Application of five-membered heterocycle pyrimidinedione compound in preparation of herbicide

Abstract

The invention relates to an application of a five-membered heterocyclic pyrimidine diketone compound in preparation of herbicides, in particular to an application of the five-membered heterocyclic pyrimidine diketone compound in preparation of herbicides for preventing and controlling dicotyledonous weeds such as oilseed rape and amaranthus retroflexus. The compound disclosed by the invention has a good control effect on dicotyledonous weeds under the dosage of 100g / mu, and the weeding effect on amaranthus retroflexus is 100% during stem and leaf treatment. Chemical structural formula of five-membered heterocycle pyrimidinedione compound is as follows: # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of agricultural chemicals and relates to use of a five-membered heterocyclic pyrimidinedione compound in preparing a herbicide, in particular to use of the five-membered heterocyclic pyrimidinedione compound in preparing a herbicide for preventing and controlling dicotyledonous weeds rape and Amaranthus retroflexus. Technical Background

[0002] Three branched-chain amino acids, such as valine, leucine and isoleucine, can only be synthesized in plants and microorganisms. There is no such biochemical process in mammals. Therefore, chemicals that can inhibit the biosynthesis of branched-chain amino acids can be used as herbicides or antibacterial drugs, and are biosafe for humans and animals (McCourt JA, et al. Amino Acids, 2006, 31 (2), 173-210). In fact, the first enzyme in this process, acetolactate synthase (acetohydroxyacid synthase, AHAS, EC2.2.1.6), is a very successful herbicide target. Herbicides targeting AHAS generally include sulfonylureas, imidazolinones, pyrimidineoxybenzoic acid and triazole pyrimidine sulfonamide, with a total of more than 60 commercial varieties to date. These herbicides effectively control farmland weeds and play a huge role in ensuring food security and promoting increased production and harvest (Wang Jianguo, Journal of Pesticide Science, 2014, 16 (4), 367-374).

[0003] However, with the widespread use of AHAS herbicides, weed resistance has gradually become an agricultural problem that cannot be ignored. Generally, once weeds become resistant to a certain herbicide, they will soon become resistant to herbicides with the same mechanism of action to varying degrees (Yu Q, et al. Pest Manag. Sci., 2014, 70(9), 1340-1350). Studies have shown that weed resistance is divided into two types: target resistance and non-target resistance, of which target resistance accounts for the largest proportion. Therefore, research and development of herbicides with new targets has become an important choice.

[0004] Ketol-acid reductoisomerase (KARI, EC1.1.1.86) is the second enzyme in the biosynthesis of branched-chain amino acids and is located downstream of AHAS. People have always placed high hopes on KARI, hoping to discover super-efficient herbicides like AHAS inhibitors. Among them, Hoe 704, IpOHA and cyclopropanedicarboxylic acid (CPD) as shown in the figure below are representative compounds with relatively strong inhibitory activity against plant-derived KARI found internationally (Wang BL, et al., Bioorg. Med. Chem. Lett. 2017, 27 (24), 5457-5462; Schulz A, et al., FEBS Lett. 1988, 238 (2), 375-378; Lee YT, et al. Plant Sci. 2005, 168, 1035-1040.), but these inhibitors have weak herbicidal effects under potted conditions. Among them, the most active compound Hoe704 can only show a control effect of > 80% on weeds such as barnyard grass and Amaranthus retroflexus at a dosage of 10,000 g / hectare (Bauer KR, et al. al., EP0106114, 1986-06-10).

[0005]

[0006] Recently, Lin, Guddat and others searched the compound database of the National Cancer Institute (NCI) and found a KARI inhibitor codenamed NSC116565 (as shown below), which showed good inhibition against Mycobacterium tuberculosis. The minimum inhibitory concentration (MIC) of the two strains H37Ra and H37Rv in DMM medium without branched-chain amino acids was 90%. 90 ) were 9.86 μM and 20.42 μM, respectively, indicating that this is a new type of KARI inhibitor with a new skeleton (Lin X., et al.; Chem. Eur. J. 2021, 27, 3130-3141). However, the document does not report any herbicidal activity of this compound and its analogs.

[0007] Pei Jianfeng et al. reported in Chinese invention patent CN114539148A that a compound with a similar structure to NSC116565 (codenamed JK-5-67 in this patent) has inhibitory activity against human flap endonuclease 1 (FEN-1), and its IC 50The concentration of 1 μg / ml of the compound was 0.125 μM, and it was inferred that it may have the potential to cure hepatitis B, and the biological activity was protected. However, patent CN114539148A did not mention any data on the herbicidal activity of the compound.

[0008] Summary of the invention

[0009] The object of the present invention is to provide a use of a five-membered heterocyclic pyrimidine dione compound in the preparation of a herbicide. The compound has a strong inhibition rate on the root growth of rapeseed in a plate model, and has a strong control effect on dicotyledonous weeds rapeseed and Amaranthus retroflexus in a potted plant model, whether it is soil treatment or stem and leaf treatment.

[0010] The present invention provides a five-membered heterocyclic pyrimidine dione compound.

[0011]

[0012] In the use, the herbicide has a good control effect on rapeseed and Amaranthus retroflexus at a dosage of 100 g / mu. The herbicide comprises the five-membered heterocyclic pyrimidine dione compound and one or more agriculturally acceptable carriers. Its dosage form is emulsifiable concentrate, wettable powder, soluble powder, aqueous emulsion, microemulsion, aqueous solution, suspension, microcapsule or water-dispersible granule. Its use method is soil treatment or stem and leaf treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 This is a graph showing the herbicidal effect of compound JK-5-67 on Amaranthus retroflexus when treated with 100 g / mu of stems and leaves. DETAILED DESCRIPTION

[0014] The essential features of the present invention can be reflected in the following embodiments, but these embodiments are only for illustration rather than limitation of the present invention.

[0015] Example 1. Preparation of Compound JK-5-67

[0016]

[0017] Among them, conditions a to e are as follows:

[0018] a). Liquid bromine, ether, -15°C to room temperature, overnight; b). 1. Thioformamide, sodium bicarbonate, tetrahydrofuran, 0°C to room temperature, overnight; 2. Tetrahydrofuran, pyridine, trifluoroacetic anhydride, 0°C to room temperature, overnight; c). Hydroxylamine hydrochloride, ethanol; d). Benzenesulfonyl chloride, sodium hydroxide; e). Sodium hydroxide aqueous solution, heating.

[0019] The experimental operation was basically carried out according to the reference method (Bauer, Let al.; J. Heterocylic Chem.; 1968, 5, 331-335). The preparation steps of intermediate 2 are: in a 250mL round-bottom flask, add 150mL of ether, add diethyl oxaloacetate sodium salt (raw material 1, 12.6g, 60mmol), stir and cool to -15°C, then slowly add liquid bromine (9.6g, 60mmol), after the addition is complete, restore to room temperature, and stay overnight. Filter the reaction system, wash the precipitate with ether (50mL×2), collect the organic phase, dry it with anhydrous magnesium sulfate (20g), filter and concentrate under reduced pressure to obtain light yellow liquid 2-bromo-3-oxosuccinic acid diethyl ester 2, the yield is 67%, no purification is required, and it can be directly used in the next step.

[0020] Intermediate 3 was prepared by suspending thioformamide (1.10 g, 18.0 mmol, 1.5 eq) and NaHCO3 (4.03 g, 47.9 mmol, 4 equivalents) in anhydrous tetrahydrofuran at 0°C. A solution of diethyl 2-bromo-3-oxosuccinate 2 (3.20 g, 11.98 mmol, 1 equivalent) in anhydrous tetrahydrofuran was added. The reaction was stirred overnight and heated to room temperature. The white precipitate was filtered out and washed with ether. The filtrate was concentrated in vacuo and then redissolved in anhydrous tetrahydrofuran. A cooled (0°C) solution of trifluoroacetic anhydride (4.22 mL, 29.9 mmol, 2.5 equivalents) and anhydrous pyridine (5.43 mL, 67.4 mmol, 5.6 equivalents) in anhydrous tetrahydrofuran was added dropwise to the reaction mixture at 0°C and stirred overnight at room temperature. The solvent was evaporated in vacuo, and the remaining mixture was resuspended in dichloromethane and washed with 5% hydrochloric acid and water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel column chromatography (20% ethyl acetate / hexane) gave the title compound 3 (1.70 g, 53%) as a light yellow oil.

[0021] The preparation steps of intermediate 4 are: in a 250mL three-necked flask, hydroxylamine hydrochloride (9.4g, 135mmol) is added to ethanol, and an ethanol solution of sodium ethoxide (5.4g, 135mmol) is added under argon protection, and a neutralization reaction occurs. After 30 minutes, the sodium chloride precipitate generated is rapidly filtered, the filtrate is collected, and an ethanol solution of intermediate 3 (6.2g, 27mmol) is injected under argon protection overnight. After the reaction is completed, the solid is filtered, collected, and dried, and the yield of intermediate 4 is 60%. No purification is required, and it is directly used in the next step of the reaction.

[0022] The preparation steps of intermediates 5 and 6 are as follows: Intermediate 4 (387 mg, 1.90 mmol, 1 equivalent) was dissolved in 15 mL of NaOH (304 mg, 7.26 mmol, 4 equivalents) aqueous solution. Benzenesulfonyl chloride (486 μL, 3.81 mmol, 2 equivalents) was added, and the reaction mixture was heated to 60°C. A precipitate formed after 1.5 hours. The reaction mixture was then cooled and acidified with 15% hydrochloric acid to pH <3 and more precipitate formed. It was collected by filtration and dried in a vacuum dryer to produce a mixture of two isomers (530 mg, 86%, the ratio of intermediates 5 and 6 was 5:4). It was suspended in acetone and the insoluble solid was collected on a Buchner funnel as intermediate 6 (53 mg). The filtrate was then suspended with silica, dried, and loaded into a silica column. Intermediate 5 was eluted with 90% ethyl acetate / n-hexane, and intermediate 6 was then eluted with 10% methanol / ethyl acetate. The combined yield of the two isomers was 72%.

[0023] The preparation steps of JK-5-67 are: add hot NaOH (1M) solution to 5,7-dioxo-4,7-dihydrothiazolo[4,5-d]pyrimidine-6(5H)-alkylbenzenesulfonate (intermediate 5) (176 mg, 0.54 mmol), and reflux until all solids are dissolved (15 minutes). Acidify the reaction mixture with 15% hydrochloric acid. After standing overnight at 4°C, beige crystals are formed. Collect these on a Buchner funnel and dry in a dryer to obtain the title compound JK-5-67 (i.e., compound No. 7) (72 mg, 72%). The physical and chemical characterization data of JK-5-67 are as follows: melting point > 260°C 1 H NMR (300MHz, DMSO-d6): δ12.79 (s, 1H, OH), 10.62 (s, 1H, NH), 9.44 (s, 1H, CH). 13 C NMR (125 MHz, DMSO-d6): δ 162.5, 155.5, 154.1, 149.3, 104.4. HRMS, found m / z 185.9971, C5H4N3O3S + Theoretical value 185.9968.IR v max (cm -1 ): 3454, 3340, 3099, 1726, 1697, 1658, 1389, 1140, 886, 729.

[0024] Example 2. Inhibition of Rice KARI Enzyme by Compound JK-5-67

[0025] Plant-derived KARI comes from rice, and its cDNA code is J013002N13. It was overexpressed in the commonly used Escherichia coli system BL21 (DE3), and purified by immobilized metal affinity chromatography IMAC to obtain pure KARI. The test temperature was controlled at 30°C, and the test was carried out in a buffer system with a concentration of 0.1M Tris-HCl (pH 8.0). The reaction solution contained 0.2mM NADPH, 1mMMgCl2, 0.1mM acetolactate, and small molecule inhibitors at different concentrations. During the experiment, the buffer solution used in the experiment was added to a 1mL quartz test tube, and then 10μL of rice KARI was added to the buffer solution to dynamically monitor the changes in the disappearance rate of NADPH. Its inhibition constant K i It can be calculated by the following formula:

[0026] v=v o / (1+[I] / K i )

[0027] Among them, v o represents the maximum catalytic reaction rate when rice KARI is not inhibited, [I] represents the concentration of the compound, and v represents the reaction rate. Table 1 lists the K values ​​of JK-5-67 and NSC116565 for rice KARI. i value.

[0028] Table 1. Effects of test compounds on the K of rice KARI i value

[0029] Compound code <![CDATA[Inhibiting the K of rice KARI i value]]> JK-5-67 1.8±0.14μM NSC116565 2.4±0.22μM

[0030] Example 3. Herbicidal effect of compound JK-5-67 in a plate model

[0031] A filter paper with a diameter of 5.6 cm was laid in a culture dish with a diameter of 6 cm, 2 mL of a certain concentration of the test compound solution was added, and 10 rapeseed seeds soaked for 4 hours were sown. After 72 hours of dark culture at 28°C, the radicle length was measured to detect the herbicidal activity of the compound. When conducting the root growth recovery test with exogenous branched-chain amino acids, a mixed solution consisting of leucine, isoleucine and valine was added to the compound solution, each with a concentration of 0.5 mM, and each treatment was repeated twice. A blank control and an amino acid treatment control were set up. The plant height was measured. The variance analysis was performed using DPS18.10. Table 2 lists the inhibition rates of JK-5-67 and NSC116565 on rapeseed root length at concentrations of 100 mg / L and 10 mg / L.

[0032] Table 2. Inhibition rate of test compounds on rapeseed root growth

[0033] Compound code 100mg / L 10mg / L JK-5-67 98.8％ 94.1％ NSC116565 98.8％ 77.5％

[0034] It can be seen that at a dose of 100 mg / L, both JK-5-67 and NSC116565 had a strong inhibitory effect on rapeseed root growth. However, at a dose of 10 mg / L, JK-5-67 still showed a 94.1% inhibition on rapeseed root growth, while the inhibition rate of NSC116565 dropped to 77.5%.

[0035] Example 4. Potted weed control effect of compound JK-5-67

[0036] A certain amount of soil is placed in a plastic cup with a diameter of 8 cm, and a certain amount of water is added. After sowing, a certain thickness of soil is covered. The seedlings are covered with plastic film before they emerge, and a certain amount of clean water is added every day. The pre-seedling method is to treat the soil before emergence. The post-seedling method is to cover the seedlings with plastic film before they emerge, and spray the stems and leaves when the seedlings grow to a certain period. After 30 days, the fresh weight inhibition percentage is used to express the efficacy. The test weeds include four model plants, namely, the grass weeds barnyard grass and crabgrass, and the broad-leaved weeds rape and Amaranthus retroflexus. When the pot method is measured, the dosage of the compound is 100 grams / mu. Table 3 lists the potted weeding effect of JK-5-67.

[0037] Table 3. Potted weed control effect of test compounds (100 g / mu)

[0038]

[0039] It can be seen that JK-5-67 showed a weed control effect in the potted model, especially against the dicotyledonous weeds rapeseed and Amaranthus retroflexus. Especially when the stems and leaves were treated, the weed control effect on Amaranthus retroflexus was 100%.

Claims

1. Use of a five-membered heterocyclic pyrimidinedione compound or a salt thereof in preparing a herbicide, wherein the five-membered heterocyclic pyrimidinedione compound has the following structure:

2. The use according to claim 1, characterized in that The herbicide is a herbicide targeting weeds.

3. The use according to claim 1, characterized in that The herbicide is a herbicide targeting dicotyledonous weeds.

4. The use according to claim 1, characterized in that The herbicide is a herbicide for rapeseed and Amaranthus retroflexus.

5. The use according to claim 1, wherein the herbicide is in the form of emulsifiable concentrate, wettable powder, soluble powder, aqueous emulsion, microemulsion, aqueous solution, suspension, microcapsule or water-dispersible granule.

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