Perilla alcohol yl-1, 2, 4-triazole thioether derivative as well as preparation method and application thereof

Abstract

The invention discloses a perillyl alcohol-1, 2, 4-triazole thioether derivative as well as a preparation method and application thereof, and belongs to the technical field of pesticides, the chemical structural formula of the derivative is # imgabs0, during preparation, perillyl alcohol is taken as a raw material, and chlorinated perillyl alcohol acetate is synthesized through esterification and allyl chlorination reaction; various substituted benzoyl chloride and heterocyclic acyl chloride are used as raw materials, and 1, 2, 4-triazole mercaptan is synthesized through substitution and cyclization reactions; the preparation method comprises the following steps: reacting chlorinated perillyl alcohol acetate with 1, 2, 4-triazole mercaptan to synthesize a series of perillyl alcohol-1, 2, 4-triazole thioether derivatives. The derivative disclosed by the invention not only has an excellent biological activity effect in the aspects of sterilization and weeding, but also is low in drug concentration and relatively good in safety, and can be applied as a herbicide and / or a bactericide.

Description

Technical Field

[0001] The present invention relates to the technical field of pesticides, and more specifically to a perillyl alcohol-1,2,4-triazole sulfide derivative and a preparation method and application thereof. Background Art

[0002] Diseases, weeds and insect pests are the three major hazards that seriously threaten global food security. The use of pesticides is an important measure to ensure food security in modern agriculture. However, traditional pesticides have problems such as high toxicity, easy residue and drug resistance. Therefore, it is urgent to develop new green pesticides with high efficiency and low toxicity. 1,2,4-triazole, as an important active structural unit, exhibits different biological activities with different substituents on the 1,2,4-triazole ring. 1,2,4-triazole drugs synthesized by modification at different sites are widely used in the fields of pesticides such as weed control, bactericidal and insecticide, but the effectiveness of such drugs still needs to be further improved. Perillyl alcohol is a non-toxic monocyclic monoterpene alcohol that naturally exists in a variety of plants. It itself and its derivatives have biological activities such as anticancer, bactericidal and weed control. The present invention actively splices the perillyl alcohol structure with the 1,2,4-triazole pharmacophore to provide a compound with excellent biological activity in bactericidal and weed control, providing more efficient candidate compound selection for the creation of new herbicides and bactericides. Summary of the invention

[0003] In view of the above problems, the present invention provides a new perillyl alcohol-1,2,4-triazole sulfide derivative and a preparation method thereof, as well as application as a herbicide and / or fungicide. The method has the characteristics of low raw material cost, simple synthesis method, and few steps. The derivative not only has excellent biological activity effects in bactericidal and weed control, but also has low drug concentration and good safety.

[0004] In order to achieve these objectives of the present invention, the present invention provides a perillyl alcohol-1,2,4-triazole sulfide derivative, whose chemical structure is as follows:

[0005]

[0006] R 1 Selected from: hydrogen, acetyl;

[0007] R 2Selected from methyl, phenyl, p-methylphenyl, o-methylphenyl, m-methylphenyl, 1-phenylpropyl, p-fluorophenyl, o-fluorophenyl, m-fluorophenyl, p-trifluoromethylphenyl, m-trifluoromethylphenyl, o-trifluoromethylphenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, m-bromophenyl, o-bromophenyl, p-bromophenyl, p-nitrophenyl, m-nitrophenyl, o-nitrophenyl, o-methoxyphenyl, p-methoxyphenyl, m-methoxyphenyl, o-ethoxyphenyl, p-ethoxyphenyl, (1-methyl-3-trifluoromethyl)-pyrazolyl, (1-methyl-3-difluoromethyl)-pyrazolyl, (3-chloro-5-(trifluoromethyl)pyridinyl), (3-bromo-1-(3-chloropyridin-2-yl)-pyrazolyl), p-trifluoromethylpyridinyl, 3-trifluoromethylpyridinyl.

[0008] The preparation method of the perillyl alcohol-1,2,4-triazole sulfide derivative provided by the present invention comprises:

[0009] Using perillyl alcohol as a raw material, chloroperillyl alcohol acetate is synthesized through esterification and allyl chlorination reaction; various substituted benzoyl chlorides and heterocyclic acid chlorides are used as raw materials to synthesize 1,2,4-triazole thiol through substitution and cyclization reactions, and then chloroperillyl alcohol acetate reacts with 1,2,4-triazole thiol to synthesize a series of perillyl alcohol-1,2,4-triazole thioether derivatives.

[0010] The invention provides an application of the perillyl alcohol-1,2,4-triazole sulfide derivative as a fungicide and / or a herbicide.

[0011] Preferably, the perillyl alcohol-1,2,4-triazole sulfide derivative has a chemical structural formula:

[0012]

[0013] When used as a fungicide, the fungicide inhibition rates against wheat fusarium head blight, cucumber gray mold, rice sheath blight, wheat sheath blight, and apple ring rot pathogen reach 55.6%, 58.3%, 65.4%, 77.4%, and 83.3%. When used as a herbicide, the herbicidal activity against rapeseed and barnyard grass at concentrations of 10 mg / L and 100 mg / L are 89.1%, 91.1%, 4.6%, and 39.8%, respectively. Therefore, it can also be used as a pesticide with both fungicidal and herbicidal effects.

[0014]

[0015] When used as a fungicide, the fungicide inhibition rates against wheat fusarium rust, cucumber gray mold, rice sheath blight, wheat sheath blight and apple ring rot are 26.2%, 64.9%, 17.3%, 76.5% and 69.2% respectively.

[0016]

[0017] When used as a herbicide, the herbicidal activity of the herbicide at concentrations of 10 mg / L and 100 mg / L on rapeseed and barnyard grass is 90.3%, 90.9%, 0%, and 8.0%, respectively.

[0018] The present invention has at least the following beneficial effects:

[0019] 1. The present invention uses perillyl alcohol with good herbicidal activity, safety, non-toxicity and easy degradation as the starting material, and according to the principle of activity superposition, uses thioether bonds for bridging, and structurally modifies it to introduce 1,2,4-triazole pharmacophores with high efficiency and broad-spectrum herbicidal activity, antibacterial activity and safety, and designs and synthesizes perillyl alcohol-based 1,2,4-triazole thioether derivatives to improve the herbicidal activity and antibacterial activity, so as to solve the problem of high toxicity of existing herbicides and fungicides.

[0020] 2. The preparation method and application of the perillyl alcohol-based 1,2,4-triazole sulfide derivatives and intermediates of the present invention have the characteristics of low raw material cost, simple synthesis method, few steps, etc.

[0021] 3. The perillyl alcohol-based 1,2,4-triazole sulfide derivatives prepared by the present invention have excellent biological activity effects in sterilization and weed control, as shown by biological activity test data, and the drug concentration used is low and has good safety. Such derivatives are new compounds with good biological activity. This invention provides a basis for the research and development of new fungicides and / or herbicides.

[0022] Other advantages, objectives and features of the present invention will be embodied in part through the following description, and in part will be understood by those skilled in the art through study and practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 is the general chemical structure formula of the perillyl alcohol-1,2,4-triazole sulfide derivative of the present invention;

[0024] Figure 2 This is a picture of rice seeds germinating on the third day of the present invention;

[0025] Figure 3 It is a picture of the survival of the seedlings of the present invention. DETAILED DESCRIPTION

[0026] The present invention is further described in detail below with reference to examples so that those skilled in the art can implement the invention with reference to the description.

[0027] It should be understood that the terms "having", "comprising" and "including" used herein do not exclude the presence or addition of one or more other elements or their combinations. It should be noted that the experimental methods described in the following embodiments are conventional methods unless otherwise specified, and the reagents and materials can be obtained from commercial sources unless otherwise specified.

[0028] Example 1

[0029] The general chemical structure of the perillyl alcohol-1,2,4-triazole sulfide derivative of the present invention is as follows:

[0030]

[0031] Among them, R 1 Selected from: hydrogen, acetyl; R 2 Selected from methyl, phenyl, p-methylphenyl, o-methylphenyl, m-methylphenyl, 1-phenylpropyl, p-fluorophenyl, o-fluorophenyl, m-fluorophenyl, p-trifluoromethylphenyl, m-trifluoromethylphenyl, o-trifluoromethylphenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, m-bromophenyl, o-bromophenyl, p-bromophenyl, p-nitrophenyl, m-nitrophenyl, o-nitrophenyl, o-methoxyphenyl, p-methoxyphenyl, m-methoxyphenyl, o-ethoxyphenyl, p-ethoxyphenyl, (1-methyl-3-trifluoromethyl)-pyrazolyl, (1-methyl-3-difluoromethyl)-pyrazolyl, (3-chloro-5-(trifluoromethyl)pyridinyl), (3-bromo-1-(3-chloropyridin-2-yl)-pyrazolyl), p-trifluoromethylpyridinyl, 3-trifluoromethylpyridinyl.

[0032] The synthesis route of the perillyl alcohol-1,2,4-triazole sulfide derivative of the present invention is as follows:

[0033]

[0034] 1. Preparation of Compound II: Add 19.7 mmol of Compound I (perillyl alcohol) and 6.3 mL of acetic anhydride (Ac 2 O), 6.2 mL pyridine (Py), stirred at room temperature for 5 h, and the reaction was complete after TLC detection. The reaction solution was poured into a separatory funnel and 40 mL ethyl acetate was added, washed with saturated sodium bicarbonate and saturated sodium chloride aqueous solutions, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (developing solvent: V 石油醚 :V 乙酸乙酯 =200:1) to obtain 3.5 g of colorless transparent liquid, which is compound II, with a yield of 91.6%.

[0035] 2. Preparation of Compound III: Add 15.5 mmol of Compound II and 25 mL of CH 2 Cl2 , 1.4 mL of glacial acetic acid, and slowly drop 18 mL of sodium hypochlorite aqueous solution (containing 11-15% effective chlorine) under ice bath. Continue the reaction for 1.5 h after addition, and monitor the reaction to be complete by TLC. Add appropriate amount of NaSO 3 The organic layer was separated and the aqueous layer was washed with CH 2 Cl 2 (20mLx3: extract three times, use 20mL each time) to extract, combine the organic phase, wash the organic phase twice with water and saturated sodium chloride aqueous solution respectively, dry over anhydrous sodium sulfate. Concentrate, and purify by silica gel column chromatography (developing solvent: V 石油醚 :V 乙酸乙酯 =200:1) to separate 2.4 g of colorless liquid, which is compound III, with a yield of 67.9%.

[0036] 3. Preparation method of compound IV:

[0037] Method 1: Under ice bath conditions, 1.4 g (10 mmol) of benzoyl chloride was dissolved in 15 mL of tetrahydrofuran, cooled to room temperature, and 1.0 g (11 mmol) of thiosemicarbazide was added in batches, and stirred at room temperature for 6 h. The reaction was completed by TCL monitoring, and then 30 mL of ethyl acetate was added, extracted with saturated sodium bicarbonate solution (20 mL x 3), and the organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate to obtain 1.25 g of benzoylthiosemicarbazide, with a yield of 64.1%.

[0038] 0.33 g (1.69 mmol) of benzoylaminothiourea was dissolved in 10% potassium hydroxide solution (3 mL), refluxed at 125 ° C for 1 h, cooled to room temperature after the reaction, adjusted to pH = 3 with hydrochloric acid, filtered and dried to obtain 0.285 g of 5-phenyl-4H-[1,2,4]-triazole-3-thiol solid, which is compound IV, with a yield of 95.3%. Referring to this method, 1,2,4-triazole thiol derivatives with different substituents can be prepared, and the amount of compound IV prepared and the volume of the reaction container can be expanded or reduced in a corresponding proportion.

[0039] Method 2: Dissolve 2 g (10.47 mmol) of 3-trifluoromethylpyridine-2-carboxylic acid in 8 mL of thionyl chloride, catalyze with DMF, reflux at 80 ° C for 6 h, and remove the excess thionyl chloride by distillation under reduced pressure to obtain 1.9 g of 5-(trifluoromethyl)pyridine-2-carbonyl chloride with a yield of 87.2%. Its triazole thiol derivative can be prepared by referring to method 1.

[0040] 4. Preparation method of compound V: The perillyl alcohol-based 1,2,4-triazole sulfide derivative of the present invention includes the perillyl alcohol-based 1,2,4-triazole sulfide derivative prepared by the following method 1 or the perillyl alcohol acetate-based 1,2,4-triazole sulfide derivative prepared by method 2.

[0041] Method 1: When base = NaOH, R 1＝ When H, a perillyl alcohol 1,2,4-triazole sulfide derivative is prepared.

[0042] Preparation of compound 1: 0.15 g (0.85 mmol) of 5-phenyl-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.19 g (0.83 mmol) of compound III were added in sequence into a 50 mL round-bottom flask, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 19 h. The reaction was monitored by TCL. After the reaction was completed, ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.26 g of the product with a yield of 93.6%.

[0043] Preparation of compound 2: In a 50 mL round-bottom flask, 0.15 g (0.68 mmol) of 5-(2-ethoxyphenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.2 g (0.88 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 12 h. The reaction was monitored by TCL. After the reaction was completed, ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.12 g of the product with a yield of 48.0%.

[0044] Preparation of compound 3: In a 50 mL round-bottom flask, 0.10 g (0.52 mmol) of 5-(2-methylphenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.15 g (0.66 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 14 h. The reaction was monitored by TCL. After the reaction was completed, the ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.09 g of the product with a yield of 50.8%.

[0045] Preparation of compound 4: In a 50 mL round-bottom flask, 0.11 g (0.50 mmol) of 5-(1-phenylpropyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.15 g (0.66 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 14 h. The reaction was monitored by TCL. After the reaction was completed, ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.15 g of the product with a yield of 81.3%.

[0046] Preparation of compound 5: In a 50 mL round-bottom flask, 0.20 g (1.02 mmol) of 5-(4-fluorophenyl)-4H-[1,2,4]-triazole-3-thiol, 20 mL of anhydrous ethanol, and 0.30 g (1.31 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 14 h. The reaction was monitored by TCL. After the reaction was completed, the ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.27 g of the product with a yield of 76.7%.

[0047] Preparation of compound 6: In a 50 mL round-bottom flask, 0.15 g (0.78 mmol) of 5-(4-methylphenyl)-4H-[1,2,4]-triazole-3-thiol, 25 mL of anhydrous ethanol, and 0.23 g (1.01 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 14 h. The reaction was monitored by TCL. After the reaction was completed, the ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.20 g of the product with a yield of 75.2%.

[0048] Preparation of compound 7: 0.10 g (0.87 mmol) of 5-methyl-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.26 g (1.14 mmol) of compound III were added in sequence into a 50 mL round-bottom flask, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 24 h. The reaction was monitored by TCL. After the reaction was completed, the ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.15 g of the product with a yield of 64.9%.

[0049] Preparation of compound 8: In a 50 mL round-bottom flask, 0.17 g (0.87 mmol) of 5-(2-fluorophenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.25 g (1.13 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 14 h. The reaction was monitored by TCL. After the reaction was completed, the ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.25 g of the product with a yield of 83.3%.

[0050] Preparation of compound 9: In a 50 mL round-bottom flask, 0.15 g (0.77 mmol) of 5-(3-fluorophenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.23 g (1.01 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 14 h. The reaction was monitored by TCL. After the reaction was completed, ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.24 g of the product with a yield of 90.0%.

[0051] Preparation of compound 10: In a 50 mL round-bottom flask, 0.15 g (0.78 mmol) of 5-(3-methylphenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.23 g (1.00 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 12.5 h. The reaction was monitored by TCL. After the reaction was completed, ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.16 g of the product with a yield of 60.1%.

[0052] Preparation of compound 11: In a 50 mL round-bottom flask, 0.15 g (0.71 mmol) of 5-(3-chlorophenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.21 g (0.92 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 13 h. The reaction was monitored by TCL. After the reaction was completed, ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.09 g of product with a yield of 35.1%.

[0053] Preparation of compound 12: In a 50 mL round-bottom flask, 0.15 g (0.67 mmol) of 5-(2-nitrophenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.20 g (0.88 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 11 h. The reaction was monitored by TCL. After the reaction was completed, the ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.17 g of the product with a yield of 68.3%.

[0054] Preparation of compound 13: In a 50 mL round-bottom flask, 0.20 g (0.90 mmol) of 5-(3-nitrophenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.26 g (1.14 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 11 h. The reaction was monitored by TCL. After the reaction was completed, the ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.31 g of the product with a yield of 92.6%.

[0055] Preparation of compound 14: In a 50 mL round-bottom flask, 0.20 g (0.90 mmol) of 5-(4-nitrophenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.26 g (1.14 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 12 h. The reaction was monitored by TCL. After the reaction was completed, ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.18 g of product with a yield of 53.8%.

[0056] Preparation of compound 15: In a 50 mL round-bottom flask, 0.20 g (0.97 mmol) of 5-(2-methoxyphenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.28 g (1.2 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 12 h. The reaction was monitored by TCL. After the reaction was completed, ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.21 g of product with a yield of 60.7%.

[0057] Preparation of compound 16: In a 50 mL round-bottom flask, 0.20 g (0.97 mmol) of 5-(3-methoxyphenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.28 g (1.2 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 12 h. The reaction was monitored by TCL. After the reaction was completed, ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.27 g of the product with a yield of 78.0%.

[0058] Preparation of compound 17: In a 50 mL round-bottom flask, 0.20 g (0.97 mmol) of 5-(4-methoxyphenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.28 g (1.2 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 12 h. The reaction was monitored by TCL. After the reaction was completed, ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.21 g of product with a yield of 60.7%.

[0059] Preparation of compound 18: In a 50 mL round-bottom flask, 0.20 g (0.90 mmol) of 5-(4-ethoxyphenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.27 g (1.18 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 11 h. The reaction was monitored by TCL. After the reaction was completed, ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.28 g of the product with a yield of 83.8%.

[0060] Preparation of compound 19: In a 50 mL round-bottom flask, 0.15 g (0.61 mmol) of 5-(3-trifluoromethylphenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.18 g (0.79 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 19 h. The reaction was monitored by TCL. After the reaction was completed, ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.16 g of product with a yield of 66.4%.

[0061] Preparation of compound 20: In a 50 mL round-bottom flask, 0.20 g (0.82 mmol) of 5-(4-trifluoromethylphenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.24 g (1.05 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 18.5 h. The reaction was monitored by TCL. After the reaction was completed, ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.19 g of product with a yield of 58.6%.

[0062] Preparation of compound 21: In a 50 mL round-bottom flask, 0.20 g (0.78 mmol) of 5-(3-bromophenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.23 g (1.00 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 12 h. The reaction was monitored by TCL. After the reaction was completed, ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.17 g of product with a yield of 53.8%.

[0063] Preparation of compound 22: In a 50 mL round-bottom flask, 0.20 g (0.78 mmol) of 5-(4-bromophenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.23 g (1.01 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 9 h. The reaction was monitored by TCL. After the reaction was completed, ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.16 g of product with a yield of 50.6%.

[0064] Preparation of compound 23: In a 50 mL round-bottom flask, 0.13 g (0.51 mmol) of 5-(2-bromophenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.15 g (0.66 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 5.5 h. The reaction was monitored by TCL. After the reaction was completed, ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.07 g of product with a yield of 34.0%.

[0065] Preparation of compound 24: In a 50 mL round-bottom flask, 0.15 g (0.54 mmol) of 5-(3-chloro-5-trifluoromethylpyridinyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.15 g (0.66 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 7 h. The reaction was monitored by TCL. After the reaction was completed, ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.15 g of product with a yield of 65.2%.

[0066] Preparation of compound 25: In a 50 mL round-bottom flask, 0.20 g (0.80 mmol) of 5-(1-methyl-3-trifluoromethylpyrazol)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.23 g (1.01 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 10 h. The reaction was monitored by TCL. After the reaction was completed, ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.10 g of product with a yield of 31.3%.

[0067] Preparation of compound 26: In a 50 mL round-bottom flask, 0.20 g (0.86 mmol) of 5-(1-methyl-3-difluoromethylpyrazolyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.25 g (1.10 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 10 h. The reaction was monitored by TCL. After the reaction was completed, ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.09 g of the product with a yield of 27.3%.

[0068] Preparation of compound 27: In a 50 mL round-bottom flask, 0.20 g (0.56 mmol) of 5-(3-bromo-1-(3-chloropyridyl-pyrazolyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.16 g (0.70 mmol) of compound III were added in sequence, and then the pH was adjusted to 12 with 10% NaOH and reacted at room temperature for 11 h. The reaction was monitored by TCL. After the reaction was completed, ethanol was distilled off under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.06 g of the product with a yield of 21.2%.

[0069] Method 2: When base = K 2 CO 3, R 1＝ -COCH 3 When the perillyl alcohol acetate 1,2,4-triazole sulfide derivative is prepared.

[0070] Preparation of compound 28: 0.15 g (0.78 mmol) of 5-(2-methylphenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.23 g (1.01 mmol) of compound III were added to a 50 mL round-bottom flask, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 10 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.24 g of product with a yield of 80.3%.

[0071] Preparation of compound 29: In a 50 mL round-bottom flask, 0.15 g (0.78 mmol) of 5-(3-methylphenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.23 g (1.01 mmol) of compound III were added in sequence, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 10 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.14 g of product with a yield of 46.7%.

[0072] Preparation of compound 30: In a 50 mL round-bottom flask, 0.15 g (0.78 mmol) of 5-(4-methylphenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.23 g (1.01 mmol) of compound III were added in sequence, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 18 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.25 g of product with a yield of 83.7%.

[0073] Preparation of compound 31: 0.16 g (0.82 mmol) of 5-(2-fluorophenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.24 g (1.05 mmol) of compound III were added to a 50 mL round-bottom flask, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.18 g of product with a yield of 56.8%.

[0074] Preparation of compound 32: In a 50 mL round-bottom flask, 0.15 g (0.77 mmol) of 5-(3-fluorophenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.22 g (0.96 mmol) of compound III were added in sequence, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 15.5 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.19 g of product with a yield of 63.7%.

[0075] Preparation of compound 33: In a 50 mL round-bottom flask, 0.20 g (1.02 mmol) of 5-(4-fluorophenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.30 g (1.31 mmol) of compound III were added in sequence, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.20 g of product with a yield of 50.6%.

[0076] Preparation of compound 34: 0.15 g (0.67 mmol) of 5-(2-nitrophenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.20 g (0.88 mmol) of compound III were added to a 50 mL round-bottom flask, and then 10% K 2 CO 3The pH was adjusted to 11 and the reaction was carried out at room temperature for 11.5 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.15 g of product with a yield of 54.1%.

[0077] Preparation of compound 35: 0.20 g (0.90 mmol) of 5-(3-nitrophenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.26 g (1.14 mmol) of compound III were added to a 50 mL round-bottom flask, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 11 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.26 g of product with a yield of 69.7%.

[0078] Preparation of compound 36: 0.20 g (0.90 mmol) of 5-(4-nitrophenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.26 g (1.14 mmol) of compound III were added to a 50 mL round-bottom flask, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.12 g of product with a yield of 32.2%.

[0079] Preparation of compound 37: 0.20 g (0.97 mmol) of 5-(2-methoxyphenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.29 g (1.28 mmol) of compound III were added to a 50 mL round-bottom flask, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.21 g of product with a yield of 54.3%.

[0080] Preparation of compound 38: 0.20 g (0.97 mmol) of 5-(3-methoxyphenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.28 g (1.23 mmol) of compound III were added to a 50 mL round-bottom flask, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.34 g of product with a yield of 87.8%.

[0081] Preparation of compound 39: 0.20 g (0.97 mmol) of 5-(4-methoxyphenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.28 g (1.23 mmol) of compound III were added to a 50 mL round-bottom flask, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.24 g of product with a yield of 62.0%.

[0082] Preparation of compound 40: In a 50 mL round-bottom flask, 0.15 g (0.68 mmol) of 5-(2-ethoxyphenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.20 g (0.88 mmol) of compound III were added in sequence, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 13 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.17 g of product with a yield of 60.5%.

[0083] Preparation of compound 41: 0.20 g (0.90 mmol) of 5-(4-ethoxyphenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.26 g (1.14 mmol) of compound III were added to a 50 mL round-bottom flask, and then 10% K 2 CO 3The pH was adjusted to 11 and the reaction was carried out at room temperature for 11 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.28 g of product with a yield of 75.3%.

[0084] Preparation of compound 42: 0.20 g (0.95 mmol) of 5-(2-chlorophenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.28 g (1.23 mmol) of compound III were added to a 50 mL round-bottom flask, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 9.5 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.20 g of product with a yield of 52.2%.

[0085] Preparation of compound 43: In a 50 mL round-bottom flask, 0.15 g (0.71 mmol) of 5-(3-chlorophenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.20 g (0.88 mmol) of compound III were added in sequence, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.19 g of product with a yield of 66.4%.

[0086] Preparation of compound 44: 0.20 g (0.95 mmol) of 5-(4-chlorophenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.28 g (1.23 mmol) of compound III were added to a 50 mL round-bottom flask, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.16 g of product with a yield of 41.8%.

[0087] Preparation of compound 45: 0.12 g (0.68 mmol) of 5-phenyl-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.20 g (0.88 mmol) of compound III were added to a 50 mL round-bottom flask, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.21 g of product with a yield of 83.6%.

[0088] Preparation of compound 46: 0.10 g (0.41 mmol) of 5-(4-trifluoromethylphenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.12 g (0.53 mmol) of compound III were added to a 50 mL round-bottom flask, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.1 g of product with a yield of 55.9%.

[0089] Preparation of compound 47: 0.20 g (0.82 mmol) of 5-(2-trifluoromethylphenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.24 g (1.05 mmol) of compound III were added to a 50 mL round-bottom flask, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.07 g of product with a yield of 19.6%.

[0090] Preparation of compound 48: 0.14 g (0.55 mmol) of 5-(2-bromophenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.16 g (0.70 mmol) of compound III were added to a 50 mL round-bottom flask, and then 10% K 2 CO 3The pH was adjusted to 11 and the reaction was carried out at room temperature for 12.5 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.04 g of product with a yield of 16.3%.

[0091] Preparation of compound 49: 0.20 g (0.78 mmol) of 5-(3-bromophenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.23 g (1.01 mmol) of compound III were added to a 50 mL round-bottom flask, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.16 g of product with a yield of 45.8%.

[0092] Preparation of compound 50: In a 50 mL round-bottom flask, 0.20 g (0.78 mmol) of 5-(4-bromophenyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.23 g (1.01 mmol) of compound III were added in sequence, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 10 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.18 g of product with a yield of 51.6%.

[0093] Preparation of compound 51: In a 50 mL round-bottom flask, 0.10 g (0.87 mmol) of 5-methyl-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.25 g (1.10 mmol) of compound III were added in sequence, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 8 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.22 g of product with a yield of 82.4%.

[0094] Preparation of compound 52: In a 50 mL round-bottom flask, 0.15 g (0.54 mmol) of 5-(3-chloro-5-trifluoromethylpyridinyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.15 g (0.66 mmol) of compound III were added in sequence, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 7 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.17 g of product with a yield of 66.7%.

[0095] Preparation of compound 53: In a 50 mL round-bottom flask, 0.20 g (0.80 mmol) of 5-(1-methyl-3-trifluoromethylpyrazolyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.24 g (1.05 mmol) of compound III were added in sequence, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 10 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.15 g of product with a yield of 42.5%.

[0096] Preparation of compound 54: 0.20 g (0.86 mmol) of 5-(1-methyl-3-difluoromethylpyrazolyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.26 g (1.14 mmol) of compound III were added to a 50 mL round-bottom flask, and then 10% K 2 CO 3 The pH value was adjusted to 11 by H and the reaction was carried out at room temperature for 10 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.24 g of product with a yield of 65.9%.

[0097] Preparation of compound 55: In a 50 mL round-bottom flask, 0.20 g (0.56 mmol) of 5-(3-bromo-1-(3-chloropyridyl-pyrazolyl)-4H-[1,2,4]-triazole-3-thiol, 20 mL of anhydrous ethanol, and 0.17 g (0.75 mmol) of compound III were added in sequence, and then 10% K 2 CO 3The pH was adjusted to 11 and the reaction was carried out at room temperature for 10 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.08 g of product with a yield of 26.1%.

[0098] Preparation of compound 56: 0.20 g (0.81 mmol) of 5-(3-trifluoromethylpyridyl)-4H-[1,2,4]-triazole-3-thiol, 15 mL of anhydrous ethanol, and 0.26 g (1.14 mmol) of compound III were added to a 50 mL round-bottom flask, and then 10% K 2 CO 3 The pH was adjusted to 11 and the reaction was carried out at room temperature for 10 hours. The reaction was monitored by TCL. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and then the organic layer was separated by extraction with distilled water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 0.05 g of product with a yield of 14.1%.

[0099] The structural formula and physicochemical parameters of the obtained perillyl alcohol-1,2,4-triazole sulfide derivatives are shown in Table 1. 1 HNMR and high-resolution mass spectra are shown in Table 2.

[0100] Table 1 Structural formula and physicochemical parameters of the obtained perillyl alcohol-1,2,4-triazole sulfide derivatives

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107] Table 2 The obtained perillyl alcohol-1,2,4-triazole sulfide derivatives 1 H NMR and high-resolution mass spectrometry

[0108]

[0109]

[0110]

[0111]

[0112] Example 2

[0113] 1. Determination of in vitro fungicidal activity of the perillyl alcohol-1,2,4-triazole sulfide derivative (Compound V) prepared in Example 1 of the present invention:

[0114] (I) Bactericidal activity:

[0115] In vitro method: Dissolve the test drug in acetone, then dilute it with 200ppm sorporl-144 emulsifier to a 500ppm solution. Take 1mL of the solution and inject it into a culture dish, then add 9mL PSA culture medium to make a drug-containing plate with a final concentration of 50ppm.

[0116] Punch the cultured test bacteria with a hole puncher to get a 4mm diameter cake, and place three cakes in each dish in an equilateral triangle on the drug-containing plate, with no drug added as a blank control. After culturing each treatment in a 24±1℃ incubator for 48 hours, measure the expansion diameter of the hyphae of each treatment, and compare it with the control to calculate the relative inhibition percentage. Activity grading index: Grade A: ≥90%; Grade B: 70-90%; Grade C: 50-70%; Grade D: <50%.

[0117] The bactericidal activity structure is shown in Table 3

[0118] Table 3 Pesticide activity (I) - in vitro fungicidal activity (relative inhibition percentage)

[0119]

[0120]

[0121] 2. Determination of the herbicidal activity of the perillyl alcohol-1,2,4-triazole sulfide derivative (Compound V) prepared in Example 1 of the present invention:

[0122] (II) Herbicidal activity:

[0123] Barnyard grass cup method: After laying glass beads and filter paper in a 50 ml beaker, add 6 ml of a certain concentration of the test compound solution, and sow 10 barnyard grass seeds that have just turned white. Measure the height of the seedlings after 72 hours of light culture at 28±1℃. The herbicidal activity of the compound is detected by the growth inhibition of the compound on the height of barnyard grass seedlings under light conditions. Test concentration: 10 mg / L and 100 mg / L. Each treatment is repeated twice. Activity index: plant height growth inhibition rate (%). Activity grading index: Grade A: ≥80%; Grade B: 60~79%; Grade C: 40~59%; Grade D: ≤39%.

[0124] Rapeseed plate method: Place a 5.6 cm diameter filter paper in a 6 cm diameter culture dish, add 2 ml of a certain concentration of the test compound solution, and sow 10 rapeseed seeds that have been soaked for 4 hours. Measure the radicle length after 72 hours of dark culture at 28±1°C. The herbicidal activity of the compound is detected by the inhibition of the growth of the rapeseed radicle under dark conditions. Test concentrations: 10 mg / L and 100 mg / L. Each treatment is repeated twice. Activity index: radicle elongation inhibition rate (%). Activity grading index: Grade A: ≥80%; Grade B: 60-79%; Grade C: 40-59%; Grade D: ≤39%.

[0125] Table 4 Pesticide Biological Activity (II) - Herbicidal Activity (Plate Cup Method, Growth Inhibition %)

[0126]

[0127]

[0128]

[0129] From the data in Tables 3 and 4 above, we can see that:

[0130] 1. When the perillyl alcohol-1,2,4-triazole sulfide derivative has the chemical structural formula (No. 1): When used as a fungicide, the fungicide inhibition rates against wheat fusarium rust, cucumber gray mold, rice sheath blight, wheat sheath blight and apple ring rot pathogen reach 55.6%, 55.6%, 63.5%, 80.6% and 88.9% respectively.

[0131] 2. When the perillyl alcohol-1,2,4-triazole sulfide derivative has the chemical structural formula (No. 2): When used as a fungicide, the fungicide inhibition rates against wheat fusarium head blight, cucumber gray mold, rice sheath blight, wheat sheath blight, and apple ring rot pathogen reach 55.6%, 58.3%, 65.4%, 77.4%, and 83.3%. When used as a herbicide, the herbicidal activity against rapeseed and barnyard grass at concentrations of 10 mg / L and 100 mg / L are 89.1%, 91.1%, 4.6%, and 39.8%, respectively. Therefore, it can also be used as a pesticide with both fungicidal and herbicidal effects.

[0132] 3. When the perillyl alcohol-1,2,4-triazole sulfide derivative has the chemical structural formula (No. 4):

[0133] When used as a fungicide, the fungicide inhibition rates (%) against wheat fusarium rust, cucumber gray mold, rice sheath blight, wheat sheath blight and apple ring rot are 48.1%, 50.0%, 65.4%, 58.1% and 75.0% respectively.

[0134] 4. When the perillyl alcohol-1,2,4-triazole sulfide derivative has the chemical structural formula (No. 5):

[0135] When used as a fungicide, the fungicide inhibition rates against wheat fusarium rust, cucumber gray mold, rice sheath blight, wheat sheath blight and apple ring rot are 48.1%, 55.6%, 65.4%, 67.7% and 86.1% respectively.

[0136] 5. When the perillyl alcohol-1,2,4-triazole sulfide derivative has the chemical structural formula (No. 22):

[0137] When used as a fungicide, the fungicide inhibition rates against wheat fusarium rust, cucumber gray mold, rice sheath blight, wheat sheath blight and apple ring rot are 27.9%, 67.5%, 42.0%, 83.8% and 78.8% respectively.

[0138] 6. When the perillyl alcohol-1,2,4-triazole sulfide derivative has the chemical structural formula (No. 24):

[0139] When used as a fungicide, the fungicide inhibition rates against wheat fusarium rust, cucumber gray mold, rice sheath blight, wheat sheath blight and apple ring rot are 24.6%, 64.9%, 22.2%, 76.5% and 46.2% respectively.

[0140] 7. When the perillyl alcohol-1,2,4-triazole sulfide derivative has the chemical structural formula (No. 27):

[0141] When used as a fungicide, the fungicide inhibition rates against wheat fusarium rust, cucumber gray mold, rice sheath blight, wheat sheath blight and apple ring rot are 21.3%, 63.6%, 17.3%, 60.3% and 50.0% respectively.

[0142] 8. When the perillyl alcohol-1,2,4-triazole sulfide derivative has the chemical structural formula (No. 50):

[0143] When used as a fungicide, the fungicide inhibition rates of the invention against wheat fusarium rust, cucumber gray mold, rice sheath blight, wheat sheath blight and apple ring rot are 16.4%, 57.1%, 21.0%, 54.4% and 65.4% respectively.

[0144] 9. When the perillyl alcohol-1,2,4-triazole sulfide derivative has the chemical structural formula (No. 52):

[0145] When used as a fungicide, the fungicide inhibition rates against wheat fusarium rust, cucumber gray mold, rice sheath blight, wheat sheath blight and apple ring rot are 26.2%, 64.9%, 17.3%, 76.5% and 69.2% respectively.

[0146] 10. When the perillyl alcohol-1,2,4-triazole sulfide derivative has the chemical structural formula (No. 54):

[0147] When used as a fungicide, the fungicide inhibition rates against wheat fusarium rust, cucumber gray mold, rice sheath blight, wheat sheath blight and apple ring rot are as follows: 49.2%, 51.9%, 14.8%, 44.1% and 59.6%, respectively.

[0148] 11. When the perillyl alcohol-1,2,4-triazole sulfide derivative has the chemical structural formula (No. 56):

[0149] When used as a fungicide, the fungicide inhibition rates against wheat fusarium head blight, cucumber gray mold, rice sheath blight, wheat sheath blight, and apple ring rot are 32.8%, 42.9%, 21.0%, 30.9%, and 63.5%, respectively. When used as a herbicide, the herbicidal activity against rapeseed and barnyard grass at concentrations of 10 mg / L and 100 mg / L are 77.9%, 78.4%, 36.6%, and 49.6%, respectively. Therefore, it can also be used as a pesticide with both fungicidal and herbicidal effects.

[0150] 12. When the perillyl alcohol-1,2,4-triazole sulfide derivative has the chemical structural formula (No. 15):

[0151] When used as a herbicide, the herbicidal activities of the herbicide at concentrations of 10 mg / L and 100 mg / L against rapeseed and barnyard grass are as follows: 85.1%, 92.0%, 0%, and 48.4%, respectively.

[0152] 13. When the perillyl alcohol-1,2,4-triazole sulfide derivative has the chemical structural formula (No. 16):

[0153] When used as a herbicide, the concentration of 10mg / L and 100mg / L is effective against rapeseed and barnyard grass.

[0154] The herbicidal activities against grass were: 10.5%, 46.0%, 0%, and 3%, respectively.

[0155] 14. When the perillyl alcohol-1,2,4-triazole sulfide derivative has the chemical structural formula (No. 24):

[0156] When used as a herbicide, the herbicidal activities of the herbicide at concentrations of 10 mg / L and 100 mg / L on rapeseed and barnyard grass are 28.1%, 61.9%, 0% and 3.0% respectively.

[0157] 15. When the perillyl alcohol-1,2,4-triazole sulfide derivative has the chemical structural formula (No. 37):

[0158] When used as a herbicide, the herbicidal activity of the herbicide at concentrations of 10 mg / L and 100 mg / L on rapeseed and barnyard grass is 90.3%, 90.9%, 0%, and 8.0%, respectively.

[0159] 16. When the perillyl alcohol-1,2,4-triazole sulfide derivative has the chemical structural formula (No. 40):

[0160] When used as a herbicide, the herbicidal activity of the herbicide at concentrations of 10 mg / L and 100 mg / L against rapeseed and barnyard grass is 84.6%, 91.6%, 15.6% and 30.8% respectively.

[0161] 17. When the perillyl alcohol-1,2,4-triazole sulfide derivative has the chemical structural formula (No. 42):

[0162] When used as a herbicide, the herbicidal activities of the herbicide at concentrations of 10 mg / L and 100 mg / L on rapeseed and barnyard grass are 34.7%, 80.8%, 0% and 13.2% respectively.

[0163] The above perillyl alcohol-1,2,4-triazole sulfide derivatives are significantly better than perillyl alcohol in terms of fungicidal activity and herbicidal activity; some derivatives are comparable to traditional fungicides such as oxazolidinone, or even significantly better than such traditional fungicides; some derivatives are comparable to herbicides such as fluazifop-butyl and oxazolidinone, or even significantly better than such traditional herbicides; therefore, the perillyl alcohol-1,2,4-triazole sulfide derivatives of the present invention can provide more efficient candidate compound selections for the creation of new herbicides and fungicides.

[0164] Example 3

[0165] The compounds No. 2, No. 37 and No. 52 of the present invention were selected for biosafety testing.

[0166] 1. Rice safety test

[0167] The rice seeds used in this experiment are: High-yield drought-resistant upland rice seed No. 1.

[0168] Test pesticides: 50% thiophanate-methyl wettable powder, 30% mefenamic acid aqueous solution, 51% fluazifop-butyl water dispersible granules, and 25.5% oxadiazon emulsifiable concentrate.

[0169] The compounds 2, 37 and 52 which showed excellent fungicidal and herbicidal activities in previous biological activity tests were selected and subjected to biological toxicity experimental tests.

[0170] 1. Drying rice seeds before sowing: Turning the seeds over and drying them for 6-8 hours before soaking and germinating can enhance the permeability of the seed coat, promote enzyme activity, and effectively eliminate the difference in water content between seeds, making the water absorption more uniform after soaking, and germination more uniform during germination. It can also improve the germination rate and germination potential.

[0171] 2. Seed soaking with chemicals: In the early stage, select rice seeds with normal development, no mold, no insects, complete and without any damage. There are 200 rice seeds in each experimental group, of which tap water is the blank control (CK), thiophanate-methyl, mefenacet, fluazifop-butyl and oxadiazine-methyl are the positive controls, and numbers 2, 37, and 52 are the drug groups. They are soaked at room temperature for 1 day at a drug concentration of 200 mg / L.

[0172] 3. Germination: After soaking the rice seeds, drain the seeds, use tweezers to put 2 layers of filter paper into the water, take them out after absorbing enough water, drain off the excess water, put them into the culture dish, randomly select 50 rice seeds that have been soaked for 1 day and put them in the culture dish, arrange the seeds evenly on the paper bed, keep a certain distance between the seeds, cover the top with a wet cloth and keep it moist, for each sample three groups of parallel samples, lift the cloth every day to observe the germination, and sow when the sprouts are long and the roots are about the length of one grain.

[0173] 4. Germination rate statistics

[0174] Table 5: 3d germination rate of rice seeds

[0175]

[0176] Rice seeds germinate on the third day Figure 2As shown, among them, CK is numbered 1-3; compound No. 2 is numbered 4-6; compound No. 37 is numbered 7-9; compound No. 52 is numbered: 10-12; thiophanate-methyl is numbered 13-15; fluazifop-butyl is numbered 16-18; oxadiazine is numbered 19-21; and oxadiazine is numbered 22-24.

[0177] 5. Sowing and seedling raising

[0178] Randomly select 10 rice seeds from each culture dish that has been germinated, sow them in moistened nutrient soil, and make three parallel samples in each group. Record the germination rate, the survival rate of the seedlings on the seventh day, the seedling height, and the fresh seedling weight.

[0179] 5.1 Seedling rate

[0180] Table 6: Seedling Emergence Rate

[0181] serial number Seedling rate% CK 100 2 100.0 37 98.3 52 96.0 Chlorothalonil 91.6 Fluazifop-butyl 3.3 Methadone 86.0 Oxadiazole 80

[0182] 5.2 Seedling survival rate, seedling height and fresh seedling weight on the seventh day

[0183] Table 7: Seedling survival rate, seedling height, and fresh seedling weight on the seventh day

[0184] serial number Average seedling height (cm) Survival rate (%) Fresh seedling weight (g) CK 13.8 85.0 2.20 2 13.1 90.0 2.28 37 14.3 100 2.62 52 12.9 90.0 2.50 Chlorothalonil 12.7 90.0 2.07 Fluazifop-butyl 0 0 0 Methadone 13.6 75.0 2.24 Oxadiazole 11.5 95.0 2.07

[0185] Seedling survival pictures Figure 3 As shown, CK corresponds to the blank group, and the others are compound No. 2, compound No. 37, compound No. 52, and the positive controls are chlorothalonil, fluazifop-butyl, mefenamic acid, and oxadiazine.

[0186] Results and Analysis

[0187] 6.1 Rice seed germination

[0188] As shown in Table 5, after soaking for 1 day, the average germination rate of rice seeds treated with experimental drugs 2, 37, 52 and positive controls such as chlorothalonil, oxadiazine, fluazifop-butyl, oxadiazine and blank was more than 99%, and the experimental drugs and positive control drugs used had no effect on the germination rate of rice seeds.

[0189] 6.2 Security

[0190] Experimental drugs 2, 37, 52 and positive controls chlorothalonil, mefenamic acid, fluazifop-butyl, oxadiazine and blank had no effect on the germination rate of rice seeds, but it was found through observation that the experimental group of fluazifop-butyl caused the rice buds to turn yellow seriously and wilt, and it was difficult to form seedlings. The emergence rate was only 3.3, and the safety of rice was extremely low, as shown in Table 6. As shown in Table 7, the average seedling height, survival rate and fresh seedling weight of experimental drugs 2 and 37 were better than those of the blank group, which shows that they are safer for rice, and are also better than the positive controls chlorothalonil, fluazifop-butyl and oxadiazine, and are equivalent to mefenamic acid.

[0191] 2. Zebrafish toxicity test

[0192] Perillyl alcohol-based 1,2,4-triazole derivatives No. 2 and No. 37 were selected and subjected to biosafety tests according to the national standard (test method number: GB / T312070).

[0193] 1. Source of experimental fish

[0194] The zebrafish used in the experiment were normal in shape and size, with a body length of 1.8-2.5 cm. They were purchased and raised in the laboratory for 7 days, with water changed once a day and food given once a day, except for the day before the experiment. The water used in this experiment was dechlorinated tap water that had been exposed to the sun.

[0195] 2. Biological activity test

[0196] 2.1 Test sample preparation

[0197] The experiment set up 5 concentration gradients of 0.4, 0.6, 0.8, 1.0, and 1.2 (mg / L). Seven zebrafish were placed in each sample group, and the test duration was set to 96 hours. The sample was dissolved in acetone and prepared into a 12g / L acetone solution to prepare the required experimental concentration (mg / L). Before the experiment, the miscibility of the sample's acetone solution with water was tested. The results showed that the sample's acetone solution and water were not stratified, and the experiment could be carried out.

[0198] 2.2 Experimental Phase

[0199] This experiment adopted a static test method, that is, the test solution was not replaced during the test, and no feeding was carried out. Dead fish were picked out at any time. The body of the fish was poked with tweezers, and if it did not move, it was determined to be dead. The experiment lasted for 96 hours, and observations and photos were taken at each observation node of 6h, 12h, 24h, 36h, 48h, 72h, and 96h.

[0200] Table 8 Mortality of zebrafish at different exposure times

[0201]

[0202]

[0203] Table 9 LC of biosafety test on zebrafish after 96h drug exposure 50 result

[0204]

[0205] Results and Discussion

[0206] The zebrafish toxicity test data in Tables 8 and 9 show that the LC values ​​of compound 2, compound 37, fluazifop-butyl, oxadiazine, and oxadiazine on zebrafish at 96 h are 50 The results were 5.750, 1.734, 1.725, 1.608, and 4.068 mg ai / L, respectively. Among them, all zebrafish died at a drug concentration of 0.4-0.6 mg / L of chlorothalonil after 6 hours, and the LC value could not be calculated. 50 From the zebrafish biological toxicity test data in Table 8, it can be seen that the No. 2 and No. 37 drugs are not very toxic to aquatic organisms, and the zebrafish mortality rate is lower than that of the positive controls fluazifop and oxadiazine.

[0207] Although the embodiments of the present invention have been disclosed above, they are not limited to the applications listed in the specification and the embodiments. They can be applied to various fields suitable for the present invention. For those familiar with the art, additional modifications can be easily realized.

Claims

1. A perillyl alcohol-1,2,4-triazole sulfide derivative, characterized in that: The chemical structure is as follows; Wherein, R1 is selected from: hydrogen, acetyl; R2 is selected from: methyl, phenyl, p-methylphenyl, o-methylphenyl, m-methylphenyl, 1-phenylpropyl, p-fluorophenyl, o-fluorophenyl, m-fluorophenyl, p-trifluoromethylphenyl, m-trifluoromethylphenyl, o-trifluoromethylphenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, m-bromophenyl, o-bromophenyl, p-bromophenyl, p-nitrophenyl, m-nitrophenyl, o-nitrophenyl, o-methoxyphenyl, p-methoxyphenyl, m-methoxyphenyl, o-ethoxyphenyl, p-ethoxyphenyl, (1-methyl-3-trifluoromethyl)-pyrazolyl, (1-methyl-3-difluoromethyl)-pyrazolyl, (3-chloro-5-(trifluoromethyl)pyridinyl), (3-bromo-1-(3-chloropyridin-2-yl)-pyrazolyl), p-trifluoromethylpyridinyl, 3-trifluoromethylpyridinyl.

2. A method for preparing the perillyl alcohol-1,2,4-triazole sulfide derivative according to claim 1, characterized in that: include: Using perillyl alcohol as raw material, chloroperillyl alcohol acetate was synthesized through esterification and allyl chlorination reaction. Various substituted benzoyl chlorides and heterocyclic acid chlorides are used as raw materials to synthesize 1,2,4-triazole thiol through substitution and cyclization reactions; A series of perillyl alcohol-1,2,4-triazole thioether derivatives were synthesized by the reaction of chloroperillyl alcohol acetate and 1,2,4-triazole thioether.

3. Use of the perillyl alcohol-1,2,4-triazole sulfide derivative according to claim 1 or the perillyl alcohol-1,2,4-triazole sulfide derivative prepared by the preparation method according to claim 2 as a fungicide.

4. The use according to claim 3, characterized in that The chemical structural formula of the perillyl alcohol-1,2,4-triazole sulfide derivative is: Any of .

5. Use of the perillyl alcohol-1,2,4-triazole sulfide derivative according to claim 1 or the perillyl alcohol-1,2,4-triazole sulfide derivative prepared by the preparation method according to claim 2 as a herbicide.

6. The use according to claim 5, characterized in that The chemical structural formula of the perillyl alcohol-1,2,4-triazole sulfide derivative is: Any one of.

7. Use of the perillyl alcohol-1,2,4-triazole sulfide derivative according to claim 1 or the perillyl alcohol-1,2,4-triazole sulfide derivative prepared by the preparation method according to claim 2 as a bactericidal and herbicidal synergistic pesticide, characterized in that: The chemical structural formula of the perillyl alcohol-1,2,4-triazole sulfide derivative is:

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