Electrochemical preparation method and application of 2,3-dihydrobenzothiophene compounds

Abstract

The application belongs to the field of green synthesis, and particularly relates to an electrochemical preparation method and application of 2,3-dihydrobenzothiophene compounds. The preparation method is as follows: taking benzothiophene as a reaction raw material, adding an electrolyte, an additive and an organic solvent, and performing electrolysis reaction to obtain the 2,3-dihydrobenzothiophene compound. The preparation method does not need the participation of a transition metal catalyst, does not need to use a flammable and explosive hydrogen atmosphere, is simple to operate, has high atomic utilization, and can greenly synthesize 2,3-dihydrobenzothiophene. The 2,3-dihydrobenzothiophene has good activity to G protein-coupled receptor 119, and has important application value in the preparation of a drug for treating a G protein-coupled receptor 119-mediated disorder.

Description

Technical Field

[0001] The present invention belongs to the field of green synthesis, and specifically relates to an electrochemical preparation method and application of 2,3-dihydrobenzothiophene oxide compounds. Background Art

[0002] Metikrane is a commercially available small molecule antagonist commonly used to treat acute muscle spasm pain. The key backbone of the drug molecule, Metikrane, is 3,4-dihydroxysulfurchromene, a six-membered sulfide compound derived from benzothiophene. Based on pharmacodynamic structural analysis, replacing the six-membered sulfide compound in the 3,4-dihydroxysulfurchromene molecule with a five-membered sulfide compound (i.e., 2,3-dihydrobenzothiophene oxide) would not only introduce new biological activities but also potentially overcome patent restrictions and enable the development of antagonist drug molecules with different molecular backbones. Based on this approach, the efficient synthesis of 2,3-dihydrobenzothiophene oxide compounds is crucial for achieving these goals. A literature review revealed that the commonly used synthesis method for 2,3-dihydrobenzothiophene oxide compounds is to use palladium on carbon (Pd / C) as a catalyst to reduce benzothiophene oxide in a hydrogen atmosphere, thereby synthesizing 2,3-dihydrobenzothiophene oxide. However, this type of method has the following obvious disadvantages: first, the use of precious metal palladium not only brings high process costs, but also causes heavy metal residues in the environment; second, the use of flammable and explosive hydrogen will undoubtedly bring huge challenges to safe production.

[0003] Given the important application of 2,3-dihydrobenzothiophene oxide in drug development, developing a safe, low-cost synthesis process that does not require chemical redox reagents and can be used to synthesize biologically active 2,3-dihydrobenzothiophene oxide compounds is of great research significance and potential application value. However, the development of such a green synthesis process remains a challenging problem, with no corresponding literature or patent reports to date. Summary of the Invention

[0004] In view of the shortcomings of the prior art, the first object of the present invention is to provide an electrochemical preparation method for 2,3-dihydrobenzothiophene oxide compounds; the preparation method has the advantages of simple operation, low cost, and no need for chemical redox reagents.

[0005] The second object of the present invention is to provide the application of the above-mentioned 2,3-dihydrobenzothiophene oxide compounds, which have good pharmacological activity against G protein-coupled receptor 119 (GPR119) and have potential application value in the development of GPR119 agonist drugs.

[0006] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0007] A method for electrochemically preparing 2,3-dihydrobenzothiophene oxide compounds comprises using benzothiophene oxide represented by Formula I as a reaction raw material, adding an electrolyte, an organic solvent, and an additive, and conducting an electrolytic reaction to obtain the 2,3-dihydrobenzothiophene oxide compound represented by Formula II. The reaction scheme is as follows:

[0008]

[0009] wherein R is methyloxycarbonyl, ethyloxycarbonyl, allyloxycarbonyl, acetyl, benzoyl, benzenesulfonyl or p-toluenesulfonyl.

[0010] Furthermore, the structural formula of the 2,3-dihydrobenzothiophene oxide compound is any one of the following:

[0011]

[0012] Furthermore, the molar volume ratio of the benzothiophene oxide, electrolyte, additive and organic solvent is 1.0 mmol: 1.0 mmol: 2.0 mmol: 1.5 mL.

[0013] Furthermore, the electrolyte is tetrabutylammonium tetrafluoroborate; the additive is 1,4-diazabicyclo[2.2.2]octane (DBACO); and the organic solvent consists of acetonitrile and hexafluoroisopropanol.

[0014] Furthermore, the volume ratio of acetonitrile to hexafluoroisopropanol is 8:1.

[0015] Furthermore, the anode and cathode of the electrolysis reaction are both graphite sheets, and the current density is 5 mA / cm 2 , the temperature is room temperature, and the time is 5h.

[0016] Furthermore, after the reaction is completed, the reaction solution needs to be extracted, dried, distilled under reduced pressure and purified by column chromatography.

[0017] Furthermore, the extraction solvent is dichloromethane.

[0018] The application of the above-mentioned 2,3-dihydrobenzothiophene oxide compounds can be used to prepare drugs for treating diseases mediated by G protein coupled receptor 119.

[0019] The preparation method of 2,3-dihydrobenzothiophene oxide compounds provided by the present invention is based on the electrochemical reduction reaction of benzothiophene oxide, and can prepare 2,3-dihydrobenzothiophene oxide compounds in an environmentally friendly and low-cost manner without the need for adding external chemical redox reagents.

[0020] Beneficial effects

[0021] (1) The present invention reports for the first time a method for preparing 2,3-dihydrobenzothiophene oxide compounds by electrolytic synthesis. The preparation method uses benzothiophene oxide compounds as reaction raw materials and clean electrons as reducing agents to carry out electrolytic reactions. Without the participation of precious metal catalysts and toxic and harmful chemical redox reagents, benzothiophene oxide can be reduced to prepare 2,3-dihydrobenzothiophene oxide compounds, and can efficiently synthesize 2,3-dihydrobenzothiophene oxide compounds.

[0022] (2) The preparation process provided by the present invention has significant advantages such as low cost, simple operation, green process and high safety factor.

[0023] (3) The 2,3-dihydrobenzothiophene oxide compounds prepared by the present invention have good pharmacological activity against G protein coupled receptor 119 (GPR119). The 2,3-dihydrobenzothiophene oxide compounds can be used to prepare drugs for treating diseases mediated by G protein coupled receptor 119. The 2,3-dihydrobenzothiophene oxide compounds have important application value in the development of GPR119 agonist drugs. DETAILED DESCRIPTION

[0024] The following description further elaborates on the specific details of the present invention for a full understanding of the present invention. The terms used in the description of the present invention are only used to illustrate the advantages and features of the present invention and are not intended to limit the present invention.

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those understood by those skilled in the art within the technical field of the present invention. Unless otherwise specified, the drugs and reagents used herein were used in accordance with the product instructions or conventional methods in the art. The process of the present invention is now further described based on the specification and specific embodiments.

[0026] The route for synthesizing 2,3-dihydrobenzothiophene oxide compounds of the present invention is:

[0027]

[0028] wherein R is methyloxycarbonyl, ethyloxycarbonyl, allyloxycarbonyl, acetyl, benzoyl, benzenesulfonyl or p-toluenesulfonyl.

[0029] Example 1

[0030] Into an electrolysis cell, the starting material benzothiophene analogue (0.3 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), 1,4-diazabicyclo[2.2.2]octane (0.6 mmol), acetonitrile (4 mL), hexafluoroisopropanol (0.5 mL) were added, respectively. Then, two pieces of graphite were inserted into the electrolysis cell as anode and cathode. The above mixed solution was electrolyzed at room temperature for 5 h under a current density of 5 mA / cm 2 The solution was then transferred into a separatory funnel, 15 mL of water was added, and the solution was extracted with dichloromethane (15 mL x 3), dried, and the solvent was removed by distillation under reduced pressure. Finally, the target product was isolated and purified by column chromatography. The structure of the product is shown below. Yield: 63%.

[0031]

[0032] Example 2

[0033] Into an electrolysis cell, the starting material benzothiophene analogue (0.3 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), 1,4-diazabicyclo[2.2.2]octane (0.6 mmol), acetonitrile (4 mL), hexafluoroisopropanol (0.5 mL) were added, respectively. Then, two pieces of graphite were inserted into the electrolysis cell as anode and cathode. The above mixed solution was electrolyzed at room temperature for 5 h under a current density of 5 mA / cm 2 The solution was then transferred into a separatory funnel, 15 mL of water was added, and the solution was extracted with dichloromethane (15 mL x 3), dried, and the solvent was removed by distillation under reduced pressure. Finally, the target product was isolated and purified by column chromatography. The structure of the product is shown below. Yield: 65%.

[0034]

[0035] Example 3

[0036] Into an electrolysis cell, the starting material benzothiophene analogue (0.3 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), 1,4-diazabicyclo[2.2.2]octane (0.6 mmol), acetonitrile (4 mL), hexafluoroisopropanol (0.5 mL) were added, respectively. Then, two pieces of graphite were inserted into the electrolysis cell as anode and cathode. The above mixed solution was electrolyzed at room temperature for 5 h under a current density of 5 mA / cm 2 The solution was then transferred into a separatory funnel, 15 mL of water was added, and the solution was extracted with dichloromethane (15 mL x 3), dried, and the solvent was removed by distillation under reduced pressure. Finally, the target product was isolated and purified by column chromatography. The structure of the product is shown below. Yield: 59%.

[0037]

[0038] Example 4

[0039] The raw materials benzothiophene oxide analog (0.3 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), 1,4-diazabicyclo[2.2.2]octane (0.6 mmol), acetonitrile (4 mL), and hexafluoroisopropanol (0.5 mL) were added to the electrolytic cell. Then, two graphite sheets were inserted into the electrolytic cell as the anode and cathode. At room temperature, the above mixed solution was charged at 5 mA / cm 2 Electrolysis was performed at a current density of 100 nm for 5 h. Subsequently, the solution was transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with dichloromethane (15 mL x 3). The mixture was dried and the solvent was removed by vacuum distillation. Finally, column chromatography was used for separation and purification to obtain the desired product, with the structural formula shown below. Yield: 69%.

[0040]

[0041] Example 5

[0042] The raw materials benzothiophene oxide analog (0.3 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), 1,4-diazabicyclo[2.2.2]octane (0.6 mmol), acetonitrile (4 mL), and hexafluoroisopropanol (0.5 mL) were added to the electrolytic cell. Then, two graphite sheets were inserted into the electrolytic cell as the anode and cathode. At room temperature, the above mixed solution was charged at 5 mA / cm 2 Electrolysis was performed at a current density of 100 nm for 5 h. Subsequently, the solution was transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with dichloromethane (15 mL x 3). The mixture was dried and the solvent was removed by vacuum distillation. Finally, column chromatography was used for separation and purification to obtain the desired product, with the structural formula shown below. Yield: 67%.

[0043]

[0044] Example 6

[0045] The raw materials benzothiophene oxide analog (0.3 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), 1,4-diazabicyclo[2.2.2]octane (0.6 mmol), acetonitrile (4 mL), and hexafluoroisopropanol (0.5 mL) were added to the electrolytic cell. Then, two graphite sheets were inserted into the electrolytic cell as the anode and cathode. At room temperature, the above mixed solution was charged at 5 mA / cm 2 Electrolysis was performed at a current density of 100 nm for 5 h. Subsequently, the solution was transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with dichloromethane (15 mL x 3). The mixture was dried and the solvent was removed by vacuum distillation. Finally, column chromatography was used for separation and purification to obtain the desired product, with the structural formula shown below. Yield: 71%.

[0046]

[0047] Example 7

[0048] The raw materials benzothiophene oxide analog (0.3 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), 1,4-diazabicyclo[2.2.2]octane (0.6 mmol), acetonitrile (4 mL), and hexafluoroisopropanol (0.5 mL) were added to the electrolytic cell. Then, two graphite sheets were inserted into the electrolytic cell as the anode and cathode. At room temperature, the above mixed solution was charged at 5 mA / cm 2 Electrolysis was performed at a current density of 100 nm for 5 h. Subsequently, the solution was transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with dichloromethane (15 mL x 3). The mixture was dried and the solvent was removed by vacuum distillation. Finally, column chromatography was used for separation and purification to obtain the desired product, with the structural formula shown below. Yield: 73%.

[0049]

[0050] Performance testing:

[0051] The pharmaceutical use of the 2,3-dihydrobenzothiophene oxide compounds synthesized by the present invention was tested. G protein coupled receptor 119 (GPR119) was selected as the research object to test the EC of the 2,3-dihydrobenzothiophene oxide compounds against GPR119. 50 The experimental results show that the EC values ​​of the 2,3-dihydrobenzothiophene oxide compounds synthesized in Examples 1, 2 and 3 are 50 The values ​​were 220nM, 255nM and 203nM, respectively. From the above data, it can be found that the 2,3-dihydrobenzothiophene oxide compounds synthesized in the present invention have good pharmacological activity against GPR119, have potential application value in the development of agonist drugs, and can be used to prepare drugs for treating diseases mediated by G protein-coupled receptor 119.

Claims

1. A method for electrochemically preparing 2,3-dihydrobenzothiophene oxide compounds, characterized in that: The preparation method comprises using benzothiophene oxide as a reaction raw material, adding an electrolyte, an organic solvent and an additive, and performing an electrolytic reaction to obtain a 2, 3-dihydrobenzothiophene oxide compound as shown in Formula II. The reaction scheme is as follows: ； The structural formula of the 2,3-dihydrobenzothiophene oxide compound is any one of the following: ； The electrolyte is tetrabutylammonium tetrafluoroborate; the additive is 1,4-diazabicyclo[2.2.2]octane; and the organic solvent consists of acetonitrile and hexafluoroisopropanol.

2. The preparation method according to claim 1, characterized in that The molar volume ratio of the benzothiophene oxide, electrolyte, additive and organic solvent is 1.0 mmol: 1.0 mmol: 2.0 mmol: 1.5 mL.

3. The preparation method according to claim 1, characterized in that The volume ratio of acetonitrile to hexafluoroisopropanol is 8:

1.

4. The preparation method according to claim 1, characterized in that The anode and cathode of the electrolysis reaction were both graphite sheets, and the current density was 5 mA / cm 2 , the temperature is room temperature, and the time is 5 h.

5. The preparation method according to claim 1, characterized in that After the reaction is completed, the reaction solution needs to be extracted, dried, distilled under reduced pressure and separated and purified by column chromatography.

6. The preparation method according to claim 5, characterized in that The extraction solvent is dichloromethane.

Images