Method for electrochemical synthesis of 3-selenium cyano indolizine compound and application of 3-selenium cyano indolizine compound

Abstract

The invention relates to the technical field of organic synthesis, in particular to a method for electrochemical synthesis of a 3-selenium cyano indolizine compound and application of the 3-selenium cyano indolizine compound. According to the method for electrochemical synthesis of the 3-selenium cyano indolizine compound, an indolizine compound, potassium selenide and an electrolyte are added into a solvent to form a reaction system, a graphite felt serves as an anode, a platinum sheet serves as a cathode, a constant-current reaction is conducted at the room temperature in the air atmosphere, the adopted current is 7 mA, and after the reaction is completed, the 3-selenium cyano indolizine compound is obtained. Carrying out post-treatment on the reactant to obtain a compound; the molar ratio of the indolizine compound to the potassium selenide cyanate is 1: (2-3), and the molar concentration of the electrolyte is 0.05 mol / L. The method has the advantages of wide substrate range, simple post-treatment and the like, and a new synthesis route and method are developed for the 3-selenium cyano indolizine compound. The obtained 3-selenium cyano indolizine compound shows remarkable anti-atherosclerosis activity and has the potential of being developed into an anti-atherosclerosis medicine.

Description

Technical Field

[0001] This invention relates to the field of organic synthetic chemistry, and in particular to a method and application for the electrochemical synthesis of 3-selenocyanoindoleazine compounds. Background Technology

[0002] Selenium is an important element in nature with both biological activity and industrial value, playing a crucial role in maintaining metabolic balance, enhancing crop stress resistance, and preparing special functional materials. Organoselenium compounds, with their unique reactivity and physicochemical properties, show broad application potential in cutting-edge fields such as catalytic synthesis, biomedicine, and optoelectronic materials. As a representative structure, selenocyanates have attracted widespread attention in recent years. Researchers have developed various new methods to directly introduce selenocyanide groups into organic molecules and have successfully synthesized a series of novel selenocyanate compounds, whose diverse biological activities are particularly noteworthy.

[0003] Indoleazines are a class of nitrogen-containing heterocyclic compounds widely found in nature, with important applications in pharmaceuticals, dyes, fragrances, and pesticides. Therefore, introducing a selenocyano group into the indoleazine skeleton to construct novel indoleazine derivatives with potential physiological activity not only provides an important framework for expanding organoselenium compound chemistry but also opens up significant research directions for exploring novel bioactive molecules. However, currently reported synthetic methods in this field are relatively limited, and commonly used selenocyanidation reagents are mostly expensive. Therefore, developing efficient and low-cost selenocyanidation reagents and establishing green and efficient methods for the selenocyanidation of indoleazine rings remains a challenging research task.

[0004] Therefore, developing an efficient, mild, simple and low-cost method for synthesizing 3-selenocyanindoleazine remains of significant research value, which is also the starting point and innovation of this application. Summary of the Invention

[0005] The purpose of this invention is to provide a method for the electrochemical synthesis of 3-selenocyanoindoleazine compounds and its application, so as to solve the problems mentioned in the background art.

[0006] To achieve the above objectives, the present invention provides the following technical solution: a method for electrochemical synthesis of 3-selenocyanoindoleazine compounds, comprising the following steps:

[0007] Indoleazine with the structure shown in formula (I), potassium selenocyanate with the structure shown in formula (II), and an electrolyte were added to an organic solvent. A graphite felt was used as the anode and a platinum sheet as the cathode. The reaction was carried out under constant current and at room temperature with stirring. After the reaction was completed, the solvent was removed from the reaction solution under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain a 3-selenocyanoindoleazine compound with the structure shown in formula (III). The reaction equation is shown below:

[0008]

[0009] In the compound of formula (I), R1 and R2 are each independently selected from aryl and alkyl groups.

[0010] Preferably, the molar ratio of indoleazine with the structure shown in formula (I) to potassium selenocyanate with the structure shown in formula (II) is 1:2 to 1:3, preferably 1:2.

[0011] Preferably, the anode material is one of graphite felt, platinum sheet, zinc sheet, aluminum sheet, and carbon rod, with graphite felt being the most preferred. The cathode material is one of platinum sheet, nickel sheet, tin sheet, lead sheet, and copper sheet, with platinum sheet being the most preferred.

[0012] Preferably, the reaction time is 2.5-5.0 h, the current is 5-10 mA, and here preferably 7 mA; a diaphragmless single-chamber electrolytic cell is used, and the reaction temperature is room temperature.

[0013] Preferably, the organic solvent is any one of solvents such as acetonitrile, dichloromethane, dichloroethane, N,N-dimethylformamide, and dimethyl sulfoxide, with acetonitrile being the most preferred.

[0014] Preferably, the electrolyte is any one of tetrabutylammonium tetrafluoroborate, sodium tetrafluoroborate, sodium perchlorate, and lithium perchlorate, with tetrabutylammonium tetrafluoroborate being the most preferred; the molar concentration of the electrolyte is 0.05 mol / L.

[0015] Preferably, after the reaction is completed, the reaction solution is concentrated under reduced pressure, and the concentrate is separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent, wherein the volume ratio of petroleum ether to ethyl acetate is (1-15):1. The eluent is collected, and the solvent is rotary evaporated to obtain 3-selenocyanindoleazine as shown in formula (III).

[0016] A pharmaceutical composition comprising a 3-selenocyanoindoleazine compound prepared by the above method, a medically acceptable salt, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutically acceptable carrier includes an inert solid filler or diluent and a sterile aqueous solution or organic solution. This 3-selenocyanoindoleazine compound exhibits excellent anti-atherosclerotic properties.

[0017] The present invention also provides the use of the above-described pharmaceutical composition in the preparation of a drug for treating and / or preventing atherosclerosis.

[0018] Compared with the prior art, the beneficial effects of the present invention are:

[0019] 1. This invention uses inexpensive and readily available indoleazine compounds and potassium selenocyanate as raw materials.

[0020] 2. This invention provides a method for electrochemically constructing indoleazine compounds, and the reaction process is green and environmentally friendly.

[0021] 3. This invention can obtain the target product in just one step, has good functional group compatibility, simple post-processing, and has good application potential.

[0022] 4. Experiments have demonstrated that the 3-selenocyanoindoleazine compounds prepared in this invention possess excellent anti-atherosclerotic activity. Therefore, the compounds of this invention have significant potential for pharmaceutical applications. Detailed Implementation

[0023] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0024] This invention provides the following technical solution: a method for electrochemical synthesis of 3-selenocyanoindoleazine compounds, comprising the following steps:

[0025] Indoleazine with the structure shown in formula (I), potassium selenocyanate with the structure shown in formula (II), and an electrolyte were added to an organic solvent. A graphite felt was used as the anode and a platinum sheet as the cathode. The reaction was carried out under constant current and at room temperature with stirring. After the reaction was completed, the solvent was removed from the reaction solution under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain a 3-selenocyanoindoleazine compound with the structure shown in formula (III). The reaction equation is shown below:

[0026]

[0027] In the compound of formula (I), R1 and R2 are each independently selected from aryl and alkyl groups.

[0028] Example 1

[0029] The reaction equation is shown below:

[0030]

[0031] In an air atmosphere, 0.2 mmol of 2-phenylindoleazine, 0.4 mmol of potassium selenocyanate, and 10 mL of 0.05 mol / L tetrabutylammonium tetrafluoroborate / acetonitrile solution were added to a 25 mL diaphragm-free three-necked flask equipped with a magnetic stirrer. After the addition was complete, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The electrolysis current was set to 7.0 mA, and the electrolysis reaction was continued for 3.5 hours in an air atmosphere at room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 15:1) to obtain 48.1 mg of a yellow oily liquid, with a yield of 81%.

[0032]

[0033] Example 2

[0034] The reaction equation is shown below:

[0035]

[0036] In an air atmosphere, 0.2 mmol of 2-(p-tolyl)indoleazine, 0.4 mmol of potassium selenocyanate, and 10 mL of 0.05 mol / L tetrabutylammonium tetrafluoroborate / acetonitrile solution were added to a 25 mL diaphragm-free three-necked flask equipped with a magnetic stirrer. After the addition was complete, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The electrolysis current was set to 7.0 mA, and the electrolysis reaction was continued for 3.5 hours in an air atmosphere at room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 12:1) to obtain 48.5 mg of a green oily liquid, with a yield of 78%.

[0037] Example 3

[0038]

[0039] In an air atmosphere, 0.2 mmol of 2-(2-bromophenyl)indoleazine, 0.4 mmol of potassium selenocyanate, and 10 mL of 0.05 mol / L tetrabutylammonium tetrafluoroborate / acetonitrile solution were added to a 25 mL diaphragm-free three-necked flask equipped with a magnetic stirrer. After the addition was complete, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The electrolysis current was set to 7.0 mA, and the electrolysis reaction was continued for 3.5 hours in an air atmosphere at room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 8:1) to obtain 45.9 mg of a yellow oily liquid, with a yield of 61%.

[0040] Example 4

[0041] The reaction equation is shown below:

[0042]

[0043] In an air atmosphere, 0.2 mmol of 2-(2-fluorophenyl)indoleazine, 0.4 mmol of potassium selenocyanate, and 10 mL of 0.05 mol / L tetrabutylammonium tetrafluoroborate / acetonitrile solution were added to a 25 mL diaphragm-free three-necked flask equipped with a magnetic stirrer. After the addition was complete, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The electrolysis current was set to 7.0 mA, and the electrolysis reaction was continued for 3.5 hours in an air atmosphere at room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 9:1) to obtain 37.1 mg of a red oily liquid, with a yield of 59%.

[0044]

[0045] Example 5

[0046] The reaction equation is shown below:

[0047]

[0048] In an air atmosphere, 0.2 mmol of 2-(4-chlorophenyl)indoleazine, 0.4 mmol of potassium selenocyanate, and 10 mL of 0.05 mol / L tetrabutylammonium tetrafluoroborate / acetonitrile solution were added to a 25 mL diaphragm-free three-necked flask equipped with a magnetic stirrer. After the addition was complete, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The electrolysis current was set to 7.0 mA, and the electrolysis reaction was continued for 3.5 hours in an air atmosphere at room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 5:1) to obtain 44.4 mg of a blue-green solid, with a yield of 67%.

[0049] Example 6

[0050] The reaction equation is shown below:

[0051]

[0052] In an air atmosphere, 0.2 mmol of 2-(2-naphthyl)indoleazine, 0.4 mmol of potassium selenocyanate, and 10 mL of 0.05 mol / L tetrabutylammonium tetrafluoroborate / acetonitrile solution were added to a 25 mL diaphragm-free three-necked flask equipped with a magnetic stirrer. After the addition was complete, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The electrolysis current was set to 7.0 mA, and the electrolysis reaction was continued for 3.5 hours in an air atmosphere at room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 4:1) to obtain 43.0 mg of a red oily liquid, with a yield of 62%.

[0053]

[0054] Example 7

[0055] The reaction equation is shown below:

[0056]

[0057] In an air atmosphere, 0.2 mmol of 2-(thiophen-2-yl)indoleazine, 0.4 mmol of potassium selenocyanate, and 10 mL of 0.05 mol / L tetrabutylammonium tetrafluoroborate / acetonitrile solution were added to a 25 mL diaphragm-free three-necked flask equipped with a magnetic stirrer. After the addition was complete, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The electrolysis current was set to 7.0 mA, and the electrolysis reaction was continued for 3.5 hours in an air atmosphere at room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 10:1) to obtain 48.5 mg of a black oily liquid, with a yield of 80%.

[0058]

[0059] Example 8

[0060] The reaction equation is shown below:

[0061]

[0062] In an air atmosphere, 0.2 mmol of 2-(furan-2-yl)indoleazine, 0.4 mmol of potassium selenocyanate, and 10 mL of 0.05 mol / L tetrabutylammonium tetrafluoroborate / acetonitrile solution were added to a 25 mL diaphragm-free three-necked flask equipped with a magnetic stirrer. After the addition was complete, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The electrolysis current was set to 7.0 mA, and the electrolysis reaction was continued for 3.5 hours in an air atmosphere at room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 10:1) to obtain 45.3 mg of a red oily liquid, with a yield of 79%.

[0063]

[0064] Example 9

[0065] The reaction equation is shown below:

[0066]

[0067] In an air atmosphere, 0.2 mmol of 1-(2-indolazinyl)acetone, 0.4 mmol of potassium selenocyanate, and 10 mL of 0.05 mol / L tetrabutylammonium tetrafluoroborate / acetonitrile solution were added to a 25 mL diaphragm-free three-necked flask equipped with a magnetic stirrer. After the addition was complete, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The electrolysis current was set to 7.0 mA, and the electrolysis reaction was continued for 3.5 hours in an air atmosphere at room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 3:1) to give 34.2 mg of red solid, with a yield of 65%.

[0068]

[0069] Example 10

[0070] The reaction equation is shown below:

[0071]

[0072] In an air atmosphere, 0.2 mmol of 7-methyl-2-phenylindoleazine, 0.4 mmol of potassium selenocyanate, and 10 mL of 0.05 mol / L tetrabutylammonium tetrafluoroborate / acetonitrile solution were added to a 25 mL diaphragm-free three-necked flask equipped with a magnetic stirrer. After the addition was complete, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The electrolysis current was set to 7.0 mA, and the electrolysis reaction was continued for 3.5 hours in an air atmosphere at room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 10:1) to give 47.3 mg of red solid, with a yield of 76%.

[0073]

[0074] Example 11

[0075] The reaction equation is shown below:

[0076]

[0077] In an air atmosphere, 0.2 mmol of 7-ethyl-2-phenylindoleazine, 0.4 mmol of potassium selenocyanate, and 10 mL of 0.05 mol / L tetrabutylammonium tetrafluoroborate / acetonitrile solution were added to a 25 mL diaphragm-free three-necked flask equipped with a magnetic stirrer. After the addition was complete, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The electrolysis current was set to 7.0 mA, and the electrolysis reaction was continued for 3.5 hours in an air atmosphere at room temperature. After the reaction was completed, the solvent was removed from the reaction mixture by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 10:1) to give 46.2 mg of red solid, with a yield of 71%.

[0078]

[0079] Example 12: Study on anti-atherosclerotic activity

[0080] This invention provides 3-selenocyanoindoleazine compounds with anti-atherosclerotic activity, their synthesis methods, and applications. These 3-selenocyanoindoleazine compounds exhibit significant inhibitory activity against 15-lipoxygenase (15-LO), a key enzyme catalyzing the oxidation of polyunsaturated fatty acids. Overactivation of 15-LO leads to the oxidation of low-density lipoprotein, thereby promoting the development of atherosclerosis. Therefore, 15-LO is an important drug target for cardiovascular disease treatment. Detailed test results are shown in the table below:

[0081]

[0082] Test results show that most of the compounds of this invention have significant anti-atherosclerotic activity, and are superior to the positive control natural inhibitor quercetin. In particular, compounds 1b, 1c, and 1g have significant antioxidant free radical activity. They also showed good inhibitory effects on 15-LO from different species, and are expected to become anti-atherosclerotic drugs.

[0083] In summary, this invention uses inexpensive and readily available indoleazine and potassium selenocyanate as raw materials, eliminating the need for chemical oxidants. The reaction is green and environmentally friendly, with high atom economy. The reaction conditions are relatively mild, the operation is simple, the cost is low, and the reaction efficiency is high. This invention requires only one step to obtain the target product, has good functional group compatibility, and simplifies post-processing, demonstrating excellent application potential.

[0084] Any aspects of this invention not described in detail are well-known to those skilled in the art.

[0085] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within the present invention.

Claims

1. A method for the electrochemical synthesis of 3-selenocyanoindoleazine compounds, characterized in that: Indoleazine with the structure shown in formula (I), potassium selenocyanate with the structure shown in formula (II), and an electrolyte were added to an organic solvent. A graphite felt was used as the anode and a platinum sheet as the cathode. The reaction was carried out under constant current and room temperature with stirring. After the reaction was completed, the solvent was removed from the reaction solution under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain a 3-selenocyanoindoleazine compound with the structure shown in formula (III). The reaction equation is shown below: In the compound of formula (I), R1 and R2 are each independently selected from aryl and alkyl groups.

2. The method for electrochemical synthesis of 3-selenocyanoindoleazine compounds according to claim 1, characterized in that: The molar ratio of indoleazine with the structure shown in formula (I) to potassium selenocyanate with the structure shown in formula (II) is 1:2-1:

3.

3. The method for electrochemical synthesis of 3-selenocyanoindoleazine compounds according to claim 1, characterized in that: The reaction time was 2.5-5.0 h, the current was 5-10 mA, a diaphragmless single-chamber electrolytic cell was used, and the reaction temperature was room temperature.

4. The method for electrochemical synthesis of 3-selenocyanoindoleazine compounds according to claim 1, characterized in that: The organic solvent is any one of dichloromethane, dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, and acetonitrile.

5. The method for electrochemical synthesis of 3-selenocyanoindoleazine compounds according to claim 1, characterized in that: The electrolyte is any one of tetrabutylammonium tetrafluoroborate, sodium tetrafluoroborate, sodium perchlorate, and lithium perchlorate; the molar concentration of the electrolyte is 0.05 mol / L.

6. The method for electrochemical synthesis of 3-selenocyanoindoleazine compounds according to claim 1, characterized in that: After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent, wherein the volume ratio of petroleum ether to ethyl acetate was (1-15):

1. The eluent was collected, and the solvent was evaporated by rotary evaporation to obtain 3-selenocyanindoleazine as shown in formula (III).

7. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a 3-selenocyanoindoleazine compound prepared by the method of any one of claims 1-6, a medically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.

8. The use of the pharmaceutical composition of claim 7 in the preparation of a medicament for treating and / or preventing atherosclerosis.

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