阅读说明：本技术 一种七元环并环戊[b]吲哚类衍生物及其合成方法和应用 (Seven-membered ring fused cyclopenta [ b ] indole derivative and synthesis method and application thereof ) 是由 李艳忠 王孟丹 尹利强 杨亚婕 宋博 徐穆榕 穆远洋 王野 袁洋 冯烨 于 2020-04-28 设计创作，主要内容包括：本发明公开了一种七元环并环戊[b]吲哚类衍生物的合成方法,以炔酮类化合物和环己酮酯类化合物为原料,采取“一锅法”合成如式(b)所示的七元环并环戊[b]吲哚类衍生物。所述合成方法具体为,第一步通过碱促进C-C键插入实现扩化反应得到七元环类化合物,第二步在对甲苯磺酸作用下发生亲核加成反应。本发明制备方法具有原料简单易得、普适性好、后处理简便、收率良好、对环境友好等优点。本发明还提供了式(b)所示的七元环并环戊[b]吲哚类衍生物在药物中的应用。(The invention discloses a synthesis method of seven-membered cyclo-penta [ b ] indole derivatives, which takes an alkynone compound and a cyclohexanone ester compound as raw materials to synthesize the seven-membered cyclo-penta [ b ] indole derivatives shown in the formula (b) by a one-pot method. The synthesis method specifically comprises the steps of firstly, promoting C-C bond insertion through alkali to realize an amplification reaction to obtain a seven-membered ring compound, and secondly, carrying out a nucleophilic addition reaction under the action of p-toluenesulfonic acid. The preparation method has the advantages of simple and easily obtained raw materials, good universality, simple and convenient post-treatment, good yield, environmental friendliness and the like. The invention also provides application of the seven-membered ring pentacyclo [ b ] indole derivative shown in the formula (b) in medicines.)

1. The seven-membered ring pentacyclo [ b ] indole derivative is characterized by having a structure shown in a formula (b):

wherein the content of the first and second substances,

R¹selected from H, alkyl, halogen;

R²is phenyl, alkyl substituted phenyl, halogen substituted aryl;

R³is an electron-withdrawing group selected from ester group and cyano group;

R⁴is a protecting group selected from alkyl, hydrogen, benzyl.

2. The seven-membered ring fused cyclopenta [ b ] of claim 1]Indole derivatives characterized in that R¹Selected from H, C1-C10 alkyl, halogen; r²Is phenyl, C1-C10 alkyl substituted aryl, halogen substituted aryl; r³Is an electron-withdrawing group selected from ester group and cyano group; r⁴Is a protecting group selected from C1-C10 alkyl, hydrogen, benzyl.

3. A synthetic method of seven-membered ring-fused cyclopenta [ b ] indole derivatives is characterized in that under the action of a catalyst and an accelerant, raw materials of an alkynone compound and a cyclohexanone ester compound react to obtain the seven-membered ring-fused cyclopenta [ b ] indole derivatives shown in the formula (b), and the reaction process is shown in the formula (II):

wherein the content of the first and second substances,

R¹selected from H, alkyl, halogen;

R²is phenyl, alkyl substituted aryl, halogen substituted aryl;

R³is an electron-withdrawing group selected from ester group and cyano group;

R⁴is a protecting group selected from alkyl, hydrogen, benzyl.

4. A synthesis method according to claim 3, characterized by the specific steps of: firstly, in a solvent, taking the alkynone compound and the cyclohexanone ester compound as raw materials, and carrying out C-C bond insertion reaction under the action of the accelerator to obtain a medium-ring compound shown in a formula (a); and secondly, adding the additive to perform nucleophilic addition reaction to obtain the seven-membered cyclo-cyclopenta [ b ] indole derivative.

5. The synthesis method according to claim 3 or 4, wherein the promoter is a base comprising: DABCO, t-BuOK, K₂CO₃、Cs₂CO₃One of (1); and/or the additive is one of protonic acid additives selected from TsOH & H₂O, HCl or TFA.

6. The method of synthesis according to claim 3 or 4, wherein the acetylenic ketone compound: the molar ratio of the cyclohexanone ester compound to the accelerator is 1:2 (1-2).

7. A process according to claim 3 or 4, wherein the amount of the said acetylenic ketone compound is 6.0-8.0 equivalents.

8. The method of claim 4, wherein the solvent is one or more of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, toluene, and tetrahydrofuran.

9. The synthesis method according to claim 4, characterized in that the temperature of the reaction in the first step is 60-100 ℃; and/or the temperature of the reaction in the second step is 100-120 ℃; and/or the reaction time in the first step is 1-4 hours; and/or the reaction time in the second step is 2 to 4 hours.

10. The use of the seven-membered cyclo-cyclopenta [ b ] indole derivative according to claim 1 or 2 for preparing an antitumor medicament.

Technical Field

The invention belongs to the field of organic compound synthesis, and particularly relates to a seven-membered cyclo-penta [ b ] indole derivative, and a synthesis method and application thereof.

Background

The cyclopenta [ b ] indole compounds are important organic compounds, are main structural units in a plurality of natural products and medicines, and mostly have stronger biological activity. Can be used for organic synthesis intermediates and has great value in the aspect of drug synthesis. Therefore, much attention has been paid to the synthesis of cyclopenta [ b ] indoles. At present, the synthetic methods of the compounds have more reports in the literature and have also made great progress. For example, under the action of silver and polyphosphoric acid, cyclopenta [ b ] indole derivatives can be obtained. The seven-membered ring compound also has high biological activity, but is complex in synthesis and generally requires transition metal to participate. For example: document (1) Jiang, l.; jin, w.; hu, w., ACS Catalysis 2016,6,6146.(2) Santos, m.s.; fernandes, d.c.; rodrigues, m.t., jr.; regiani, T.; andricopoulo, a.d.; ruiz, a.l.; Vendramini-Costa, d.b.; de Carvalho, j.e.; eberlin, m.n.; coelho, f., JOrgChem 2016,81,6626.(3) Vickerman, k.l.; stanley, l.m., catalytics, OrgLett2017,19,5054.

Disclosure of Invention

The invention aims to provide a seven-membered cyclo-cyclopenta [ b ] indole derivative and a synthesis method thereof, wherein the method is a synthesis method for obtaining the seven-membered cyclo-cyclopenta [ b ] indole derivative with low cost and environmental friendliness by carrying out a C-C bond insertion reaction under the promotion of an accelerant and a nucleophilic addition reaction under the action of an additive, and the two reactions are connected in series.

The invention provides an unreported seven-membered cyclo-cyclopenta [ b ] indole derivative, which has a structure shown in a formula (b):

in the formula (b), the reaction mixture is,

R¹selected from H, alkyl, halogen;

R²is phenyl, alkyl substituted aryl, halogen substituted aryl;

R³is an electron-withdrawing group selected from ester group and cyano group;

R⁴is a protecting group selected from alkyl, hydrogen, benzyl.

Preferably, the first and second electrodes are formed of a metal,

R¹selected from H, C1-C10 alkyl, halogen;

R²is phenyl, C1-C10 alkyl substituted aryl, halogen substituted aryl;

R³is an electron-withdrawing group selected from ester group and cyano group;

R⁴is a protecting group selected from C1-C10 alkyl, hydrogen, benzyl.

It is further preferred that the first and second liquid crystal compositions,

R¹is H, 6-methyl;

R²is phenyl, 4-methylphenyl;

R³cyano, ethyl formate, ethyl acetate;

R⁴is methyl, hydrogen or benzyl.

The invention also provides a preparation method of the seven-membered cyclo-cyclopenta [ b ] indole derivative shown in the formula (b), which synthesizes the seven-membered cyclo-cyclopenta [ b ] indole derivative shown in the formula (b) by taking an alkynone compound and a cyclohexanone ester compound as raw materials under the action of an accelerator and an additive.

The preparation method specifically comprises the steps of firstly, taking an alkynone compound and a cyclohexanone ester compound as raw materials in a solvent, and carrying out C-C bond insertion reaction under the action of an accelerant to obtain a middle ring compound; secondly, adding an additive to perform nucleophilic addition reaction to obtain the seven-membered cyclo-penta [ b ] indole derivative shown in the formula (b); the reaction formula is shown as formula (II):

wherein the content of the first and second substances,

R¹selected from H, alkyl, halogen;

R²is phenyl, alkyl substituted aryl, halogen substituted aryl;

R³is an electron-withdrawing group selected from ester group and cyano group;

R⁴is a protecting group selected from alkyl, hydrogen, benzyl.

Preferably, the first and second electrodes are formed of a metal,

R¹selected from H, C1-C10 alkyl, halogen;

R²is phenyl, C1-C10 alkyl substituted aryl, halogen substituted aryl;

R³is an electron-withdrawing group selected from ester group and cyano group;

R⁴is a protecting group selected from C1-C10 alkyl, hydrogen, benzyl.

It is further preferred that the first and second liquid crystal compositions,

R¹is H, 6-methyl;

R²is phenyl, 4-methylphenyl;

R³cyano, ethyl formate, ethyl acetate;

R⁴is methyl, hydrogen or benzyl.

In the invention, the alkynone compound is an alkynone compound with an electron donating group connected to a benzene ring and cyclopentanone with an electron withdrawing group connected to the benzene ring.

In the invention, the accelerant is alkali selected from DABCO and K₂CO₃、t-BuOK、Cs₂CO₃One or more of the following; preferably, it is Cs₂CO₃。

In the invention, the additive is one of protonic acid additives and is selected from TsOH & H₂One or more of O, HCl, TFA; preferably, TsOH H₂O。

In the invention, the raw material of the alkynone compound is as follows: raw material cyclohexanone ester compound: the molar ratio of the accelerator is 1:2 (1-2); preferably, 1:2: 2.

wherein, the dosage of the acetylenic ketone compound is used as reference, and the dosage of the additive is 6.0-8.0 equivalent; preferably 6.0 equivalents, 7.0 equivalents or 8.0 equivalents; more preferably, it is 8.0 equivalents.

In the invention, the solvent is one or more of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, toluene, tetrahydrofuran and the like; preferably, it is dimethyl sulfoxide.

In the invention, the reaction temperature in the first step is 60-100 ℃; preferably 60 deg.C

In the invention, the reaction time in the first step is 1-4 hours; preferably, the reaction is carried out at 60 ℃ for 2 hours.

In the invention, in the second step, the reaction temperature is 100-120 ℃; preferably, it is 120 ℃.

In the invention, in the second step, the reaction time is 2-4 hours; preferably, the reaction is carried out at 120 ℃ for 2 hours.

In the present invention, the first reaction step is preferably carried out under nitrogen protection.

In the present invention, the second reaction is preferably carried out in air.

In a preferred embodiment, the preparation process of the present invention is represented by the following reaction scheme:

wherein, R is¹、R²、R³、R⁴Is as defined in formula (II).

In one embodiment, Cs is used in the preparation method of the invention₂CO₃TsOH. H as an accelerator₂O is an additive, and is shown in the following reaction formula (II-2):

wherein R is¹、R²、R³、R⁴Is as defined in formula (II).

The invention adopts a one-pot synthesis method, meets the modern requirement on the economy of the synthesis method, does not use transition metal, and is environment-friendly.

The reaction in the first step of the invention can obtain the seven-membered ring compound with high yield only under the action of alkali promotion. The synthesis of seven-membered ring compounds is reported to be difficult, transition metals are generally used, and the substrate limitation is large. The second step of the reaction realizes the nucleophilic addition reaction of indole C3 to carbonyl. The invention connects two reactions in series, and has convenient operation and easily obtained raw materials.

The invention also provides application of the seven-membered cyclo-cyclopenta [ b ] indole derivative in preparation of antitumor drugs

The invention has the following advantages: the method has the advantages of environmental friendliness, good reaction universality, simple and easily-obtained raw materials, simple and convenient post-treatment, good yield (46-99%), environmental friendliness and the like. The seven-membered ring pentacyclo [ b ] indole derivative provided by the invention is a main structural unit in a plurality of natural products and medicines, and most of the derivatives have stronger biological activity. Can be used for organic synthesis intermediates and has great value in the aspect of drug synthesis.

Detailed Description

The present invention will be described in further detail with reference to the following specific examples, but the present invention is not limited to the following examples. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected. The procedures, conditions, reagents, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.