claim 10,
when the solvent comprises a sulfoxide solvent, the sulfoxide solvent is dimethyl sulfoxide;
and/or, when the solvent comprises an amide solvent, the amide solvent is N, N-dimethylformamide;
and/or, when the solvent comprises an alcohol solvent, the alcohol solvent is one or more of methanol, ethanol and tert-butyl alcohol;
and/or, when the solvent comprises a nitrile solvent, the nitrile solvent is acetonitrile;
and/or, when the solvent comprises an ether solvent, the ether solvent is one or more of methyl tert-butyl ether, 1, 4-dioxane, diethyl ether and tetrahydrofuran;
and/or the reducing agent is one or more of sodium ascorbate, tri (2-carboxyethyl) phosphine and glutathione;
and/or, when the copper salt comprises a monovalent copper salt, the monovalent copper salt is one or more of cuprous halide, cuprous acetate, cuprous trifluoromethanesulfonate and tetraacetonitrilato copper hexafluorophosphate;
and/or, when the copper salt comprises a divalent copper salt, the divalent copper salt can be one or more of copper chloride, copper acetate and copper sulfate;
and/or, when the cycloaddition reaction is carried out in the presence of a buffer system, the buffer system is a citric acid-disodium hydrogen phosphate and/or disodium hydrogen phosphate-sodium dihydrogen phosphate buffer system;
and/or, when the cycloaddition reaction is carried out in the presence of a buffer system, the pH of the buffer system is between pH 4 and pH 8.
12. A catalytic system comprising a compound of formula I according to any one of claims 1 to 7 or a salt thereof, a copper salt and a reducing agent;
the copper salt and the reducing agent are defined as in claim 10 or 11.
13. A process for the preparation of a compound of formula I' above, comprising the steps of: in a solvent, in the presence of a reducing agent and copper salt, performing cycloaddition reaction on a compound shown as a formula 1 and a compound shown as a formula 2 as shown in the specification;
Figure FDA0002612427010000131
wherein R is1As defined in any one of claims 1 to 7.
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