A tetrahydropyridopyrazole derivative containing an oxazole ring, its preparation method and use as a herbicide

Abstract

The present invention discloses an oxazole ring-containing tetrahydropyridopyrazole derivative, its preparation method, and its application as a herbicide. The oxazole ring-containing tetrahydropyridopyrazole derivative has the following molecular structure and can be prepared by mixing bispyribac and ethanolamine hydrochloride in a solvent, followed by the addition of a catalyst and an acid-binding agent. The oxazole ring-containing tetrahydropyridopyrazole derivative is typically used as a rice field herbicide.

Description

Technical Field

[0001] The present invention relates to an organic derivative, in particular to an oxazole ring-containing tetrahydropyridopyrazole derivative, a preparation method thereof and application as a herbicide. Background Art

[0002] Pyraclonil, a tetrahydropyridopyrazole derivative, is a type of protoporphyrinogen oxidase (PPO)-inhibiting rice field herbicide. Its mechanism of action is to target protoporphyrinogen oxidase (PPO) and inhibit chlorophyll synthesis in weeds.

[0003] As a PPO-inhibiting herbicide, bispyribac has the following characteristics:

[0004] (1) High selectivity, using chlorophyll in plant cells as the site of action, reducing toxicity to animals;

[0005] (2) The probability of weeds developing drug resistance is low. PPO inhibitors competitively inhibit the binding of PPO to plants, reducing the synthesis of chlorophyll in weeds themselves, making it difficult for weeds to develop drug resistance;

[0006] (3) Low dosage: PPO is a low-abundance protein. PPO inhibitors have a high affinity for this enzyme, and ideal effects can be achieved at relatively low dosages.

[0007] (4) It has no pollution to the environment, can be quickly decomposed in the soil, and has no impact on the groundwater system.

[0008] Bispyribac herbicide achieves its weed control by mimicking substrate-enzyme binding and occupying the active catalytic site, producing competitive inhibition. Due to the relatively conservative nature of the PPO active cavity, the potential for weed resistance is significantly reduced. This advantageous property has garnered significant attention in the pesticide market. Since its launch, it has achieved widespread recognition and remarkable success in the Japanese rice field herbicide market. Therefore, the development of novel tetrahydropyridopyrazole derivatives and the exploration of their improved bioactivity are of great significance. Summary of the Invention

[0009] To solve the above technical problems, the present invention provides a tetrahydropyridopyrazole derivative containing an oxazole ring, a preparation method thereof, and its use as a herbicide. The tetrahydropyridopyrazole derivative containing an oxazole ring exhibits a significantly enhanced biological activity as a rice field herbicide compared to bispyribac.

[0010] To achieve the above object, the technical solutions adopted by the present invention are as follows:

[0011] First, a tetrahydropyridopyrazole derivative containing an oxazole ring has the following molecular structure expression:

[0012]

[0013] Secondly, a method for preparing the tetrahydropyridopyrazole derivative containing an oxazole ring as described above comprises the following steps:

[0014] After mixing bispyribac and ethanolamine hydrochloride in a solvent, a catalyst and an acid binding agent are added to carry out a reaction; after the reaction is completed, extraction and purification are carried out to obtain a product.

[0015] As a preferred embodiment of the preparation method of the present invention, the catalyst is selected from one or more of copper trifluoromethanesulfonate, zinc acetate, and trichloroisocyanuric acid; and / or,

[0016] The acid binding agent is one or more of potassium carbonate, sodium carbonate, sodium acetate, triethylamine, pyridine and piperidine.

[0017] As a preferred embodiment of the preparation method of the present invention, the amount of the catalyst added is 1-20% of the molar amount of bispyribac, such as 1%, 5%, 8%, 10%, 15%, 18%, 20%, etc.; and / or,

[0018] The amount of the acid binding agent is 1.2-2 times the molar amount of bispyribac, for example, 1.2 times, 1.4 times, 1.5 times, 1.8 times, 2.0 times, etc.

[0019] As a preferred embodiment of the preparation method of the present invention, the mixing amount of the bispyribac and ethanolamine hydrochloride is 1:(1-6) in a molar ratio, for example, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, etc.

[0020] As a preferred embodiment of the preparation method of the present invention, the reaction conditions are as follows: heating to 120-170°C for 10-30h, reaction temperature such as 125°C, 130°C, 135°C, 140°C, 145°C, 150°C, 155°C, 160°C, 165°C, etc., reaction time such as 12h, 15h, 18h, 20h, 24h, 30h, etc.

[0021] As a preferred embodiment of the preparation method of the present invention, the solvent is one or more of tetrahydrofuran, ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile and water.

[0022] As a preferred embodiment of the preparation method of the present invention, after the reaction is completed, the reaction is filtered, the solution is evaporated to dryness or extracted without evaporation to dryness, the organic layer is collected, dried by spin drying, recrystallized, and purified to obtain the product.

[0023] The above preparation method is based on the consideration of saving production process, and the target product can be produced in a single reaction. It has the advantages of simple process and low production cost. However, this method should not be used as a limitation to obtain the target product. Those skilled in the art can select different preparation processes according to actual needs to obtain the same product. In general, this will not affect the basic properties of the product.

[0024] Furthermore, the present invention also provides a use of the above-mentioned tetrahydropyridopyrazole derivative containing an oxazole ring or the above-mentioned tetrahydropyridopyrazole derivative containing an oxazole ring prepared by the method described above in a rice field herbicide.

[0025] The oxazole ring-containing tetrahydropyridopyrazole derivatives provided by the present invention have a broad spectrum of herbicidal activity, especially showing significant herbicidal activity against barnyard grass, Leptochloa chinensis, Digitaria sanguinalis, Japanese alopecuroides, and Lolium multiflorum. This provides a direction for the further development of new herbicides and lays a foundation for the preparation of compositions / formulations with oxazole ring-containing tetrahydropyridopyrazole derivatives as the main herbicide active ingredient. DETAILED DESCRIPTION

[0026] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0027] It should be understood that the terms described herein are intended only to describe particular embodiments and are not intended to limit the present invention. In addition, for numerical ranges herein, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Each smaller range between any intermediate value within a stated value or stated range and any other stated value or intermediate value within the stated range is also encompassed by the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded within the scope.

[0028] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of any conflict with any incorporated document, the contents of this specification shall prevail.

[0029] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments described herein without departing from the scope or spirit of the invention. Other embodiments will be apparent to those skilled in the art from the description of the invention. The description and examples are intended to be illustrative only.

[0030] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0031] The bispyribac herbicide used in the examples of the present invention was purchased from Hefei Ai Shang Agricultural Technology Co., Ltd.

[0032] The ethanolamine hydrochloride, zinc acetate, and triethylamine used in the examples of the present invention were purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.

[0033] Trichloroisocyanuric acid (TCCA) used in the examples of the present invention was purchased from Titan Technology Exploration Platform.

[0034] Unless otherwise specified, other raw materials and reagents can be purchased from commercially available products.

[0035] In the following examples of the present invention, room temperature refers to 25±2°C.

[0036] [Example 1]

[0037] At room temperature, oxadiazole and ethanolamine hydrochloride were mixed in a molar ratio of 1:6 and dissolved in acetonitrile. Trichloroisocyanuric acid (3% of the molar ratio of oxadiazole) and triethylamine (200% of the acid-binding agent) were added as a catalyst. The temperature was raised to 120°C and the reaction was allowed to react for 24 hours. After the reaction, the mixture was filtered, the solvent evaporated, and extraction with water and ethyl acetate was performed. The organic layer was further evaporated to dryness and recrystallized to obtain the product, a tetrahydropyridopyrazole derivative containing an oxazole ring.

[0038] 1 H NMR (600MHz, CDCl3) δ7.63(s,1H),4.54(t,J=9.5Hz,2H),4.31(t,J=9.5Hz,2H),4.04(t,J=6.1H z,2H),3.80(s,2H),3.29(s,1H),3.20(s,3H),2.70(t,J=6.5Hz,2H),2.07(s,2H),1.88(s,2H).

[0039] [Example 2]

[0040] At room temperature, bispyribac and ethanolamine hydrochloride were mixed in a molar ratio of 1:3.5 and dissolved in N,N-dimethylformamide. Zinc acetate (15% of the molar weight of bispyribac) was added as a catalyst, and 150% of pyridine was added as an acid-binding agent. The reaction was allowed to proceed at 170°C for 15 hours. After completion of the reaction, the mixture was filtered, the solvent evaporated, and extraction with water and ethyl acetate was performed. The organic layer was further evaporated to dryness, recrystallized, and the product was collected.

[0041] [Example 3]

[0042] At room temperature, bispyribac and ethanolamine hydrochloride were mixed in a molar ratio of 1:2 and dissolved in ethanol. Copper trifluoromethanesulfonate (12% of the molar ratio of bispyribac) was added as a catalyst, and sodium carbonate (120% of the molar ratio) was added as an acid-binding agent. The mixture was reacted at 140°C for 30 hours. After completion of the reaction, the mixture was filtered, the solvent evaporated, and extraction with water and ethyl acetate was performed. The organic layer was further evaporated to dryness, recrystallized, and the product was collected.

[0043]

Application Testing

[0044] The target products prepared in Example 1, tetrahydropyridopyrazole derivatives containing an oxazole ring, and bispyribac were used as herbicides to conduct efficacy and phytotoxicity tests. The specific methods are as follows:

[0045] Test weeds: Echinochloa crus-galli, Leptochloa chinensis, Digitaria sanguinalis, Japanese alopecuroides, and Perennial ryegrass.

[0046] Test crops: rice, wheat.

[0047] Sowing: Prepare multiple foam boxes (40 × 35 × 30 cm) and label them according to crop / weed species. For each sample, assign nine foam boxes to each group and divide them into three groups, with three boxes per group for parallel testing. Label each group as: experimental, control, and blank. Plant the corresponding crop / weed in the foam boxes according to the labeling, sowing 48 seeds evenly per box.

[0048] Preparation of the experimental group: 1 g of a tetrahydropyridopyrazole derivative containing an oxazole ring was weighed and dissolved in 4 mL of dimethyl sulfoxide, and Tween was added and ultrasonic oscillation was assisted. The amount of Tween was adjusted to 3% of the total volume to obtain the experimental group drug solution.

[0049] Preparation of the control group: 1 g of bispyribac was weighed and dissolved in 4 mL of dimethyl sulfoxide, Tween was added and ultrasonic oscillation was assisted. The amount of Tween was adjusted to 3% of the total volume to obtain the control group drug solution.

[0050] Preparation of blank group medicine: take 4 mL of dimethyl sulfoxide, add Tween and assist with ultrasonic oscillation, and the amount of Tween is configured according to 3% of the total volume to obtain the blank group medicine solution.

[0051] The above solutions were diluted with water to the same multiple before use.

[0052] Spraying experiment: 7 days after sowing, the spraying amount was 210g.ai / hm 2 Each group of samples was sprayed with pesticides. 21 days after sowing, the efficacy and damage of each pesticide were observed and calculated.

[0053] Efficacy experiments

[0054] (1) Calculate the herbicidal activity of the liquid on each weed by the number of weeds and fresh weight inhibition rate according to the following formula, and record it in Table 1; where the treatment group refers to the experimental group or control group of the corresponding test;

[0055] Plant number inhibition rate (%) = (T 空白组 -T 处理组 ) / T 空白組 x 100%

[0056] T represents the number of germinated weed seeds (unit: plant);

[0057] Fresh weight inhibition rate (%) = (G 空白组 -G 处理组 ) / G 空白組 x 100%

[0058] G represents the fresh weight of each weed seed after germination (unit: g);

[0059] Table 1. Efficacy test results

[0060]

[0061]

[0062] (2) Calculate the plant number inhibition rate and fresh weight inhibition rate of the drug solution on each crop according to the following formula to characterize the phytotoxicity activity and record it in Table 2; where the treatment group refers to the experimental group or control group of the corresponding test;

[0063] Plant number inhibition rate (%) = (L 空白组 -L 处理组 ) / L 空白組 x 100%

[0064] Wherein, L represents the number of germinated plants of each crop seed (unit: cm)

[0065] Fresh weight inhibition rate (%) = (M 空白组 -M 处理组 ) / M 空白組 x 100%

[0066] Where M represents the fresh weight of each crop seed after germination (unit: g)

[0067] Table 2. Results of pesticide damage test

[0068]

[0069] As can be seen from the above test results, the tetrahydropyridopyrazole derivatives containing an oxazole ring provided by the present invention have significant herbicidal activity against all five selected weeds. Not only do they maintain their particularly outstanding herbicidal activity against Leptochloa chinensis, but they also have significantly higher plant population inhibition rates against barnyardgrass, crabgrass, Japanese alopecurus, and multiflora ryegrass than oxadiazon, demonstrating significantly enhanced herbicidal activity. In addition, phytotoxicity tests show that the tetrahydropyridopyrazole derivatives containing an oxazole ring provided by the present invention have minimal phytotoxicity against rice and wheat, with plant population inhibition rates of 4.14% and 3.64%, respectively, which are less than the 5.11% and 4.00% of oxadiazon. The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several improvements and supplements without departing from the method of the present invention, and these improvements and supplements should also be considered within the scope of protection of the present invention.

Claims

1. A tetrahydropyridopyrazole derivative containing an oxazole ring, characterized in that: It has the following molecular structure expression: 。 2. A method for preparing a tetrahydropyridopyrazole derivative containing an oxazole ring according to claim 1, characterized in that: The following steps are involved: After mixing bispyribac and ethanolamine hydrochloride in a solvent, a catalyst and an acid binding agent are added to carry out a reaction; after the reaction is completed, extraction and purification are carried out to obtain a product.

3. The method for preparing a tetrahydropyridopyrazole derivative containing an oxazole ring according to claim 2, wherein: The catalyst is selected from one or more of copper trifluoromethanesulfonate, zinc acetate, and trichloroisocyanuric acid; and / or, The acid binding agent is one or more of potassium carbonate, sodium carbonate, sodium acetate, triethylamine, pyridine and piperidine.

4. The method for preparing a tetrahydropyridopyrazole derivative containing an oxazole ring according to claim 2 or 3, wherein: The amount of the catalyst added is 1-20% of the molar amount of bispyribac; and / or, The amount of the acid binding agent is 1.2-2 times the molar amount of bispyribac.

5. The method for preparing a tetrahydropyridopyrazole derivative containing an oxazole ring according to claim 2 or 3, wherein: The mixing amount of the bispyribac and ethanolamine hydrochloride is 1:(1-6) in terms of molar ratio.

6. The method for preparing a tetrahydropyridopyrazole derivative containing an oxazole ring according to claim 2 or 3, characterized in that: The reaction conditions are: heating to 120-170°C and reacting for 10-30 hours.

7. The method for preparing a tetrahydropyridopyrazole derivative containing an oxazole ring according to claim 2 or 3, wherein: The solvent is one or more of tetrahydrofuran, ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile and water.

8. The method for preparing a tetrahydropyridopyrazole derivative containing an oxazole ring according to claim 2 or 3, wherein: After the reaction is completed, the solution is filtered, evaporated to dryness or extracted without evaporation, and the organic layer is collected, dried by spin drying, recrystallized, and purified to obtain the product.

9. Use of the tetrahydropyridopyrazole derivative containing an oxazole ring according to claim 1 or the tetrahydropyridopyrazole derivative containing an oxazole ring obtained by the method according to any one of claims 2 to 8 in a rice field herbicide.

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