Method for synthesizing 2-(hetero) aryl-3-cyano indole skeleton by one-step method based on photochemical reaction and application of 2-(hetero) aryl-3-cyano indole skeleton

Abstract

The invention discloses a method for synthesizing a 2-(hetero) aryl-3-cyano indole skeleton through a one-step method based on photochemical reaction and application, and relates to the technical field of organic synthesis.The method is technically characterized by comprising the steps that an indole derivative, a (hetero) aryl derivative, alkali and a solvent are added into a reaction container, under the nitrogen atmosphere, visible light or ultraviolet light is adopted for irradiation, and the 2-(hetero) aryl-3-cyano indole skeleton is obtained; reacting at room temperature for 12 hours; and after the reaction is completed, concentrating the reaction liquid and purifying to obtain the 2-(hetero) aryl-3-cyano indole derivative. The 2-aryl-3-cyano indole skeleton synthesized by the method has significant drug research and development potential, especially in the development of HCV inhibitors and aldosterone synthetase inhibitors, the method has the advantages of being green and environment-friendly, efficient and simple, cheap and easily available in raw materials, strong in modification of molecular structures and the like, and the 2-aryl-3-cyano indole skeleton can be synthesized by adjusting reaction conditions or initial raw materials. Therefore, diversified construction of target molecules can be realized, and great flexibility is provided for optimization and research and development of drug molecules.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a method and application for one-step synthesis of 2-(hetero)aryl-3-cyanoindole skeletons based on photochemical reactions. Background Art

[0002] Chronic hepatitis C virus (HCV) infection is a major public health problem worldwide and has been proven to be closely related to the occurrence of cirrhosis, liver failure, and hepatocellular carcinoma. In recent years, direct-acting antiviral drugs (DAAs) have become the mainstream strategy for HCV treatment, and the core structures of many drugs are based on the 2-aryl-3-cyanoindole skeleton. The molecular structure of this skeleton not only has good drug activity but also provides rich functionalization sites for further molecular modification and optimization. Similarly, as an important drug for the treatment of primary aldosteronism and related cardiovascular diseases, the core structure of aldosterone synthase inhibitors often contains the 2-aryl-3-cyanoindole skeleton. Therefore, developing efficient and green synthesis methods to construct this skeleton structure is of great significance for drug research and development.

[0003] Currently, traditional methods for synthesizing 2-(hetero)aryl-3-cyanoindole skeletons usually require complex multi-step syntheses, specifically including multiple functionalization reactions of aniline compounds, involving steps such as cyclization, cyanation, and arylation. These methods have the following significant disadvantages:

[0004] 1. Complex steps and long reaction cycles: Traditional methods often require multiple steps, with the number of steps increasing and the yields gradually decreasing, resulting in low overall efficiency.

[0005] 2. Use of highly toxic reagents: Cyanation reactions usually require the use of highly toxic cyanide reagents (such as chlorosulfonyl isocyanate or potassium cyanide), posing safety hazards during operation and causing environmental pollution.

[0006] 3. Dependence on noble metal catalysts: Cyclization and arylation reactions usually require the dependence on noble metal (such as palladium or platinum) catalysts, which not only have high costs but also the residues of noble metals may have an adverse impact on the quality and safety of drugs. Summary of the Invention

[0007] The purpose of the present invention is to solve the above problems and provide a method and application for one-step synthesis of 2-(hetero)aryl-3-cyanoindole skeletons based on photochemical reactions.

[0008] To achieve the above purpose, the technical solution of the present invention is as follows:

[0009] The present invention provides a method for the one-step synthesis of 2-(hetero)aryl-3-cyanoindole skeletons based on photochemical reactions. An indole derivative, a (hetero)aryl derivative, a base, and a solvent are added to a reaction vessel. Under a nitrogen atmosphere, it is irradiated with visible light or ultraviolet light and reacted at room temperature for 12 hours. After the reaction is completed, the reaction solution is concentrated and purified to obtain the 2-(hetero)aryl-3-cyanoindole derivative. The reaction formula is as follows:

[0010]

[0011] The present invention is further configured for use in the development of HCV inhibitors and aldosterone synthase inhibitors.

[0012] The present invention is further configured to simplify the multi-step reaction process in the traditional method and improve the synthesis efficiency.

[0013] The present invention is further configured to achieve the diverse construction of target molecules by adjusting reaction conditions or starting materials, thereby improving the flexibility of drug molecule optimization and research and development.

[0014] Compared with the prior art, the beneficial effects of this solution are as follows:

[0015] Mild reaction conditions: The entire reaction is carried out at room temperature or near room temperature, without the need for high-temperature and high-pressure equipment, with simple operation and high safety.

[0016] Green and environmentally friendly: The use of highly toxic reagents such as cyanides is avoided, and at the same time, it does not rely on precious metal catalysts, significantly reducing environmental pollution and production costs.

[0017] Efficient and concise: This method realizes the one-step construction of 2-aryl-3-cyanoindole skeletons, significantly simplifies the multi-step reaction process in the traditional method, and greatly improves the synthesis efficiency.

[0018] Cheap and easily available raw materials: The starting materials used are commercially available compounds or intermediates that are easy to prepare, with low costs and high operability.

[0019] Strong modifiability of molecular structure: This method can achieve the diverse construction of target molecules by adjusting reaction conditions or starting materials, providing great flexibility for the optimization and research and development of drug molecules.

[0020] The 2-aryl-3-cyanoindole skeletons synthesized by this method have significant potential for drug research and development, especially in the development of HCV inhibitors and aldosterone synthase inhibitors. The present invention not only provides a green, concise, and efficient synthesis route for these drugs, but also provides important technical support and solutions for research in related fields, with broad application prospects and industrialization potential. Detailed implementation manners

[0021] In order to enable those skilled in the art to better understand the solution of the present invention, the technical solution of the present invention will be further described in detail below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without making creative efforts shall fall within the scope of protection of the present invention.

[0022] It should be noted that, without conflict, the embodiments in the present invention and the features in the embodiments may be combined with each other. The present invention will be described in detail below in conjunction with the embodiments.

[0023] Embodiment:

[0024] A method and application for the one-step synthesis of 2-(hetero)aryl-3-cyanoindole skeletons based on photochemical reactions, including,

[0025] Embodiment 1: Synthesis of 1-methyl-2-(4-pyridyl)-3-cyanoindole

[0026] Under a nitrogen atmosphere, N-methylindole (1.0 mmol, 131 mg), 4-cyanopyridine (2.0 mmol, 208 mg), potassium carbonate (2.0 mmol, 276 mg) and dimethyl sulfoxide (5.0 mL) were added to a reaction flask equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature under visible light at 425 nm for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the white solid product 1-methyl-2-(4-pyridyl)-3-cyanoindole (203 mg, 87%). 1 H NMR (400 MHz, CDCl3): δ = 7.31 (t, J = 7.5 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.47 - 7.53 (m, 1H), 7.65 (d, J = 6.0 Hz, 2H), 7.88 (d, J = 8.2 Hz, 1H), 8.75 (d, J = 5.1 Hz, 2H) ppm. 13 C NMR (100 MHz, CDCl3): δ = 31.90, 108.56, 110.65, 113.41, 120.98, 122.55, 122.98, 124.23, 124.25, 126.73, 138.31, 139.87, 150.55 ppm. HRMS (ESI + ): Calculated value: C 15 H 11 N3Na [M+Na] + 256.0846, measured value: 256.0850.

[0027] Example 2: Synthesis of 1-Methyl-2-(3-thienyl)-3-cyanoindole

[0028] Under a nitrogen atmosphere, N-methylindole (1.0 mmol, 131 mg), 3-cyanothiophene (2.0 mmol, 218 mg), potassium carbonate (2.0 mmol, 276 mg) and dimethyl sulfoxide (5.0 mL) were added to a reaction flask equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature under ultraviolet light at 380 nm for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the white solid product 1-methyl-2-(4-pyridyl)-3-cyanoindole (193 mg, 81%). 1 H NMR (400 MHz, CDCl3): δ = 3.95 (s, 3H), 7.27 (d, J = 9.6 Hz, 1H), 7.41 - 7.47 (m, 1H), 7.60 (d, J = 6.0 Hz, 2H), 7.77 (d, J = 8.7 Hz, 1H), 8.76 (d, J = 5.6 Hz, 2H) ppm. 13 C NMR (100 MHz, CDCl3): δ = 32.12, 109.36, 110.72, 113.04, 122.13, 122.89, 122.98, 123.66, 124.61, 133.28, 138.70, 139.39, 150.79 ppm. HRMS (ESI + ): Calculated value: C 14 H 10 N2NaS [M+Na] + 261.0457, Found: 261.0458.

[0029] The above specific embodiments are merely explanations of the present invention, and they are not limitations of the present invention. Those skilled in the art can make modifications to this embodiment without creative contributions according to needs after reading this specification, but as long as they are within the scope of the claims of the present invention, they are protected by the patent law.

Claims

1. A method for the one-step synthesis of 2-(hetero)aryl-3-cyanoindole skeletons based on photochemical reactions and its applications, characterized in that: An indole derivative, a (hetero)aryl derivative, a base and a solvent are added to a reaction vessel, and under a nitrogen atmosphere, irradiated with visible light or ultraviolet light, and reacted at room temperature for 12 hours; after the reaction is completed, the reaction solution is concentrated and purified to obtain a 2-(hetero)aryl-3-cyanoindole derivative, and the reaction formula is as follows:

2. The method for one-step synthesis of 2-(hetero)aryl-3-cyanoindole skeleton based on photochemical reaction according to claim 1, characterized in that: Applications in the development of HCV inhibitors and aldosterone synthase inhibitors.

3. The method for one-step synthesis of 2-(hetero)aryl-3-cyanoindole skeleton based on photochemical reaction as claimed in claim 2, characterized in that: The multi-step reaction process in the traditional method is simplified, and the synthesis efficiency is improved.

4. The method for one-step synthesis of 2-(hetero)aryl-3-cyanoindole skeleton based on photochemical reaction according to claim 2, characterized in that: By adjusting the reaction conditions or starting materials, the diversity construction of the target molecule is realized, and the flexibility of drug molecule optimization and research and development is improved.

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