Process for the preparation of a diphenylmethane quinoxaline ketone derivative
The preparation of diphenylmethylquinoxalinone derivatives by a cross-dehydrogenation coupling strategy solves the problems of high efficiency and environmental friendliness of existing quinoxalin-2(1H)-one C-3 alkylation reactions, and realizes the efficient synthesis and antibacterial activity of quinoxalinone derivatives.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-17
- Publication Date
- 2026-07-21
Smart Images
Figure CN120817905B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of biomedical technology, specifically relating to a method for preparing a diphenylmethylquinoxalone derivative. Background Technology
[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.
[0003] Quinoxaline-2(1H)-one is an important nitrogen-containing heterocyclic unit, widely used in the pharmaceutical, natural product, and materials industries due to its excellent chemical properties and strong biological activity, and has significant application value. Among them, C-3 substituted quinoxaline-2(1H)-one exhibits a wide range of biological properties, including antihistamine, antibacterial, antimalarial, antiviral, and anticancer activities. Many effective methods have been developed to construct 3-substituted quinoxaline derivatives through C3-position functionalization of quinoxaline. A series of functional groups, such as aryl, acyl, alkoxy, amino, oxoalkyl, cyano, phosphorus, and sulfonyl groups, can be readily introduced into this framework. However, CH alkylation reactions of quinoxaline-2(1H)-one remain rare.
[0004] Current synthetic methods for C-3 alkyl-substituted quinoxaline-2(1H)-one compounds typically suffer from several drawbacks, such as requiring multiple reaction steps, high reaction temperatures, the use of expensive photocatalysts or photosensitizers, pre-functionalization of the substrate, a narrow substrate range, and relatively harsh or complex reaction conditions. Therefore, developing novel and efficient green synthetic methods for C-3 alkyl-substituted quinoxaline-2(1H)-ones is essential in the field of pharmaceutical research and development. Summary of the Invention
[0005] To address the shortcomings of existing technologies, the present invention aims to provide a method for preparing diphenylmethylquinoxalinone derivatives. The present invention employs a cross-dehydrogenation coupling strategy, which achieves 3-position alkylation of quinoxalinone through direct activation of alkane accompanied by a hydrogen atom transfer process, exhibiting more efficient and environmentally friendly advantages.
[0006] To achieve the above objectives, the technical solution of the present invention is as follows: A first aspect of the present invention provides a method for preparing a diphenylmethylquinoxalone derivative, comprising: In the presence of an oxidant and a ferrous salt, 1-methylquinoxalone and diphenylmethane undergo a coupling reaction in an organic solvent to yield a diphenylmethylquinoxalone derivative. The structure of the diphenylmethylquinoxalone derivative is as follows: .
[0007] The method for preparing diphenylmethylquinoxalinone derivatives provided by this invention employs a cross-dehydrogenation coupling strategy, which achieves 3-position alkylation of quinoxalinone through direct activation of alkane accompanied by hydrogen atom transfer, exhibiting advantages of higher efficiency and environmental friendliness.
[0008] In some embodiments of the present invention, the oxidant is N-chlorosuccinimide (NCS). NCS acts as the final oxidant for dehydrogenation coupling, promoting coupling. Furthermore, NCS is inexpensive and effective.
[0009] In some embodiments of the present invention, the ferrous salt includes any one of ferrous chloride, ferrous sulfate, and ferrous carbonate.
[0010] In some embodiments of the present invention, the ferrous salt is ferrous chloride.
[0011] In this invention, NCS is selected as the final oxidant for dehydrogenation coupling. Ferrous chloride reacts with NCS to obtain ferric chloride and nitrogen free radicals, which are then dehydrogenated to obtain alkyl free radicals. The alkyl free radicals are coupled with 1-methylquinoxalinone, and then dehydrogenated to obtain the target product, namely the diphenylmethylquinoxalinone derivative.
[0012] In some embodiments of the present invention, the organic solvent includes any one of dichloroethane, dichloromethane, and chloroform.
[0013] In some embodiments of the present invention, the coupling reaction is carried out at a temperature of 20-70°C and for a time of 12-30 hours.
[0014] The preparation method provided by this invention has advantages such as mild reaction conditions, inexpensive and readily available reagents, and short reaction time.
[0015] In some embodiments of the present invention, the molar ratio of 1-methylquinoxalone, diphenylmethane, oxidant and ferrous salt is 1.0:(1.0-1.5):(1.0-1.5):(0.1-0.2).
[0016] Preferably, the molar ratio of 1-methylquinoxalone, diphenylmethane, N-chlorosuccinimide and ferrous salt is 1.0:1.2:1.2:0.1.
[0017] Preferably, the molar ratio of 1-methylquinoxalone, diphenylmethane, N-chlorosuccinimide and ferrous salt is 1.0:1.5:1.2:0.1.
[0018] In a second aspect, the present invention provides the use of a diphenylmethylquinoxalone derivative prepared by the above-described preparation method in the preparation of a product for treating plant fungal infections.
[0019] The diphenylmethylquinoxalone derivative prepared by this invention has antibacterial properties and can inhibit fungi. It can be used in the field of pesticides and in the preparation of fungal inhibitors and other products.
[0020] In some embodiments of the present invention, the fungal infection includes any one or more of the following: cucumber wilt, peanut brown spot, apple ring rot, wheat scab, rice bakanae disease, rapeseed sclerotinia stem rot, pepper blight, corn leaf blight, watermelon anthracnose, potato late blight, rice sheath blight, and cucumber gray mold.
[0021] A third aspect of the present invention provides a product for treating plant eukaryotic infections, comprising a diphenylmethylquinoxalone derivative; The structure of the diphenylmethylquinoxalone derivative is as follows: .
[0022] The diphenylmethylquinoxalone derivative provided by this invention has highly efficient broad-spectrum antifungal activity and exhibits inhibitory effects against a variety of common plant pathogenic fungi, and can be developed into a product for treating plant fungal infections.
[0023] The beneficial effects of this invention are as follows: This invention provides a method for preparing diphenylmethylquinoxalinone derivatives, which adopts a cross-dehydrogenation coupling strategy to achieve 3-position alkylation of quinoxalinone through direct activation of alkane accompanied by hydrogen atom transfer. The reaction conditions are mild, the reagents used are inexpensive and readily available, and it exhibits the advantages of being more efficient and environmentally friendly. Detailed Implementation
[0024] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.
[0025] Example 1 A method for preparing a diphenylmethylquinoxalone derivative includes the following steps: The structure of the diphenylmethylquinoxalone derivative is shown below:
[0026] Synthesis route:
[0027] Specifically, the steps include the following: Add 20 mL of chloroform, 1.60 g (10 mmol) of 1-methylquinoxalone, and 2.02 g (12 mmol) of diphenylmethane to a 50 mL thick-walled pressure-resistant tube. N1.60 g (12 mmol) of chlorosuccinimide and 0.13 g (1 mmol) of ferrous chloride were reacted and stirred at 40 °C for 24 hours. After the reaction was complete, the organic solvent was removed by rotary evaporation and the diphenylmethylquinoxalone derivative was separated by column chromatography, yielding 2.71 g, with a yield of 83%.
[0028] 1 H NMR (500 MHz, CDCl3) δ 7.84 (dd, J = 8.0, 1.3 Hz, 1H), 7.55 – 7.50(m, 1H), 7.43 – 7.37 (m, 4H), 7.33 – 7.26 (m, 6H), 7.25 – 7.12 (m, 2H), 6.29(s, 1H), 3.68 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 160.7, 154.6, 141.0, 133.0,132.6, 130.5, 130.0, 129.5, 128.3, 126.6, 123.4, 113.5, 52.4, 29.3. Example 2 A method for preparing a diphenylmethylquinoxalone derivative: Synthesis route:
[0029] Specifically, the steps include the following: Add 20 mL of 1,2-dichloroethane, 1.60 g (10 mmol) of 1-methylquinoxalone, and 2.02 g (12 mmol) of diphenylmethane to a 50 mL thick-walled pressure-resistant tube. N 1.60 g (12 mmol) of chlorosuccinimide and 0.13 g (1 mmol) of ferrous chloride were reacted and stirred at 40 °C for 24 hours. After the reaction was complete, the organic solvent was removed by rotary evaporation and the diphenylmethylquinoxalone derivative was separated by column chromatography, yielding 2.48 g, with a yield of 76%.
[0030] Upon testing, the structure of the obtained diphenylmethylquinoxalone derivative was found to be consistent with that of the diphenylmethylquinoxalone derivative obtained in Example 1.
[0031] Example 3 A method for preparing a diphenylmethylquinoxalone derivative: Synthesis route:
[0032] Specifically, the steps include the following: Add 20 mL of chloroform, 1.60 g (10 mmol) of 1-methylquinoxalone, and 2.02 g (12 mmol) of diphenylmethane to a 50 mL thick-walled pressure-resistant tube. N 1.60 g (12 mmol) of chlorosuccinimide and 0.13 g (1 mmol) of ferrous chloride were reacted, and the reaction mixture was stirred at 50 °C for 24 hours. After the reaction was complete, the organic solvent was removed by rotary evaporation, and 2.61 g of the diphenylmethylquinoxalinone derivative was obtained by column chromatography, with a yield of 80%. Upon testing, the structure of the obtained diphenylmethylquinoxalone derivative was found to be consistent with that of the diphenylmethylquinoxalone derivative obtained in Example 1.
[0033] Example 4 A method for preparing a diphenylmethylquinoxalone derivative: Synthesis route:
[0034] Specifically, the steps include the following: Add 20 mL of chloroform, 1.60 g (10 mmol) of 1-methylquinoxalone, and 2.52 g (15 mmol) of diphenylmethane to a 50 mL thick-walled pressure-resistant tube. N 1.60 g (12 mmol) of chlorosuccinimide and 0.13 g (1 mmol) of ferrous chloride were reacted and stirred at 40 °C for 24 hours. After the reaction was complete, the organic solvent was removed by rotary evaporation and the diphenylmethylquinoxalone derivative was separated by column chromatography, yielding 2.68 g, with a yield of 82%.
[0035] Upon testing, the structure of the obtained diphenylmethylquinoxalone derivative was found to be consistent with that of the diphenylmethylquinoxalone derivative obtained in Example 1.
[0036] Example 5 Antifungal activity verification The fungal inhibitory activity of the diphenylmethylquinoxalone derivative synthesized in Example 1 was tested against common plant fungi.
[0037] The test method is: agar plate diffusion method. The drug was spread on an agar plate, and after incubation, the size of the inhibition zone around the drug was observed. The antifungal activity was assessed by the diameter of the inhibition zone.
[0038] The inhibitory activity of the diphenylmethylquinoxalone derivative against common plant fungi is shown in Table 1. As can be seen from Table 1, the diphenylmethylquinoxalone derivative prepared in this invention exhibits a certain inhibitory effect on the tested fungi.
[0039] Table 1. Results of the inhibitory activity of diphenylmethylquinoxalone derivatives against plant fungal diseases.
[0040] Table 1 shows the in vitro antifungal activity of the diphenylmethylquinoxalone derivative synthesized in Example 1 against 12 common plant fungal diseases, including cucumber wilt, peanut brown spot, apple ring rot, wheat scab, rice bakanae disease, rapeseed sclerotinia, pepper phytosis, corn small spot, watermelon anthracnose, potato late blight, rice sheath blight, and cucumber gray mold, at a concentration of 50 mg / L. The diphenylmethylquinoxalone derivative exhibited certain antifungal activity, especially against peanut brown spot, apple ring rot, and cucumber gray mold, showing inhibitory activity comparable to carbendazim and chlorothalonil.
[0041] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.
Claims
1. The application of diphenylmethylquinoxalone derivatives in the preparation of products for treating plant fungal infections, characterized in that, The preparation method of the diphenylmethylquinoxalone derivative includes: In the presence of an oxidant and a ferrous salt, 1-methylquinoxalone and diphenylmethane undergo a coupling reaction in an organic solvent to yield a diphenylmethylquinoxalone derivative. The structure of the diphenylmethylquinoxalone derivative is as follows: ; The oxidant is N-chlorosuccinimide; The molar ratio of 1-methylquinoxalone, diphenylmethane, oxidant, and ferrous salt is 1.0:(1.0-1.5):(1.0-1.5):(0.1-0.2); The fungal infection is any one or more of peanut brown spot, apple ring rot, and cucumber gray mold.
2. The application as described in claim 1, characterized in that, The ferrous salt includes any one of ferrous chloride, ferrous sulfate, and ferrous carbonate.
3. The application as described in claim 2, characterized in that, The ferrous salt is ferrous chloride.
4. The application as described in claim 1, characterized in that, The organic solvent includes any one of dichloroethane, dichloromethane, and chloroform.
5. The application as described in claim 1, characterized in that, The coupling reaction is carried out at a temperature of 20-70℃ for a time of 12-30 h.