阅读说明：本技术 一种苯并噻吩类化合物及其制备与应用方法 (Benzothiophene compound and preparation and application method thereof ) 是由 徐慧婷 蔡涛 吴春雷 沈润溥 盛国栋 高晓忠 于 2020-05-26 设计创作，主要内容包括：本申请提供一种苯并噻吩类化合物及其制备与应用方法,属于杂环化合物合成技术领域。以丙酮为溶剂,DTPB为自由基引发剂,2-乙炔基苯甲硫醚衍生物为原料,在磷酸二氢钠存在下,于氮气氛围中一步反应制备得粗品,精制后即得苯并噻吩类化合物。本申请制备的化合物均为新化合物,步骤简短,操作简单,成本低,为苯并噻吩类化合物的制备提供了一种通用的新方法。(The application provides a benzothiophene compound and preparation and application methods thereof, belonging to the technical field of heterocyclic compound synthesis. Acetone is used as a solvent, DTPB is used as a free radical initiator, 2-ethynyl methyl sulfide derivatives are used as raw materials, a crude product is prepared by one-step reaction in a nitrogen atmosphere in the presence of sodium dihydrogen phosphate, and the benzothiophene compound is obtained after refining. The compounds prepared by the method are all new compounds, the steps are short, the operation is simple, the cost is low, and a universal new method is provided for preparing benzothiophene compounds.)

1. A benzothiophene compound characterized by: benzothiophenes have the following structure:

2. The 3-ethylcyanobenzothiophene compound according to claim 1, wherein: the benzothiophene compound is any one of compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, compound 13, compound 14 and compound 15, and the structural formulas of compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, compound 13, compound 14 and compound 15 are respectively as follows:

3. the method for producing benzothiophenes according to claim 1, wherein: taking a 2-ethynyl methyl sulfide derivative as a raw material, acetone as a solvent, controlling the reaction temperature to be 120-140 ℃ in the presence of disodium hydrogen phosphate, initiating free radicals through DTPB under the protection of nitrogen, preparing a crude product through one-step reaction, wherein the reaction time of the one-step reaction is 22-25 h, and then refining to obtain a target product, namely a benzothiophene compound; the amount of DTPB added is 3.4 to 4.5 equiv, and the amount of disodium hydrogen phosphate is 0.6 to 1.6 equiv.

4. The method for producing benzothiophenes as claimed in claim 3, wherein: the amount of DTPB added was 4.0 equiv, and the amount of disodium hydrogen phosphate added was 1.0 equiv.

5. The method for producing benzothiophenes as claimed in claim 3, wherein: the reaction temperature is 130-135 ℃.

6. The method for preparing benzothiophenes according to any one of claims 3 to 5, wherein the reaction is completed in one step, and then a crude product is obtained by extraction with dichloromethane and spin-drying, and a refined product is obtained by column chromatography using a petroleum ether: ethyl acetate 2: 1.

7. The method of using benzothiophenes of claim 1 or 2, wherein: benzothiophenes are used as active ingredients of dermatophyte inhibitors.

8. The method for using benzothiophenes, as claimed in claim 7, wherein: the structural formula of the benzothiophene compound applied to the effective component of the pesticide is shown in the specification

Technical Field

The application relates to a benzothiophene compound and preparation and application methods thereof, belonging to the technical field of heterocyclic compound synthesis.

Background

Benzothiophene and its derivatives are one of the sulfur atom-containing aromatic heterocyclic compounds, and the derivatives thereof are widely used in the fields of medicines, dyes, novel polymers, luminescent materials, and the like. In the aspect of medicine, the medicine taking benzothiophene as a pharmacophore comprises brexpiprazole, rig-clean L-proline salt, sertaconazole nitrate and the like; meanwhile, the benzothiophene derivative can also be used for synthesizing new materials such as liquid crystal polymers, superconductors and the like, is a novel organic photoelectric material, has good application prospect in the field of organic electronic materials such as novel batteries and the like, and is a good luminescent material. However, compared with nitrogen-containing heterocycles, benzothiophene has lower activity, and the research on derivatives of benzothiophene mostly uses transition metals, and has more complex preparation process and high cost, so the research operation is simple, and the novel synthetic method with universality has very important significance.

Currently, the following methods are commonly used for synthesizing benzothiophenes: intramolecular cyclization of aryl alkenyl thioether; intramolecular cyclization of aryl alkynyl thioether; ③ intramolecular cyclization of o-alkynyl thiophenol (thioether); intramolecular cyclization of o-alkenylthiophenol; intramolecular cyclization of aryl carbonyl methyl sulfide; reacting beta halo-o-halostyrene with an inorganic sulfur-containing compound; reaction of o-halophenylalkyne with inorganic sulfur-containing compounds; reacting benzene disulfide with substituted alkyne; ninthly, reacting thiophenol with substituted alkyne; the o-amino (diazonium salt) thioanisole in R is reacted with terminal alkyne.

Wherein, the method for preparing benzothiophene compounds by the intramolecular cyclization of o-alkynyl thiophenol (thioether) mainly comprises ① which takes Pd/Cu as the catalystAgent, by I₂、Br₂、NBS、p-O₂NC₆H₄② A benzothiophene compound is prepared by cyclization reaction with Au (I) -IPr as catalyst, which has good substrate adaptability but expensive catalyst and harsh reaction conditions, ③ sulfonyl, acyl or phosphorus free radical initiates intramolecular series cyclization reaction of alkyne to prepare benzothiophene compound, which can simultaneously construct multiple chemical bonds to obtain benzothiophene derivatives with diverse structures, but the reaction selectivity is poor, the number of byproducts is large and the yield is not high.

Disclosure of Invention

The present application first provides a benzothiophene compound having the following structure, which can be expressed as:wherein R is₁Is H or fluorine; r₂Is any one of H, methoxy, fluorine and bromine; r₃Is any one of phenyl, p-methoxyphenyl, p-methylphenyl, p-bromophenyl, p-chlorophenyl, m-fluorophenyl, p-fluorophenyl, m-methylphenyl, naphthyl and pyridyl.

The representative structures of the compounds are 15, and the specific structures are as follows:

the technical scheme adopted for preparing the compound is as follows:

acetone is used as a solvent, DTPB is used as a free radical initiator, 2-ethynyl methyl sulfide derivatives are used as raw materials, the temperature is controlled to be 120-140 ℃ in the presence of disodium hydrogen phosphate, the benzothiophene compound (I) is prepared by the next reaction under the protection of nitrogen, after the reaction is completed, dichloromethane is used for extraction and spin-drying to obtain a crude product, and a refined compound (I) is obtained by passing through a column, wherein the specific reaction equation is as follows:

wherein R is₁Is H or fluorine; r₂Is any one of H, methoxy, fluorine and bromine; r₃Is any one of phenyl, p-methoxyphenyl, p-methylphenyl, p-bromophenyl, p-chlorophenyl, m-fluorophenyl, p-fluorophenyl, m-methylphenyl, naphthyl and pyridyl.

Further settings are as follows:

the amount of DTPB added in the reaction is 3.5 to 4.5 equiv, preferably 4.0 equiv, and the amount of disodium hydrogen phosphate is 0.6 to 1.6 equiv, preferably 1.0 equiv; the reaction temperature should be controlled at 120-140 deg.C, preferably 130-135 deg.C.

The reaction time is 22-25 h, the reaction time obtained according to detection data is too short, the reaction is incomplete, the yield is low, the yield is basically unchanged when the reaction time exceeds 25h, the energy consumption is high, the cost is increased, side reactions are increased when the reaction time is too long, and the reaction yield is reduced.

After complete reaction, selecting dichloromethane as an extraction solvent, carrying out spin drying to obtain a crude product, and refining by adopting a column chromatography, wherein the column chromatography solvent is petroleum ether: ethyl acetate 2: 1.

The beneficial effect of this application is as follows:

(1) according to the method, DTPB is used as a free radical initiator, and the benzothiophene compound is prepared in one step in the presence of disodium hydrogen phosphate, so that a new method is provided for preparing the compound.

(2) The method takes acetone which is one of reaction raw materials as a solvent, so that the types of reagents are reduced, the reaction is simplified, the operation difficulty is reduced, and the synthesis cost is reduced.

(3) The method has wide applicable substrates, the catalyst, the solvent and the inorganic salt involved in the reaction are all conventional reagents, the reaction process has no particularly harsh external requirement, the expansibility is good, the substituent R on the framework structure has good reaction activity, and the yield of the finished product can reach 80 percent at most.

(4) Experiments show that the benzothiophene new compound prepared by the method has a certain inhibiting effect on dermatophytes, and provides a lead compound for the research on the aspect of subsequent medical intermediates.

The present application is further described below with reference to specific embodiments.

Drawings

FIGS. 1A-1B are, in order, Compound 1¹H spectrogram,¹³C, spectrum;

FIGS. 2A-2B are, in sequence, Compound 2¹H spectrogram,¹³C, spectrum;

FIGS. 3A-3B are, in sequence, Compound 3¹H spectrogram,¹³C, spectrum;

FIGS. 4A-4C are, in order, Compound 4¹H spectrogram,¹³C spectrum,¹⁹F, spectrum;

FIGS. 5A-5B are, in sequence, Compound 5¹H spectrogram,¹³C, spectrum;

FIGS. 6A-6B are, in sequence, Compound 6¹H spectrogram,¹³C, spectrum;

FIGS. 7A-7B are, in order, Compound 7¹H spectrogram,¹³C, spectrum;

FIGS. 8A-8C are, in order, Compound 8¹H spectrogram,¹³C spectrum,¹⁹F, spectrum;

FIGS. 9A-9C are, in order, Compound 9¹H spectrogram,¹³C, spectrum;

FIGS. 10A-10B are, in order, Compound 10¹H spectrogram,¹³C spectrum,¹⁹F, spectrum;

FIGS. 11A-11C are, in order, Compound 11¹H spectrogram,¹³C spectrum,¹⁹F, spectrum;

FIGS. 12A-12B are, in sequence, Compound 12¹H spectrogram,¹³C, spectrum;

FIGS. 13A-13B are, in order, Compound 13¹H spectrogram,¹³C, spectrum;

FIGS. 14A-14B are, in sequence, Compound 14¹H spectrogram,¹³C, spectrum;

FIGS. 15A-15B are, in sequence, Compound 15¹H spectrogram,¹³And C, spectrum.

Detailed Description

Analytical instrumentation and equipment used in this example:

nuclear magnetic resonance apparatus, AVANCE DMXIII 400M (TMS internal standard, Bruker Corp.);

high performance liquid chromatograph: agilent Technologies 1200 Series.

The benzothiophene compound provided by the scheme has a structural general formula:

wherein R is₁Is H or fluorine; r₂Is any one of H, methoxy, fluorine and bromine; r₃Is any one of phenyl, p-methoxyphenyl, p-methylphenyl, p-bromophenyl, p-chlorophenyl, m-fluorophenyl, p-fluorophenyl, m-methylphenyl, naphthyl and pyridyl.

And specifically provides fifteen representative structures, namely compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, compound 13, compound 14, compound 15, of which the structural formulae are respectively:

the fifteen compounds are respectively subjected to¹H spectrogram,¹³Spectrum C (Compound 4, Compound 8, Compound 10, Compound 11, each supplement¹⁹F spectrum was measured), the results are shown in fig. 1A to 15B.

The process for synthesizing the benzothiophenes can be summarized as follows:

the following describes specific processes for preparing compound 1, compound 2, compound 3, and compound 4 to illustrate the synthesis of the benzothiophenes.