Electrochemical preparation method and application of 2, 3-dihydrobenzothiophene oxide compound

Abstract

The invention belongs to the field of green synthesis, and particularly relates to an electrochemical preparation method and application of a 2, 3-dihydrobenzothiophene oxide compound. The preparation method comprises the following steps: taking benzothiophene oxide as a reaction raw material, adding an electrolyte, an additive and an organic solvent, and carrying out an electrolytic reaction to obtain the 2, 3-dihydrobenzothiophene oxide compound. According to the preparation method, participation of a transition metal catalyst is not needed, a flammable and explosive hydrogen atmosphere does not need to be used, operation is easy, the atom utilization rate is high, and the 2, 3-dihydrobenzothiophene oxide can be synthesized in a green mode; the 2, 3-dihydrobenzothiophene oxide has better activity on the G protein coupled receptor 119, and has important application value in preparation of drugs for treating diseases mediated by the G protein coupled receptor 119.

Description

Technical Field

[0001] The 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] Meticrane is a commercialized small molecule antagonist drug commonly used to treat acute muscle spasm pain. For the drug molecule Meticrane, the key skeleton for its efficacy is 3,4-dihydrosulfur chromene, that is, a six-membered sulfide compound of benzoxide. According to the pharmacodynamic structure analysis, replacing the six-membered sulfide compound in the 3,4-dihydrosulfur chromene molecule with a five-membered sulfide compound (i.e., 2,3-dihydrobenzoxide thiophene) will not only bring new biological activities, but also be more likely to break through the restrictions of foreign patents and develop antagonist drug molecules with different molecular skeletons. According to the above ideas, the efficient synthesis of 2,3-dihydrobenzoxide thiophene compounds is of decisive significance for achieving the above goals. Through literature review, it is found that the commonly used synthesis method of 2,3-dihydrobenzoxide thiophene compounds is to use palladium carbon (Pd / C) as a catalyst to reduce benzoxide thiophene in a hydrogen atmosphere to synthesize 2,3-dihydrobenzoxide thiophene. However, this type of method has the following obvious disadvantages: first, the use of precious metal palladium will not only bring high process costs, but also cause heavy metal residues in the environment; second, the use of flammable and explosive hydrogen will undoubtedly bring huge challenges to safe production.

[0003] In view of the important use of 2,3-dihydrobenzothiophene oxide in drug development, it is of great research significance and potential application value to develop a safe, low-cost synthesis process that does not require the participation of chemical redox reagents and use this process to synthesize biologically active 2,3-dihydrobenzothiophene oxide compounds. However, the development of the above green synthesis process is still a challenging problem, and there is no corresponding literature or patent report yet. 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 of 2,3-dihydrobenzothiophene oxide compounds; the preparation method has the advantages of simple operation, low cost, and no need to use 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 purpose, the technical solution adopted by the present invention is as follows:

[0007] An electrochemical preparation method of 2,3-dihydrobenzothiophene oxide compounds, the preparation method is to use benzothiophene oxide shown in formula I as a reaction raw material, add electrolyte, organic solvent and additives, and perform electrolysis reaction to obtain 2,3-dihydrobenzothiophene oxide compounds shown in formula II; the reaction route 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 electrolytic 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 separated 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 an external chemical redox reagent.

[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. The method can reduce benzothiophene oxide to prepare 2,3-dihydrobenzothiophene oxide compounds without the participation of precious metal catalysts and toxic and harmful chemical redox reagents, 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 describes 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 professional and scientific terms used in the present invention have the same meanings as those understood by those skilled in the art of the present invention. Unless otherwise specified, the drugs or reagents used in the present invention are used in accordance with the product instructions or in the conventional methods of use in the relevant field. The process of the present invention is further described based on the instructions 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] 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. The mixed solution was heated at 5 mA / cm at room temperature. 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with dichloromethane (15 mL x 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 63%.

[0031]

[0032] Example 2

[0033] 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. The mixed solution was heated at 5 mA / cm at room temperature. 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with dichloromethane (15 mL x 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 65%.

[0034]

[0035] Example 3

[0036] 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. The mixed solution was heated at 5 mA / cm at room temperature. 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with dichloromethane (15 mL x 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula 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. The mixed solution was heated at 5 mA / cm at room temperature. 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with dichloromethane (15 mL x 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is 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. The mixed solution was heated at 5 mA / cm at room temperature. 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with dichloromethane (15 mL x 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is 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. The mixed solution was heated at 5 mA / cm at room temperature. 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with dichloromethane (15 mL x 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is 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. The mixed solution was heated at 5 mA / cm at room temperature. 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with dichloromethane (15 mL x 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is 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 ​​are 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. An electrochemical preparation method of 2,3-dihydrobenzothiophene oxide compounds, characterized in that: The preparation method is to use benzothiophene oxide shown in formula I as a reaction raw material, add electrolyte, organic solvent and additives, and perform electrolysis reaction to obtain 2,3-dihydrobenzothiophene oxide compounds shown in formula II; the reaction route is as follows: Wherein, R is methyloxycarbonyl, ethyloxycarbonyl, allyloxycarbonyl, acetyl, benzoyl, benzenesulfonyl or p-toluenesulfonyl.

2. The preparation method according to claim 1, characterized in that: The structural formula of the 2,3-dihydrobenzothiophene oxide compound is any one of the following:

3. 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.

4. The preparation method according to claim 1, characterized in that: The electrolyte is tetrabutylammonium tetrafluoroborate; the additive is 1,4-diazabicyclo[2.2.2]octane; and the organic solvent is composed of acetonitrile and hexafluoroisopropanol.

5. The preparation method according to claim 4, characterized in that: The volume ratio of acetonitrile to hexafluoroisopropanol is 8:

1.

6. The preparation method according to claim 1, characterized in that: 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.

7. 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.

8. The preparation method according to claim 7, characterized in that: The extraction solvent is dichloromethane.

9. Use of 2,3-dihydrobenzothiophene oxide compounds prepared by the method according to any one of claims 1 to 8, characterized in that: The 2,3-dihydrobenzothiophene oxide compound can be used to prepare a drug for treating diseases mediated by G protein coupled receptor 119.

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