Use of a five-membered heterocyclic pyrimidinedione compound for the preparation of herbicides

Abstract

The present application relates to a kind of five-membered heterocyclic pyrimidine diketones compound in the preparation of herbicide purposes, especially its in the preparation of herbicide purposes for preventing and controlling dicotyledonous weed rape and amaranthus retroflexus.The compound of the present application has good prevention and control effect on dicotyledonous weed at the dosage of 100 g / acre, and the herbicidal effect on amaranthus retroflexus is 100% when stem and leaf are treated.The chemical structural formula of the five-membered heterocyclic pyrimidine diketones compound is as follows:

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of agricultural chemicals, and relates to a use of a five-membered heterocyclic pyrimidinedione compound in preparation of a herbicide, in particular, a use of the five-membered heterocyclic pyrimidinedione compound in preparation of a herbicide for preventing and controlling dicotyledonous weeds such as oilseed rape and amaranth. BACKGROUND

[0002] Valine, leucine and isoleucine, three branched-chain amino acids, can only be synthesized in vivo by plants and microorganisms, and there is no such biochemical process in the mammalian body. Therefore, a chemical substance capable of inhibiting the biosynthesis of branched-chain amino acids can be used as a herbicide or an antibacterial drug, and has biological safety to humans and animals (McCourt JA, et al. Amino Acids, 2006, 31(2), 173-210). In fact, the first enzyme in this process, acetohydroxy acid synthase (AHAS, E.C. 2.2.1.6), is a very successful herbicide target. Herbicides targeting AHAS include sulfonylurea, imidazolinone, pyrimidinyl oxybenzoic acid and triazolopyrimidine sulfamide, and so on, and there are more than 60 commercialized varieties. These herbicides effectively control weeds in farmland, and play a huge role in ensuring food security and promoting yield increase (Wang JG, J. Pestic. Sci., 2014, 16(4), 367-374).

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

[0004] Ketol-acid reductoisomerase (KARI, E.C. 1.1.1.86) is the second enzyme in the biosynthesis of branched-chain amino acids, downstream of AHAS, and has long been the hope of people to find super-high-efficiency herbicides like AHAS inhibitors. Among them, Hoe 704, IpOHA and cyclopropane dicarboxylic acid (CPD) shown in the following figure are representative compounds found internationally that have relatively strong inhibitory activity on plant-derived KARI (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 pot conditions. The most active compound Hoe 704 can only show >80% control effect on barnyard grass, and pigweed and other weeds at a dose of 10000 g / ha (Bauer KR, et al., EP0106114, 1986-06-10).

[0005]

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

[0007] Pei Jianfeng et al. reported in Chinese invention patent CN114539148A that a compound similar in structure to NSC116565 (coded as JK-5-67 in this patent) has inhibitory activity on human flap endonuclease 1 (FEN-1), with an IC 50The IC50 value of the compound is 0.125 μM, and it is inferred that it has the potential to cure hepatitis B, and the biological activity is protected. However, the patent CN114539148A does not mention any data of the herbicidal activity of the compound.

[0008] SUMMARY

[0009] The purpose of the present application is to provide a use of a five-membered heterocyclic pyrimidinedione compound in the preparation of a herbicide. The compound has a strong inhibition rate on rape root length in a plate model, and has a strong control effect on dicotyledonous weeds such as rape and amaranthus retroflexus in a pot model whether soil treatment or stem-leaf treatment.

[0010] The five-membered heterocyclic pyrimidinedione compound provided by the present application is

[0011]

[0012] In the use, the herbicide has a good control effect on rape and amaranthus retroflexus at a dose of 100 g / acre. The herbicide comprises the five-membered heterocyclic pyrimidinedione compound and one or more agriculturally acceptable carriers. The dosage form is emulsifiable concentrate, wettable powder, soluble powder, emulsion in water, microemulsion, water agent, suspension concentrate, microcapsule or water dispersible granule. The use mode is soil treatment or stem-leaf treatment. BRIEF DESCRIPTION OF DRAWINGS

[0013] Figure 1 is a herbicidal effect diagram of compound JK-5-67 on amaranthus retroflexus at 100 g / acre stem-leaf treatment. DETAILED DESCRIPTION

[0014] The substantial features of the present application can be embodied in the following examples, but these examples are only illustrative and not limiting to the present application.

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

[0016]

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

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

[0019] The experimental procedure was performed essentially as described in the literature (Bauer, Let al.; J. Heterocylic Chem.; 1968, 5, 331-335). The preparation of intermediate 2 was performed by adding diethyl oxalate sodium salt (starting material 1, 12.6 g, 60 mmol) in 150 mL of diethyl ether in a 250 mL round bottom flask, stirring and cooling to -15 °C, then slowly adding liquid bromine (9.6 g, 60 mmol), after the addition was complete, the temperature was allowed to return to room temperature overnight. The reaction was filtered, the precipitate was washed with diethyl ether (50 mL x 2), the organic phase was collected and dried over anhydrous magnesium sulfate (20 g), filtered and concentrated under reduced pressure to give 2-bromo-3-oxosuccinic acid diethyl ester 2 as a light yellow liquid in 67% yield, which was used in the next step without purification.

[0020] The preparation of intermediate 3 was performed by suspending thioformamide (1.10 g, 18.0 mmol, 1.5 eq) and NaHC03(4.03 g, 47.9 mmol, 4 eq) in anhydrous tetrahydrofuran at 0 °C. A solution of 2-bromo-3-oxosuccinic acid diethyl ester 2 (3.20 g, 11.98 mmol, 1 eq) in anhydrous tetrahydrofuran was added. The reaction was stirred overnight, heating to room temperature. The white precipitate was filtered and washed with diethyl ether. The filtrate was concentrated under vacuum and then redissolved in anhydrous tetrahydrofuran. A cooled (0 °C) solution of trifluoroacetic anhydride (4.22 mL, 29.9 mmol, 2.5 eq) and anhydrous pyridine (5.43 mL, 67.4 mmol, 5.6 eq) in anhydrous tetrahydrofuran was added dropwise to the reaction mixture at 0 °C and stirred at room temperature overnight. The solvent was evaporated under vacuum 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 under vacuum. Purification by column chromatography on silica gel (20% ethyl acetate / hexane) gave the title compound 3 as a light yellow oil (1.70 g, 53%).

[0021] The preparation of intermediate 4 was performed by adding hydroxylamine hydrochloride (9.4 g, 135 mmol) in ethanol in a 250 mL three-necked flask, under argon protection, sodium ethoxide (5.4 g, 135 mmol) in ethanol was added, a neutralization reaction occurred, after 30 minutes, the sodium chloride precipitate was quickly filtered, the filtrate was collected, under argon protection, a solution of intermediate 3 (6.2 g, 27 mmol) in ethanol was injected, overnight. After the reaction was completed, it was filtered, the solid was collected and oven dried, the yield of intermediate 4 was 60%. It was used directly in the next step without purification.

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

[0023] The preparation of JK-5-67 was as follows: Hot NaOH (1 M) solution was added to 5,7-dioxo-4,7-dihydrothiazolo[4,5-d]pyrimidine-6(5H)-alkyl benzenesulfonate (intermediate 5) (176 mg, 0.54 mmol) and refluxed until all solid was dissolved (15 min). The reaction mixture was acidified with 15% hydrochloric acid. After standing at 4 °C overnight, beige crystals formed. These were collected on a Buchner funnel and dried in a desiccator to give the title compound JK-5-67 (i.e. compound no. 7) (72 mg, 72%). Characterisation data for JK-5-67 are as follows: m.p. > 260 °C 1 H NMR (300 MHz, DMSO-d6): δ 12.79 (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 + Calcd 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] KARI from plant source is from rice, and its cDNA code is J013002N13. The super-expression was carried out through the common E. coli system BL21 (DE3), and the pure KARI was obtained after the purification by the fixed metal affinity chromatography IMAC. The test temperature was controlled at 30°C, and the reaction was carried out in the buffer system of 0.1M Tris-HCl (pH 8.0), and the reaction solution contained 0.2mM NADPH, 1mM MgCl2, 0.1mM acetyllactate, and different concentrations of small molecule inhibitors. In the experiment, the buffer solution used in the experiment was added into 1mL quartz test tube, and 10μL rice KARI was added into the buffer solution, and the change of NADPH disappearance rate was dynamically monitored. The inhibition constant K i The inhibition constant K

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

[0027] wherein v o represents the maximum catalytic reaction rate of rice KARI without being inhibited, [I] represents the concentration of the compound, and v represents the reaction rate. Table 1 lists the K i values of rice KARI of JK-5-67 and NSC116565.

[0028] Table 1. K i values of test compounds on rice KARI

[0029] Compound Code Inhibition of KARI in rice K i values JK-5-67 1.8 ± 0.14 μM NSC 116565 2.4 ± 0.22 μM

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

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

[0032] Table 2. Inhibition rates of test compounds on the radicle length of rape

[0033] Compound Code 100 mg / L 10 mg / L JK-5-67 98.8％ 94.1％ NSC 116565 98.8％ 77.5％

[0034] It can be seen that both JK-5-67 and NSC116565 have strong rape root length inhibition at the 100 mg / L dosage, but at the 10 mg / L dosage, JK-5-67 still exhibits 94.1% rape root length inhibition, while the inhibition rate of NSC116565 is reduced to 77.5%.

[0035] Example 4. Potting weeding effect of compound JK-5-67

[0036] A certain amount of soil is put into a plastic cup with a diameter of 8 cm, a certain amount of water is added, and after sowing, a certain thickness of soil is covered, and before the seedlings emerge, a plastic film is covered, and a certain amount of clean water is added every day, and the pre-emergence method inhibits soil treatment before emergence. The post-emergence method covers the seedlings with a plastic film before emergence, and when the seedlings grow to a certain period, stem and leaf spraying treatment is carried out. After 30 days, the fresh weight inhibition percentage is used to represent the efficacy. The test weeds include four types of plants, namely the grass weeds Echinochloa crus-galli and Digitaria sanguinalis, and the broadleaf weeds Brassica napus and Amaranthus retroflexus. When the potting method is used for determination, the dosage of the compound is 100 g / m2. Table 3 lists the potting weeding effect of JK-5-67.

[0037] Table 3. Potting weeding effect of test compounds (100 g / m2)

[0038]

[0039] It can be seen that JK-5-67 exhibits weeding effect in the potting model, especially for the dicotyledonous weeds Brassica napus and Amaranthus retroflexus, especially when stem and leaf treatment is used, and the weeding effect on Amaranthus retroflexus is 100%.

Claims

1. Use of a five-membered heterocyclic pyrimidine dione compound or a salt thereof in the preparation of a herbicide, said five-membered heterocyclic pyrimidine dione compound having the following structure: The herbicide is a herbicide against oilseed rape and amaranth.

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

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