Myrtenyl-isoxazolecarboxylic hydrazide compounds and methods of making and using the same

Abstract

The application discloses a myrtenyl-isoxazole formylhydrazine compound and a preparation method and application thereof, and belongs to the technical field of pesticide synthesis. The myrtenyl-isoxazole formylhydrazine compound has a structural formula as shown in the specification, wherein R is selected from -4-H, -4-F, -4-Cl, -4-Br, -4-I, -4-CH3, -2-F, -3-F, -2-Cl, -3-Cl, -2-Br and -3-Br. The compound has good prevention and treatment effects on Sclerotinia sclerotiorum and Botryosphaeria dothidea under an in-vitro condition, and can be used for preventing and treating fungal diseases of agricultural or forestry plants. The preparation method of the compound is simple, the yield is high, and the product is stable in property.

Description

Technical Field

[0001] This invention belongs to the field of pesticide synthesis technology, specifically relating to myrtyl-isoxazole carbamoyl hydrazide compounds, their preparation methods, and their applications. Background Technology

[0002] Crop diseases and pests are a significant constraint on the sustainable and healthy development of agricultural products and forest resources. Pesticides, as a special commodity for controlling biological hazards such as diseases and pests in agricultural and forestry crops, play a crucial role in protecting the normal growth of crops, improving agricultural production, and promoting food security.

[0003] Long-term use of a single pesticide can lead to pesticide resistance in plant pathogens, pests, and weeds. Therefore, developing new targeted pesticides is crucial for the effective control of plant diseases.

[0004] To date, there have been no reports of myrtleenyl-isoxazocarbazide compounds being used as agricultural fungicides. Summary of the Invention

[0005] The purpose of this section is to outline some aspects of the embodiments of the present invention and to briefly describe some preferred embodiments.

[0006] In view of the problems existing in the above and / or prior art, the present invention is proposed.

[0007] Therefore, the purpose of this invention is to overcome the shortcomings of the prior art and provide a myrtyl-isoxazole carboxylhydrazine compound.

[0008] To solve the above-mentioned technical problems, the present invention provides the following technical solution: a myrtyl-isoxazole carboxylhydrazine compound, wherein the myrtyl-isoxazole carboxylhydrazine compound has the following structural formula: R is selected from -4-H, -4-F, -4-Cl, -4-Br, -4-I, -4-CH3, -2-F, -3-F, -2-Cl, -3-Cl, -2-Br and -3-Br.

[0009] Another object of the present invention is to overcome the shortcomings of the prior art and provide a method for preparing myristic-isoxazole carbamoyl hydrazide compounds, comprising, Myrtol is reacted with hydroxyamine chloride to generate myrtol oxime; Myrtene oxime was reacted with methyl propargyl ester to generate myrtene-isoxazole methyl ester; Myrtyl-isoxazole methyl ester was reacted with substituted phenylhydrazine to give myrtyl-isoxazole carboxylhydrazine compounds.

[0010] As a preferred embodiment of the preparation method described in this invention, the myrtleene oxime is prepared by a method comprising: Myrtol was dissolved in ethanol, and hydroxylamine chloride and sodium acetate were dissolved in water. The three were mixed in a single-necked flask at room temperature and reacted at 80°C for 12 h. The reaction was detected by TLC. After the reaction was completed, the ethanol was removed by rotary concentration, and ethyl acetate was added for extraction. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary concentration to obtain the target compound, myrtol oxime, in an oily form. The molar ratio of myrtol, hydroxychloroamine, and sodium acetate is 1:2.5:1.2.

[0011] As a preferred embodiment of the preparation method described in this invention, the myrtyl-isoxazole methyl ester is prepared by a method comprising: Myrtol oxime, methyl propargylate and potassium chloride were dissolved in water, and then potassium peroxymonosulfate complex salt was added while stirring. The reaction was carried out at room temperature for 3 hours. TLC analysis showed that the reaction of the raw materials was complete. Ethyl acetate was added for extraction, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotation to obtain crude myrtyl-isoxazole methyl ester. The crude product was then separated and purified by silica gel column chromatography with a 200-300 mesh filter and purified by petroleum ether to ethyl acetate at a volume ratio of 300:1 to 150:1 to obtain the target compound myrtyl-isoxazole methyl ester. The molar ratio of the complex salt of myrtleene oxime, methyl propargylate, potassium chloride, and potassium peroxymonosulfate is 1:2.5:1:1.5.

[0012] As a preferred embodiment of the preparation method described in this invention, the myrtyl-isoxazole carbamoyl hydrazide is prepared by a method comprising: Myrtyl-isoxazole methyl ester was dissolved in anhydrous TEA in a pressure-resistant tube, substituted phenylhydrazine was added, and finally TBD was added. The reaction was stopped after heating to 80℃ for 12 hours, the solvent was removed, and ethyl acetate was added for extraction. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotation to obtain myrtyl-isoxazole carboxyhydrazides with each substituent. The compounds were separated and purified by silica gel column chromatography with a petroleum ether / ethyl acetate volume ratio of 30:1 to 10:1 to obtain myrtyl-isoxazole carboxyhydrazides with the target compounds. The molar ratio of myrtyl-isoxazole methyl ester, each substituted phenylhydrazine and TBD is 1:2.5:0.3.

[0013] In a preferred embodiment of the preparation method described in this invention, the substituent acylhydrazide includes benzoylhydrazide, 4-methylbenzoylhydrazide, 2-fluorobenzoylhydrazide, 3-fluorobenzoylhydrazide, 4-fluorobenzoylhydrazide, 2-chlorobenzoylhydrazide, 3-chlorobenzoylhydrazide, 4-chlorobenzoylhydrazide, 2-bromobenzoylhydrazide, 3-bromobenzoylhydrazide, 4-bromobenzoylhydrazide, and 4-iodobenzoylhydrazide.

[0014] Another objective of this invention is to overcome the shortcomings of the prior art and provide an application of myrtyl-isoxazole carbamoyl hydrazide compounds in the control of plant fungi in agriculture or forestry.

[0015] As a preferred embodiment of the application described in this invention, the plant fungi include apple rot fungus, grape rot fungus, rapeseed sclerotinia fungus, tomato gray mold fungus, potato late blight fungus, pepper phytophthora fungus, and wheat scab fungus.

[0016] Beneficial effects of this invention: (1) The compound described in this invention is a derivative containing myrtyl-isoxazole carboxylhydrazine, with a novel molecular structure. All of them are new compounds with distinct chemical structural features. The structural formula contains myrtyl, isoxazole group and hydrazine. The preparation method of the compound described in this invention is simple, the raw materials are readily available, and the reaction conditions are mild and easy to control.

[0017] (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 grape bud fungus, rapeseed sclerotinia rot fungus, apple rot fungus and wheat scab fungus. Attached Figure Description

[0018] 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: Figure 1 This is a schematic diagram illustrating the preparation method of myrtyl-isoxazole carboxylhydrazide compounds in an embodiment of the present invention.

[0019] Figure 2 This is a schematic diagram illustrating the in vitro antifungal activity of compound I-2 against Sclerotinia sclerotiorum var. sclerotiorum at different concentrations in embodiments of the present invention.

[0020] Figure 3 This is a schematic diagram illustrating the in vivo protective effect (A) and therapeutic effect (B) of compound I-2 and chlorothalonil on rapeseed seedling leaves infected with Sclerotinia sclerotinia in an embodiment of the present invention after 2 days of treatment. Detailed Implementation

[0021] 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.

[0022] A schematic diagram of the preparation method of the myrtyl-isoxazole carbamoyl hydrazide compound of the present invention is shown below. Figure 1 This includes the following steps: (1) Myrtol is converted into myrtol oxime by aldol condensation; (2) Reaction of myrtene oxime with methyl propargylate produces myrtene-isoxazole methyl ester; (3) React myrtyl-isoxazole methyl ester with each substituted phenylhydrazine to synthesize myrtyl-isoxazole carboxylhydrazine compounds.

[0023] The specific steps are as follows: (1) Preparation of myrtleene oxime Myrtol (300 mg, 2 mmol) was dissolved in 8 ml of ethanol, and ammonium hydroxychloride (347 mg, 5 mmol) and sodium acetate (197 mg, 2.4 mmol) were dissolved in 8 ml of water. The three were mixed in a single-necked flask at room temperature and reacted at 80 °C for 12 h. The reaction was monitored by TLC. After the reaction was completed, the ethanol was removed by rotary condensation, and ethyl acetate was added for extraction. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary condensation to obtain 270 mg of the target compound, myrtol oxime, in an oily form. (2) Preparation of myrtleenyl-isoxazole methyl ester Myrtol oxime (330 mg, 2 mmol), methyl propargylate (420 mg, 5 mmol), and potassium chloride (149 mg, 2 mmol) were dissolved in 6 ml of water. Then, potassium peroxymonosulfate complex salt (1.84 g, 3 mmol) was added while stirring. The reaction was carried out at room temperature for 3 h. The reaction of the starting material was detected by TLC and the reaction was completed. Ethyl acetate was added for extraction, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain crude myrtolyl-isoxazole methyl ester. The crude product was purified by silica gel column chromatography with a 200-300 mesh filter and a petroleum ether / ethyl acetate volume ratio of 300:1 to 150:1 to obtain 200 mg of the target compound myrtolyl-isoxazole methyl ester.

[0024] (3) Preparation of each substituted myrtyl-isoxazole carbamoyl hydrazide Myrtyl-isoxazole methyl ester (500 mg, 2 mmol) was dissolved in 5 ml of anhydrous TEA in a 15 ml pressure-resistant tube. Each substituted phenylhydrazine (5 mmol) was added, and finally TBD was added. The reaction was stopped after heating to 80 °C for 12 hours. The solvent was removed, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotation to obtain myrtyl-isoxazole carboxyhydrazides with each substituted compound. The compounds were purified by silica gel column chromatography with a 200-300 mesh screen and a petroleum ether / ethyl acetate volume ratio of 30:1 to 10:1 to obtain the myrtyl-isoxazole carboxyhydrazides with the target compound.

[0025] Example 1 Myrtyl-isoxazole methyl ester was prepared (3): Myrtol oxime (330 mg, 2 mmol), methyl propargylate (420 mg, 5 mmol), and potassium chloride (149 mg, 2 mmol) were dissolved in 6 ml of water. Then, potassium peroxymonosulfate complex salt (1.84 g, 3 mmol) was added while stirring. The reaction was carried out at room temperature for 3 h. TLC analysis showed complete reaction of the starting material. Ethyl acetate was added for extraction, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain crude myrtolyl-isoxazole methyl ester. This crude product was purified by 200-300 mesh silica gel column chromatography at a petroleum ether / ethyl acetate volume ratio of 300:1 to 150:1 to obtain the target compound, myrtolyl-isoxazole methyl ester (3). The product was a colorless viscous liquid; yield: 60.6%.

[0026] Colorless viscous liquid; Yield: 60.6%; 1 H NMR (600 MHz, CDCl3) δ 7.03(s, 1H), 6.25 (m, J = 3.3, 1.4 Hz, 1H), 3.96 (s, 3H), 3.00 (td, J = 5.6, 1.5 Hz,1H), 2.55 – 2.41 (m, 3H), 2.20 (m, J = 5.8, 2.7 Hz, 1H), 1.37 (s, 3H), 1.26 (d, J = 9.1 Hz, 1H), 0.85 (s, 3H). 13 C NMR (150 MHz, CDCl3): d162.94, 159.74, 157.58,137.37, 128.07, 106.70, 52.91, 42.61, 40.60, 38.03, 32.39, 31.35, 26.09,21.02.MS ESI m / z : calcd for C 14 H 17 NO3[M+H] + : 248.1208; found 248.1285. Example 2 Preparation of myrtyl-isoxazole carbamoyl hydrazide derivative (I-1): Myrtyl-isoxazole methyl ester (500 mg, 2 mmol) was dissolved in 5 mL of anhydrous TEA in a 15 mL pressure-resistant tube. Phenylhydrazine (540 mg, 5 mmol) was added, followed by TBD. The reaction was heated to 80 °C and stopped after 12 hours. The solvent was removed, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotation to obtain myrtyl-isoxazole carboxyhydrazides with various substituents. The compounds were purified by silica gel column chromatography (200-300 mesh) at a petroleum ether / ethyl acetate ratio of 30:1 to 10:1 (v / v) to give the myrtyl-isoxazole carboxyhydrazide derivatives (Ⅰ-1) with the target compounds. Yellow solid; yield, 31.5%.

[0027] Yellow solid; Yield: 31.5%; 1 H NMR (600 MHz, CDCl3): d 8.59 (s, 1H), 7.25– 7.20 (m, 2H), 7.08 (s, 1H), 6.93 (m, J = 7.3, 1.1 Hz, 1H), 6.90 – 6.85 (m,2H), 6.27 (m, J = 3.4, 1.5 Hz, 1H), 2.98 (td, J = 5.6, 1.5 Hz, 1H), 2.56 – 2.39(m, 3H), 2.26 – 2.12(m, 1H), 1.35 (s, 3H), 1.25 (d, J = 9.1 Hz, 1H), 0.85 (s, 3H). 13 C NMR (150 MHz, CDCl3): d163.29, 161.41, 156.41, 147.20, 137.06, 129.41,128.84, 121.87, 113.89, 105.42, 42.63, 40.56, 38.03, 32.43, 31.30, 26.04,21.01.MS ESI m / z : calcd for C 19 H 21 N3O2[M+H] + : 324.1634; found 324.1715. Example 3 Preparation of myrtyl-isoxazole carbamoyl hydrazide derivative (I-2): Myrtyl-isoxazole methyl ester (500 mg, 2 mmol) was dissolved in 5 mL of anhydrous TEA in a 15 mL pressure-resistant tube. 4-fluorophenylhydrazine (630 mg, 5 mmol) was added, followed by TBD. The reaction was heated to 80 °C and stopped after 12 hours. The solvent was removed, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotation to obtain myrtyl-isoxazole carboxyhydrazides with various substituents. These were purified by 200-300 mesh silica gel column chromatography at a petroleum ether / ethyl acetate volume ratio of 30:1 to 10:1 to give the myrtyl-isoxazole carboxyhydrazide derivatives (Ⅰ-2) with the target compounds. Yellow solid; yield: 38.5%.

[0028] Yellow solid; Yield: 38.5%; 1 H NMR (600 MHz, CDCl3): d 8.58 (s, 1H), 7.07 (s, 1H), 6.94 (dd, J = 9.6, 7.7 Hz, 2H), 6.88 – 6.82 (m, 2H), 6.29 – 6.25(m,1H), 2.97 (td, J = 5.6, 1.5 Hz, 1H), 2.56 – 2.41 (m, 3H), 2.23 – 2.16 (m, 1H), 1.35 (s, 3H), 1.25 (d, J = 9.1 Hz, 1H), 0.84 (s, 3H). 13 C NMR (150 MHz, CDCl3): d163.33, 161.26, 159.19, 156.51, 143.34 (d, J = 3 Hz), 137.03, 128.95, 116.01(d, J = 24 Hz), 115.49 (d, J = 7.5 Hz), 105.50, 42.64, 40.56, 38.04, 32.44,31.31, 26.05, 21.02.MS ESI m / z : calcd for C 19 H 20 FN3O2[M+H] + : 342.1540; found 342.1621. Example 4 Preparation of myrtyl-isoxazole carbamoyl hydrazide derivative (I-3): Myrtyl-isoxazole methyl ester (500 mg, 2 mmol) was dissolved in 5 mL of anhydrous TEA in a 15 mL pressure-resistant tube. 4-Chlorophenylhydrazine (710 mg, 5 mmol) was added, followed by TBD. The reaction was heated to 80 °C and stopped after 12 hours. The solvent was removed, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotation to obtain the myrtyl-isoxazole carboxyhydrazides of each substituent. These were purified by 200-300 mesh silica gel column chromatography at a petroleum ether / ethyl acetate volume ratio of 30:1 to 10:1 to give the myrtyl-isoxazole carboxyhydrazide derivatives of the target compound (Ⅰ-3). Yellow solid; Yield: 37.5% Yellow solid; Yield: 37.5%; 1 H NMR (600 MHz, DMSO): d 10.81 (d, J = 2.5Hz, 1H), 8.27 (d, J = 2.6 Hz, 1H), 7.47 (s, 1H), 7.29 – 7.12 (m, 2H), 6.84 –6.72 (m, 2H), 6.53 – 6.45(m, 1H), 2.92 (td, J = 5.6, 1.5 Hz, 1H), 2.55 – 2.50(m, 2H), 2.42 (dt, J= 19.2, 3.0 Hz, 1H), 2.21 – 2.15 (m, 1H), 1.35 (s, 3H), 1.19 (d, J = 8.9 Hz, 1H), 0.82 (s, 3H). 13 C NMR (150 MHz, DMSO): d 162.28, 161.92,156.02, 147.58, 136.36, 128.60, 128.37, 122.29, 113.82, 104.01, 41.79, 37.38,31.78, 30.65, 25.81, 20.78. MS ESI m / z : calcd for C 19 H 20 ClN3O2[M+H] + : 358.1244; found 358.1323. Example 5 Preparation of myrtyl-isoxazole carbamoyl hydrazide derivative (I-4): Myrtyl-isoxazole methyl ester (500 mg, 2 mmol) was dissolved in 5 mL of anhydrous TEA in a 15 mL pressure-resistant tube. 4-Bromophenylhydrazine (935 mg, 5 mmol) was added, followed by TBD. The reaction was heated to 80 °C and stopped after 12 hours. The solvent was removed, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotation to obtain the myrtyl-isoxazole carboxyhydrazides of each substituent. These were purified by 200-300 mesh silica gel column chromatography at a petroleum ether / ethyl acetate volume ratio of 30:1 to 10:1 to give the myrtyl-isoxazole carboxyhydrazide derivatives (I-4) of the target compound. Yellow solid; Yield: 35.5% Yellow solid; Yield: 35.5%; 1 H NMR (600 MHz, DMSO): d 10.92 – 10.70 (m,1H), 8.29 (s, 1H), 7.47 (s, 1H), 7.31 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.2 Hz,2H), 6.49 (s, 1H), 2.92 (t, J = 5.5 Hz, 1H), 2.53 (d,J = 5.3 Hz, 2H), 2.42 (d, J =17.3 Hz, 1H), 2.19 (d, J = 6.3 Hz, 1H), 1.35 (s, 3H), 1.19 (d, J = 8.9 Hz, 1H), 0.82 (s, 3H). 13 C NMR (150 MHz, DMSO): d 162.29, 161.91, 156.00, 147.98, 136.35,131.43, 128.37, 114.31, 109.81, 104.02, 41.79, 37.38, 31.78, 30.65, 25.81,20.78.MS ESI m / z : calcd for C 19 H 20 BrN3O2[M+H] + : 402.0739; found 402.0817 Example 6 Preparation of myrtyl-isoxazole carbamoyl hydrazide derivative (I-5): Myrtyl-isoxazole methyl ester (500 mg, 2 mmol) was dissolved in 5 mL of anhydrous TEA in a 15 mL pressure-resistant tube. 4-Iodophenylhydrazine (1170 mg, 5 mmol) was added, followed by TBD. The reaction was heated to 80 °C and stopped after 12 hours. The solvent was removed, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotation to obtain the myrtyl-isoxazole carboxyhydrazides of each substituent. These were purified by 200-300 mesh silica gel column chromatography at a petroleum ether / ethyl acetate volume ratio of 30:1 to 10:1 to give the myrtyl-isoxazole carboxyhydrazide derivatives (I-5) of the target compounds. Yellow solid; Yield: 30.5% Yellow solid; Yield: 30.5%; 1 H NMR (600 MHz, DMSO): d 10.78 (s, 1H),8.25 (s, 1H), 7.48 – 7.39 (m, 3H), 6.63 – 6.56 (m, 2H), 6.49 – 6.44(m, 1H),2.89 (td, J= 5.6, 1.5 Hz, 1H), 2.48 (td, J = 6.1, 5.1, 2.9 Hz, 2H), 2.39 (dt, J =19.1, 3.0 Hz, 1H), 2.19 – 2.12(m, 1H), 1.33 (s, 3H), 1.17 (d, J = 8.9 Hz, 1H), 0.79 (s, 3H). 13 C NMR (150 MHz, DMSO): d 162.28, 161.90, 155.97, 148.48, 137.19,136.34, 128.38, 114.85, 104.02, 80.35, 41.78, 37.38, 31.78, 30.65, 25.82,20.79.MS ESI m / z : calcd for C 19 H 20 IN3O2[M+H] + : 450.0600; found 450.0679. Example 7 Preparation of myrtyl-isoxazole carbamoyl hydrazide derivative (I-6): Myrtyl-isoxazole methyl ester (500 mg, 2 mmol) was dissolved in 5 mL of anhydrous TEA in a 15 mL pressure-resistant tube. 4-Methylphenylhydrazine (610 mg, 5 mmol) was added, followed by TBD. The reaction was heated to 80 °C and stopped after 12 hours. The solvent was removed, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotation to obtain the myrtyl-isoxazole carboxyhydrazides of each substituent. These were purified by 200-300 mesh silica gel column chromatography at a petroleum ether / ethyl acetate volume ratio of 30:1 to 10:1 to give the myrtyl-isoxazole carboxyhydrazide derivatives (I-6) of the target compound. Yellow solid; Yield: 28.5% Yellow solid; Yield: 28.5%; 1 H NMR (600 MHz, CDCl3): d 8.40 (s, 1H), 7.08– 7.02 (m, 3H), 6.84 – 6.77 (m, 2H), 6.27 (tt, J= 3.3, 1.4 Hz, 1H), 2.99 (td, J = 5.6, 1.5 Hz, 1H), 2.57 – 2.42 (m, 3H), 2.27 (s, 3H), 2.24 – 2.18 (m, 1H), 1.37 (s, 3H), 1.27 (d, J = 9.1 Hz, 1H), 0.86 (s, 3H). 13 C NMR (150 MHz, CDCl3): d 163.29, 161.45, 156.33, 144.78, 137.11, 131.50, 129.95, 128.78, 114.23,105.37, 42.68, 40.59, 38.06, 32.45, 31.33, 26.09, 21.04, 20.72. MS ESI m / z :calcd for C 20 H 23 N3O2[M+Na] + : 360.1790; found 360.1690. Example 8 Preparation of myrtyl-isoxazole carbamoyl hydrazide derivative (I-7): Myrtyl-isoxazole methyl ester (500 mg, 2 mmol) was dissolved in 5 mL of anhydrous TEA in a 15 mL pressure-resistant tube. 2-Fluorophenylhydrazine (630 mg, 5 mmol) was added, followed by TBD. The reaction was heated to 80 °C and stopped after 12 hours. The solvent was removed, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotation to obtain the myrtyl-isoxazole carboxyhydrazides of each substituent. These were purified by 200-300 mesh silica gel column chromatography at a petroleum ether / ethyl acetate ratio of 30:1 to 10:1 (v / v) to give the myrtyl-isoxazole carboxyhydrazide derivatives of the target compound (I-7). White solid; yield: 43.5% White solid; Yield: 43.5%; 1 H NMR (600 MHz, DMSO): d 10.81 (d, J = 2.2 Hz, 1H), 8.03 (t, J = 1.8 Hz, 1H), 7.48 (s, 1H), 7.11 (ddd,J = 12.1, 8.1, 1.4 Hz,1H), 7.00 (td, J = 7.7, 1.4 Hz, 1H), 6.85 – 6.80 (m, 1H), 6.79 – 6.73(m, 1H), 6.49 (tt, J = 3.3, 1.4 Hz, 1H), 2.92 (td, J = 5.6, 1.5 Hz, 1H), 2.54 – 2.50 (m,2H), 2.42 (dt, J = 19.2, 3.0 Hz, 1H), 2.23 – 2.15 (m, 1H), 1.36 (s, 3H), 1.19(d, J = 8.9 Hz, 1H), 0.82 (s, 3H). 13 C NMR (150 MHz, DMSO): d 162.29, 161.94,156.10, 149.39, 136.35, 136.16 (d, J = 10.5 Hz, ), 128.39, 124.59 (d, J = 3 Hz,), 119.17 (d, J = 7.5 Hz, ), 114.99 (d, J = 16.5 Hz, ), 113.67, 104.01, 41.79,37.38, 31.78, 30.65, 25.81, 20.79.MS ESI m / z : calcd for C 19 H 20 FN3O2[M+H] + :342.1540; found 342.1619. Example 9 Preparation of myrtyl-isoxazole carbamoyl hydrazide derivative (I-8): Myrtyl-isoxazole methyl ester (500 mg, 2 mmol) was dissolved in 5 mL of anhydrous TEA in a 15 mL pressure-resistant tube. 3-fluorophenylhydrazine (630 mg, 5 mmol) was added, followed by TBD. The reaction was heated to 80 °C and stopped after 12 hours. The solvent was removed, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotation to obtain the myrtyl-isoxazole carboxyhydrazides of each substituent. These were purified by 200-300 mesh silica gel column chromatography at a petroleum ether / ethyl acetate volume ratio of 30:1 to 10:1 to give the myrtyl-isoxazole carboxyhydrazide derivatives (I-8) with the target compounds. White solid; yield: 41.5% White solid; Yield: 41.5%; 1 H NMR (600 MHz, DMSO): d 10.81 (d, J = 1.9 Hz, 1H), 8.37 (d, J = 2.5 Hz, 1H), 7.47 (s, 1H), 7.17 (td, J = 8.2, 6.5 Hz, 1H), 6.63– 6.57 (m, 1H), 6.55 – 6.44 (m, 3H), 2.92 (td, J = 5.6, 1.5 Hz, 1H), 2.54 –2.49 (m, 2H), 2.41 (dt, J = 19.2, 3.1 Hz, 1H), 2.20 – 2.13(m, 1H), 1.34 (s,3H), 1.18 (d, J = 8.9 Hz, 1H), 0.81 (s, 3H). 13 C NMR (150 MHz, DMSO): d 163.96, 162.33 (d, J = 12 Hz,), 161.89, 156.04, 150.83 (d, J = 10.5 Hz,), 136.37, 130.46(d, J = 10.5 Hz), 128.36, 108.30, 105.10 (d, J = 21 Hz,), 104.06, 98.86 (d, J =25.5 Hz), 41.80, 37.38, 31.78, 30.65, 25.81, 20.78.MS ESIm / z : calcd forC 19 H 20 FN3O2[M+H] + : 342.1540; found 342.1621. Example 10 Preparation of myrtyl-isoxazole carbamoyl hydrazide derivative (I-9): Myrtyl-isoxazole methyl ester (500 mg, 2 mmol) was dissolved in 5 mL of anhydrous TEA in a 15 mL pressure-resistant tube. 2-Chlorophenylhydrazine (710 mg, 5 mmol) was added, followed by TBD. The reaction was heated to 80 °C and stopped after 12 hours. The solvent was removed, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotation to obtain the myrtyl-isoxazole carboxyhydrazides of each substituent. These were purified by 200-300 mesh silica gel column chromatography at a petroleum ether / ethyl acetate volume ratio of 30:1 to 10:1 to give the myrtyl-isoxazole carboxyhydrazide derivatives (I-9) of the target compound. White solid; yield: 40.5% White solid; Yield: 40.5%; 1 H NMR (600 MHz, CDCl3): d 8.45 (s, 1H), 7.31 (dd, J = 8.0, 1.4 Hz, 1H), 7.19 – 7.14 (m, 1H), 7.09 (s, 1H), 6.93 (dd, J = 8.1, 1.5 Hz, 1H), 6.87 (td, J = 7.7, 1.5 Hz, 1H), 6.59 (s, 1H), 6.32 – 6.25 (m, 1H), 2.98 (td, J = 5.7, 1.5 Hz, 1H), 2.57 – 2.42 (m, 3H), 2.24 – 2.18 (m, 1H), 1.35(s, 3H), 1.26 (d, J = 9.1 Hz, 1H), 0.85 (s, 3H). 13 C NMR (150 MHz, CDCl3): d163.35, 161.22, 156.20, 143.17, 137.05, 129.77, 128.98, 127.91, 122.11,119.95, 113.82, 105.62, 42.66, 40.57, 38.05, 32.45, 31.32, 26.04, 21.04.MSESI m / z : calcd for C 19 H 20 ClN3O2[M+H] + : 358.1244; found 358.1325. Example 11 Preparation of myrtyl-isoxazole carbamoyl hydrazide derivative (I-10): Myrtyl-isoxazole methyl ester (500 mg, 2 mmol) was dissolved in 5 mL of anhydrous TEA in a 15 mL pressure-resistant tube. 3-Chlorophenylhydrazine (710 mg, 5 mmol) was added, followed by TBD. The reaction was heated to 80 °C and stopped after 12 hours. The solvent was removed, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotation to obtain myrtyl-isoxazole carboxyhydrazides of various substituents. These were purified by 200-300 mesh silica gel column chromatography at a petroleum ether / ethyl acetate volume ratio of 30:1 to 10:1 to give the myrtyl-isoxazole carboxyhydrazide derivatives of the target compound (I-10). Yellow solid; yield: 39.5%. Yellow solid; Yield: 39.5%; 1 H NMR (600 MHz, DMSO): d 10.83 (s, 1H), 8.37 (d, J = 2.6 Hz, 1H), 7.48 (s, 1H), 7.17 (t, J = 7.9 Hz, 1H), 6.76 (dd, J =8.7, 1.8 Hz, 2H), 6.73 – 6.70 (m, 1H), 6.53 – 6.45 (m, 1H), 2.91 (td, J = 5.7,1.5 Hz, 1H), 2.54 – 2.49 (m, 2H), 2.41 (dt, J= 19.2, 3.1 Hz, 1H), 2.21 – 2.14(m, 1H), 1.35 (s, 3H), 1.18 (d, J = 8.9 Hz, 1H), 0.81 (s, 3H). 13 C NMR (150 MHz, DMSO): d 162.31, 161.85, 156.03, 150.21, 136.35, 133.56, 130.52, 128.41,118.44, 111.55, 110.95, 104.12, 41.79, 37.39, 31.78, 30.66, 25.82, 20.79.MSESI m / z : calcd for C 19 H 20 ClN3O2[M+H] + : 358.1244; found 358.1321. Example 12 Preparation of myrtyl-isoxazole carbamoyl hydrazide derivative (I-11): Myrtyl-isoxazole methyl ester (500 mg, 2 mmol) was dissolved in 5 mL of anhydrous TEA in a 15 mL pressure-resistant tube. 2-Bromophenylhydrazine (935 mg, 5 mmol) was added, followed by TBD. The reaction was heated to 80 °C and stopped after 12 hours. The solvent was removed, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotation to obtain myrtyl-isoxazole carboxyhydrazides with various substituents. These were purified by 200-300 mesh silica gel column chromatography at a petroleum ether / ethyl acetate volume ratio of 30:1 to 10:1 to give the myrtyl-isoxazole carboxyhydrazide derivatives (Ⅰ-11) with the target compounds. White solid; yield: 41.3%. White solid; Yield: 41.3%; 1 H NMR (600 MHz, DMSO): d 10.92 (d, J = 1.7 Hz, 1H), 7.61 (d, J = 1.6 Hz, 1H), 7.50 – 7.44 (m, 2H), 7.23 – 7.17 (m, 1H), 6.80(dd, J = 8.2, 1.5 Hz, 1H), 6.73 (td,J = 7.6, 1.5 Hz, 1H), 6.53 – 6.48 (m, 1H), 2.92 (td, J = 5.6, 1.5 Hz, 1H), 2.54 – 2.50 (m, 2H), 2.42 (dt, J = 19.2, 3.0 Hz,1H), 2.23 – 2.15 (m, 1H), 1.36 (s, 3H), 1.19 (d, J = 8.9 Hz, 1H), 0.82 (s, 3H). 13 C NMR (150 MHz, DMSO): d 162.31, 161.87, 155.96, 145.02, 136.33, 132.47,128.45, 128.42, 120.54, 113.19, 106.94, 104.12, 41.79, 37.39, 31.79, 30.65,25.82, 20.80.MS ESI m / z : calcd for C 19 H 20 BrN3O2[M+H] + : 402.0739; found 402.0815. Example 13 Preparation of myrtyl-isoxazole carbamoyl hydrazide derivative (I-12): Myrtyl-isoxazole methyl ester (500 mg, 2 mmol) was dissolved in 5 mL of anhydrous TEA in a 15 mL pressure-resistant tube. 3-Bromophenylhydrazine (935 mg, 5 mmol) was added, followed by TBD. The reaction was heated to 80 °C and stopped after 12 hours. The solvent was removed, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotation to obtain myrtyl-isoxazole carboxyhydrazides with various substituents. These were purified by 200-300 mesh silica gel column chromatography at a petroleum ether / ethyl acetate ratio of 30:1 to 10:1 (v / v) to give the myrtyl-isoxazole carboxyhydrazide derivatives (I-12) with the target compounds. White solid; yield: 43.7%. White solid; Yield: 43.7%; 1 H NMR (600 MHz, DMSO): d 10.83 (d, J= 2.4 Hz, 1H), 8.37 (d, J = 2.5 Hz, 1H), 7.48 (s, 1H), 7.11 (t, J = 8.3 Hz, 1H), 6.97 –6.86 (m, 2H), 6.81 – 6.72 (m, 1H), 6.54 – 6.45 (m, 1H), 2.92 (td, J = 5.6, 1.5Hz, 1H), 2.55 – 2.50 (m, 2H), 2.42 (dt, J = 19.2, 3.0 Hz, 1H), 2.21 – 2.15 (m,1H), 1.35 (s, 3H), 1.19 (d, J = 8.9 Hz, 1H), 0.82 (s, 3H). 13 C NMR (150 MHz, DMSO): d 162.31, 161.84, 156.01, 150.33, 136.35, 130.83, 128.41, 122.10,121.33, 114.41, 111.31, 104.12, 41.79, 37.38, 31.78, 30.65, 25.82, 20.79.MSESI m / z : calcd for C 19 H 20 BrN3O2[M+H] + : 402.0739; found 402.0821. Example 14 Bactericidal activity (in vitro) test: All experimental strains used in this experiment were purchased from the China Agricultural Microbial Culture Collection Center (ACCC) and the China Forestry Culture Collection Center (CFCC), and were Fusarium graminearum (ACCC 31060), Rhizoctonia solani (ACCC 38870), Phytophthora capsici (ACCC 36279), Botrytis cinerea (ACCC 36027), Sclerotinia sclerotiorum (ACCC 30096), Anthracnose causal agent (ACCC 37623), and Late blight causal agent (ATCC® MYA-1113™).

[0029] The culture medium used was potato agar-dextrose medium (PDA). PDA medium formula: 200 g potato (peeled), 20 g glucose, 15 g agar, 1000 mL distilled water. Preparation method: Wash and peel the potato, weigh 200 g, cut into small pieces, add water and boil until tender (boil for 20-30 minutes, until easily pierced with a glass rod). Filter through eight layers of gauze into a beaker. Add 15-20 g agar and 20 g glucose as needed, stir well, and after fully dissolving, cool slightly. Add water to a final volume of 1000 mL, dispense, and sterilize at 121 °C for 15 minutes. Cool before use.

[0030] Experimental method: The growth rate method was used.

[0031] (1) First, culture the seven kinds of plant fungi on PDA plates at 25 ℃ for about 3-6 days before use; (2) Heat the PDA medium to melt it, cool it to 45-50 ℃, add 50 mg / L of the test compound to prepare a medium containing 50 mg / L of drug solution, and pour it into petri dishes to cool. Bixafen is used as a positive control. (3) Using aseptic operation, 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 status as consistent as possible), and then use an inoculation needle to pick them up and place them in the center of the drug-containing plate. Then, place the petri dish upside down in an incubator (28 ℃) for culture. (4) Observe and measure the growth of hyphae at different time points after treatment, and use the cross-cross method to measure the diameter and process the data to calculate the inhibition rate. Inhibition rate (%) = (control hyphae diameter - treated hyphae diameter) / (control hyphae diameter - 0.5) × 100. Each treatment is repeated 3 times.

[0032] The results of the bactericidal activity determination of experimental groups I-1~I-12 and the control agent chlorothalonil are shown in Table 1.

[0033] Table 1. Results of inhibitory activity tests of myristic-isoxazocarbazide compounds against seven agricultural pathogenic fungi.

[0034] Note: Each treatment was repeated three times in the experiment. The data in the table is the average of the three repetitions.

[0035] Table 2 shows the EC50 of some compounds. 50 Value (mg / L)

[0036] As shown in Tables 1 and 2, at a concentration of 50 mg / L, compounds I-1 to I-12 exhibited varying degrees of antifungal activity against seven plant fungi. Some compounds showed relatively good antifungal activity against *Sclerotinia sclerotiorum*, *Botrytis cinerea*, and *Fusarium graminearum*, while they showed moderate inhibitory activity against *Phytophthora macrantha*, *Phytophthora nigra*, and *Phytophthora capsici*. Some compounds showed higher inhibition rates against *Sclerotinia sclerotiorum* than the control fungicide chlorothalonil. This indicates that the inhibitory activity of these compounds against this fungus is comparable to that of the positive control fungicide chlorothalonil, suggesting their potential for development as antifungal agents. A schematic diagram of the in vitro antifungal activity of compound I-2 against *Sclerotinia sclerotiorum* at different concentrations is provided below. Figure 2 .

[0037] Example 15 In vivo sterilization test: Purchase rapeseed seedlings with uniform texture and size and intact leaves from the market, wash them with sterilized water, then wash them with 75% ethanol, and air dry them at room temperature.

[0038] Weigh an appropriate amount of compound I-2 and prepare two concentrations of 200 mg / L and 100 mg / L with a 0.2% Tween-80 aqueous solution.

[0039] Protective activity test method: Spray each leaf surface (spray volume is 1.5 mL, one concentration), spray evenly, and then let it air dry naturally.

[0040] After the leaf surface is free of liquid, pierce the leaf with an inoculation needle and inoculate with a 0.5 cm diameter mycelium cake of rapeseed sclerotinia rot. One mycelium cake is inoculated on each leaf. Chlorothalonil is used as the positive control. The leaves are cultured in an indoor environment (25 ± 2℃ and 95% relative humidity) for 2 days. The diameter of the lesions is measured and the inhibition rate is calculated.

[0041] Inhibition rate (%) = (diameter of blank control lesions - diameter of test compound lesions) / (diameter of blank control lesions - 0.5) × 100%.

[0042] Protective activity test method: Spray the surface of each rapeseed leaf (1.5 mL, one concentration) evenly, and then allow it to air dry naturally. After the leaf surface is free of liquid, pierce the leaf with an inoculation needle and inoculate with a 0.5 cm diameter mycelium cake of rapeseed sclerotinia sclerotinia, one mycelium cake per leaf. The positive control is chlorothalonil. Incubate under indoor conditions (25 ± 2℃ and 95% relative humidity) for 2 days, measure the diameter of the lesions, and calculate the inhibition rate.

[0043] Protective activity inhibition rate (%) = (diameter of blank control lesions - diameter of test compound lesions) / (diameter of blank control lesions - 0.5) × 100%.

[0044] Therapeutic activity test method: Leaves were pierced with an inoculation needle and inoculated with 0.5 cm diameter mycelium cakes of Sclerotinia sclerotiorum var. sclerotiorum, one mycelium cake per leaf. The surface of each rapeseed leaf was then sprayed evenly (1.5 mL, one concentration; chlorothalonil was used as a positive control). The leaves were then allowed to air dry naturally. After the fruit surface was free of liquid, the leaves were incubated indoors (25 ± 2℃ and 95% relative humidity) for 2 days. The diameter of the lesions was measured, and the inhibition rate was calculated.

[0045] Therapeutic activity inhibition rate (%) = (diameter of blank control lesions - diameter of test compound lesions) / (diameter of blank control lesions - 0.5) × 100%.

[0046] Table 3. In vivo bioactivity of compound I-2 against Sclerotinia sclerotinia, the causal agent of rapeseed disease (in live rapeseed leaves).

[0047] At a concentration of 200 mg / L, compound I-2 exhibited 98% protective activity and 95.13% therapeutic activity, both superior to the positive control chlorothalonil (93.73% and 86.84%, respectively).

[0048] When the concentration was further reduced to 100 mg / L, the protective and curative activities of compound I-2 were 91.73% and 88.03%, respectively, which were also superior to the positive control chlorothalonil (81.33% and 73.68%). The results indicate that compound I-2 has the potential value for developing antifungal pesticides. See the schematic diagram for the in vivo protective effects (A) and curative effects (B) of compound I-2 and chlorothalonil on rapeseed seedling leaves infected with Sclerotinia sclerotinia after 2 days of treatment. Figure 3 .

[0049] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the present invention.

Claims

1. A myrtyl-isoxazole carbamoylhydrazine compound, characterized in that: The myrtyl-isoxazole carbamoyl hydrazide compound has the following structural formula: R is selected from -4-H, -4-F, -4-Cl, -4-Br, -4-I, -4-CH3, -2-F, -3-F, -2-Cl, -3-Cl, -2-Br and -3-Br.

2. The method for preparing the myrtyl-isoxazoleformylhydrazine compound as described in claim 1, characterized in that: include, Myrtol is reacted with hydroxyamine chloride to generate myrtol oxime; Myrtene oxime was reacted with methyl propargyl ester to generate myrtene-isoxazole methyl ester; Myrtyl-isoxazole methyl ester was reacted with substituted phenylhydrazine to give myrtyl-isoxazole carboxylhydrazine compounds.

3. The preparation method according to claim 1, characterized in that: The preparation method of the myrtlene oxime includes, Myrtol was dissolved in ethanol, and hydroxylamine chloride and sodium acetate were dissolved in water. The three were mixed in a single-necked flask at room temperature and reacted at 80°C for 12 h. The reaction was detected by TLC. After the reaction was completed, the ethanol was removed by rotary concentration, and ethyl acetate was added for extraction. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary concentration to obtain the target compound, myrtol oxime, in an oily form. The molar ratio of myrtol, hydroxychloroamine, and sodium acetate is 1:2.5:1.

2.

4. The preparation method according to claim 2 or 3, characterized in that: The preparation method of the myrtyl-isoxazole methyl ester includes: Myrtol oxime, methyl propargylate and potassium chloride were dissolved in water, and then potassium peroxymonosulfate complex salt was added while stirring. The reaction was carried out at room temperature for 3 hours. TLC analysis showed that the reaction of the raw materials was complete. Ethyl acetate was added for extraction, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotation to obtain crude myrtyl-isoxazole methyl ester. The crude product was then separated and purified by silica gel column chromatography with a 200-300 mesh filter and purified by petroleum ether to ethyl acetate at a volume ratio of 300:1 to 150:1 to obtain the target compound myrtyl-isoxazole methyl ester. The molar ratio of the complex salt of myrtleene oxime, methyl propargylate, potassium chloride, and potassium peroxymonosulfate is 1:2.5:1:1.

5.

5. The preparation method according to claim 2 or 3, characterized in that: The preparation method of the myrtyl-isoxazole carbamoyl hydrazide includes: Myrtyl-isoxazole methyl ester was dissolved in anhydrous TEA in a pressure-resistant tube, substituted phenylhydrazine was added, and finally TBD was added. The reaction was stopped after heating to 80℃ for 12 hours, the solvent was removed, and ethyl acetate was added for extraction. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotation to obtain myrtyl-isoxazole carboxyhydrazides with each substituent. The compounds were separated and purified by silica gel column chromatography with a petroleum ether / ethyl acetate volume ratio of 30:1 to 10:1 to obtain myrtyl-isoxazole carboxyhydrazides with the target compounds. The molar ratio of myrtyl-isoxazole methyl ester, each substituted phenylhydrazine and TBD is 1:2.5:0.

3.

6. The preparation method according to claim 5, characterized in that: The substituted acylhydrazides include benzoylhydrazide, 4-methylbenzoylhydrazide, 2-fluorobenzoylhydrazide, 3-fluorobenzoylhydrazide, 4-fluorobenzoylhydrazide, 2-chlorobenzoylhydrazide, 3-chlorobenzoylhydrazide, 4-chlorobenzoylhydrazide, 2-bromobenzoylhydrazide, 3-bromobenzoylhydrazide, 4-bromobenzoylhydrazide, and 4-iodobenzoylhydrazide.

7. The application of the myrtyl-isoxazole carbamoyl hydrazide compound as described in claim 1 in the control of plant fungi in agriculture or forestry.

8. The application as described in claim 7, characterized in that: The plant fungi mentioned include apple rot fungus, grape rot fungus, rapeseed sclerotium rot fungus, tomato gray mold fungus, potato late blight fungus, pepper phytophthora fungus, and wheat scab fungus.

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