CN113105400B - 1,2, 3-triazole derivative and preparation method and application thereof - Google Patents
1,2, 3-triazole derivative and preparation method and application thereof Download PDFInfo
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- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
Abstract
The disclosure belongs to the technical field of organic synthetic chemistry, and particularly provides a 1,2, 3-triazole derivative and a preparation method and application thereof. The disclosure provides a method for realizing functionalization of 1,2, 3-triazole derivatives by bimetal catalysis of terminal alkyne. The method takes terminal alkyne and phenol substituted alkenyl azide and ester compound as raw materials for one-step synthesis, and is low in cost, simple to operate, mild in condition, easy to control and suitable for large-scale production; the 1,2, 3-triazole derivative has rich functional groups and stable chemical properties, and has important significance in the fields of medicine synthesis, industrial production and the like.
Description
Technical Field
The disclosure belongs to the technical field of organic synthetic chemistry, and particularly provides a 1,2, 3-triazole derivative and a preparation method and application thereof.
Background
The statements herein merely provide background information related to the present disclosure and may not necessarily constitute prior art.
The 1,2, 3-triazole is a five-membered aromatic heterocyclic compound constructed by three nitrogen atoms and two carbon atoms. The 1,2, 3-triazole compound has unique chemical structural properties, is an important structural unit for constructing a heterocyclic compound, and can introduce different substituents by utilizing alkyne and azide. The 1,2, 3-triazole compound has rich physiological activity, easy preparation and strong stability, and can be widely applied to various fields. In the biomedical field, 1,2, 3-triazole is a well-known structural unit skeleton widely existing in many biological compounds. The three-dimensional structure, the steric hindrance and the electronic effect of the substituent can change the electron density on the triazole ring, so that the triazole ring can show various biological properties; in the field of materials, 1,2, 3-triazole is widely applied in the field of chemical sensors; in the field of organic synthesis, 1,2, 3-triazole can be used as an important intermediate for biological drug synthesis because a special parent structure provides a plurality of donor sites for a plurality of metal ligands. Therefore, the improvement of functional groups of triazole compounds has led to a wide search.
The 1,2,3-triazole was first discovered by Michael and in 1893 a triazole ring structure rich in nitrogen atoms was reported, but he did not proceed to further studies. Until 1963, huisgen studied deeply that terminal alkynes and azides undergo 1, 3-dipolar cycloaddition to give polysubstituted triazoles, which was identified as the Huisgen reaction. However, the selectivity of the reaction is poor, 1, 4-disubstituted-1, 2, 3-triazole and 1, 5-disubstituted-1, 2, 3-triazole are obtained at the same time, the requirement on temperature is high, and the temperature needs to be heated to more than 100 ℃. In 2002, shapless and his group unexpectedly found that Cu (I) promoted the preparation of 1, 4-disubstituted-1, 2, 3-triazoles from terminal alkynes and azides by a 1, 3-dipolar cycloaddition reaction. The reaction has the advantages of simple operation, high yield, mild reaction conditions, high stereospecificity and regioselectivity, and is named as CuAAC reaction. In recent years, the research on 1,2, 3-triazole is more and more endless. 2014. In the year, jabeena Khazir et al used parthenin as a starting material, designed and synthesized a series of 1,2, 3-triazole homologs by a click chemistry method, and evaluated the cytotoxicity of 6 human tumor cell lines (PC-3, THP-1, HCT-15, heLa, A-549 and MCF-7); in 2016, mohammad Mahdavi topic group studied an effective approach for synthesizing novel 1,2, 3-triazole derivatives of 2, 3-dihydroquinazolin-4 (1H) -one by three-step reaction using isatoic anhydride as starting material. 2-amino-N-substituted benzamide obtained by the reaction of indigo anhydride and benzylamine and benzaldehyde are subjected to coupling cyclization reaction, and then click reaction with an in-situ synthesized organic azide compound is carried out, so that a title compound with high yield is obtained; in 2019, martina Tireli et al designed and synthesized a series of linoleic acid-based 1,2, 3-triazole derivatives, and performed cell-based NF- κ B inhibition screening experiments. Among the compounds tested, compound 6k exhibited significant NF- κ B inhibitory activity with IC50 values in the low micromolar range. Molecular docking studies reveal a key interaction between 6k and NF- κ B, wherein the hydroxyl groups of the 1,2, 3-triazole moiety and the AA backbone are important for enhancing inhibitory activity; in 2020, ayse Tan et al studied the synthesis of 1,2, 3-triazoles containing sugar skeleton by copper-catalyzed azidoalkyne cycloaddition and examined their in vitro inhibitory effect on xanthine oxidase.
However, in the course of research by the inventors of the present disclosure, the following problems exist in the method of functionalizing the 1,2, 3-triazole compound: the catalyst used in (1) is expensive and the cost is high. And (2) the reaction conditions are complicated and difficult to control. And (3) the reaction steps are multiple, and the yield is low. (4) The synthesized 1,2, 3-triazole compound has single functional group and cannot exert the advantages in the drug synthesis.
Disclosure of Invention
Aiming at solving the problems that the 1,2, 3-triazole derivative synthesized product in the prior art has single functional group and is difficult to give full play to the advantages of the product in medicinal chemistry; meanwhile, the synthetic method has the problems of complicated steps, expensive raw material price and low yield. The method has the advantages that the functions of various functional groups in the 1,2, 3-triazole are exerted simultaneously, the groups and the products are protected, the method that three functional groups are introduced into the compound is realized for the first time, and the method that the 1,2, 3-triazole derivative is functionalized by using terminal alkyne and phenol substituted alkenyl azide compounds and ester compounds in a one-pot method is realized.
In order to achieve the purpose, the technical scheme of the disclosure is as follows:
in one or more embodiments of the present disclosure, a 1,2, 3-triazole derivative is provided, which has a structure represented by formula (1),
wherein A is 1 Selected from cyano, carboxymethyl, carboxypropyl; a. The 2 Selected from H, ether, C 1 -C 8 A linear or branched alkyl group;
b is selected from aryl, electron donating or electron withdrawing substituted aryl, electron donating or electron withdrawing heteroaryl, C 1 -C 8 Straight-chain or branched alkyl, C 1 -C 2 A linear or branched alkoxy group;
preferably, B is selected from phenyl,
A hexyl group.
In one or some embodiments of the present disclosure, a method for synthesizing a compound represented by formula (1) is provided, wherein the method comprises using terminal alkyne, phenol-substituted alkenyl azide compound and ester compound as raw materials, and synthesizing the compound represented by formula (1) by a one-pot method under the catalysis of monovalent copper salt and divalent palladium salt;
wherein the terminal alkyne has
The structural formula of (1) is represented as formula II;
r is selected from aryl, electron-donating or electron-withdrawing substituted aryl, electron-donating or electron-withdrawing heteroaryl, C 1 -C 8 Straight or branched alkyl, C 1 -C 2 A linear or branched alkoxy group;
wherein A is 1 、A 2 B is as defined in claim 1
Wherein the phenol-substituted alkenyl azide has a structure shown in a formula III;
wherein the ester compound is selected from
The method is carried out according to the following reaction route:
one or some of the above technical solutions have the following advantages or beneficial effects:
1) The disclosure provides a method for functionalizing a 1,2, 3-triazole derivative by double-metal catalytic terminal alkyne for the first time, enriches the medicinal properties of triazole compounds, and fully exerts the advantages of the triazole compounds in the field of medicinal synthetic chemistry. The method is simple, convenient and efficient, the used raw materials and the catalyst are easy to obtain and are non-toxic, the steps are few, the cost is low, the condition is mild and controllable, and the method provided by the disclosure is suitable for large-scale production.
2) The invention discloses a method for synthesizing a 1,2, 3-triazole derivative with a symmetrical structure by a one-pot method under the catalytic action of cuprous salt and divalent palladium salt by taking terminal alkyne and phenol substituted alkenyl azide and ester compounds as raw materials for the first time. The compound introduces three functional groups of cyano, propenyl and ester group, has stable chemical property and wide application range, and has great significance in medicine synthesis. Meanwhile, the method disclosed by the invention is low in cost, simple to operate and easy to control conditions.
Drawings
The accompanying drawings, which are included to provide a further understanding of the disclosure, illustrate embodiments of the disclosure and together with the description serve to explain the disclosure and are not to be construed as limiting the disclosure.
FIG. 1 is a drawing of Compound 4a, prepared according to example 9 of the present disclosure 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 2 is a photograph of Compound 4a prepared in example 9 of the present disclosure 13 Nuclear magnetic resonance spectrum of C-NMR;
FIG. 3 is a drawing of Compound 4b, prepared according to example 10 of the present disclosure 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 4 is a drawing of Compound 4b, prepared according to example 10 of the present disclosure 13 Nuclear magnetic resonance spectrum of C-NMR;
FIG. 5 is a photograph of Compound 4c, prepared according to example 11 of the present disclosure 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 6 is a drawing of Compound 4c, prepared according to example 11 of the present disclosure 13 Nuclear magnetic resonance spectrum of C-NMR;
FIG. 7 is a drawing of Compound 4d, prepared according to example 12 of the present disclosure 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 8 is a drawing of Compound 4d, prepared according to example 12 of the present disclosure 13 Nuclear magnetic resonance spectrum of C-NMR;
FIG. 9 is a drawing of Compound 4e, prepared according to example 13 of the present disclosure 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 10 is a drawing of Compound 4e, prepared according to example 13 of the present disclosure 13 Nuclear magnetic resonance spectrum of C-NMR;
FIG. 11 is a photograph of Compound 4f, prepared according to example 14 of the present disclosure 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 12 is a drawing of Compound 4f prepared according to example 14 of the present disclosure 13 Nuclear magnetic resonance spectrum of C-NMR;
FIG. 13 is a photograph of 4g of compound prepared in example 15 of the present disclosure 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 14 is a photograph of 4g of compound prepared in example 15 of the present disclosure 13 Nuclear magnetic resonance spectrum of C-NMR.
Detailed Description
The technical solutions in the embodiments of the present disclosure will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present disclosure, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the disclosure without making any creative effort, shall fall within the protection scope of the disclosure.
Aiming at solving the problems that the functional group of the 1,2, 3-triazole derivative synthesized product in the prior art is single, and the advantages of the product in medicinal chemistry are difficult to be fully exerted; meanwhile, the synthetic method has the problems of complicated steps, expensive raw material price and low yield. The method has the advantages that the functions of various functional groups in the 1,2, 3-triazole are exerted simultaneously, the groups and the products are protected, the method that three functional groups are introduced into the compound is realized for the first time, and the method that the 1,2, 3-triazole derivative is functionalized by using terminal alkyne and phenol substituted alkenyl azide compounds and ester compounds in a one-pot method is realized.
In one or more embodiments of the present disclosure, a 1,2, 3-triazole derivative is provided, which has a structure represented by formula (1),
wherein, A 1 Selected from cyano, carboxymethyl, carboxypropyl; a. The 2 Selected from H, ether group, C 1 -C 8 A linear or branched alkyl group;
b is selected from aryl, electron-donating or electron-withdrawing substituted aryl, electron-donating or electron-withdrawing heteroaryl, C 1 -C 8 Straight or branched alkyl, C 1 -C 2 A linear or branched alkoxy group;
preferably, B is selected from phenyl,
A hexyl group.
In one or more embodiments of the present disclosure, a 1,2, 3-triazole derivative is provided, which has a structure represented by formula (2), formula (3), and formula (4),
wherein B is selected from aryl, substituted aryl which donates or attracts electrons, heteroaryl which donates or attracts electrons, C 1 -C 8 Straight-chain or branched alkyl, C 1 -C 2 A linear or branched alkoxy group;
preferably, B is selected from phenyl,
A hexyl group;
y is selected from H and C 1 -C 8 Linear or branched alkyl groups, ether groups.
In one or some embodiments of the present disclosure, there is provided a 1,2, 3-triazole derivative selected from the following compounds:
in one or some embodiments of the present disclosure, a method for synthesizing a compound represented by formula (1) is provided, wherein the method comprises using terminal alkyne, phenol-substituted alkenyl azide compound and ester compound as raw materials, and synthesizing the compound represented by formula (1) by a one-pot method under the catalysis of monovalent copper salt and divalent palladium salt;
wherein the terminal alkyne has
The structural formula (II);
r is selected from aryl, electron-donating or electron-withdrawing substituted aryl, electron-donating or electron-withdrawing heteroaryl, C 1 -C 8 Straight-chain or branched alkyl, C 1 -C 2 A linear or branched alkoxy group;
wherein A is 1 、A 2 B is the same as claim 1
Wherein the phenol-substituted alkenyl azide has a structure shown in a formula III;
wherein the ester compound is selected from
The method is carried out according to the following reaction route:
preferably, the monovalent copper salt is CuI, cuTc, cu 2 S、Cu 2 One of O and CuCl;
or, the divalent palladium salt is Pd (PPh) 3 ) 4 、Pd(PPh 3 ) 2 Cl 2 、Pd(OAC) 2 One of (1);
the catalyst can improve the conversion rate of raw materials and the yield of products.
In one or more embodiments of this embodiment, when the monovalent copper salt is cuprous iodide, the palladium (II) salt is Pd (PPh) 3 ) 4 When the method is used, the yield of the 1,2, 3-triazole derivative can be further improved.
Or the additive is one or more of triethylamine, DBU, naOH and PMDETA; when the additive is triethylamine, the conversion rate of raw materials and the yield of products can be improved.
Or the solvent is dimethyl sulfoxide (DMSO), acetonitrile (CH) 3 CN), N-Dimethylformamide (DMF), toluene, 1, 2-Dichloroethane (DCE) and methanol. The solvent improves the conversion rate of the raw materials and simultaneously improves the yield of the product. When the solvent is acetonitrile, the conversion rate of raw materials and the yield of products are higher.
Preferably, the aryl group is selected from phenyl and substituted phenyl;
further, the aryl group is selected from phenyl and phenyl substituted with halogen, alkyl or alkoxy;
further, the halogen is selected from F, cl, br;
further, the alkyl group is selected from C 1 -C 8 A linear or branched alkyl group;
further, said C 1 -C 8 The linear alkyl is selected from methyl, ethyl, n-propyl and n-butyl;
further, said C 1 -C 8 The branched alkyl is selected from tert-butyl, n-pentyl;
further, the alkoxy group is selected from C 1 -C 2 A linear or branched alkoxy group;
further, said C 1 -C 2 The linear or branched alkoxy is selected from methoxy, ethoxy, etc.
Further, the heteroaryl group contains one or more heteroatoms selected from N, O and S;
specifically, R is selected from n-butyl, n-pentyl, phenyl, 4-ethoxyphenyl and 4-fluorophenyl.
Preferably, the mol ratio of the terminal alkyne, the phenol substituted alkenyl azide compound and the ester compound is 1-3: 1 to 8:1 to 7;
preferably, the mol ratio of the terminal alkyne, the phenol substituted alkenyl azide compound and the ester compound is 1:7:6;
or, the addition amount of the cuprous salt is 10 to 50 percent of the total mass of the raw materials, and the addition amount of the divalent palladium salt is 10 percent of the total mass of the raw materials;
preferably, the addition amount of the cuprous salt is 30% of the total mass of the raw materials, and the addition amount of the divalent palladium salt is 2% of the total mass of the raw materials;
or the reaction time is 0-6 h and is not 0;
preferably, the reaction time is 4 +/-0.5 h;
or the reaction temperature is 50-100 ℃; preferably 70 + -6 deg.C. The selection of this temperature range enables further increases in the conversion of the starting material and the yield of the product.
Preferably, the method further comprises a purification process, wherein the purification process comprises the following steps: adding an extraction solvent into the reacted solution for extraction to obtain an organic phase, removing the solvent in the organic phase, and performing silica gel column chromatography to obtain a compound with higher purity;
preferably, the extraction solvent used for extraction is one or more of 1, 2-dichloroethane, toluene, ethyl acetate, diethyl ether, n-hexane, cyclohexane, petroleum ether or dichloromethane;
further preferably, the extraction solvent used for extraction is dichloromethane;
preferably, the extraction is carried out for 1 to 3 times, and 5 to 20mL of extraction solvent is used each time;
preferably, the obtained organic phase is dried by adopting anhydrous magnesium sulfate, and then the organic solvent is removed;
preferably, the eluent of the silica gel column chromatography is petroleum ether and ethyl acetate;
preferably, the volume ratio of the petroleum ether to the ethyl acetate is 1-30;
preferably, the volume ratio of petroleum ether to ethyl acetate is 2. The 1,2, 3-triazole derivative with higher purity can be obtained by adopting the eluent.
Preferably, in order to mix the terminal alkyne, the phenol-substituted alkenyl azide compound and the ester compound uniformly, in one or more embodiments of the present embodiment, the reaction comprises the following steps: the raw materials are added into a solvent to be dissolved, and are heated to react under the action of adding an additive and a catalyst.
In one or more embodiments of the present disclosure, there is provided an application of the above 1,2, 3-triazole derivative or the compound prepared by the above method in preparing an anti-inflammatory drug.
Example 1
Compound 1a, namely phenylacetylene (0.0370mL, 0.25mmol), compound 2, namely phenol-substituted alkenyl azide (0.0683g, 0.25mmol), compound 3a, namely ethyl cyanoacetate (0.0330mL, 0.25 mmol),Triethylamine (0.0700mL, 2.5mmol) was added to 1mL of acetonitrile, and the mixture was dissolved at 70 ℃ to which CuTC (0.0143g, 0.075mmol) and tetrakis (triphenylphosphine) palladium (0.0100g, 0.005mmol) were added, and the mixture was stirred under nitrogen protection for 4 hours. TLC detects the disappearance of the substrate and the reaction is finished. Cooling the reaction solution, pouring into 30mL of water, extracting with dichloromethane (3X 10 mL), mixing organic phases, drying with anhydrous magnesium sulfate, vacuum filtering, distilling under reduced pressure to remove organic solvent to obtain viscous liquid, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Ethyl acetate = 2) compound 4a was obtained in 46% yield.
Example 2
Compound 1a, i.e., phenylacetylene (0.0370mL, 0.25mmol), compound 2, i.e., a phenol-substituted alkenyl azide (0.0683g, 0.25mmol), compound 3a, i.e., ethyl cyanoacetate (0.0330mL, 0.25 mmol), and triethylamine (0.0700mL, 2.5 mmol) were added to 1mL of acetonitrile, and dissolved at 70 ℃ followed by addition of cuprous chloride (0.0108g, 0.075mmol) and tetrakis (triphenylphosphine) palladium (0.0100g, 0.005mmol), and the mixture was further heated and stirred under nitrogen protection for 4 hours. TLC detects the disappearance of the substrate and the reaction is finished. Cooling the reaction solution, pouring into 30mL of water, extracting with dichloromethane (3X 10 mL), mixing organic phases, drying with anhydrous magnesium sulfate, vacuum filtering, distilling under reduced pressure to remove organic solvent to obtain viscous liquid, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Ethyl acetate = 2) to obtain compound 4a in 40% yield.
Example 3
Compound 1a, i.e., phenylacetylene (0.0370mL, 0.25mmol), compound 2, i.e., a phenol-substituted alkenyl azide (0.0683g, 0.25mmol), compound 3a, i.e., ethyl cyanoacetate (0.0330mL, 0.25 mmol), and triethylamine (0.0700mL, 2.5 mmol) were added to 1mL of DMF, and dissolved at 70 ℃ followed by addition of cuprous iodide (0.0143g, 0.0075mmol) and tetrakis (triphenylphosphine) palladium (0.0100g, 0.005mmol) to the system, and the mixture was further heated and stirred under nitrogen protection for 4 hours. TLC detects the disappearance of the substrate and the reaction is finished. Will be reversedCooling the reaction solution, pouring into 30mL of water, extracting with dichloromethane (3X 10 mL), combining organic phases, drying with anhydrous magnesium sulfate, filtering, distilling under reduced pressure to remove organic solvent to obtain viscous liquid, and subjecting to silica gel column chromatography (eluent V) Petroleum ether :V Acetic acid ethyl ester = 2) to obtain compound 4a in 55% yield.
Example 4
Compound 1a, i.e., phenylacetylene (0.0370mL, 0.25mmol), compound 2, i.e., a phenol-substituted alkenyl azide (0.0683g, 0.25mmol), compound 3a, i.e., ethyl cyanoacetate (0.0330mL, 0.25 mmol), triethylamine (0.0700mL, 2.5 mmol), was added to 1mL of toluene, and dissolved at 70 ℃ and cuprous iodide (0.0143g, 0.075mmol), tetrakis (triphenylphosphine) palladium (0.0100g, 0.005mmol) was added to the system, and the mixture was further heated and stirred under nitrogen protection for 4 hours. TLC detects the disappearance of the substrate and the reaction is finished. Cooling the reaction solution, pouring into 30mL water, extracting with dichloromethane (3X 10 mL), mixing organic phases, drying with anhydrous magnesium sulfate, vacuum filtering, distilling under reduced pressure to remove organic solvent to obtain viscous liquid, and subjecting to silica gel column chromatography (eluent V) Petroleum ether :V Acetic acid ethyl ester = 2) gave compound 4a in 60% yield.
Example 5
Compound 1a, i.e., phenylacetylene (0.0370mL, 0.25mmol), compound 2, i.e., a phenol-substituted alkenyl azide (0.0683g, 0.25mmol), compound 3a, i.e., ethyl cyanoacetate (0.0330mL, 0.25 mmol), triethylamine (0.0700mL, 2.5 mmol), was added to 1mL of acetonitrile and dissolved at 70 ℃ and, subsequently, cuprous iodide (0.0143g, 0.075mmol), tetrakis (triphenylphosphine) palladium (0.0100g, 0.005mmol) were added to the system, and the mixture was further heated and stirred under nitrogen protection for 4 hours. TLC detects the disappearance of the substrate and the reaction is finished. Cooling the reaction solution, pouring into 30mL of water, extracting with dichloromethane (3X 10 mL), mixing organic phases, drying with anhydrous magnesium sulfate, vacuum filtering, distilling under reduced pressure to remove organic solvent to obtain viscous liquid, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Acetic acid ethyl ester 1) to obtain a compoundThe yield of 4a was 91%.
Example 6
Compound 1a, i.e., phenylacetylene (0.0370mL, 0.25mmol), compound 2, i.e., phenol-substituted alkenyl azide (0.0683g, 0.25mmol), and compound 3a, i.e., ethyl cyanoacetate (0.0330mL, 0.25mmol), triethylamine (0.0700mL, 2.5 mmol), were added to 1mL of DCE, and dissolved at 70 ℃ followed by addition of cuprous iodide (0.0143g, 0.075mmol), tetrakis (triphenylphosphine) palladium (0.0100 g,0.005 mmol) to the system, and stirring was continued under nitrogen protection for 4 hours. TLC detects the disappearance of the substrate and the reaction is finished. Cooling the reaction solution, pouring into 30mL of water, extracting with dichloromethane (3X 10 mL), mixing organic phases, drying with anhydrous magnesium sulfate, vacuum filtering, distilling under reduced pressure to remove organic solvent to obtain viscous liquid, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Ethyl acetate = 2) to give compound 4a in 65% yield.
Example 7
Compound 1a, i.e., phenylacetylene (0.0370mL, 0.25mmol), compound 2, i.e., a phenol-substituted alkenyl azide (0.0683g, 0.25mmol), compound 3a, i.e., ethyl cyanoacetate (0.0330mL, 0.25mmol), and triethylamine (0.0700mL, 2.5 mmol) were added to 1mL of acetonitrile, and dissolved at 70 ℃ followed by addition of cuprous iodide (0.0143g, 0.075mmol) and palladium acetate (0.0011g, 0.005mmol), and the mixture was further heated and stirred under nitrogen protection for 4 hours. TLC detects the disappearance of the substrate and the reaction is finished. Cooling the reaction solution, pouring into 30mL water, extracting with dichloromethane (3X 10 mL), mixing organic phases, drying with anhydrous magnesium sulfate, vacuum filtering, distilling under reduced pressure to remove organic solvent to obtain viscous liquid, and subjecting to silica gel column chromatography (eluent V) Petroleum ether :V Ethyl acetate = 2) compound 4a was obtained in 72% yield.
Example 8
Compound 1a, i.e., phenylacetylene (0.0370mL, 0.25mmol), compound 2, i.e., phenol-substituted alkenyl azide (0.0683g, 0.25mmol), compound 3a, i.e., ethyl cyanoacetate (0.0330mL, 0.25 mmol)) Sodium hydroxide (0.0470ml, 2.5 mmol) was added to 1mL of acetonitrile and dissolved at 70 ℃, and then cuprous iodide (0.0143g, 0.075 mmol) and tetrakis (triphenylphosphine) palladium (0.0062g, 0.005mmol) were added to the system, and the mixture was stirred under nitrogen protection for 4 hours. TLC detects the disappearance of the substrate and the reaction is finished. Cooling the reaction solution, pouring into 30mL of water, extracting with dichloromethane (3X 10 mL), mixing organic phases, drying with anhydrous magnesium sulfate, vacuum filtering, distilling under reduced pressure to remove organic solvent to obtain viscous liquid, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Ethyl acetate = 2) to obtain compound 4a in 47% yield.
Example 9
Compound 1a, i.e., phenylacetylene (0.0370mL, 0.25mmol), compound 2, i.e., a phenol-substituted alkenyl azide (0.0683g, 0.25mmol), compound 3a, i.e., ethyl cyanoacetate (0.0330mL, 0.25 mmol), and PMDETA (0.5220mL, 2.5 mmol) were added to 1mL of acetonitrile, and dissolved at 70 ℃ followed by addition of cuprous iodide (0.0143g, 0.075mmol) and tetrakis (triphenylphosphine) palladium (0.0100g, 0.005mmol) to the system, and the mixture was further heated and stirred under nitrogen protection for 4 hours. TLC detects the disappearance of the substrate and the reaction is finished. Cooling the reaction solution, pouring into 30mL water, extracting with dichloromethane (3X 10 mL), mixing organic phases, drying with anhydrous magnesium sulfate, vacuum filtering, distilling under reduced pressure to remove organic solvent to obtain viscous liquid, and subjecting to silica gel column chromatography (eluent V) Petroleum ether :V Ethyl acetate = 2) compound 4a was obtained in 58% yield.
The reactions of examples 1 to 9 are as follows:
example 10
Compound 1b, i.e. methyl 4-ethynylbenzoate (0.0390mL, 0.25mmol), compound 2, i.e. phenol-substituted alkenyl azide (0.0683g, 0.25mmol), compound 3a, i.e. ethyl cyanoacetate (0.0330 mL, 0.25mmo)l) and triethylamine (0.0700mL, 2.5 mmol) were added to 1mL of acetonitrile, and the mixture was dissolved at 70 ℃ to obtain a solution, and cuprous iodide (0.0143g, 0.075mmol) and tetrakis (triphenylphosphine) palladium (0.0100g, 0.005mmol) were added to the solution, and the mixture was further heated and stirred under nitrogen protection for 4 hours. TLC detects the disappearance of the substrate and the reaction is finished. Cooling the reaction solution, pouring into 30mL water, extracting with dichloromethane (3X 10 mL), mixing organic phases, drying with anhydrous magnesium sulfate, vacuum filtering, distilling under reduced pressure to remove organic solvent to obtain viscous liquid, and subjecting to silica gel column chromatography (eluent V) Petroleum ether :V Ethyl acetate = 2) to obtain compound 4b in 87% yield.
The reaction is shown below:
compound 4b:
1 H NMR(400MHz,CDCl 3 ) As shown in fig. 3, δ 8.15 (s, 2H), 7.97 (d, J =8.2hz, 4H), 7.72 (d, J =8.2hz, 4H), 5.65 (d, J =2.4hz, 2h), 5.40 (d, J =2.3hz, 2h), 4.1 (q, J =7.1hz, 1h), 4.04 (q, J =7.2hz, 2h), 3.68 (d, J =14.8hz, 2h), 3.52 (d, J =1.8hz, 2h), 2.05 (s, 2H), 1.24 (d, J =19.9,7.1hz, 6h), HRMS (ESI) m/z calvated for C 31 H 29 N 7 O 6 [M+Na] + :618.2098,found:618.2068. 13 C NMR(100MHz,CDCl 3 ) Delta 166.59, 146.45,137.57,134.13,132.80,126.31,119.24,118.61, 1.24, 112.05,110.84,63.89,53.46,48.71,39.04,13.81 as shown in FIG. 4.
Example 11
Compound 1c, i.e., 4-ethylphenylacetylene (0.0330mL, 0.25mmol), compound 2, i.e., a phenol-substituted alkenyl azide (0.0683g, 0.25mmol), compound 3a, i.e., ethyl cyanoacetate (0.0330 mL,0.25 mmol), triethylamine (0.0700mL, 2.5 mmol), was added to 1mL of acetonitrile and dissolved at 70 ℃ and cuprous iodide (0.0143g, 0.075mmol), tetrakis (triphenylphosphine) palladium (0.0100g, 0.005mmol) were then added to the system and under nitrogen protection, followed by further additionThe mixture was stirred hot for 4 hours. TLC detects the disappearance of the substrate and the reaction is finished. Cooling the reaction solution, pouring into 30mL water, extracting with dichloromethane (3X 10 mL), mixing organic phases, drying with anhydrous magnesium sulfate, vacuum filtering, distilling under reduced pressure to remove organic solvent to obtain viscous liquid, and subjecting to silica gel column chromatography (eluent V) Petroleum ether :V Ethyl acetate = 2) gave compound 4c in 85% yield.
The reaction is shown below:
1 H NMR(400MHz,CDCl 3 ) As shown in fig. 5, δ 7.99 (s, 1H), 7.89-7.70 (m, 2H), 7.39-7.18 (m, 2H), 5.60 (d, J =2.3hz, 1h), 5.33 (d, J =2.3hz, 1h), 3.9 (q, J =7.2hz, 1h), 3.68 (d, J =14.8hz, 1h), 3.47 (d, J =14.9hz, 1h), 2.6 (q, J =7.6hz, 2h), 1.26 (t, J =7.6hz, 4h), 1.15 (t, J =7.1hz, 2h), HRMS (ESI) m/z calced for C 31 H 33 N 2 O 2 [M+Na] + :558.2598,found:558.2576. 13 C NMR(10 0MHz,CDCl 3 ) Delta 166.62,148.34,144.88,137.70,128.41,127.25,1 25.92,117.58,116.66,109.81,63.75,48.91,39.04,28.71,15.51,13.72, as shown in FIG. 6.
Example 12
Compound 1d, i.e., 1-heptyne (0.0340mL, 0.25mmol), compound 2, i.e., a phenol-substituted alkenyl azide (0.0683g, 0.25mmol), compound 3a, i.e., ethyl cyanoacetate (0.0330mL, 0.25 mmol), triethylamine (0.0700mL, 2.5 mmol), was added to 1mL of acetonitrile, dissolved at 70 ℃ and cuprous iodide (0.0143g, 0.075mmol), tetrakis (triphenylphosphine) palladium (0.0100g, 0.005mmol) were added to the system, and the mixture was further heated and stirred under nitrogen protection for 4 hours. TLC detects the disappearance of the substrate and the reaction is finished. The reaction solution was cooled and poured into 30mL of water, extracted with dichloromethane (3X 10 mL), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered with suction, and then the organic solvent was distilled off under reduced pressure to give a viscous liquidSubjecting to silica gel column chromatography (eluent V) Petroleum ether :V Ethyl acetate = 2) compound 4d was obtained in 90% yield.
The reaction is shown below:
1 H NMR(400MHz,CDCl 3 ) As shown in fig. 7, δ 7.54 (s, 2H), 5.49 (d, J =2.1hz, 2H), 5.25 (d, J =2.1hz, 2h), 3.97 (q, J =7.2hz, 2h), 3.61 (d, J =14.8hz, 2h), 3.4 (d, J =14.8hz, 2h), 2.77-2.66 (m, 4H), 1.69 (q, J =7.5hz, 4h), 1.30-1.35 (m, 8H), 1.20 (t, J =7.2hz, 3h), HRMS (ESI) m/z calcaled for C 25 H 37 N 7 O 2 [M+Na] + : 490.2898,found:490.2834. 13 C NMR(100MHz,CDCl 3 ) As shown in fig. 8, δ 166.6, 149.09,137.78,119.11,116.55,109.07,63.51,48.82,39.00,31.36,28.97, 2.52, 22.39,13.99,13.74.
Example 13
Compound 1a, i.e., phenylacetylene (0.0370mL, 0.25mmol), compound 2, i.e., a phenol-substituted alkenyl azide (0.0683g, 0.25mmol), compound 3b, i.e., methoxyethyl acetoacetate (0.0370 mL,0.25 mmol), and triethylamine (0.0700mL, 2.5 mmol) were added to 1mL of acetonitrile, and dissolved at 70 ℃ followed by addition of cuprous iodide (0.0143g, 0.075mmol) and tetrakis (triphenylphosphine) palladium (0.0100g, 0.005mmol) to the system, and the mixture was further heated and stirred under nitrogen protection for 4 hours. TLC detects the disappearance of the substrate and the reaction is finished. Cooling the reaction solution, pouring into 30mL of water, extracting with dichloromethane (3X 10 mL), mixing organic phases, drying with anhydrous magnesium sulfate, vacuum filtering, distilling under reduced pressure to remove organic solvent to obtain viscous liquid, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Ethyl acetate = 2) compound 4e was obtained in 83% yield.
The reaction is shown below:
1 H NMR(400MHz,CDCl 3 ) As shown in fig. 9, δ 7.92 (s, 2H), 7.86 to 7.79 (m, 4H), 7.42 (t, J =7.5hz, 4h), 7.34 (t, J =8.5,6.2hz, 2h), 5.50 (d, J =1.7hz, 2h), 5.1 (d, J =1.8hz, 2h), 4.15 to 4.04 (m, 2H), 3.61 (d, J =15.8hz, 2h), 3.55 to 3.40 (m, 4H), 3.37 to 3.26 (m, 6H), 2.12 (s, 3H), 1.26 (d, J =3.6hz, 2h). 13 C NMR(100MHz, CDCl 3 ) As shown in FIG. 10, δ 202.52,170.42,147.94,139.12,129.91,128.90, 128.50, 125.84,118.34,110.39,69.78,64.89,61.82,58.78,34.56,29.35,27.04.H RMS (ESI) M/z calculated for C30H32N6O4[ M + Na 6O4 ]] + :563.2398,found:563. 2367.
Example 14
Compound 1a, i.e., phenylacetylene (0.0370mL, 0.25mmol), compound 2, i.e., a phenol-substituted alkenyl azide (0.0683g, 0.25mmol), compound 3c, i.e., n-pentyl acetoacetate (0.0450 mL,0.25 mmol), triethylamine (0.0700mL, 2.5 mmol), was added to 1mL of acetonitrile and dissolved at 70 ℃ and, subsequently, cuprous iodide (0.0143g, 0.075mmol), tetrakis (triphenylphosphine) palladium (0.0100g, 0.005mmol) were added to the system, and the mixture was further heated and stirred under nitrogen protection for 4 hours. TLC detects the disappearance of the substrate and the reaction is finished. Cooling the reaction solution, pouring into 30mL of water, extracting with dichloromethane (3X 10 mL), mixing organic phases, drying with anhydrous magnesium sulfate, vacuum filtering, distilling under reduced pressure to remove organic solvent to obtain viscous liquid, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Acetic acid ethyl ester = 2) to obtain compound 4f in 85% yield.
The reaction is shown below:
1 H NMR(400MHz,CDCl 3 ) As shown in FIG. 11, δ7.91(s,2H),7.82(d,J＝7.3H z,4H),7.42(t,J＝7.5Hz,4H),7.34(t,J＝8.5,6.2Hz,2H),5.50(d,J＝1.8Hz,2 H),5.15(d,J＝1.7Hz,2H),3.91(t,J＝6.8Hz,2H),3.61(d,J＝15.8Hz,2H),3.4 7(d,J＝15.8Hz,2H),2.12(s,3H),1.55(t,J＝6.8Hz,2H),1.35–1.13(m,6H),0.8 5(t,J＝6.9Hz,3H). 13 C NMR(100MHz,CDCl 3 ) Delta 202.44, 147.93, 139.17,129.85,128.86,128.47,125.80,118.17,109.98,76.81,66.57,61.7, 34.43,27.88,27.77,26.95,22.18,13.89 HRMS (ESI) m/z calculated for C, shown in FIG. 12 32 H 36 N 6 O 3 [M+Na] + :575.2698,found:575.2654.
Example 15
Compound 1a, i.e., phenylacetylene (0.0370mL, 0.25mmol), compound 2, i.e., a phenol-substituted alkenyl azide (0.0683g, 0.25mmol), compound 3d, i.e., methyl n-butyrylacetate (0.0430mL, 0.25mmol), and triethylamine (0.0700mL, 2.5 mmol) were added to 1mL of acetonitrile, and dissolved at 70 ℃ followed by addition of cuprous iodide (0.0143g, 0.075mmol) and tetrakis (triphenylphosphine) palladium (0.0100g, 0.005mmol), and the mixture was further heated and stirred under nitrogen protection for 4 hours. TLC detects the disappearance of the substrate and the reaction is finished. Cooling the reaction solution, pouring into 30mL water, extracting with dichloromethane (3X 10 mL), mixing organic phases, drying with anhydrous magnesium sulfate, vacuum filtering, distilling under reduced pressure to remove organic solvent to obtain viscous liquid, and subjecting to silica gel column chromatography (eluent V) Petroleum ether :V Ethyl acetate = 2) compound 4g was obtained in 87% yield.
The reaction is shown below:
1 H NMR(400MHz,CDCl 3 ) As shown in fig. 13, δ 7.91 (s, 2H), 7.81 (d, J =7.4hz, 4h), 7.42 (t, J =7.5hz, 4h), 7.35 (t, J =8.5,6.1hz, 2h), 5.50 (d, J =1.9hz, 2H), 5.13 (d, J =1.8hz, 2h), 3.69-3.45 (m, 7H), 2.44 (t, J =7.3hz, 2h), 1.4 (d, J =7.4hz, 2h), 1.26 (d, 4H),J＝3.8Hz,1H),0.84(t,J＝7.4Hz,3H). 13 C NMR(10 0MHz,CDCl 3 ) As shown in FIG. 14,. Delta.204.77, 170.97,147.91,139.26,129.92,128.93, 128.90, 128.49,125.85,118.21,109.94,61.42,52.94,41.11,34.55,16.94,13.52 HRMS (ESI) m/z calculated for C 30 H 32 N 6 O 3 [M+Na] + :547.2398,found:547.2 385.
Example 16
This example provides compounds 4a, 4b, 4c, 4d, 4e, 4f, 4g anti-inflammatory efficacy testing comprising the steps of:
1. the liver cancer HepG2 cells were seeded at a cell density of 6X 104/mL in a plate at a concentration of 100. Mu.L per well and at 37 ℃ with a CO content of 5% 2 And culturing overnight under the condition of saturated humidity.
2. After the attachment of the membrane, compounds 4a, 4b, 4c, 4d, 4e, 4f and 4g are respectively added to make the final concentration reach 1 mug/ml, 2 mug/ml, 3 mug/ml, 4 mug/ml and 5 mug/ml, each group is provided with 5 multiple wells, and the final volume of each well is 200 mug. The control group was added with an equal amount of DMEM medium.
3. After 24h and 48h of incubation, 20. Mu.L of MTT (5 mg/mL)) was added to each well and incubation was continued for 4h.
4. The supernatant was centrifuged off and 150. Mu.L of DMSO was added to each well to dissolve the crystalline particles.
5. And (3) measuring the absorbance (D) at the wavelength of 570nm by using a microplate reader, calculating the proliferation inhibition rate of the adriamycin with different time and different concentration on the HepG2 cells, and repeating the experiment for 3 times.
6. The growth inhibition rate = [ (control D570 — experimental D570)/control D570] × 100% was calculated.
IC50 refers to the concentration of drug required to reduce the number of viable cells by half after administration. In the MTT method, the IC50 is the concentration of the drug required to reduce the OD value of the absorbance of the control group by half. In addition, the meaning of median inhibitory concentration corresponds to the average of the minimum lethal doses of drugs on cultured cells, and is widely used in screening various drugs as a quantitative index reflecting the drug efficacy.
Specifically, according to the formula: inhibition = 1-OD value of addition group/OD value of control group, IC50 value of compound was calculated
All compounds tested had IC50 values below 4.75. Mu.g/kg,
as can be seen from the above test results, all compounds in the examples of the present disclosure have anti-inflammatory effects.
The disclosure of the present invention is not limited to the specific embodiments, but rather to the specific embodiments, the disclosure is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (20)
1. A preparation method of 1,2, 3-triazole derivatives is characterized in that the synthetic route is shown as follows,
wherein, the terminal alkyne
Is composed of
The azide compound is
The ester compound Z is
The preparation method comprises the following steps: terminal alkyne, azide and ester compounds are used as raw materials, under the catalytic action of cuprous salt and divalent palladium salt, additive and solvent are added, and 1,2, 3-triazole derivative is synthesized by a one-pot method;
whereinThe cuprous salt is one of cuprous chloride, cuprous iodide and cuprous thiophene-2-formate; the divalent palladium salt is Pd (PPh) 3 ) 4 、Pd(PPh 3 ) 2 Cl 2 One of palladium acetate; the additive is one of triethylamine, DBU, PMDETA and NaOH;
wherein the terminal alkyne, the ester compound and the reaction product are respectively selected from the following combinations:
1) Terminal alkyne is
The ester compound is
The reaction product is
2) Terminal alkyne is
The ester compound is
The reaction product is
3) Terminal alkynes are
The ester compound is
The reaction product is
4) Terminal alkyne is
The ester compound is
The reaction product is
5) Terminal alkyne is
The ester compound is
The reaction product is
6) Terminal alkyne is
The ester compound is
The reaction product is
7) Terminal alkyne is
The ester compound is
The reaction product is
。
2. The method according to claim 1,
the solvent is dimethyl sulfoxide (DMSO) or acetonitrile (CH) 3 CN), N-Dimethylformamide (DMF), toluene, 1, 2-Dichloroethane (DCE) and methanol.
3. The method of claim 1, wherein the solvent is one or more of dimethylsulfoxide and acetonitrile.
4. The method of claim 3, wherein the solvent is dimethyl sulfoxide.
5. The method of claim 1, wherein the one-pot reaction time is 0 to 6 hours and the reaction time is not 0.
6. The method of claim 5, wherein the one-pot reaction time is 4 ± 0.5h.
7. The method of claim 1, wherein the molar ratio of terminal alkyne, phenol-substituted alkenyl azide, ester compound is 1 to 3:1 to 8:1 to 7.
8. The method of claim 1, wherein the molar ratio of terminal alkyne, phenol-substituted alkenyl azide, ester compound is 1:7:6.
9. the method according to claim 1, wherein the amount of the cuprous salt added is 10 to 50% by mass based on the total mass of the raw materials.
10. The method according to claim 9, wherein the amount of the monovalent copper salt added is 30% by mass based on the total mass of the starting materials.
11. The method according to claim 1, wherein the divalent palladium salt is added in an amount of 10% by mass based on the total mass of the raw materials;
12. the method according to claim 1, wherein the divalent palladium salt is added in an amount of 2% by mass based on the total mass of the raw materials.
13. The method of claim 1, further comprising the steps of: and adding the solution after the reaction into an extraction solvent for extraction to obtain an organic phase, removing the solvent in the organic phase, and performing silica gel column chromatography to obtain the 1,2, 3-triazole derivative.
14. The method of claim 13, wherein the extraction solvent used for the extraction is one or more of 1, 2-dichloroethane, toluene, ethyl acetate, diethyl ether, n-hexane, cyclohexane, petroleum ether, or dichloromethane.
15. The method of claim 14, wherein the extraction solvent used for extraction is dichloromethane.
16. The method of claim 13, wherein the extraction is performed 1 to 3 times using 5 to 20mL of extraction solvent each time.
17. The process according to claim 13, wherein the organic phase obtained is dried over anhydrous magnesium sulfate and the organic solvent is removed.
18. The method of claim 13, wherein the eluent from the silica gel column chromatography is petroleum ether or ethyl acetate.
19. The method of claim 18, wherein the volume ratio of petroleum ether to ethyl acetate is 1 to 30.
20. The method of claim 18, wherein the volume ratio of petroleum ether to ethyl acetate is 2.
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