阅读说明：本技术 一种吲哚类化合物的制备方法 (A kind of preparation method of Benzazole compounds ) 是由 徐慧婷 蔡涛 沈润溥 杜奎 余乐茂 骆翔 罗蒙强 丰诚杰 于 2019-08-15 设计创作，主要内容包括：本申请提供一种吲哚类化合物的制备方法,属于杂环化合物制备技术领域。以1,2-二氯甲烷为溶剂,氧化银为催化剂,2-乙炔基苯胺及其衍生物为原料,在一水合对甲基苯磺酸存在下,在(10-60)℃反应完全,旋干得粗品,过柱分离得精品,即吲哚类化合物。本申请制备步骤简短,反应条件温和,产品收率高,成本低,为吲哚类化合物的制备提供了一种通用的新方法。(The application provides a kind of preparation method of Benzazole compounds, belongs to heterocyclic compound preparation technical field.With 1,2- methylene chloride for solvent, silver oxide is catalyst, and 2- acetylenylaniline and its derivative are raw material, in the presence of a hydration p-methyl benzenesulfonic acid, in (10-60) DEG C fully reacting, is spin-dried for obtaining crude product, column separation obtains fine work, i.e. Benzazole compounds.The application preparation step is brief, and reaction condition is mild, and product yield is high, at low cost, provides a kind of general new method for the preparation of Benzazole compounds.)

1. a kind of preparation method of Benzazole compounds, it is characterised in that: with 1,2- methylene chloride for solvent, silver oxide is catalysis Agent, 2- acetylenylaniline and its derivative are raw material, in the presence of a hydration p-methyl benzenesulfonic acid, have been reacted at (10-60) DEG C Entirely, it is spin-dried for obtaining crude product, column separation obtains fine work, i.e. Benzazole compounds.

2. a kind of preparation method of Benzazole compounds according to claim 1, it is characterised in that: catalyst loading is (1-10) mol% of raw material.

3. a kind of preparation method of Benzazole compounds according to claim 2, it is characterised in that: catalyst loading is (3-9) mol% of raw material.

4. a kind of preparation method of Benzazole compounds according to claim 1, it is characterised in that: a hydration is to methylbenzene Sulfonic acid additive amount is (50-150) mol% of raw material.

5. a kind of preparation method of Benzazole compounds according to claim 1, it is characterised in that: reaction temperature (30- 55) DEG C, reaction time (1-5) h.

6. a kind of preparation method of Benzazole compounds according to claim 1, it is characterised in that: cross column solvent by petroleum Ether and ethyl acetate are constituted, petroleum ether: ethyl acetate=50:1.

7. a kind of preparation method of Benzazole compounds according to claim 1-7, which is characterized in that indoles The general formula of compound are as follows:R₁For in phenyl, 4- aminomethyl phenyl, 4- methoxyphenyl, 4- fluorophenyl, 4- chlorphenyl It is any；R₂For hydrogen or methyl.

8. a kind of preparation method of Benzazole compounds according to claim 8, it is characterised in that: the indoles chemical combination In the general formula of object, R₂When for hydrogen, R₁For phenyl.

9. a kind of preparation method of Benzazole compounds according to claim 8, it is characterised in that: the silver oxide addition Amount be raw material 5mol%, one hydration p-methyl benzenesulfonic acid additive amount be raw material 100mol%, 40 DEG C of reaction temperature.

Technical field

This application involves a kind of preparation methods of Benzazole compounds, belong to heterocyclic compound preparation technical field.

Background technique

The basic framework of Benzazole compounds is benzopyrrole ring, and such compound is widely present in active biology In body, natural products and drug molecule.Have antitumor, anti-inflammatory, antibacterial etc. more with the compound that indoles is basic mother nucleus structure Kind pharmacological activity.It is reported that di-indole methyl hydride can not only inhibit the apoptosis of the growth of tumour cell, inducing cell, can also press down Revascularization processed.Agent vincristine with efficient antitumaous effect also has this basic framework of indoles, this makes increasingly More pharmacy workers produce great interest to the study on the synthesis of Benzazole compounds.

Currently, the common method of synthesis of indole class compound basic framework have it is following several:

(1) in the presence of CO, using ortho-nitrophenyl ethylene as raw material, THF is solvent, through transition metal (PdCl₂/PPh₃/B (OH)₃) catalysis-reduction obtains nitroso aromatic hydrocarbons or nitrence intermediate, then cyclisation obtains indoles skeleton, reaction temperature 80 DEG C, reaction time 20h.

The method is easy to operate, but the reaction time is long, and higher to catalyst requirement, and different catalysts obtain different productions Object.

(2) under nitrogen protection, using 2- (2- aminophenyl) ethyl alcohol and its derivative as raw material, tBuOK, CaCl2 is added, it is molten Agent ortho-xylene and catalyst CuAl-HT2, the one pot reaction 12h at 140 DEG C obtain target product, yield highest order 98%, The recyclable recycling of catalyst 6 times.

The method raw material is simple, high income, and catalyst recoverable, but reaction temperature is high, the time is long, and catalyst For self-control, market purchase difficulty, it is difficult to effectively be promoted.

(3) using 2- acetylenylbenzene amine derivative as raw material under the action of catalyst, prepare corresponding indoles through annulation Compound.

Used catalyst includes following 3 class formation a, b, c:

Such method high income, but used catalyst is more complex, it is expensive, and mostly high temperature system.

Summary of the invention

In view of this, the application provides a kind of preparation method of silver oxide catalysis progress Benzazole compounds, on overcoming State defect present in the prior art.

Specifically, the application, using 2- acetylenylbenzene amine derivative as raw material, formation has the characteristics that succinct, inexpensive, efficient Benzazole compounds new synthetic method, shown in compound structure such as formula (I):

It is as follows that the application prepares the technical solution that above compound is taken:

With 1,2- methylene chloride for solvent, silver oxide is catalyst, and 2- acetylenylbenzene amine derivative is raw material, in a hydration In the presence of p-methyl benzenesulfonic acid, control reaction temperature is (10-60) DEG C, and single step reaction prepares Benzazole compounds (I), reacted Quan Hou is spin-dried for, and obtains crude product, is crossed column, is obtained fine work Benzazole compounds (I).

Reaction equation is as follows:

Wherein, R₁For phenyl, 4- aminomethyl phenyl, 4- first Any one of phenyl, 4- fluorophenyl, 4- chlorphenyl；R₂Selected from any one of hydrogen, methyl.

In above scheme, effectively mentioned in the presence of a hydration p-methyl benzenesulfonic acid by means of silver oxide as catalyst The high activity of raw material, can not only complete the synthesis of Benzazole compounds, reaction item in 60 DEG C of middle cryogenic conditions below Part is mild, can also be spin-dried in 5h or so fully reacting after reaction, cross column and obtain fine work, yield can guarantee in (90- 95) %, it is even higher under partial picture.Compared with customary preparation methods, catalyst only needs to be oxidized silver-colored one kind, constitutes letter It is single, easily obtain, bare catalyst this part can significantly reduce the preparation cost of Benzazole compounds very much, industrialization and Popularization is easier.

On the basis of above scheme, we have done further research to the additive amount of catalyst, and determination is preferably urged Agent additive amount meets: the additive amount of silver oxide is (1-10) mol% of gross mass of feeding intake, and catalyst, can in the range Guarantee that reactivity good, raw material reaction rate and conversion ratio 85% or more, and can control cost well.It was testing Cheng Zhong, it has been found that: when catalyst loading is (3-9) mol%, catalytic effect is best, at this point, reaction speed is fast and reacts Stablize, transformation efficiency is 90% or more.

On the basis of above scheme, we have done further research to reaction atmosphere, and determine that preferred atmosphere agent is The additive amount of one hydration p-methyl benzenesulfonic acid meets: the additive amount of a hydration p-methyl benzenesulfonic acid is 0.5 equivalent (50mol%)- 1.5 equivalents (150mol%), reaction, which is maintained under middle acid condition, to be carried out, and silver oxide is come into full contact with raw material, and effectively Reaction speed and the Direction of Reaction are controlled, ensure that finished product yield.In the course of the research, it has been found that: when a hydration is to methylbenzene It is best to the control effect of conversion rate and the Direction of Reaction when sulfonic acid additive amount is 1 equivalent (100mol%).

On the basis of above scheme, we have done system research to reaction temperature, and determine that preferred response parameter meets: In 60 DEG C of middle low-temp reaction sections below, when reaction temperature is controlled at 30 DEG C -55 DEG C, finished product yield can be met in 92- In 95% range, the excessively high dimensionally stable for being unfavorable for the auxiliary materials such as raw material, catalyst, atmosphere solvent of temperature, temperature is too low, reacts Activity is bad, and reaction yield can be reduced to 65% hereinafter, therefore, under comprehensively considering, reaction temperature is (30-55) DEG C, especially When reaction temperature is selected at 40 DEG C, reaction effect is best；In above-mentioned temperature preferred scope, we to the reaction time done into The research of one step, and determine under 60 DEG C of middle cryogenic conditions below, reaction is sufficiently needed (2-4) h；When reaction is in (30- DEG C 55) when especially (35-55) DEG C temperature section carries out, optimum reacting time can be controlled in 3h, can sufficiently complete.

After basic reaction condition has been determined, we study subtractive process, and the preferred column condition excessively of determination Are as follows: cross the mixture that column uses petroleum ether and ethyl acetate, petroleum ether: ethyl acetate=50:1.

The application's has the beneficial effect that:

(1) for the application by the control of reaction atmosphere, indoles is prepared in the single step reaction realized under silver oxide catalysis Class compound, this provides new method for the preparation of such compound, and reactions steps of this method is few, is middle low-temp reaction, not only Reaction is mild, reaction time is short, and the original of participation reaction, auxiliary material are that composition is simple and easy to get, reduce synthesis cost.

(2) the application is easy to operate, and suitable substrates are wide, and under above-mentioned catalyst, atmosphere reagent and solvent, reaction process does not have There is particularly harsh external requirement, there is good expansion, each substituent group (i.e. R in skeleton structure₁、R₂) all have very well Reactivity, product yield can be controlled in 90% or more.

(3) Benzazole compounds that the above method is prepared, work as R₂When selecting methyl, R₁In above-mentioned alternative substituent group (benzene Base, 4- aminomethyl phenyl, 4- methoxyphenyl, 4- fluorophenyl, 4- chlorphenyl) in optionally；R₂When selecting hydrogen, R₁Phenyl is selected, this two Kind situation application effect is best；Especially in compound structure, R₂Select methyl, R₁Select 4- methoxyphenyl or 4- chlorobenzene When base, corresponding Benzazole compounds are more excellent to the extracorporeal extracorporeal suppression of A549 lung carcinoma cell, are applied to biological medicine side Face has very big potentiality.

The application is described further With reference to embodiment.

Detailed description of the invention

Figure 1A is 1- methyl -2-phenylindone (A in the application₁)¹H spectrogram；

Figure 1B is 1- methyl -2-phenylindone (A in the application₁)¹³C spectrogram.

Specific embodiment

Analysis instrument and equipment used in the present embodiment: Nuclear Magnetic Resonance, II I 400M of AVANCE DMX (TMS internal standard, Bruker company)；High performance liquid chromatograph: Agilent Technologies 1200Series.