Synthesis method and application of c3-substituted quinoxaline ketone derivatives

Abstract

The application discloses a synthesis method of C3-substituted quinoxaline ketone derivatives and application thereof. A series of C3-substituted quinoxaline ketone derivatives with both terpene and quinoxaline ketone biological activity skeletons are obtained by using N-alkoxy phthalimide and quinoxaline ketone as starting substrates, under the catalysis of a photocatalyst and visible light irradiation, and at a temperature of 55-65 DEG C for 10-15 h. The application has the advantages of stable and easy-to-prepare raw materials, mild reaction conditions, simple experimental operation, good chemical selectivity and functional group tolerance, and is a green chemical synthesis method with good application prospect. The activity experiment results show that the synthesized C3-substituted quinoxaline ketone derivatives have good inhibiting effect on the growth of plant pathogenic fungi.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and pharmaceutical synthesis technology, and relates to a method for synthesizing C3-substituted quinoxaline derivatives and their applications. Background Technology

[0002] Quinoxalones and their derivatives are a class of compounds with remarkable pharmacological and biological activities, widely found in drug molecules and natural products. In particular, C3-alkylquinoxalone derivatives exhibit outstanding pharmacological activities, encompassing anticancer, anti-inflammatory, and anti-asthmatic effects. Furthermore, terpenoid natural products, such as camphor, menthol, and pinene, possess broad biological activities due to their unique terpene skeleton structures. These natural products have attracted considerable attention due to their potential therapeutic efficacy, demonstrating encouraging research results in the fields of medicine, agriculture, and cosmetics. Here, we use sodium sulfide as a photocatalyst to deeply recombine the carbon structure of terpenes, efficiently combining quinoxaline-2(1H)-ones and various terpenoid compounds into a series of potential drug-active molecules possessing two different biologically active skeletons, providing a new approach for the design and synthesis of novel drug-active molecules. Summary of the Invention

[0003] Purpose of the invention: In view of the above-mentioned technical problems existing in the prior art, the present invention aims to provide a photocatalytic method for synthesizing C3-substituted quinoxalone derivatives, using inexpensive anionic catalyst sodium sulfide as a catalyst to provide a green, economical and efficient catalytic condition.

[0004] To solve the above-mentioned technical problems, the present invention provides the following technical solution.

[0005] A method for preparing a C3-substituted quinoxalinone derivative and its application: The quinoxalinone derivative, N-alkoxyphthalimide, and sodium sulfide are dissolved in an organic solvent and reacted at 55–65°C for 10–15 h under visible light irradiation. After the reaction is completed, the reaction system is separated and purified to obtain the C3-substituted quinoxalinone derivative.

[0006] Specifically, the C3-substituted quinoxalone derivative is a compound having the following structural formula:

[0007]

[0008] R1 and R2 are independent groups, with R1 selected from hydrogen, halogen or methyl; and R2 selected from hydrogen, methyl, ethyl, n-propyl, allyl, propargyl or benzyl.

[0009] Preferably, the method for synthesizing the above-mentioned C3-substituted quinoxalinone derivatives involves dissolving quinoxalinone derivative 1, N-alkoxyphthalimide 2, 3, or 4, and sodium sulfide photocatalyst in an organic solvent, reacting the mixture under visible light irradiation at a temperature of 55–65°C for 10–15 h, and after the reaction is completed, separating and purifying the reaction system to obtain C3-substituted quinoxalinone derivatives 5, 6, or 7, as shown in the following reaction formula:

[0010]

[0011] The method for synthesizing a C3-substituted quinoxalinone derivative, wherein the molar ratio of the quinoxalinone derivative to the N-alkoxyphthalimide is 1:2.

[0012] The method for synthesizing a C3-substituted quinoxalone derivative, wherein the photocatalyst is sodium sulfide, sodium sulfide nonahydrate, or sodium thiophene, preferably sodium sulfide.

[0013] The method for synthesizing a C3-substituted quinoxalinone derivative, wherein the molar ratio of the N-alkoxyphthalimide to the photocatalyst is 1:0.2.

[0014] The method for synthesizing a C3-substituted quinoxaline derivative, wherein the visible light is blue light with a wavelength of 420-430 nm.

[0015] The method for synthesizing a C3-substituted quinoxalone derivative uses N,N-dimethylacetamide as the organic solvent.

[0016] The method for synthesizing a C3-substituted quinoxalone derivative comprises the following steps for separating and purifying the reaction system: water and dichloromethane are added to the reaction system, and the layers are separated into an aqueous layer and an organic layer. The organic layer is washed with saturated brine and then dried with anhydrous sodium sulfate. The dried organic layer is concentrated under reduced pressure, and the concentrate is separated and purified by column chromatography using silica gel. The eluent is a mixture of petroleum ether and ethyl acetate. The eluent is collected and the solvent is evaporated to obtain the target product.

[0017] Another objective of this invention is to overcome the shortcomings of the prior art and provide an application of a C3-substituted quinoxalone derivative in the control of plant fungi in agriculture or forestry, wherein the plant fungi include Sclerotinia sclerotiorum, apple rot fungus, Chlorella vulgaris, and rice sheath blight fungus.

[0018] Compared with the prior art, the beneficial effects of this invention are as follows:

[0019] (1) The synthesis method of the present invention has stable and easy-to-prepare raw materials, mild reaction conditions, simple experimental operation, good chemical selectivity and functional group tolerance, and is a green chemical synthesis method with good application prospects.

[0020] (2) The compound described in this invention is an agent for controlling plant fungi in the agricultural or forestry field. This agent has shown good effects in controlling Sclerotinia sclerotiorum var. sclerotiorum, apple rot fungus, Chlorella vulgaris and rice sheath blight fungus. Attached Figure Description

[0021] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. Wherein:

[0022] Figure 1 It is a C3-substituted quinoxaline derivative;

[0023] Figure 2 The proton NMR spectrum of compound 5a prepared for the example;

[0024] Figure 3 The carbon NMR spectrum of compound 5a prepared for the example;

[0025] Figure 4 The proton NMR spectrum of compound 6a prepared for the example;

[0026] Figure 5 The carbon NMR spectrum of compound 6a prepared for the example;

[0027] Figure 6 The proton NMR spectrum of compound 7a prepared for the example;

[0028] Figure 7 The carbon NMR spectrum of compound 7a prepared for the example. Detailed Implementation

[0029] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.

[0030] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0031] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.

[0032] Example 1

[0033] The reaction equation is as follows:

[0034]

[0035] 1-Methylquinoxalin-2(1H)-one 1a (0.1 mmol, 16.0 mg), N-alkoxyphthalimide 2 (0.2 mmol, 2.0 equiv., 59.8 mg), Na₂S (20 mol%, 1.8 mg), and DMA (2 mL, 0.05 M) were sequentially added to a 4 mL clear glass vial equipped with a magnetic stir bar. After bubbling with nitrogen for 5 minutes to remove oxygen, the vial was sealed and irradiated under blue light at 60 °C for 12 h. The reaction mixture was monitored by TLC until the starting material N-alkoxyphthalimide 2 was consumed. After the reaction was complete, the reaction was quenched with water (2 mL), extracted with dichloromethane, and the organic phase was washed with saturated brine and dried with anhydrous sodium sulfate. The dried organic phase was concentrated under vacuum and purified by column chromatography to give product 5a (14.7 mg, 52%).

[0036] Characterization data: Yellow oily substance; 1 H NMR (400MHz, CDCl3) δ7.86 (dd, J=1.3, 7.9Hz, 1H), 7.53 (m, J=2.9Hz, 1H), 7.33 (m, J=4.2Hz, 2H), 5.63 (m, J=3.2Hz, 2H), 3.69 (s, 3H) 13C NMR (101MHz, CDCl3) δ165.1, 153.8, 133.2, 132.1, 130.2, 129.5, 127.0 (2C), 123 .2, 113.3, 45.5, 38.7, 28.8, 27.4, 26.6, 24.2, 22.7, 22.0.HRMS(ESI, m / z)calcd for C 18 H 23 N₂O(M+H)+ :283.1805, found:283.1801.

[0037] Example 2:

[0038] The reaction equation is as follows:

[0039]

[0040] 1-Methylquinoxalin-2(1H)-one 1a (0.1 mmol, 16.0 mg), N-alkoxyphthalimide 2 (0.2 mmol, 2.0 equiv., 63.0 mg), Na₂S (20 mol%, 1.8 mg), and DMA (2 mL, 0.05 M) were sequentially added to a 4 mL clear glass vial equipped with a magnetic stir bar. After bubbling with nitrogen for 5 minutes to remove oxygen, the vial was sealed and irradiated under blue light at 55 °C for 10 h. The reaction mixture was monitored by TLC until the starting material N-alkoxyphthalimide 3 was consumed. After the reaction was complete, the reaction was quenched with water (2 mL), extracted with dichloromethane, and the organic phase was washed with saturated brine and dried with anhydrous sodium sulfate. The dried organic phase was concentrated under vacuum and purified by column chromatography to give product 6a (16.7 mg, 51%).

[0041] Characterization data: Yellow oily substance; 1 H NMR (400MHz, CDCl3) δ8.06 (s, 1H), 7.84 (d, J = 7.5Hz, 1H), 7.53 (t, J = 7.5Hz, 1H), 7.35-7.26 (m, 2H), 4.27-4.09 (m, 2H), 3 .68(s, 3H), 2.93-2.72(m, 1H), 2.21-2.05(m, 2H), 1.67-1.51(m, 4H), 1.46-1.40(m, 1H), 1.12(s, 3H), 0.99-0.91(m, 3H); 13 C NMR (101MHz, CDCl3) δ164.1, 161.3, 154.6, 133.2, 131.9, 130.3, 129.8, 123.1, 113.2 ,66.1,57.2,48.1,46.5,37.9,29.1,27.3,26.3,21.7,19.9.HRMS(ESI,m / z)calcdfor C 19 H 25 N2O3(M+H)+: 329.1860, found: 329.1853.

[0042] Example 3:

[0043] The reaction equation is as follows:

[0044]

[0045] 1-Methylquinoxalin-2(1H)-one 1a (0.1 mmol, 16.0 mg), N-alkoxyphthalimide 4 (0.2 mmol, 2.0 equiv., 63.0 mg), Na₂S·9H₂O (20 mol%, 4.8 mg), and DMA (2 mL, 0.05 M) were sequentially added to a 4 mL clear glass vial equipped with a magnetic stir bar. After bubbling with nitrogen for 5 minutes to remove oxygen, the vial was sealed and irradiated under blue light at 65 °C for 15 h. The reaction mixture was monitored by TLC until the starting material N-alkoxyphthalimide 4 was consumed. After the reaction was complete, the reaction was quenched with water (2 mL), extracted with dichloromethane, and the organic phase was washed with saturated brine and dried with anhydrous sodium sulfate. The dried organic phase was concentrated under vacuum and purified by column chromatography to give product 7a (20.8 mg, 67%).

[0046] Characterization data: Yellow oily substance; 1 H NMR (400MHz, CDCl3) δ7.89 (d, J=7.5Hz, 1H), 7.55 (t, J=7.6Hz, 1H), 7.37 (q, J=8.7 Hz, 2H), 4.05 (t, J = 11.5Hz, 1H), 3.93-3.64 (m, 5H), 3.50 (t, J = 7.2Hz, 1H), 2.48 (t ,J=6.2Hz, 1H), 2.39(s, 1H), 1.97(s, 1H), 1.90(t, J=5.2Hz, 1H), 1.73(t, J=10.3H z, 1H), 1.50 (d, J=10.0Hz, 1H), 1.30 (d, J=10.1Hz, 1H), 1.06 (s, 3H), 0.93 (s, 3H); 13 C NMR (101MHz, CDCl3) δ161.4, 155.5, 132.7, 132.6, 129.9, 129.5, 123.8, 113.7, 60. 1, 52.0, 49.6, 45.6, 37.2, 35.2, 33.7, 32.1, 29.3, 26.1, 20.4.HRMS(ESI, m / z)calcd for C 19 H 25 N2O2(M+H) + :300.1594, found:300.1587.

[0047] Example 4:

[0048] The compounds 5a-7a prepared in Examples 1-3 were subjected to bioactivity testing experiments. The specific procedures are as follows: The plant fungi used in this experiment were strains preserved in the laboratory at 4℃, namely *Sclerotinia sclerotiorum*, *Pseudomonas auricula-judae*, *Cyclocarya paliurus*, and *Rhizoctonia solani*. The culture medium used was potato agar-dextrose medium (PDA). PDA medium formula: 200g potato (peeled), 20g glucose, 15g agar, 1000mL distilled water. Preparation method: Wash and peel the potato, weigh 200g, cut into small pieces, add water and boil until soft (boil for 20-30 minutes, until it can be pierced by a glass rod). Filter through eight layers of gauze into a beaker, add 15-20g agar and 20g glucose as needed, stir well, and after fully dissolving, cool slightly. Add water to 1000mL, dispense, sterilize at 121℃ for 15 minutes, and cool for later use.

[0049] Experimental method: The growth rate method was used.

[0050] (1) First, culture the two kinds of plant fungi on PDA plates at 25℃ for about 3-6 days before use;

[0051] (2) Heat the PDA medium to melt it, cool it to 45-50℃, add 250μL of the test compound 5a-7a at a concentration of 10g / L to prepare a medium containing 50mg / L drug solution, and pour it into petri dishes and cool it. Boscalid is used as a positive control.

[0052] (3) Using aseptic technique, use a punch to make round mycelial cakes (0.50 cm in diameter) at the edge of the hyphae of each strain after 6 days of culture (with the growth conditions as consistent as possible), then use an inoculation needle to pick them up and place them in the center of the drug-containing plate, and then invert the petri dish in an incubator (28°C) for culture.

[0053] (4) The growth of mycelium was observed and measured at different time points after treatment, and the diameter was measured and the data was processed using the cross-cross method to calculate the inhibition rate;

[0054] (5) Inhibition rate (%) = (control hyphae diameter - treated hyphae diameter) / (control hyphae diameter - 0.5) × 100;

[0055] (6) Each treatment is repeated 3 times.

[0056] The test results are shown in Table 1.

[0057] Table 1. Results of inhibitory activity tests of C3-substituted quinoxaline derivatives against four agricultural pathogenic fungi.

[0058]

[0059] The fungicidal activity of experimental groups 5a-7a and the control agent cyazofamid is shown in Table 1. As can be seen from Table 1, at a concentration of 50 mg / L, compounds 5a-7a exhibited varying degrees of antifungal activity against four plant fungi. Compounds 5a and 6a effectively inhibited the growth of *Pseudomonas aeruginosa* and *Cyclocarya paliurus*, with inhibition rates ranging from 57.74% to 72.73%. Among the four pathogenic fungi tested, 7a showed an inhibition rate of 67.35% against *Cyclocarya paliurus*. Compound 5a exhibited good antifungal activity against *Rhizoctonia solani*, with an inhibition rate of 61.14%.

[0060] The C3-substituted quinoxalone derivatives of this invention exhibit distinct structures and clear chemical characteristics, demonstrating good efficacy against Sclerotinia sclerotiorum var. sclerotiorum and rice sheath blight. They can be used to control fungal diseases in agricultural or forestry plants. The preparation method of these compounds is simple, with high yields and stable product properties.

[0061] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for synthesizing a C3-substituted quinoxaline derivative, characterized in that... Quinoxalinone derivative 1, N-alkoxyphthalimide 2, 3 or 4, and sodium sulfide photocatalyst were dissolved in an organic solvent and reacted under visible light at a temperature of 55–65 °C for 10–15 h. After the reaction was completed, the reaction system was separated and purified to obtain C3-substituted quinoxalinone derivatives 5, 6 or 7, as shown in the following reaction formula: Wherein, R1 is selected from hydrogen; R2 is selected from methyl; the visible light is blue light with a wavelength of 420-430 nm.

2. The method for synthesizing a C3-substituted quinoxalinone derivative according to claim 1, characterized in that... The molar ratio of the quinoxalinone derivative to the N-alkoxyphthalimide is 1:

2.

3. The method for synthesizing a C3-substituted quinoxalinone derivative according to claim 1, characterized in that... The molar ratio of the N-alkoxyphthalimide to the photocatalyst is 1:0.

2.

4. The method for synthesizing a C3-substituted quinoxalone derivative according to claim 1, characterized in that... The separation and purification steps of the reaction system are as follows: water and dichloromethane as the extraction agent are added to the reaction system, the layers are extracted and separated, the organic layer is washed with saturated brine and then dried with anhydrous sodium sulfate, the dried organic layer is concentrated under reduced pressure to obtain a concentrate, the concentrate is separated and purified by column chromatography with silica gel, the eluent is a mixture of petroleum ether and ethyl acetate, the eluent is collected and the solvent is evaporated to obtain the C3-substituted quinoxalinone derivative.

5. The application of the C3-substituted quinoxalone derivative prepared by the method according to claim 1 in the control of plant fungi in agriculture or forestry.

6. The application according to claim 5, characterized in that... The plant fungi mentioned include Sclerotinia sclerotiorum var. sclerotiorum, rot fungus of apple, Chlorella vulgaris, and rice sheath blight fungus.

7. The application according to claim 6, characterized in that... The plant fungus mentioned is *Cyclocarya paliurus*.

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