阅读说明：本技术 一种吲哚类二芳基甲烷化合物及其制备方法和应用 (Indole diaryl methane compound and preparation method and application thereof ) 是由 陈冬寅 冯黎黎 李飞 杨磊 盛刚 陈轩 韩峰 于 2020-06-08 设计创作，主要内容包括：一种吲哚类二芳基甲烷化合物及其制备方法和应用,该类化合物以吲哚-3-甲醇乙酸酯衍生物和苯酚衍生物为原料,通过傅-克烷基化反应制备。本发明原料经济易得,合成过程采用一锅法,避免多步操作,操作简便,反应条件温和。CCK8检测法进行活性测试研究结果显示,该类化合物对多种肿瘤细胞株具有良好的抑制活性,具有较好的医药应用前景。(An indole diaryl methane compound and a preparation method and application thereof are disclosed, the compound takes indole-3-methanol acetate derivatives and phenol derivatives as raw materials and is prepared by Friedel-crafts alkylation reaction. The method has the advantages of economic and easily obtained raw materials, one-pot method adopted in the synthesis process, avoidance of multistep operation, simple and convenient operation and mild reaction conditions. The research result of activity test by a CCK8 detection method shows that the compounds have good inhibitory activity to various tumor cell strains and have good medical application prospect.)

1. An indole diaryl methane compound is characterized in that the structure is shown as a general formula (I):

wherein R is¹H, halogen, C1-C5 alkyl or C1-C5 alkoxy;

R²h, acyl, sulfonyl or C1-C5 alkyl;

R³h, halogen or C1-C4 alkyl;

R⁴h, halogen or C1-C4 alkyl.

2. The indole diarylmethane compound according to claim 1, wherein: r¹H, fluoro, methyl or methoxy.

3. The indole diarylmethane compound according to claim 1, wherein: r²H, acetyl, benzoyl or p-toluenesulfonyl.

4. The indole diarylmethane compound according to any one of claims 1 to 3, wherein: r³And R⁴Independently selected from H, fluoro, chloro, bromo, methyl, isopropyl or tert-butyl.

5. The indole diarylmethane compounds according to claim 1, wherein the structural formula of the preferred compounds is as follows:

6. the process for producing an indole diarylmethane compound according to any one of claims 1 to 5, characterized by the following synthetic route:

7. the method of claim 6, wherein: adding 1mol of indole-3-methanol acetate derivative and 1.0-1.2 mol of phenol derivative into an aprotic solvent according to a proportion, adding 300mg of proton exchange montmorillonite, heating and refluxing at 40-80 ℃ for 1-12 hours, after the reaction is finished, removing the proton exchange montmorillonite by suction filtration, decompressing and concentrating the filtrate, and separating by column chromatography to obtain the product.

8. The method according to claim 7, wherein the aprotic solvent is dichloromethane, chloroform, n-hexane or cyclohexane.

9. The production method according to claim 7, wherein the proton-exchanged montmorillonite is produced by heat-refluxing montmorillonite with 1.1 wt.% hydrochloric acid.

10. Use of a compound according to any one of claims 1 to 5 in the manufacture of a medicament for the treatment or prevention of tumour growth and metastasis.

Technical Field

The invention belongs to the technical field of medicines, and provides an indole diaryl methane compound and a preparation method and application thereof.

Background

Tumors are one of the most important problems to the health of humans. Worldwide, patients who die of tumors every year can reach millions, accounting for about 1/4 total deaths. The prevention and treatment of tumors have become an important problem to be solved urgently in clinical medicine, and are one of the main research topics in the field of biological medicine. The treatment method of the tumor comprises operation treatment, radiotherapy, photodynamic treatment, immunotherapy, drug therapy and the like, and the drug therapy plays an important role in the comprehensive treatment of the tumor. At present, the main research directions of antitumor drugs are: search for new action targets (receptors, enzymes, etc.), new anti-tumor active molecules and new experimental methods.

Indole compounds are secondary metabolites widely existing in plants and microorganisms, are important nitrogen heterocyclic compounds, have various biological activities and stress functions, are ideal drug lead compounds, and can also be used as tool molecules for discovering and explaining novel biological processes. Indoles are also present in animals, and the essential amino acid tryptophan is an indole compound, which is a structural component of many proteins; some endogenous substances are also indole derivatives, such as neurotransmitter serotonin, mammal hormone melatonin and the like, and have strong physiological activity. Clinically, the indole structure-containing drugs have been used to treat various diseases, such as tumors, cardiovascular and cerebrovascular diseases, inflammation and pain, viral diseases, and infectious diseases. Representative drugs are, for example, Sunitinib (Sunitinib), Eptifibatide (Eptifibatide), Reserpine (Reserpine), Sumatriptan (Sumatriptan), Indomethacin (Indomethacin), Zafirlukast (Zafirlukast), and the like. In addition, the indole compounds are also widely applied to the fields of pesticides, perfumes, dyes and other fine chemical products.

Disclosure of Invention

The technical problem to be solved is as follows: the invention provides an indole diaryl methane compound and a preparation method and application thereof, the specific synthetic process of the compound adopts indole-3-methanol acetate derivatives and phenol derivatives as raw materials, the compound is prepared by proton exchange montmorillonite mediated Friedel-crafts alkylation reaction, a (transition) metal catalyst is not used, the operation is simple and convenient, and the raw materials are economical and easy to obtain. The prepared compound can be used for preparing medicines for treating or preventing tumor growth and metastasis.

The technical scheme is as follows: an indole diaryl methane compound has a structure shown as a general formula (I):

wherein R is¹H, halogen, C1-C5 alkyl or C1-C5 alkoxy;

R²h, acyl, sulfonyl or C1-C5 alkyl;

R³h, halogen or C1-C4 alkyl;

R⁴h, halogen or C1-C4 alkyl.

Preferably, R is as defined above¹H, fluoro, methyl or methoxy.

Preferably, R is as defined above²H, acetyl, benzoyl or p-toluenesulfonyl.

Preferably, R is as defined above³And R⁴Independently selected from H, fluoro, chloro, bromo, methyl, isopropyl or tert-butyl.

The structural formula of the indole diaryl methane compound, preferably the compound is shown as follows:

the preparation method of the indole diarylmethane compound comprises the following synthetic route:

the preparation method comprises the following steps: adding 1mol of indole-3-methanol acetate derivative and 1.0-1.2 mol of phenol derivative into an aprotic solvent according to a proportion, adding 300mg of proton exchange montmorillonite, heating and refluxing at 40-80 ℃ for 1-12 hours, after the reaction is finished, removing the proton exchange montmorillonite by suction filtration, decompressing and concentrating the filtrate, and separating by column chromatography to obtain the product.

Preferably, the aprotic solvent is dichloromethane, chloroform, n-hexane or cyclohexane.

The proton-exchanged montmorillonite is prepared by heating and refluxing montmorillonite with 1.1 wt.% hydrochloric acid.

The application of the compound in preparing the medicine for treating or preventing tumor growth and metastasis.

Has the advantages that: the invention prepares a novel indole diaryl methane compound by proton exchange montmorillonite mediated Friedel-crafts alkylation reaction, the raw materials are economic and easy to obtain, the reaction condition is mild, no (transition) metal catalyst is used, the fussy multi-step operation is avoided, and the operation is simple and convenient. The activity test is carried out by adopting a CCK8 detection method, and research results show that the compounds have good inhibitory activity on various tumor cell strains and have good medical application prospects.

Detailed Description

The present invention is further described below in conjunction with specific examples so that those skilled in the art may fully understand the present invention without limiting the scope and spirit of the present invention in any way.