A phenylpyrazoline compound, its preparation method and application

Abstract

This invention relates to a phenylpyrazoline compound, its preparation method, and its application. It can improve the herbicidal activity, safety, or economy of phenylpyrazoline compounds and further reduce production costs. This invention provides an economically feasible method that is beneficial for the regionally selective preparation of intermediates on an industrial scale.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis, specifically to phenylpyrazoline compounds and their preparation methods, compositions containing said compounds, and the uses and methods of using these compounds to control weeds. Background Technology

[0002] In the field of agrochemicals, phenylpyrazoline compounds have the activity of controlling weeds, pests / mites, and harmful pathogens. Among them, pinoxaden, as one of the post-emergence selective herbicides that Syngenta has successfully developed after years of research, has become a leading product among herbicides for grass weeds in cereal fields.

[0003] With the widespread use of these compounds, phenylpyrazoline compounds have encountered problems such as increased resistance and reduced efficacy in pest control.

[0004] To further improve the herbicidal activity, safety, and economy of phenylpyrazoline compounds, it is urgent to develop new compound varieties. This invention introduces multi-substituted heterocyclic groups or alkoxycarbonyl groups into the phenylpyrazoline structure, and designs and synthesizes a series of phenylpyrazoline compounds with herbicidal activity that have not been reported in the literature. Summary of the Invention

[0005] To improve the herbicidal activity, safety, or economy of phenylpyrazoline compounds and further reduce production costs, this invention designs and synthesizes a series of previously unreported phenylpyrazoline compounds with herbicidal activity. Furthermore, this invention provides an economically feasible synthetic method for the efficient preparation of intermediates of phenylpyrazoline compounds. This method is advantageous for regioselective preparation and is carried out at extremely low palladium catalyst concentrations, making it suitable for industrial-scale implementation.

[0006] On the one hand, the present invention provides a biologically active phenylpyrazoline compound represented by formula (I).

[0007]

[0008] in,

[0009] R1, R2 and R3 may be the same or different, and each is selected from hydrogen, halogen, or C1-C6 alkyl;

[0010] R4 is selected from hydrogen, halogens, and C1-C3 alkyl groups;

[0011] R5 is selected from C1-C6 alkoxycarbonyl, C3-C6 cycloalkylcarbonyl, C3-C6 cycloalkyl, C3-C6 heterocyclic, and C6-C6 cycloalkyl groups. 10 Aryl, C6-C 10 heteroaryl, C6-C 10 heteroaryl C1-3 The alkoxy group may be substituted with one or more substituents selected from: halogens and C2-C3 alkenyl groups;

[0012] The preferred compound of this invention is the compound shown in formula (I), wherein:

[0013] R1, R2, and R3 may be the same or different, and each is selected from hydrogen, fluorine, chlorine, bromine, or C1-C3 alkyl.

[0014] R4 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, and propyl.

[0015] R5 is selected from methoxycarbonyl, ethoxycarbonyl, cyclopropyl, pyridyl, phenyl, pyridylmethoxy, and pyridylethoxy, and the group may be substituted by one or more substituents selected from: fluorine, chlorine, vinyl, and propenyl;

[0016] A further preferred compound of the present invention is the compound shown in formula (I), wherein:

[0017] R1, R2, and R3 may be the same or different, and each is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, and propyl.

[0018] R4 is selected from hydrogen;

[0019] R5 is selected from monomethyl oxaloyl, monoethyl oxaloyl, 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropaneformyl, 3,6-dichloro-2-pyridyl, 3,4,6-trichloro-2-pyridylmethoxy, and 2,3,4,5,6-pentafluorophenyl.

[0020] The compounds of formula (I) particularly preferred by the present invention are those shown below:

[0021]

[0022]

[0023] The compounds of formula (I) particularly preferred by the present invention are those shown below:

[0024]

[0025] The compounds of the present invention may exist in one or more isomers, including enantiomers, diastereomers, and geometric isomers.

[0026] On the other hand, the present invention provides efficient and low-cost methods for preparing compounds of formula (I), especially compounds of formulas (VI) and (IV).

[0027] The compound represented by formula (I) of the present invention can be obtained by the reaction formula (1) shown below, and the compound of formula (III) can be obtained by purchasing or by referring to the methods in relevant literature;

[0028] Compound (II) in reaction (1) can be obtained by reaction (2) shown below, wherein compound (V) can be synthesized by purchasing or referring to relevant literature methods;

[0029] The compound of formula (IV) in reaction (2) can be obtained by reaction (3) shown below, where R8 = NH2 and R9 = NH2;

[0030] Compound (VI) in reaction (3) can be obtained by reaction (4) as shown below, wherein compound (VI) can be obtained by reacting compound (VII) with compound (VI). The reaction is carried out in an alkaline environment, wherein X1 = CN, X2 = CN or X1 = COOR6, X2 = COOR7 or X1 = CN, X2 = COOR7, and R6 and R7 are C1-C6 alkyl groups;

[0031] (VII) in reaction (4) can be synthesized by purchasing or referring to relevant literature methods;

[0032] Unless otherwise specified, the substituents in reaction formulas (1) to (4) are as defined above, and the specific reaction formulas are as follows.

[0033] Reaction formula (1):

[0034]

[0035] Reaction (2):

[0036]

[0037] Reaction (3):

[0038]

[0039] Reaction (4):

[0040]

[0041] Compound (I) can be prepared by reacting the compound shown in formula (II) with the compound shown in formula (III) in a suitable solvent such as acetonitrile, dichloromethane, toluene, xylene, dichloroethane, chloroform or 2-methyltetrahydrofuran at 0°C to the reflux temperature of the system, in the presence of a suitable base such as triethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or sodium bicarbonate, to obtain the compound shown in formula (I) (reaction formula 1).

[0042] The compound of formula (II) can be prepared by reacting the compound of formula (IV) with the compound of formula (V) in a suitable solvent such as chlorobenzene, dichlorobenzene, toluene, or xylene at -10°C to the reflux temperature of the system to obtain the compound of formula (II) (reaction formula 2).

[0043] The compound of formula (IV) can be prepared as follows: when X1 = CN and X2 = CN, in water, in the presence of a suitable acid such as sulfuric acid, hydrochloric acid, or nitric acid, at 0°C to the reflux temperature of the system, the compound shown in formula (VI) can be transformed into the compound shown in formula (IV) (reaction formula 3).

[0044] Alternatively, the compound of formula (IV) can be prepared as follows: when X1 = CN, X2 = COOR6, R6 = C1-C6 alkyl, in water, in the presence of a suitable acid such as sulfuric acid, hydrochloric acid, nitric acid, etc., at 0°C to the reflux temperature of the system, and then refluxed with toluene under ammonia to remove water, the compound shown in formula (VI) can be transformed into the compound shown in formula (IV) (reaction formula 3).

[0045] Alternatively, the compound of formula (IV) can be prepared as follows: when X1 = COOR6, X2 = COOR7, and R6 and R7 = C1-C6 alkyl, in an alcohol solvent in the presence of ammonia, at 0°C to the reflux temperature of the system, the compound shown in formula (VI) can be transformed into the compound shown in formula (IV) (reaction formula 3).

[0046] The compound of formula (VI) can be prepared as follows: when X1 = CN and X2 = CN, in a suitable solvent such as N-methylpyrrolidone, N-ethylpyrrolidone, DMF, DMAc, toluene or xylene, at 0°C to the reflux temperature of the system, in the presence of any one or more of a suitable base such as sodium hydride, sodium methoxide, sodium hydroxide, potassium hydroxide, potassium carbonate, potassium methoxide, sodium tert-butoxide, and potassium tert-butoxide, the compound of formula (VII) reacts with malononitrile to obtain the compound shown in formula (VI). The addition of a palladium catalyst and a phosphine ligand or a palladium catalyst complexed with a phosphine ligand can promote or accelerate the reaction (reaction formula 4).

[0047] The compound of formula (VI) can be prepared as follows: when X1 = COOR6, X2 = COOR7, R6, R7 = C1-C6 alkyl, in a suitable solvent such as N-methylpyrrolidone, N-methylpyrrolidone, N-ethylpyrrolidone, DMF, DMAc, toluene or xylene, at 0°C to reflux temperature, in the presence of any one or more of a suitable base such as sodium hydride, sodium methoxide, sodium hydroxide, potassium hydroxide, potassium carbonate or potassium methoxide, sodium tert-butoxide, potassium tert-butoxide, the compound of formula (VII) reacts with a malonic acid ester to obtain the compound shown in formula (VI). The addition of a palladium catalyst and a phosphine ligand or a palladium catalyst complexed with a phosphine ligand can promote or accelerate the reaction (reaction formula 4).

[0048] The compound of formula (VI) can be prepared as follows: when X1 = CN, X2 = COOR7, R7 = C1-C6 alkyl, in a suitable solvent such as N-methylpyrrolidone, N-methylpyrrolidone, N-ethylpyrrolidone, DMF, DMAc, toluene or xylene, at 0°C to reflux temperature, in the presence of any one or more of a suitable base such as sodium hydride, sodium methoxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium tert-butoxide, potassium tert-butoxide or potassium methoxide, the compound of formula (VII) is reacted with a cyano ester to obtain the compound shown in formula (VI), and a palladium catalyst and a phosphine ligand or a palladium catalyst complexed with a phosphine ligand are added to promote or accelerate the reaction (reaction formula 4).

[0049] Furthermore, in the preparation of compounds of formula (VI), the reaction can be promoted or accelerated in an alkaline environment in the presence of a palladium catalyst composed of palladium and phosphine ligands of formula VIII, or a palladium catalyst complexed with phosphine ligands of formula VIII, wherein the amount of compound VIII accounts for 50-100% of the total amount of phosphine ligands.

[0050]

[0051] in,

[0052] R 10 R 11 and R 12 They are the same or different, each independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C3-C6 halocycloalkyl, aryl, fused ring;

[0053] n is selected from 0 to 5, and m is selected from 0 to 5.

[0054] An alkaline environment can be formed by adding an appropriate alkali, which is selected from one or more alkali metal hydroxides or one or more organic bases, such as sodium hydride, sodium methoxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium tert-butoxide, potassium tert-butoxide, or potassium methoxide.

[0055] The base is used based on the compound of formula (VII) in a ratio of 1-5 equivalents, preferably 2-4 equivalents, for example: 2 equivalents, 2.5 equivalents, 3 equivalents, 3.5 equivalents, 4 equivalents, but not limited thereto.

[0056] Suitable palladium sources are selected from palladium(II) salts, such as palladium(II) dihalide, palladium(II) chloride, palladium(II) sulfate or palladium(II) acetate or aqueous solutions thereof, or palladium complexes in which Pd is in the 0 oxidation state;

[0057] The palladium source is based on the compound of formula (VII) and is used in a low proportion of 0.0001-0.50 equivalents, preferably 0.0001-0.10 equivalents, and especially 0.0001-0.05 equivalents, such as 0.0003 equivalents, 0.0005 equivalents, 0.0007 equivalents, 0.0009 equivalents, 0.0010 equivalents, 0.0015 equivalents, and 0.002 equivalents. 0 equivalent, 0.0025 equivalent, 0.0030 equivalent, 0.0035 equivalent, 0.0040 equivalent, 0.0045 equivalent, 0.0050 equivalent, 0.0060 equivalent, 0.0070 equivalent, 0.0080 equivalent, 0.0090 equivalent, 0.010 equivalent, 0.020 equivalent, 0.030 equivalent, 0.040 equivalent, but not limited to these.

[0058] The phosphine ligands of formula VIII-1 or VIII-2 of the present invention can be used in conjunction with known phosphine ligands in the prior art to form palladium catalysts. Examples of the phosphine ligands of the present invention include (2,6-diisopropoxyphenyl)tert-butylcyclohexylphosphine, bis(2,6-diisopropoxyphenyl)cyclohexylphosphine, 2-(dicyclohexylphosphino)biphenyl (247940-06-3), dicyclohexylphenylphosphine, 2-dicyclohexylphosphine-2'-methylbiphenyl (251320-86-2), 2-dicyclohexylphosphine-2'-methoxybiphenyl (255835-82-6), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (657408-07-6), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (564483). -18-7), 2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (787618-22-8), 2-(dicyclohexylphosphine)3,6-dimethoxy-2',4',6'-triisopropyl[1,1'-biphenyl]-2-yl]phosphine (1070663-78-3), (2,6-diisopropoxyphenyl)dicyclohexylphosphine (1053657-07-0), (2,4,6-triisopropylphenyl)dicyclohexylphosphine (303111-96-8), (2-(1,3-dioxolane-2-yl)phenyl)dicyclohexylphosphine (246158-59-8), (2-methylphenyl)dicyclohexylphosphine (173593-25-4), diphenylcyclohexylphosphine (6372-42-5). Phosphine ligands known in the prior art that can be combined include tri-tert-butylphosphine, [(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine, triphenylphosphine, tri(substituted phenyl)phosphine, tricyclohexylphosphine, diphenylphosphine, dicyclohexylphosphine, etc.

[0059] The phosphine ligand is used based on a palladium source in a ratio of 2-4 equivalents, preferably 2-3 equivalents, such as 2 equivalents, 2.5 equivalents, 3 equivalents, but not limited to these.

[0060] In this invention, the amount of each of the phosphine ligands of formula VIII-1 or formula VIII-2 independently accounts for 50-100% of the total amount of phosphine ligands, preferably 60-100%, for example: 60%, 63%, 65%, 68%, 72%, 75%, 78%, 80%, 85%, 90%, 95%, 100%, but is not limited thereto.

[0061] Specifically, taking palladium(II) chloride as the palladium source as an example, the palladium catalysts involved in this invention include, but are not limited to: bis[(3,4,5-trimethoxyphenyl)dicyclohexylphosphine]palladium(II) chloride (1527485-06-8), bis[(3,5-di-tert-butylphenyl)dicyclohexylphosphine]palladium(II) chloride (1527501-28-5), and bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) chloride (945375-7). 7-9), bis[2-(dicyclohexylphosphino)biphenyl]palladium chloride (II) (2991108-80-4), [[(4-(N,N-dimethylamino)phenyl]di-tert-butyl-dicyclohexylphenylphosphine]palladium chloride (II) (1073119-76-2), bis[(2-cyclohexylphenyl)dicyclohexylphosphine]palladium chloride (II) (1197814-76-8), bis[(2,4,6-trimethylphenyl)dicyclohexylphosphine]palladium chloride ( II)(1432724-99-6), bis[(2-methoxyphenyl)dicyclohexylphosphine]palladium chloride (II))(1527501-20-7), bis[(2-methylthiophenyl)dicyclohexylphosphine]palladium chloride (II))(1197814-74-6), bis[(4-tert-butylphenyl)dicyclohexylphosphine]palladium chloride (II))(1527501-21-8), bis[(4-methoxyphenyl)dicyclohexylphosphine]palladium chloride (II) (1527501-29-6), bis[(2-methylphenyl)dicyclohexylphosphine]palladium chloride (II) (1159848-03-9), bis[(2-isopropylphenyl)dicyclohexylphosphine]palladium chloride (II) (1197814-75-7), bis[dicyclohexylphenylphosphine]palladium chloride (II) (945464-53-9), (1073119-44-4), those skilled in the art can select a suitable palladium source as needed.

[0062] For carbon-carbon coupling reactions, existing technologies have disclosed the use of aryl halides as starting materials in the presence of a palladium catalyst to obtain aryl malonate diesters or aryl malononitriles. For example, JP-A-60 197650 and WO00 / 78712 describe methods for synthesizing aryl malonate dionitriles by C-C linkage of aryl halides and malonate anions. To promote the reaction, palladium catalysts are usually used in the presence of binding ligands, with triphenylphosphine being the most commonly used ligand. Patent CN1329370C reports a method for synthesizing aryl malonate dionitriles using a combination of a palladium catalyst and triphenylphosphine. The reaction process is simple, but as a planar compound, triphenylphosphine has a weak binding force with the palladium catalyst, causing some catalyst to adhere to the wall and become unrecoverable, resulting in a less than ideal coupling catalytic effect. Furthermore, the palladium catalyst is easily decomposed, affecting the catalytic efficiency. The consumption of palladium catalyst is large and the recovery rate is low, leading to increased production costs. Given the limitations of palladium catalysts, such as limited reserves and high prices, it is of great significance to develop a combination of highly efficient and recyclable palladium catalysts and phosphine ligands for carbon-carbon coupling reactions.

[0063] Furthermore, in the reaction involved in this invention, when triphenylphosphine is used as a ligand, there is a significant problem of genomic dehalogenation during the coupling reaction, and a large number of undesirable byproducts are generated, such as impurities that cause dehalogenation of the aryl halides of the raw materials. Even with the addition of excessive amounts of triphenylphosphine, the problem cannot be solved.

[0064] Those skilled in the art will recognize that in coupling catalytic reactions, palladium complex catalysts have a decisive influence on the activity and selectivity of the reaction, and the choice of ligands plays a crucial role in the activation and stability of palladium. The inventors unexpectedly discovered that using a complex formed from palladium and a tethered compound of formula VIII as a catalyst exhibits high activity for the coupling reaction of this invention. Compared to using triphenylphosphine, the coupling catalytic reaction of aryl halides in the presence of a palladium catalyst combining palladium and the phosphine ligand of formula VIII of this invention significantly improves catalytic efficiency. Even when the amount of palladium catalyst is reduced to 50% of its original value, the reaction yield remains stable. Furthermore, the palladium catalyst, in conjunction with the phosphine ligand of formula VIII of this invention, particularly when the substituent on the phosphine ligand is an electron-donating group, unexpectedly achieves extremely high reaction yields and product purity, while the content of proton dehalogenation byproducts in the product is far lower than existing levels. The hypothesized mechanism is that when a cyclohexyl substituent is present in the phosphine ligand, the cyclohexyl group can be appropriately distorted, making the phosphine ligand a stereostructure, which can then better bind with the palladium catalyst, improve the catalytic efficiency of the coupling reaction, reduce the consumption of palladium catalyst and increase the recovery rate of palladium catalyst, which is conducive to reducing production costs and achieving high-efficiency production.

[0065] The specific synthesis method is described in more detail in the examples below.

[0066] On the other hand, the present invention provides applications of phenylpyrazoline compounds.

[0067] The compounds of formula (I) provided by this invention have herbicidal biological activity at a dosage of 15 to 2250 grams of active ingredient per hectare. Some exemplary compounds have excellent weed control effects and can achieve good results at very low doses.

[0068] The compounds of formula (I) provided by this invention are biologically active, and some compounds exhibit excellent biological activity. They show particular activity in the control of weeds, pests / mites, and harmful pathogens in agriculture, horticulture, floriculture, and sanitation. For details of the pests described herein, please refer to The Pesticide Manual.

[0069] Furthermore, the present invention provides a composition containing a bioactive amount of a compound of formula (I) and at least one other composition selected from surfactants, solid diluents and liquid diluents for weed control, wherein the compound of formula (I) of the present invention can be used alone for effective weed control.

[0070] Furthermore, the present invention also provides a composition for weed control containing a bioactive amount of the compound of formula (I) and an effective amount of at least one other bioactive compound or preparation. The compound of formula (I) of the present invention can be used with other biochemical substances, including other herbicides, insecticides / miticides, and fungicides.

[0071] Furthermore, the present invention also relates to a method for controlling weeds, comprising contacting a bioavailable amount of the compound of formula (I) with weeds, harmful pathogens, or their environment. Furthermore, weed and harmful pathogens can be controlled by contact with an effective amount of the compound of formula (I) of the present invention, or a mixture containing the compound of formula (I) and at least one other compound or preparation in a bioavailable amount.

[0072] Compared with the prior art, the advantages of the present invention are as follows:

[0073] This invention designs and synthesizes a series of previously unreported phenylpyrazoline compounds with herbicidal activity by introducing multi-substituted acyl groups into the phenylpyrazoline structure.

[0074] Furthermore, this invention unexpectedly discovers a highly efficient and low-cost method for CC coupling, which facilitates the large-scale production of intermediate VI of phenylpyrazoline compounds. In the presence of a phosphine ligand of formula VIII, the coupling reaction of aryl halides can be efficiently catalyzed in the presence of a very small amount of catalyst, improving reaction efficiency. At the same time, reaction stability and palladium recovery are significantly improved. The preparation method of this invention has high economic value.

[0075] Attached Figures and Their Descriptions

[0076] Figure 1 At a concentration of 10 g / mu, the herbicidal effect of the exemplary compounds of the present invention on *Ophiopogon japonicus* 29 days after application is shown. The left side shows the herbicidal effect of compound 10, the middle side shows the blank control, and the right side shows the herbicidal effect of clodinafop-propargyl.

[0077] Figure 2 At a concentration of 10 g / mu, the herbicidal effect of the exemplary compounds of the present invention on vetch 29 days after application is shown. The left side shows the herbicidal effect of compound 10, the middle side shows the blank control, and the right side shows the herbicidal effect of clodinafop-propargyl. Detailed Implementation

[0078] I. Synthesis of Phenyrazoline Compounds

[0079] Example 1: Preparation of Compound 01

[0080]

[0081] (1) Add 3000g N-methylpyrrolidone and 713.0g sodium methoxide (13.2mol, 3eq) to the reaction flask, add 348.8g (5.28mol, 1.2eq) malononitrile, keep the reaction at 50℃ for 1 hour, add 815.0g (4.4mol, 1eq) 2,6-dimethylbromobenzene, add 0.80g (0.0045mol, 0.001eq) palladium chloride and 4.51g (0.009mol, 0.002eq) bis(2,6-diisopropoxyphenyl)cyclohexylphosphine, keep the reaction at 140-170℃ for 10 hours.

[0082] After the reaction was completed, the palladium catalyst was recovered by filtration, the solvent was recovered by vacuum distillation of the filtrate, water was added and stirred until clear, concentrated hydrochloric acid was added, and the mixture was allowed to stand and separate into layers. The upper organic layer was distilled under vacuum to obtain 2,6-dimethylphenylmalononitrile, totaling 704.5 g, with a yield of 94.1% based on 2,6-dimethylbromobenzene.

[0083]

[0084] (2) 2800g of sulfuric acid solution was added to the reaction flask, and 704.5g (4.14mol) of 2,6-dimethylphenylmalonium was added dropwise. The temperature was controlled at 40-60℃, and the reaction was carried out for 4 hours. After the reaction was completed, the solution was poured into water, cooled to 10-20℃, filtered, washed with water, and dried to obtain a white solid 2,6-dimethylphenylmalonium dicarboxamide, totaling 810.5g. The yield was 94.9% based on 2,6-dimethylphenylmalonium dicarboxamide.

[0085]

[0086] (3) Add 10.2 g (0.10 mol) of 1,4,5-oxadiazacycloheptane (Formula V) to the reaction flask, along with 90 g of toluene and 18.5 g (0.09 mol) of 2,6-dimethylphenylpropanedicarboxamide. Heat the mixture to 100-110 °C and maintain the temperature for 10 h. Cool the mixture to 10-20 °C and add 92.5 g of 10% sodium hydroxide aqueous solution. Allow the mixture to stand and separate into layers. Adjust the pH of the aqueous layer to acidic using 30% hydrochloric acid. Filter, wash with water, and dry to obtain a white epoxy product, totaling 22.6 g. The yield, based on 2,6-dimethylphenylpropanedicarboxamide, is 91.6%.

[0087]

[0088] (4) Add 27.4 g (0.10 mol) of the product from step (3) to the reaction flask, add 137 g of dichloroethane and 15.2 g (0.15 mol) of triethylamine, cool to 10 °C, and slowly add 52.2 g (0.1 mol) of a 50% solution of 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropaneformyl chloride / dichloroethane. After the addition is complete, keep the reaction at the temperature for 1 h, and wash with 50 g of 5% dilute hydrochloric acid and 40 g of saturated sodium bicarbonate solution. Concentrate and dry the organic layer to obtain compound 01, totaling 45.4 g, with a yield of 91.0%.

[0089] Compound 01: 1 H NMR (400MHz, DMSO-d6) δ7.08(d,J=7.4Hz,1H),7.03(d,J=8.0Hz,2H),6.56(d,J=8.8Hz,1H),4.10(dd,J= 24.9,5.3Hz,4H),3.89–3.61(m,4H),2.38-2.35(m,2H),2.12(d,J=5.4Hz,6H),1.19(s,3H),0.66(s,3H).

[0090] LC-MS: (M+1)m / z = 499.3.

[0091] Example 2 Preparation of Compound 06

[0092]

[0093] 2.74 g (0.010 mol) of 8-(2-ethylphenyl)-9-hydroxy-1,2,4,5-tetrahydro-7H-pyrazolo[1,2-d][1,4,5]oxadizazo-7-one and 60 mL of tetrahydrofuran were added to a 100 mL reaction flask. 1.5 g of triethylamine (0.015 mol) was added under ice bath conditions, followed by the slow addition of 1.84 g of monomethyl oxaloyl chloride (0.015 mol). The reaction was maintained at this temperature for 3 h. Ice water was added, followed by washing with 40 g of saturated sodium bicarbonate solution. The organic layer was concentrated and dried to obtain 3.17 g of compound O6, with a yield of 88.1%.

[0094] Compound 06: 1 H NMR(400MHz,Chloroform-d)δ7.34–7.24(m,2H),7.18(s,1H),7.01(dd,J=7.5,1.0Hz,1H),4.53(s,3H),4.13(dd,J=6.4,1.5Hz ,2H),4.05(dd,J=7.0,1.5Hz,2H),3.91(dd,J=6.4,1.5Hz,2H),3.87–3.73(m,2H),2.72(d,J=7.6Hz,2H),1.28(t,J=7.6Hz,3H).

[0095] LC-MS: (M+1)m / z = 361.1.

[0096] By combining the synthesis methods of Reference Example 1 or 2 with the synthesis scheme of the present invention, using appropriate raw materials and conditions, or by referring to the preparation methods in the prior art, the target compounds in Table 1 can be obtained.

[0097] Table 1. Compound structures, names, and characterization data.

[0098]

[0099]

[0100] II. Synthetic Intermediate VI

[0101] Example 3

[0102] 3000 g of N-methylpyrrolidone and 641.7 g of sodium methoxide (11.88 mol, 3.0 eq) were added to the reaction flask. The temperature was maintained at 30–50 °C, and 627.5 g (4.75 mol, 1.2 eq) of dimethyl malonate was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 1 hour. Then, 732.8 g (3.96 mol, 1 eq) of 2,6-dimethylbromobenzene, 0.80 g (0.0045 mol, 0.001 eq) of palladium chloride, and 4.51 g (0.009 mol, 0.002 eq) of bis(2,6-diisopropoxyphenyl)cyclohexylphosphine were added. The temperature was maintained at 150 °C–170 °C, and the reaction was maintained for 3–5 hours.

[0103] After the reaction was completed, the temperature was lowered to 80℃, the palladium catalyst was recovered by filtration, and the solvent was recovered by distillation under reduced pressure of the filtrate to obtain 891.5g of dimethyl 2,6-dimethylphenylmalonate with a purity of 99.5% and a yield of 94.8% based on 2,6-dimethylbromobenzene.

[0104] Example 4

[0105] 3000 g of N-methylpyrrolidone and 614.7 g of sodium methoxide (11.88 mol, 3.0 eq) were added to the reaction flask. The temperature was maintained at 30–50 °C, and 537.3 g (4.75 mol, 1.2 eq) of ethyl cyanoacetate was added dropwise. After the addition was complete, the reaction was continued at this temperature for 1 hour. Then, 732.8 g (3.96 mol, 1 eq) of 2,6-dimethylbromobenzene, 0.80 g (0.0045 mol, 0.001 eq) of palladium chloride, and 4.51 g (0.009 mol, 0.002 eq) of bis(2,6-diisopropoxyphenyl)cyclohexylphosphine were added. The temperature was maintained at 150–170 °C, and the reaction was continued for 3–5 hours.

[0106] After the reaction was completed, the temperature was lowered to 80℃, the palladium catalyst was recovered by filtration, and the solvent was recovered by distillation under reduced pressure of the filtrate to obtain ethyl 1-(2,6-dimethylphenyl)-1-cyanoacetate, totaling 816.9 g with a purity of 99.5%. The yield was 94.5% based on 2,6-dimethylbromobenzene.

[0107] Example 5

[0108] Add 3000g N-methylpyrrolidone and 614.7g sodium methoxide (11.88mol, 3.0eq) to the reaction flask, maintain the temperature at 30-50℃, and add 313.5g (4.75mol, 1.2eq) malononitrile dropwise. After the addition is complete, continue the reaction at this temperature for 1 hour, then add 732.8g (3.96mol, 1eq) 2,6-dimethylbromobenzene, 0.64g (0.0036mol, 0.0008eq) palladium chloride, and 2.62g (0.0072mol, 0.0016eq) (2,6-diisopropoxyphenyl) tert-butylcyclohexylphosphine. Maintain the temperature at 150-170℃ and continue the reaction for 5-7 hours.

[0109] After the reaction was completed, the temperature was lowered to 80℃, and the palladium catalyst was recovered by filtration. The filtrate was heated and distilled under reduced pressure to recover 2110g of solvent. The product, 2,6-dimethylphenylmalononitrile, was 628.5g with a purity of 99.5%, and the yield was 92.8% based on 2,6-dimethylbromobenzene.

[0110] Example 6

[0111] Add 3000g N-methylpyrrolidone and 614.7g sodium methoxide (11.88mol, 3.0eq) to a reaction flask, maintain the temperature at 30–50℃, and add 313.5g (4.75mol, 1.2eq) malononitrile dropwise. After the addition is complete, maintain the temperature for 1 hour, then add 732.8g (3.96mol, 1eq) 2,6-dimethylbromobenzene, 1.2g (0.0067mol, 0.0015eq) palladium chloride, and 4.92g (0.0135mol, 0.003eq) (2,6-diisopropoxyphenyl) tert-butylcyclohexylphosphine. Maintain the temperature at 120–140℃ and react for 3–4 hours.

[0112] After the reaction was completed, the temperature was lowered to 80℃, the palladium catalyst was recovered by filtration, and the solvent was recovered by distillation under reduced pressure of the filtrate. The product, 2,6-dimethylphenylmalononitrile, was 650.4 g with a purity of 99.5%, and the yield was 96.0% based on 2,6-dimethylbromobenzene.

[0113] Example 7

[0114] Add 3000g of N-methylpyrrolidone and 666.5g of potassium hydroxide (11.88mol, 3.0eq) to a reaction flask, maintain the temperature at 30-50℃, and add 313.5g (4.75mol, 1.2eq) malononitrile dropwise. After the addition is complete, maintain the temperature for 1 hour, then add 732.8g (3.96mol, 1eq) of 2,6-dimethylbromobenzene, 1.2g (0.0067mol, 0.0015eq) of palladium chloride, and 4.92g (0.0135mol, 0.003eq) of (2,6-diisopropoxyphenyl)tert-butylcyclohexylphosphine. Maintain the temperature at 120-140℃ and react for 3-4 hours.

[0115] After the reaction was completed, the temperature was lowered to 80℃, the palladium catalyst was recovered by filtration, and the solvent was recovered by distillation under reduced pressure of the filtrate. The product, 2,6-dimethylphenylmalononitrile, was 646.0 g with a purity of 99.5%, and the yield was 95.3% based on 2,6-dimethylbromobenzene.

[0116] Example 8

[0117] Add 3000g of N-methylpyrrolidone and 641.7g of sodium methoxide (11.88mol, 3.0eq) to the reaction flask, maintain the temperature at 30-50℃, and add 627.5g (4.75mol, 1.2eq) of dimethyl malonate dropwise. After the addition is complete, continue the reaction at this temperature for 1 hour, then add 732.8g (3.96mol, 1eq) of 2,6-dimethylbromobenzene, 0.80g (0.0045mol, 0.001eq) of palladium chloride, and 2.47g (0.009mol, 0.002eq) of phenyldicyclohexylphosphine. Maintain the temperature at 120-140℃ and continue the reaction for 3-5 hours.

[0118] After the reaction was completed, the temperature was lowered to 80°C, the palladium catalyst was recovered by filtration, and the solvent was recovered by distillation under reduced pressure of the filtrate to obtain 887.2 g of dimethyl 2,6-dimethylphenylmalonate with a purity of 99.5% and a yield of 94.4% based on 2,6-dimethylbromobenzene.

[0119] Example 9

[0120] Add 3000g of N-methylpyrrolidone and 641.7g of sodium methoxide (11.88mol, 3.0eq) to the reaction flask, maintain the temperature at 30-50℃, and add 627.5g (4.75mol, 1.2eq) of dimethyl malonate dropwise. After the addition is complete, continue the reaction at this temperature for 1 hour, then add 732.8g (3.96mol, 1eq) of 2,6-dimethylbromobenzene, 0.80g (0.0045mol, 0.001eq) of palladium chloride, and 2.56g (0.009mol, 0.002eq) of dicyclohexyl(2-methylphenyl)phosphine. Maintain the temperature at 120-140℃ and continue the reaction for 3-5 hours.

[0121] After the reaction was completed, the temperature was lowered to 80°C, the palladium catalyst was recovered by filtration, and the solvent was recovered by distillation under reduced pressure of the filtrate to obtain 882.9 g of dimethyl 2,6-dimethylphenylmalonate with a purity of 99.5% and a yield of 93.9% based on 2,6-dimethylbromobenzene.

[0122] Example 10

[0123] Add 3000g of N-methylpyrrolidone and 641.7g of sodium methoxide (11.88mol, 3.0eq) to a reaction flask, maintain the temperature at 30–50℃, and add 627.5g (4.75mol, 1.2eq) of dimethyl malonate dropwise. After the addition is complete, continue the reaction at this temperature for 1 hour, then add 732.8g (3.96mol, 1eq) of 2,6-dimethylbromobenzene, 0.64g (0.0036mol, 0.0008eq) of palladium chloride, and 2.81g (0.0072mol, 0.0016eq) of (2,6-diisopropoxyphenyl)dicyclohexylphosphine. Maintain the temperature at 130–150℃ and continue the reaction for 3–5 hours.

[0124] After the reaction was completed, the temperature was lowered to 80°C, the palladium catalyst was recovered by filtration, and the solvent was recovered by distillation under reduced pressure of the filtrate to obtain 870.7 g of dimethyl 2,6-dimethylphenylmalonate with a purity of 99.5% and a yield of 92.6% based on 2,6-dimethylbromobenzene.

[0125] Example 11

[0126] 3000 g of N-methylpyrrolidone and 614.7 g of sodium methoxide (11.88 mol, 3.0 eq) were added to the reaction flask. The temperature was maintained at 30–50 °C, and 313.5 g (4.75 mol, 1.2 eq) of malononitrile was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 1 hour. Then, 732.8 g (3.96 mol, 1 eq) of 2,6-dimethylbromobenzene, 0.80 g (0.0045 mol, 0.001 eq) of palladium chloride, 1.76 g (0.0045 mol, 0.001 eq) of (2,6-diisopropoxyphenyl)dicyclohexylphosphine, and 0.91 g (0.0045 mol, 0.001 eq) of tri-tert-butylphosphine were added. The temperature was maintained at 130–150 °C, and the reaction was maintained at this temperature for 5–7 hours.

[0127] After the reaction was completed, the temperature was lowered to 80℃, the palladium catalyst was recovered by filtration, and the solvent was recovered by distillation under reduced pressure of the filtrate. The product, 2,6-dimethylphenylmalononitrile, was 615.4 g with a purity of 99.5%, and the yield was 90.8% based on 2,6-dimethylbromobenzene.

[0128] Example 12

[0129] 3000 g of N-methylpyrrolidone and 614.7 g of sodium methoxide (11.88 mol, 3.0 eq) were added to the reaction flask. The temperature was maintained at 30–50 °C, and 313.5 g (4.75 mol, 1.2 eq) of malononitrile was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 1 hour. Then, 732.8 g (3.96 mol, 1 eq) of 2,6-dimethylbromobenzene, 0.64 g (0.0036 mol, 0.0008 eq) of palladium chloride, 1.41 g (0.0036 mol, 0.0008 eq) of (2,6-diisopropoxyphenyl)dicyclohexylphosphine, and 0.73 g (0.0036 mol, 0.0008 eq) of tri-tert-butylphosphine were added. The temperature was maintained at 130–150 °C, and the reaction was maintained for 6–8 hours.

[0130] After the reaction was completed, the temperature was lowered to 80℃, the palladium catalyst was recovered by filtration, and the solvent was recovered by distillation under reduced pressure of the filtrate. The product was 595.1g of 2,6-dimethylphenylmalononitrile with a purity of 99.5%, and the yield was 87.8% based on 2,6-dimethylbromobenzene.

[0131] Example 13

[0132] 3000 g of N-methylpyrrolidone and 614.7 g of sodium methoxide (11.88 mol, 3.0 eq) were added to the reaction flask. The temperature was maintained at 30–50 °C, and 313.5 g (4.75 mol, 1.2 eq) of malononitrile was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 1 hour. Then, 732.8 g (3.96 mol, 1 eq) of 2,6-dimethylbromobenzene, 1.2 g (0.0067 mol, 0.0015 eq) of palladium chloride, 2.62 g (0.0067 mol, 0.0015 eq) of (2,6-diisopropoxyphenyl)dicyclohexylphosphine, and 1.36 g (0.0067 mol, 0.0015 eq) of tri-tert-butylphosphine were added. The temperature was maintained at 130–150 °C, and the reaction was maintained for 5–7 hours.

[0133] After the reaction was completed, the temperature was lowered to 80℃, the palladium catalyst was recovered by filtration, and the solvent was recovered by distillation under reduced pressure of the filtrate. The product, 2,6-dimethylphenylmalononitrile, was 615.6 g with a purity of 99.5%, and the yield was 90.9% based on 2,6-dimethylbromobenzene.

[0134] Comparative Example 1

[0135] 3000 g of N-methylpyrrolidone and 614.7 g of sodium methoxide (11.88 mol, 3.0 eq) were added to the reaction flask. The temperature was maintained at 30–50 °C, and 313.5 g (4.75 mol, 1.2 eq) of malononitrile was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 1 hour. Then, 732.8 g (3.96 mol, 1 eq) of 2,6-dimethylbromobenzene, 0.80 g (0.0045 mol, 0.001 eq) of palladium chloride, and 2.36 g (0.009 mol, 0.002 eq) of triphenylphosphine were added. The temperature was maintained at 130–150 °C, and the reaction was maintained for 5 hours.

[0136] After the reaction was completed, the temperature was lowered to 80℃, the palladium catalyst was recovered by filtration, and the solvent was recovered by distillation under reduced pressure of the filtrate. The product, 2,6-dimethylphenylmalononitrile, was 300.4 g with a purity of 97.0%, and the yield was 43.2% based on 2,6-dimethylbromobenzene.

[0137] Comparative Example 2

[0138] 3000 g of N-methylpyrrolidone and 614.7 g of sodium methoxide (11.88 mol, 3.0 eq) were added to the reaction flask. The temperature was maintained at 30–50 °C, and 313.5 g (4.75 mol, 1.2 eq) of malononitrile was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 1 hour. Then, 732.8 g (3.96 mol, 1 eq) of 2,6-dimethylbromobenzene, 1.60 g (0.009 mol, 0.002 eq) of palladium chloride, and 4.72 g (0.018 mol, 0.004 eq) of triphenylphosphine were added. The temperature was maintained at 130–150 °C, and the reaction was maintained for 5 hours.

[0139] After the reaction was completed, the temperature was lowered to 80℃, the palladium catalyst was recovered by filtration, and the solvent was recovered by distillation under reduced pressure of the filtrate. The product was 593.1 g of 2,6-dimethylphenylmalononitrile with a purity of 97.0%, and the yield was 85.3% based on 2,6-dimethylbromobenzene.

[0140] III. Examples of Compound Bioassay

[0141] The present invention conducted herbicidal activity tests on some exemplary compounds, and some experimental results are as follows.

[0142] Test targets: Three grassy weeds (barnyard grass, ryegrass, and wild oats) and two broadleaf weeds (quinoa and vetch) were selected as test targets. At the time of application, ryegrass had 2-3 leaves and was approximately 15 cm tall; barnyard grass and wild oats had 3-4 leaves and were approximately 10 cm tall; quinoa and vetch had 2-4 leaves and were approximately 10 cm tall.

[0143] Experimental Method: The foliar treatment activity of the herbicide was tested by spraying the stems and leaves of various potted plants using an indoor spray gun. A certain amount of stock solution or formulation was weighed and diluted in 13.5 ml of 0.5% Tween water (calculated based on 45 L / acre of water). The solution was then sprayed evenly onto five types of weeds (four pots of each type) in a 37*54 cm (0.2 m²) blue box using the spray gun until the solution was used up. The spray gun was rinsed with clean water once when the solution was changed. Before the experiment, a blank control was used to practice the spraying speed and technique to ensure that each pot of weeds was treated evenly. After spraying, the plants were returned to the indoor environment for normal cultivation.

[0144] Experimental results: Herbicidal activity of each treatment was assessed visually at 14 and 29 days post-application. Evaluation criteria are as follows:

[0145] Table 2 Evaluation Criteria for Herbicidal Activity

[0146]

[0147]

[0148] Experimental Results and Analysis:

[0149] Table 3. Efficacy statistics of each treatment 14 days after administration.

[0150]

[0151] Table 4. Efficacy statistics of each treatment 29 days after administration.

[0152]

[0153]

[0154] As can be seen from Tables 3 and 4, some exemplary compounds of the present invention exhibit outstanding technical effects in controlling three types of grass weeds (barnyard grass, ryegrass, and American privet) and two types of broadleaf weeds (white quinoa and vetch). Furthermore, compound 10 of the present invention and clopyralid show superior effects against American privet, as observed visually (see attached table). Figure 1 Both have comparable activity. Compound 10 of this invention is more effective against vetch, and its control effect is significantly better than that of clodinafop-propargyl (with added...). Figure 2 ).

[0155] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A biologically active phenylpyrazoline compound as shown in formula (I), Its features are, R1, R2 and R3 may be the same or different, and each is selected from hydrogen, halogen, or C1-C6 alkyl; R4 is selected from hydrogen, halogens, and C1-C3 alkyl groups; R5 is selected from C1-C6 alkoxycarbonyl, C3-C6 cycloalkylcarbonyl, C3-C6 cycloalkyl, C3-C6 heterocyclic, and C6-C6 cycloalkyl groups. 10 Aryl, C6-C 10 heteroaryl, C6-C 10 The group is a heteroarylalkoxy group, and the group may be substituted by one or more substituents selected from: halogens and C2-C3 alkenyl groups.

2. The phenylpyrazoline compound as described in claim 1, characterized in that: R1, R2, and R3 may be the same or different, and each is selected from hydrogen, fluorine, chlorine, bromine, or C1-C3 alkyl. R4 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, and propyl. R5 is selected from methoxycarbonyl, ethoxycarbonyl, cyclopropyl, pyridyl, phenyl, pyridylmethoxy, and pyridylethoxy, and the group may be substituted by one or more substituents selected from fluorine, chlorine, vinyl, and propenyl.

3. The phenylpyrazoline compound as described in claim 1, characterized in that: R1, R2, and R3 may be the same or different, and each is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, and propyl. R4 is selected from hydrogen; R5 is selected from monomethyl oxaloyl, monoethyl oxaloyl, 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropaneformyl, 3,6-dichloro-2-pyridyl, 3,4,6-trichloro-2-pyridylmethoxy, and 2,3,4,5,6-pentafluorophenyl.

4. The phenylpyrazoline compound as described in claim 1, characterized in that, Selected from the following compounds:

5. A method for synthesizing a phenylpyrazoline intermediate (VI), characterized in that, The intermediate compound of formula (VI) can be obtained by combining with compound of formula (VII). The reaction is carried out in an alkaline environment in the presence of a palladium catalyst and a phosphine ligand, or a palladium catalyst complexed with a phosphine ligand, wherein the ratio of the palladium catalyst to the phosphine ligand is 1:2-4. Wherein, the substituents R1, R2, R3 and R4 are as described in claim 1, X1 = CN, X2 = CN or X1 = COOR6, X2 = COOR7 or X1 = CN, X2 = COOR7, and R6 and R7 are C1-C6 alkyl groups.

6. The synthesis method as described in claim 5, characterized in that, The phosphine ligand is selected from at least one compound of formula VIII, and the amount of compound VIII accounts for 50-100% of the total amount of phosphine ligand. in, R 10 R 11 and R 12 They are the same or different, each independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C3-C6 halocycloalkyl, aryl, fused ring; n is selected from 0 to 5, and m is selected from 0 to 5.

7. The synthesis method as described in claim 5, characterized in that, An alkaline environment can be formed by adding a suitable alkali, which is selected from one or more alkali metal hydroxides or one or more organic bases.

8. The synthesis method as described in claim 6, characterized in that, The compound of formula VIII is selected from (2,6-diisopropoxyphenyl)tert-butylcyclohexylphosphine, bis(2,6-diisopropoxyphenyl)cyclohexylphosphine, 2-(dicyclohexylphosphino)biphenyl, dicyclohexylphenylphosphine, (2-methylphenyl)dicyclohexylphosphine, 2-dicyclohexylphosphine-2'-methylbiphenyl, 2-dicyclohexylphosphine-2'-methoxybiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine-2',4',6'- One or more of the following: triisopropylbiphenyl, 2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl, 2-(dicyclohexylphosphine)3,6-dimethoxy-2',4',6'-triisopropyl[1,1'-biphenyl]-2-yl]phosphine, (2,6-diisopropoxyphenyl)dicyclohexylphosphine, (2,4,6-triisopropylphenyl)dicyclohexylphosphine, (2-(1,3-dioxolane-2-yl)phenyl)dicyclohexylphosphine, and diphenylcyclohexylphosphine.

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