阅读说明：本技术 一种1,2,4-三唑类化合物及其制备方法 (1,2, 4-triazole compound and preparation method thereof ) 是由 郑绿茵 陶开亮 郭维 于 2020-05-29 设计创作，主要内容包括：本发明提供了一种1,2,4-三唑类化合物及其制备方法,涉及有机中间体技术领域。本发明提供的1,2,4-三唑类化合物具有式I所示结构,为新型结构的1,2,4-三唑类化合物,拓展了1,2,4-三唑类化合物的种类,可在药物化学中应用。本发明还提供了所述1,2,4-三唑类化合物的制备方法,将肼类化合物、异硫氰酸酯类化合物、四甲基胍、光催化剂和极性有机溶剂混合,所得混合液在光照和50～80℃温度条件下进行环化反应,得到所述1,2,4-三唑类化合物。本发明利用光照提供反应所需能量,在50～80℃温度下即可得到所述1,2,4-三唑类化合物,反应过程安全稳定,条件较为温和,操作方便,易于控制。(The invention provides a 1,2, 4-triazole compound and a preparation method thereof, and relates to the technical field of organic intermediates. The 1,2, 4-triazole compound provided by the invention has a structure shown in formula I, is a 1,2, 4-triazole compound with a novel structure, expands the variety of the 1,2, 4-triazole compound, and can be applied to pharmaceutical chemistry. The invention also provides a preparation method of the 1,2, 4-triazole compound, which comprises the steps of mixing a hydrazine compound, an isothiocyanate compound, tetramethylguanidine, a photocatalyst and a polar organic solvent, and carrying out cyclization reaction on the obtained mixed solution under the conditions of illumination and temperature of 50-80 ℃ to obtain the 1,2, 4-triazole compound. The invention provides energy required by reaction by utilizing illumination, and the 1,2, 4-triazole compound can be obtained at the temperature of 50-80 ℃, and the reaction process is safe and stable, the conditions are mild, the operation is convenient, and the control is easy.)

1. A1, 2, 4-triazole compound is characterized by having a structure shown in a formula I:

in the formula I, R¹Is phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, halogen substituted phenyl, or ring substituted phenyl; r²Is aryl or alkyl.

2. The 1,2, 4-triazole compound of claim 1, wherein R is¹In the formula, the alkyl-substituted phenyl is alkyl-substituted phenyl with 1-5 carbon atoms, the halogen-substituted phenyl is fluorine-substituted phenyl, chlorine-substituted phenyl or bromine-substituted phenyl, and the ring-substituted phenyl is pyridine ring-substituted phenyl or naphthalene ring-substituted phenyl.

3. The 1,2, 4-triazole compound of claim 2, wherein R is¹In the above formula, the alkyl-substituted phenyl group is p-methylphenyl or m-methylphenyl, and the halogen-substituted phenyl group is p-fluorophenyl, p-chlorophenyl, p-bromophenyl, m-chlorophenyl or m-bromophenyl.

4. The 1,2, 4-triazole compound of claim 1, wherein R is²In the formula (I), aryl is phenyl, benzyl, naphthyl, benzoyl, alkyl substituted phenyl, methoxy substituted phenyl, halogen substituted phenyl, trifluoromethyl substituted phenyl, p-nitro substituted phenyl or p-nitrile substituted phenyl.

5. The 1,2, 4-triazole compound of claim 4, wherein R is²Meso, alkaneThe phenyl group substituted by the substituent group is p-ethylphenyl or 2,4, 6-trimethylphenyl, the phenyl group substituted by methoxy is p-methoxyphenyl, 2, 4-dimethoxyphenyl or 3,4, 5-trimethoxyphenyl, the phenyl group substituted by halogen is fluorine substituted phenyl, chlorine substituted phenyl or bromine substituted phenyl, and the phenyl group substituted by trifluoromethyl is p-trifluoromethylphenyl, o-trifluoromethylphenyl or 3, 5-bis (trifluoromethyl) phenyl.

6. The process for producing a 1,2, 4-triazole-based compound according to any one of claims 1 to 5, comprising the steps of:

mixing a hydrazine compound, an isothiocyanate compound, tetramethylguanidine, a photocatalyst and a polar organic solvent to obtain a mixed solution; performing cyclization reaction on the mixed solution under the conditions of illumination and 50-80 ℃ to obtain the 1,2, 4-triazole compound;

the structural formula of the hydrazine compound is R¹-NHNH₂(ii) a The structural formula of the isothiocyanate compound is R²N ═ C ═ S; the photocatalyst is an organic dye and/or a metal complex.

7. The preparation method according to claim 6, wherein the molar ratio of the hydrazine compound, the isothiocyanate compound and the tetramethylguanidine is 1:1 (1-2); the dosage of the photocatalyst is 0.5-2% of the molar weight of the hydrazine compound.

8. The preparation method according to claim 6 or 7, wherein the organic dye is one or more of eosin B, eosin Y and rose bengal; the metal complex is tris (2, 2' -bipyridyl) ruthenium dichloride and/or tris (2-phenylpyridine) iridium.

9. The preparation method according to claim 6, wherein the polar organic solvent is one or more of dimethyl sulfoxide, N-dimethylformamide, toluene, ethanol, acetonitrile and dichloromethane; the ratio of the volume of the polar organic solvent to the amount of the substance of the hydrazine compound is 1L: 0.1 to 0.2 mol.

10. The method according to claim 6, wherein the light source wavelength of the light is 200 to 1000 nm; the cyclization reaction time is 1-48 h.

Technical Field

The invention relates to the technical field of organic intermediates, in particular to a 1,2, 4-triazole compound and a preparation method thereof.

Background

Chemists have great interest in the synthesis of triazole compounds, which have a wide range of biological properties, and which are useful as anticancer and antibacterial agents, as well as antitubercular agents. In particular trisubstituted 1,2, 4-triazoles, an important organic framework, are present in many pharmacologically active biomolecules. As shown in formula a, lavotidine (lavotetidine) is a drug used in the digestive system, and is mainly used for treating peptic ulcer; JNJ-39393406 (shown in formula B) is a potent positive allosteric a7nAChR modulator; azamulin (shown as formula C) is an inhibiting bacterium, and can be used for treating acne; pitrazepin (as shown in formula D) can interact with the receptors of central and peripheral nervous system, and is an antipsychotic drug. Researchers have been working on the construction of triazole compounds in an attempt to expand their application in the field of medicine. At present, most methods for constructing 1,2, 4-triazole compounds use azide as a raw material at normal temperature, and the raw material is explosive and dangerous.

Disclosure of Invention

In view of the above, the present invention aims to provide a 1,2, 4-triazole compound and a preparation method thereof. The invention constructs a novel 1,2, 4-triazole compound, and the preparation process of the 1,2, 4-triazole compound is safe and has mild conditions.

In order to achieve the above object, the present invention provides the following technical solutions:

the invention provides a 1,2, 4-triazole compound which has a structure shown in a formula I:

in the formula I, R¹Is phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, halogen substituted phenyl, or ring substituted phenyl; r²Is aryl or alkyl.

Preferably, said R is¹In the formula, the alkyl-substituted phenyl is alkyl-substituted phenyl with 1-5 carbon atoms, the halogen-substituted phenyl is fluorine-substituted phenyl, chlorine-substituted phenyl or bromine-substituted phenyl, and the ring-substituted phenyl is pyridine ring-substituted phenyl or naphthalene ring-substituted phenyl.

Preferably, said R is¹In the above formula, the alkyl-substituted phenyl group is p-methylphenyl or m-methylphenyl, and the halogen-substituted phenyl group is p-fluorophenyl, p-chlorophenyl, p-bromophenyl, m-chlorophenyl or m-bromophenyl.

Preferably, said R is²In the formula (I), aryl is phenyl, benzyl, naphthyl, benzoyl, alkyl substituted phenyl, methoxy substituted phenyl, halogen substituted phenyl, trifluoromethyl substituted phenyl, p-nitro substituted phenyl or p-nitrile substituted phenyl.

Preferably, said R is²In the formula (I), the alkyl-substituted phenyl group is p-ethylphenyl or 2,4, 6-trimethylphenyl, the methoxy-substituted phenyl group is p-methoxyphenyl, 2, 4-dimethoxyphenyl or 3,4, 5-trimethoxyphenyl, the halogen-substituted phenyl group is fluorine-substituted phenyl, chlorine-substituted phenyl or bromine-substituted phenyl, and the trifluoromethyl-substituted phenyl group is p-trifluoromethylphenyl, o-trifluoromethylphenyl or 3, 5-bis (trifluoromethyl) phenyl.

The invention provides a preparation method of a 1,2, 4-triazole compound in the technical scheme, which comprises the following steps:

mixing a hydrazine compound, an isothiocyanate compound, tetramethylguanidine, a photocatalyst and a polar organic solvent to obtain a mixed solution; performing cyclization reaction on the mixed solution under the conditions of illumination and 50-80 ℃ to obtain the 1,2, 4-triazole compound;

the structural formula of the hydrazine compound is R¹-NHNH₂(ii) a The structural formula of the isothiocyanate compound is R²N ═ C ═ S; the photocatalyst is an organic dye and/or a metal complex.

Preferably, the molar ratio of the hydrazine compound to the isothiocyanate compound to the tetramethylguanidine is 1:1 (1-2); the dosage of the photocatalyst is 0.5-2% of the molar weight of the hydrazine compound.

Preferably, the organic dye is one or more of eosin B, eosin Y and rose bengal; the metal complex is tris (2, 2' -bipyridyl) ruthenium dichloride and/or tris (2-phenylpyridine) iridium.

Preferably, the polar organic solvent is one or more of dimethyl sulfoxide, N-dimethylformamide, toluene, ethanol, acetonitrile and dichloromethane; the ratio of the volume of the polar organic solvent to the amount of the substance of the hydrazine compound is 1L: 0.1 to 0.2 mol.

Preferably, the wavelength of the light source of the illumination is 200-1000 nm; the cyclization reaction time is 1-48 h.

The invention provides a 1,2, 4-triazole compound which has a structure shown in a formula I, is a 1,2, 4-triazole compound with a novel structure, and widens the variety of the 1,2, 4-triazole compound. The 1,2, 4-triazole compound provided by the invention has the characteristics of potential antibacterial, anti-inflammatory, anticancer, antiviral and insect-resistant properties, and can be applied to biological medicines and pesticides.

The invention also provides a preparation method of the 1,2, 4-triazole compound, which comprises the steps of mixing a hydrazine compound, an isothiocyanate compound, tetramethylguanidine, a photocatalyst and a polar organic solvent, and carrying out cyclization reaction on the obtained mixed solution under the conditions of illumination and temperature of 50-80 ℃ to obtain the 1,2, 4-triazole compound. In the invention, a thiourea intermediate is easily formed by an isothiocyanate structure and tetramethylguanidine, and then under the catalysis of a photocatalyst, the C-N bond of the thiourea intermediate is dissociated to form a thiourea free radical; then adding the thiourea intermediate into the reaction product under the action of a hydrazine compound and a catalyst, and oxidizing the thiourea intermediate into free radical cations by oxygen; finally, intramolecular cyclization is carried out to obtain the 1,2, 4-triazole compound. The method utilizes illumination to provide energy required by the reaction, can obtain the 1,2, 4-triazole compound at the temperature of 50-80 ℃, and has the advantages of safe and stable reaction process, mild conditions and easy control.

Drawings

FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a product obtained in example 1 of the present invention;

FIG. 2 is a nuclear magnetic resonance carbon spectrum of the product obtained in example 1 of the present invention;

FIG. 3 is a NMR chart of a product obtained in example 2 of the present invention;

FIG. 4 is a nuclear magnetic resonance carbon spectrum of the product obtained in example 2 of the present invention;

FIG. 5 is a NMR chart of a product obtained in example 3 of the present invention;

FIG. 6 is the NMR spectrum of the product obtained in example 3 of the present invention;

FIG. 7 is a NMR chart of a product obtained in example 4 of the present invention;

FIG. 8 is the NMR spectrum of the product obtained in example 4 of the present invention;

FIG. 9 is a NMR chart of a product obtained in example 5 of the present invention;

FIG. 10 is the NMR spectrum of the product obtained in example 5 of the present invention;

FIG. 11 is a NMR chart of a product obtained in example 6 of the present invention;

FIG. 12 is a NMR spectrum of a product obtained in example 6 of the present invention;

FIG. 13 is a NMR chart of the product obtained in example 7 of the present invention;

FIG. 14 is a NMR spectrum of a product obtained in example 7 of the present invention;

FIG. 15 is a NMR chart of a product obtained in example 8 of the present invention;

FIG. 16 is a NMR spectrum of a product obtained in example 8 of the present invention;

FIG. 17 is a NMR chart of a product obtained in example 9 of the present invention;

FIG. 18 is a NMR spectrum of a product obtained in example 9 of the present invention;

FIG. 19 is a NMR spectrum of a product obtained in example 10 of the present invention;

FIG. 20 is a NMR spectrum of a product obtained in example 10 of the present invention;

FIG. 21 is a NMR chart of a product obtained in example 11 of the present invention;

FIG. 22 is a NMR spectrum of a product obtained in example 11 of the present invention;

FIG. 23 is a NMR chart of a product obtained in example 12 of the present invention;

FIG. 24 shows the NMR spectrum of the product obtained in example 12 of the present invention.

Detailed Description

The invention provides a 1,2, 4-triazole compound which has a structure shown in a formula I:

in the formula I, R¹Is phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, halogen substituted phenyl, or ring substituted phenyl; r²Is aryl or alkyl.

In the present invention, said R¹Is phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, halogen substituted phenyl, or ring substituted phenyl. In the invention, the alkyl-substituted phenyl is preferably alkyl-substituted phenyl with 1-5 carbon atoms, and is further preferably p-methylphenyl or m-methylphenyl; the alkoxy-substituted phenyl group is preferably a methoxy group or an ethoxy group, and is more preferably a methoxy group; the halogen-substituted phenyl group is preferably a fluorine-substituted phenyl group, a chlorine-substituted phenyl group or a bromine-substituted phenyl group, and is more preferably a p-fluorophenyl group, a p-chlorophenyl group, a p-bromophenyl group, an m-chlorophenyl group or an m-bromophenyl group; the ring-substituted phenyl group is preferably a pyridine ring-substituted phenyl group or a naphthalene ring-substituted phenyl group.

In the present invention, said R²Is aryl or alkyl. In the present invention, the aryl group is preferably a phenyl group, a benzyl group, a naphthyl group, a benzoyl group, an alkyl-substituted phenyl group, a methoxy-substituted phenyl group, a halogen-substituted phenyl group, a trifluoromethyl-substituted phenyl group, a p-nitro-substituted phenyl group or a p-nitrile-substituted phenyl group. In the present invention, the alkyl-substituted phenyl group is preferably a p-ethylphenyl group or a 2,4, 6-trimethylphenyl group; the methoxy-substituted phenyl is preferably p-methoxyphenyl, 2, 4-dimethoxyphenyl or 3,4, 5-trimethoxyphenyl; the halogen-substituted phenyl group is preferably a fluorine-substituted phenyl group, a chlorine-substituted phenyl group or a bromine-substituted phenyl group, and is more preferably a p-fluorophenyl group, a p-bromophenyl group, an o-chlorophenyl group, an m-chlorophenyl group or a 2, 4-difluorophenyl group; the trifluoromethyl-substituted phenyl group is preferably a p-trifluoromethylphenyl group, an o-trifluoromethylphenyl group or a 3, 5-bis (trifluoromethyl) phenyl group.

In a specific embodiment of the present invention, the specific structure of the 1,2, 4-triazole compound is as follows:

the 1,2, 4-triazole compound provided by the invention has the characteristics of potential antibacterial, anti-inflammatory, anticancer, antiviral and insect-resistant properties, and can be applied to biological medicines and pesticides.

The invention provides a preparation method of a 1,2, 4-triazole compound described in the scheme, which comprises the following steps:

mixing a hydrazine compound, an isothiocyanate compound, tetramethylguanidine, a photocatalyst and a polar organic solvent to obtain a mixed solution; performing cyclization reaction on the mixed solution under the conditions of illumination and 50-80 ℃ to obtain the 1,2, 4-triazole compound;

the structural formula of the hydrazine compound is R¹-NHNH₂(ii) a The structural formula of the isothiocyanate compound is shown in the specificationR²N ═ C ═ S; the photocatalyst is an organic dye and/or a metal complex.

According to the invention, a hydrazine compound, an isothiocyanate compound, tetramethylguanidine, a photocatalyst and a polar organic solvent are mixed to obtain a mixed solution. In the invention, the structural formula of the hydrazine compound is R¹-NHNH₂R in the structural formula of hydrazine compound¹And R in the structure shown in the formula I¹Keeping the same is not described herein. In the specific embodiment of the invention, the hydrazine compounds are specifically phenylhydrazine, 4-chlorophenylhydrazine, 4-bromophenylhydrazine, 4-trifluoromethylphenylhydrazine, 3-chlorophenylhydrazine, 3-bromophenylhydrazine, 2-methylphenylhydrazine, 2-nitrophenylhydrazine, 1-naphthylhydrazine and 3-hydrazinopyridine.

In the invention, the structural formula of the isothiocyanate compound is R²N ═ C ═ S, and R in the structural formula of hydrazine compound²And R in the structure shown in the formula I²Keeping the same is not described herein. In a specific embodiment of the invention, the isothiocyanate-based compound is phenyl isothiocyanate, phenyl p-fluoroisothiocyanate, phenyl p-methoxyisothiocyanate, phenyl p-ethylisothiocyanate, phenyl 3-methoxyisothiocyanate, phenyl 2-chloroisothiocyanate, phenyl 3,4, 5-trimethoxyisothiocyanate, phenyl 1-naphthylisothiocyanate.

In the invention, the molar ratio of the hydrazine compound, the isothiocyanate compound and the tetramethylguanidine is preferably 1:1 (1-2), and more preferably 1:1: 1.5.

In the present invention, the photocatalyst is an organic dye and/or a metal complex; the organic dye is preferably one or more of eosin B, eosin Y and rose bengal, and is further preferably rose bengal; the metal complex is preferably tris (2, 2' -bipyridyl) ruthenium dichloride and/or tris (2-phenylpyridine) iridium. In the invention, the amount of the photocatalyst is preferably 0.5-2% of the molar amount of the hydrazine compound, and more preferably 1%.

In the invention, the polar organic solvent is preferably one or more of dimethyl sulfoxide, N-dimethylformamide, toluene, ethanol, acetonitrile and dichloromethane; the ratio of the volume of the polar organic solvent to the amount of the substance of the hydrazine-based compound is preferably 1L: 0.1 to 0.2mol, more preferably 1L: 0.1 mol.

The sources of the hydrazine compound, the isothiocyanate compound, the tetramethylguanidine, the photocatalyst and the polar organic solvent are not particularly required, and corresponding commercial products which are well known to the technical personnel in the field can be adopted. According to the invention, preferably, the hydrazine compound, the isothiocyanate compound and the tetramethylguanidine are mixed with the polar organic solvent, and then the photocatalyst is added into the mixture to obtain the mixed solution. The method for mixing the components does not need to be specially required, and the method for mixing the components is used for ensuring that the components of the raw materials are uniformly mixed by adopting a method well known by the technical personnel in the field.

After a mixed solution is obtained, the mixed solution is subjected to cyclization reaction under the conditions of illumination and 50-80 ℃ to obtain the 1,2, 4-triazole compound. In the present invention, the wavelength of the light source for the illumination is preferably 200 to 1000nm, and more preferably 300 to 800 nm. The present invention does not require the light source in particular, and can provide any light source having the above-mentioned wavelength. In the present invention, the temperature of the cyclization reaction is preferably 60 ℃; the time of the cyclization reaction is preferably 1-48 h, and more preferably 6-24 h; the cyclization reaction is preferably carried out under stirring conditions, and the stirring speed in the present invention is not particularly limited.

After the cyclization reaction, the present invention preferably further performs a purification treatment on the obtained cyclization reaction liquid. In the present invention, the purification treatment is preferably column chromatography. In the present invention, the eluent for the column chromatography is preferably a mixed solvent of petroleum ether and ethyl acetate; the volume ratio of the petroleum ether to the ethyl acetate in the mixed solvent is preferably 1-30: 1, more preferably 5-20: 1, and even more preferably 5: 1. The present invention does not require any particular method for carrying out the column chromatography, and may be carried out in a manner known to those skilled in the art. According to the invention, petroleum ether and ethyl acetate are used as eluent, and the mixed solution after cyclization reaction is subjected to column chromatography purification treatment, so that the 1,2, 4-triazole compound with high purity can be obtained. In the present invention, the purity of the 1,2, 4-triazole compound is preferably 98.5 to 99.9%, and more preferably 99 to 99.9%.

The invention provides a preparation method of the 1,2, 4-triazole compound, which comprises the steps of providing energy required by cyclization reaction by utilizing illumination, matching with the selection of reaction raw materials, reacting at the temperature of 50-80 ℃ to obtain the 1,2, 4-triazole compound, wherein the whole reaction process is safe and stable, the conditions are mild, the control is easy, and the obtained 1,2, 4-triazole compound has high purity. In addition, the preparation method of the 1,2, 4-triazole compound provided by the invention has good adaptability to raw materials, and can be used for preparing 1,2, 4-triazole compounds with different substituents; and the raw materials are easy to obtain, and the cost is low.

The following examples are provided to illustrate the 1,2, 4-triazole compounds and the preparation method thereof in detail, but they should not be construed as limiting the scope of the present invention.