CN118812500A - A substituted aryl diketone nitrile compound with herbicidal activity, preparation method and application thereof - Google Patents

Abstract

The present invention belongs to the technical field of agricultural chemical synthesis, and particularly relates to a substituted aromatic diketone nitrile compound, a preparation method and an application thereof. The substituted aromatic diketone nitrile compound provided by the present invention has a structure of the following general formula (I), and its preparation method mainly comprises contacting a compound of the structure shown in formula (II) with an alkaline solvent, wherein R ₁ , R ₂ and R ₃ are each defined as described in the specification. The substituted aromatic diketone nitrile compound of the present invention has high herbicidal activity, especially has an excellent effect on preventing and controlling grass weeds, and the prevention and control effect is even better than some commercial herbicides on the market.

Description

A substituted aromatic diketone nitrile compound with herbicidal activity, preparation method and application

Technical Field

The invention belongs to the technical field of agricultural chemical synthesis, and in particular relates to a substituted aromatic diketone nitrile compound with herbicidal activity, a preparation method and application thereof.

Background Art

p-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) is a non-ferrous heme oxidase that exists in almost all aerobic organisms. It can catalyze the conversion of p-hydroxyphenylpyruvate (HPPA) produced during tyrosine metabolism into homogentisate (HGA). The mechanism of action of HPPD herbicides is to inhibit the conversion of p-hydroxyphenylpyruvate into homogentisate in plants. In plants, homogentisate is further converted into plastoquinone and tocopherol, which are essential substances for the electron chain transfer in plant photosynthesis. If HPPD in plants is inhibited, the photosynthesis process of the plants will be blocked, causing them to show albinism symptoms and die.

The developed 4-HPPD herbicides can be divided into the following five categories: triketones, pyrazoles, isoxazoles, diketonitriles and benzophenones. The commercialized HPPD inhibitor herbicide isoxathiapiprolin is a "prodrug" that is inactive and does not inhibit HPPD in plants. Its activity comes from the product of the ring-opening transformation (i.e., from isoxathiapiprolin to diketonitrile). This ring-opening transformation is a rapid non-enzymatic hydrolysis that occurs in both plants and soil. Through literature research, it was found that the ring-closing step of the isoxazole ring in isoxazole compounds has a low yield, while the synthesis step of the active ingredient diketonitrile (DKN) that exerts herbicidal effects is simple and easy, so the direct synthesis of diketonitrile and its derivatives is more likely to develop new HPPD inhibitor varieties.

At present, there are literatures on diketonitrile HPPD inhibitors: Design, synthesis and herbicidal activity of new diketonitrile HPPD inhibitors, which describes the preparation method of this type of compound. The synthesis reaction formula is as follows:

The above synthesis method only describes diketonitrile compounds containing quinoline, furan and thiophene structures, but does not mention those containing other structures.

Summary of the invention

In view of the problems existing in the prior art, the present invention provides a substituted aromatic diketone nitrile compound, a preparation method and an application thereof, aiming to solve some of the problems in the prior art or at least alleviate some of the problems in the prior art.

The present invention is achieved by providing a substituted aromatic diketone nitrile compound, the general structural formula of which is shown in the following formula (I):

Wherein: the R ₁ is selected from one of cyclopropane, thiophene, and substituted or unsubstituted phenyl;

The _R2 is selected from

wherein R ₃ represents any one of H, halogen, CF ₃ , and C ₁ to C ₆ alkyl.

The synthetic route of the substituted aryl diketone nitrile compound described above is as follows:

Based on the above synthetic route, the second object of the present invention is to provide a method for preparing the above-mentioned substituted aryl diketone nitrile compound, comprising the following steps:

Step 1: dissolving compound 1 in an organic solvent I, then adding an acyl halide reagent and a catalyst, mixing well, and reacting the resulting mixed reaction solution 1 at room temperature to 100° C. for 2 to 12 hours to obtain compound 2;

Step 2: Mix compound 3 with organic solvent II, add sodium hydride in batches, mix well, and obtain a mixed reaction solution 2; dissolve compound 2 in organic solvent II I to obtain a compound 2 solution; slowly drop the compound 2 solution into the mixed reaction solution 2 at -5°C; after the dropwise addition is completed, continue to react at -5°C for 2-10 minutes, and then transfer the reaction system to room temperature for reaction for 8-24 hours to obtain the compound (I).

Furthermore, in the above technical solution, the compound 1 in step 1 is a carboxylic acid compound, and its structural formula is as follows:

Wherein: R ₂ is selected from wherein R ₃ represents any one of H, halogen, CF ₃ , and C ₁ to C ₆ alkyl.

Furthermore, in the above technical solution, the structural formula of the compound 2 in step 1 is as follows:

Wherein: R ₂ is selected from wherein R ₃ represents any one of H, halogen, CF ₃ , and C ₁ to C ₆ alkyl.

Furthermore, in the above technical solution, the acyl halide reagent in step 1 is thionyl chloride or oxalyl chloride.

Furthermore, in the above technical solution, the catalyst in step 1 is at least one of N,N-dimethylformamide, dimethylaniline or N-methylpyrrolidone.

Furthermore, in the above technical solution, the organic solvent I in step 1 is one or any combination of dichloroethane, toluene, acetonitrile, ethyl acetate, dichloromethane, tetrahydrofuran, and ethanol, preferably one or any combination of tetrahydrofuran, dichloromethane, acetonitrile, or ethyl acetate.

Furthermore, in the above technical solution, the molar ratio of the compound 1 to the acyl halide reagent in step 1 is 1.0:1.0-3.0.

Furthermore, in the above technical solution, the preferred molar ratio of the compound 1 to the acyl halide reagent is 1.0:1.5.

Furthermore, in the above technical solution, the structural formula of the compound 3 in step 2 is as follows:

Wherein: the R ₁ is selected from cyclopropane, thiophene, and substituted or unsubstituted phenyl.

Further, in the above technical solution, the organic solvent II and the organic solvent III in step 2 may be the same or different, and both may be one or a combination of dichloroethane, anhydrous tetrahydrofuran, acetonitrile, ethyl acetate, anhydrous dichloromethane, anhydrous ethanol. Preferably, it is one or a combination of anhydrous tetrahydrofuran, anhydrous dichloromethane, anhydrous ethanol.

Furthermore, in the above technical solution, the molar ratio of compound 3 to compound 2 and sodium hydride in step 2 is 0.5-1.5:1.0:1.0-3.0.

Furthermore, in the above technical solution, the preferred molar ratio of compound 3 to compound 2 and sodium hydride is 0.8:1:1.5.

The third object of the present invention is to provide the use of the above-mentioned substituted aryl diketone nitrile compounds in controlling weeds or in preparing weed killer agents.

Furthermore, in the above technical solution, the weeds are at least one of velvetleaf, wintergrass, ryegrass, foxtail grass or barnyard grass.

The fourth object of the present invention is to provide the use of the above-mentioned substituted aryl diketone nitrile compounds as 4-HPPD inhibitors.

In summary, the advantages and positive effects of the present invention are:

The invention provides a substituted aromatic diketone nitrile compound and a preparation method thereof. The compound of the invention has high safety activity against peanuts, wheat, sorghum, soybeans and corn while maintaining excellent herbicidal activity.

The substituted aryl diketone nitrile compounds provided by the present invention have good inhibitory activity on p-hydroxyphenylpyruvate dioxygenase. The substituted aryl diketone nitrile compounds provided by the present invention have particularly excellent herbicidal activity on weeds such as velvetleaf, wintergrass, ryegrass, foxtail grass and barnyard grass. The substituted aryl diketone nitrile compounds of the present invention have high herbicidal activity, especially have excellent effect on preventing and controlling grass weeds, and the prevention and control effect is even better than some commercial herbicides on the market.

DETAILED DESCRIPTION

In order to make the purpose, technical scheme and advantages of the present invention more clear, the present invention is further described in detail below in conjunction with the embodiments. The equipment and reagents used in each embodiment and test example can be obtained from commercial sources unless otherwise specified. The specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

Example 1 Preparation of 3-(Benzo[b]thiophen-2-yl)-2-(hydroxy(phenyl)methyl)-3-oxopropionitrile

Step A: Preparation of benzothiophene-2-yl chloride

Stir benzothiophene-2-carboxylic acid (10 mmol) and tetrahydrofuran (40 mL) in a dry three-necked flask, heat to 65°C, add thionyl chloride (30 mmol) and 1 mmol N,N-dimethylformamide after the benzothiophene-2-carboxylic acid is completely dissolved, and reflux for 4 hours. After the reaction is completed, remove the solvent by rotary evaporation, and use it directly in the next step without purification.

Step B: Preparation of 3-(Benzo[b]thiophen-2-yl)-2-(hydroxy(phenyl)methyl)-3-oxopropionitrile

In a 100 mL round-bottom flask, add 20 mL of tetrahydrofuran, then add benzoylacetonitrile (1.0 mmol), and then add sodium hydride solid (2.0 mmol) in batches. In a low-temperature stirrer at -5 ° C, stir and react for 10-20 min. Then, dissolve the acyl chloride (2 mmol) obtained in the previous step in 5 mL of tetrahydrofuran, and slowly drip it into the tetrahydrofuran solution of benzoylacetonitrile using a constant pressure dropping funnel. React at -5 ° C for 5 min, and then transfer the reaction system to room temperature 25 ° C for 10 h.

After the reaction, citric acid was added to the reaction system to acidify to pH=2, and then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was dried by spin drying. Silica gel was added to mix the sample. A light yellow solid was obtained by column chromatography (the mobile phase solvents were dichloromethane and methanol). mp151.6-152.0℃. ¹ HNMR (500MHz, CDCl ₃ )δ18.35(s,1H,OH),8.84(s,1H,Ar-H),8.08-8.02(m,2H,Ar-H),7.98(d,J＝8.0Hz,1H,Ar-H),7.91(d,J＝8.1Hz,1H,Ar-H),7.69-7.62(m,1H,Ar-H),7.60-7.49(m,3H,Ar-H),7.49-7.42(m,1H,Ar-H).

Example 2 Preparation of 3-(Benzo[b]thiophen-2-yl)-2-((3-chlorophenyl)(hydroxy)methyl)-3-oxopropionitrile

Step A: Preparation of benzothiophene-2-yl chloride

Stir benzothiophene-2-carboxylic acid (10 mmol) and tetrahydrofuran (40 mL) in a dry three-necked flask, heat to 80°C, add thionyl chloride (23 mmol) and 1 mmol N,N-dimethylformamide after the benzothiophene-2-carboxylic acid is completely dissolved, and reflux for 3 hours. After the reaction is completed, remove the solvent by rotary evaporation, and use it directly in the next step without purification.

Step B: Preparation of 3-(Benzo[b]thiophen-2-yl)-2-((3-chlorophenyl)(hydroxy)methyl)-3-oxopropionitrile

In a 100 mL round-bottom flask, add 20 mL of tetrahydrofuran, then add 3-chloro-benzoylacetonitrile (1.4 mmol), and then add sodium hydride solid (3.5 mmol) in batches. In a low-temperature stirrer at -5 ° C, stir and react for 10-20 min. Then, dissolve the acyl chloride (2 mmol) obtained in the previous step in 5 mL of tetrahydrofuran, and slowly drip it into the tetrahydrofuran solution of benzoylacetonitrile using a constant pressure dropping funnel. React at -5 ° C for 5 min, and then transfer the reaction system to room temperature 25 ° C for 12 h.

After the reaction, citric acid was added to the reaction system to acidify to pH=2, and then extracted with ethyl acetate. After drying with anhydrous sodium sulfate, the solvent was dried by spin drying, and silica gel was added to mix the sample. A light yellow solid was obtained by column chromatography (the mobile phase solvents were dichloromethane and methanol). mp160.7-161.8℃. ¹ H NMR (400MHz, CDCl ₃ )δ18.40(d,J＝1.5Hz,1H,OH),8.84(s,1H,Ar-H),8.05-7.96(m,3H,Ar-H),7.95(s,2H,Ar-H),7.95-7.90(m,1H,Ar-H),7.58-7.54(m,3H,Ar-H),7.50-7.43(m,1H,Ar-H).

Example 3 Preparation of 3-(Benzo[b]thiophen-2-yl)-2-((3-fluorophenyl)(hydroxy)methyl)-3-oxopropionitrile

Step A: Preparation of benzothiophene-2-yl chloride

Stir benzothiophene-2-carboxylic acid (10 mmol) and dichloromethane (40 mL) in a dry three-necked flask, heat to 60°C, add thionyl chloride (20 mmol) and 1 mmol N,N-dimethylformamide after the benzothiophene-2-carboxylic acid is completely dissolved, and reflux for 5 hours. After the reaction is completed, remove the solvent by rotary evaporation, and use it directly in the next step without purification.

Step B: Preparation of 3-(Benzo[b]thiophen-2-yl)-2-((3-fluorophenyl)(hydroxy)methyl)-3-oxopropionitrile

In a 100 mL round-bottom flask, add 20 mL of tetrahydrofuran, then add 3-fluoro-benzoylacetonitrile (1.4 mmol), and then add sodium hydride solid (3.5 mmol) in batches. In a low-temperature stirrer at -5 ° C, stir and react for 10-20 min. Then, dissolve the acyl chloride (2 mmol) obtained in the previous step in 5 mL of tetrahydrofuran, and slowly drip it into the tetrahydrofuran solution of benzoylacetonitrile using a constant pressure dropping funnel. React at -5 ° C for 5 min, and then transfer the reaction system to room temperature 25 ° C for 10 h.

After the reaction, citric acid was added to the reaction system to acidify to pH=2, and then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was dried by spin drying. Silica gel was added to mix the sample. A pale yellow solid was obtained by column chromatography (the mobile phase solvents were dichloromethane and methanol). mp165.5-165.8℃. ¹ H NMR (600MHz, CDCl ₃ )δ18.35(s,1H,OH),8.82(s,1H,Ar-H),8.15-8.08(m,2H,Ar-H),8.00-7.95(m,1H,Ar-H),7.94-7.89(m,1H,Ar-H),7.56-7.50(m,1H,Ar-H),7.49-7.41(m,1H,Ar-H),7.28-7.20(m,2H,Ar-H).

Example 4 Preparation of 3-(Benzo[b]thiophen-2-yl)-2-((3-bromophenyl)(hydroxy)methyl)-3-oxopropionitrile

Step A: Preparation of benzothiophene-2-yl chloride

Stir benzothiophene-2-carboxylic acid (10 mmol) and dichloromethane (40 mL) in a dry three-necked flask, heat to 40°C, add thionyl chloride (23 mmol) and 1 mmol N,N-dimethylformamide after the benzothiophene-2-carboxylic acid is completely dissolved, and reflux for 4 hours. After the reaction is completed, remove the solvent by rotary evaporation, and use it directly in the next step without purification.

Step B: Preparation of 3-(Benzo[b]thiophen-2-yl)-2-((3-bromophenyl)(hydroxy)methyl)-3-oxopropionitrile

In a 100 mL round-bottom flask, add 20 mL of tetrahydrofuran, then add 3-bromo-benzoylacetonitrile (1.4 mmol), and then add sodium hydride solid (3.5 mmol) in batches. In a low-temperature stirrer at -5 ° C, stir and react for 10-20 min. Then, dissolve the acyl chloride (2 mmol) obtained in the previous step in 5 mL of tetrahydrofuran, and slowly drip it into the tetrahydrofuran solution of benzoylacetonitrile using a constant pressure dropping funnel. React at -5 ° C for 5 min, and then transfer the reaction system to room temperature 25 ° C for 14 h.

After the reaction, citric acid was added to the reaction system to acidify to pH=2, and then extracted with ethyl acetate. After drying with anhydrous sodium sulfate, the solvent was dried by spin drying, and silica gel was added to mix the sample. A light yellow solid was obtained by column chromatography (the mobile phase solvents were dichloromethane and methanol). mp158.4-159.0℃. ¹ H NMR (600MHz, CDCl ₃ )δ18.32(s,1H,OH),8.86(s,1H,Ar-H),8.01(d,J＝8.0Hz,1H,Ar-H),8.00-7.91(m,3H,Ar-H),7.77-7.69(m,2H,Ar-H),

7.58-7.53(m,1H,Ar-H),7.52-7.44(m,1H,Ar-H),3.52(s,1H,CH).

Example 5 Preparation of 3-(Benzo[b]thiophen-2-yl)-2-((3-trifluoromethylphenyl)(hydroxy)methyl)-3-oxopropionitrile

Step A: Preparation of benzothiophene-2-yl chloride

Stir benzothiophene-2-carboxylic acid (10 mmol) and dichloromethane (40 mL) in a dry three-necked flask, heat to 40°C, add thionyl chloride (23 mmol) and 1 mmol N,N-dimethylformamide after the benzothiophene-2-carboxylic acid is completely dissolved, and reflux for 6 hours. After the reaction is completed, remove the solvent by rotary evaporation, and use it directly for the next step without purification.

Step B: Preparation of 3-(Benzo[b]thiophen-2-yl)-2-((3-trifluoromethylphenyl)(hydroxy)methyl)-3-oxopropionitrile

In a 100 mL round-bottom flask, add 20 mL of tetrahydrofuran, then add 3-trifluoromethyl-benzoylacetonitrile (1.2 mmol), and then add sodium hydride solid (3.5 mmol) in batches. In a low-temperature stirrer at -5 ° C, stir and react for 10-20 min. Then, dissolve the acyl chloride (2 mmol) obtained in the previous step in 5 mL of tetrahydrofuran, and slowly drip it into the tetrahydrofuran solution of benzoylacetonitrile using a constant pressure dropping funnel. React at -5 ° C for 5 min, and then transfer the reaction system to room temperature 25 ° C for 18 h.

After the reaction, citric acid was added to the reaction system to acidify to pH=2, and then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was dried by spin drying. Silica gel was added to mix the sample. A pale yellow solid was obtained by column chromatography (the mobile phase solvents were dichloromethane and methanol). mp151.6-152.1℃. ¹ H NMR (600MHz, CDCl ₃ )δ18.28(s,1H,OH),8.88(s,1H,Ar-H),8.16(d,J＝8.1Hz,2H,Ar-H),8.02(d,J＝8.1Hz,1H,Ar-H),7.95(d,J＝8.2Hz,1H,Ar-H),7.85(d,J＝8.2Hz,2H,Ar-H),7.60-7.54(m,1H,Ar-H),7.49(t,J＝7.4Hz,1H,Ar-H).

Example 6 Preparation of 3-(Benzo[b]thiophen-2-yl)-2-((3-methylphenyl)(hydroxy)methyl)-3-oxopropionitrile

Step A: Preparation of benzothiophene-2-yl chloride

Stir benzothiophene-2-carboxylic acid (10 mmol) and dichloromethane (40 mL) in a dry three-necked flask, heat to 50°C, add thionyl chloride (30 mmol) and 1 mmol N,N-dimethylformamide after the benzothiophene-2-carboxylic acid is completely dissolved, and reflux for 6 hours. After the reaction is completed, remove the solvent by rotary evaporation, and use it directly for the next step without purification.

Step B: Preparation of 3-(Benzo[b]thiophen-2-yl)-2-((3-methylphenyl)(hydroxy)methyl)-3-oxopropionitrile

In a 100 mL round-bottom flask, add 20 mL of tetrahydrofuran, then add 3-methyl-benzoylacetonitrile (1.3 mmol), and then add sodium hydride solid (3.0 mmol) in batches. In a low-temperature stirrer at -5 ° C, stir and react for 10-20 min. Then, dissolve the acyl chloride (2 mmol) obtained in the previous step in 5 mL of tetrahydrofuran, and slowly drip it into the tetrahydrofuran solution of benzoylacetonitrile using a constant pressure dropping funnel. React at -5 ° C for 5 min, and then transfer the reaction system to room temperature 25 ° C for 18 h.

After the reaction, citric acid was added to the reaction system to acidify to pH=2, and then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was dried by spin drying. Silica gel was added to mix the sample. A light yellow solid was obtained by column chromatography (the mobile phase solvents were dichloromethane and methanol). mp139.1-140.8℃. ¹ H NMR (400MHz, CDCl ₃ )δ18.32(s,1H,OH),8.80(s,1H,Ar-H),7.98-7.93(m,3H,Ar-H),7.89(d,J＝8.2Hz,1H,Ar-H),7.52-7.48(m,1H,Ar-H),7.43(t,J＝7.6Hz,1H,Ar-H),7.34(d,J＝8.1Hz,2H,Ar-H),2.45(s,3H,CH ₃ ).

Example 7 Preparation of 2-(Benzofuran-2-carbonyl)-3-(3-methylbenzene)-3-hydroxypropionitrile

Step A: Preparation of benzofuran-2-yl chloride

Stir benzofuran-2-carboxylic acid (10 mmol) and dichloromethane (40 mL) in a dry three-necked flask, heat to 60°C, add thionyl chloride (15 mmol) and 1 mmol N-methylpyrrolidone after the benzofuran-2-carboxylic acid is completely dissolved, and reflux for 10 hours. After the reaction is completed, remove the solvent by rotary evaporation, and use it directly in the next step without purification.

Step B: Preparation of 2-(Benzofuran-2-carbonyl)-3-(3-methylbenzene)-3-hydroxypropionitrile

In a 100 mL round-bottom flask, add 20 mL of tetrahydrofuran, then add 3-methyl-benzoylacetonitrile (1.4 mmol), and then add sodium hydride solid (3.5 mmol) in batches. In a low-temperature stirrer at -5 ° C, stir and react for 10-20 min. Then, dissolve the acyl chloride (2 mmol) obtained in the previous step in 5 mL of tetrahydrofuran, and slowly drip it into the tetrahydrofuran solution of benzoylacetonitrile using a constant pressure dropping funnel. React at -5 ° C for 5 min, and then transfer the reaction system to room temperature 25 ° C for 20 h.

After the reaction, citric acid was added to the reaction system to acidify to pH=2, and then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was dried by spin drying. Silica gel was added to mix the sample. A light yellow solid was obtained by column chromatography (the mobile phase solvents were dichloromethane and methanol). mp130.6-130.8℃. ¹ H NMR (500MHz, CDCl ₃ )δ18.24(s,1H,OH),8.28(s,1H,Ar-H),8.00(d,J＝8.1Hz,2H,Ar-H),7.77(d,J＝7.8Hz,1H,Ar-H),7.66(d,J＝8.5Hz,1H,Ar-H),7.57-7.52(m,1H,Ar-H),7.39-7.34(m,3H,Ar-H),2.47(s,3H,CH ₃ ).

Example 8 Preparation of 3-(Benzo[b]thiophen-2-yl)-2-((4-chlorophenyl)(hydroxy)methyl)-3-oxopropionitrile

Step A: Preparation of benzothiophene-2-yl chloride

Stir benzothiophene-2-carboxylic acid (10 mmol) and tetrahydrofuran (40 mL) in a dry three-necked flask, heat to 90°C, add thionyl chloride (20 mmol) and 1 mmol N-methylpyrrolidone after the benzothiophene-2-carboxylic acid is completely dissolved, and reflux for 4 hours. After the reaction is completed, remove the solvent by rotary evaporation, and use it directly for the next step without purification.

Step B: Preparation of 3-(Benzo[b]thiophen-2-yl)-2-((4-chlorophenyl)(hydroxy)methyl)-3-oxopropionitrile

In a 100 mL round-bottom flask, add 20 mL of tetrahydrofuran, then add 4-chloro-benzoylacetonitrile (1.5 mmol), and then add sodium hydride solid (3.8 mmol) in batches. In a low-temperature stirrer at -5 ° C, stir and react for 10-20 min. Then, dissolve the acyl chloride (2 mmol) obtained in the previous step in 5 mL of tetrahydrofuran, and slowly drip it into the tetrahydrofuran solution of benzoylacetonitrile using a constant pressure dropping funnel. React at -5 ° C for 5 min, and then transfer the reaction system to room temperature 25 ° C for 12 h.

After the reaction, citric acid was added to the reaction system to acidify to pH=2, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was dried by spin drying. Silica gel was added to mix the sample. A pale yellow solid was obtained by column chromatography (the mobile phase solvents were dichloromethane and methanol). mp172.7-173.1℃. ¹ H NMR (500MHz, CDCl ₃ )δ18.16(s,1H,OH),8.75(s,1H,Ar-H),7.93-7.85(m,3H,Ar-H),7.83(d,J＝8.1Hz,1H,Ar-H),7.56-7.51(m,1H,Ar-H),7.49-7.33(m,3H,Ar-H).

Example 9 Preparation of 3-(Benzo[b]thiophen-2-yl)-2-((4-fluorophenyl)(hydroxy)methyl)-3-oxopropionitrile

Step A: Preparation of benzothiophene-2-yl chloride

Stir benzothiophene-2-carboxylic acid (10 mmol) and tetrahydrofuran (40 mL) in a dry three-necked flask, heat to 70°C, add thionyl chloride (30 mmol) and 1 mmol N-methylpyrrolidone after the benzothiophene-2-carboxylic acid is completely dissolved, and reflux for 6 hours. After the reaction is completed, remove the solvent by rotary evaporation, and use it directly in the next step without purification.

Step B: Preparation of 3-(Benzo[b]thiophen-2-yl)-2-((4-fluorophenyl)(hydroxy)methyl)-3-oxopropionitrile

In a 100 mL round-bottom flask, add 20 mL of tetrahydrofuran, then add 4-fluoro-benzoylacetonitrile (1.5 mmol), and then add sodium hydride solid (3.0 mmol) in batches. In a low-temperature stirrer at -5 ° C, stir and react for 10-20 min. Then, dissolve the acyl chloride (2 mmol) obtained in the previous step in 5 mL of tetrahydrofuran, and slowly drip it into the tetrahydrofuran solution of benzoylacetonitrile using a constant pressure dropping funnel. React at -5 ° C for 5 min, and then transfer the reaction system to room temperature 25 ° C for 16 h.

After the reaction, citric acid was added to the reaction system to acidify to pH=2, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was dried by spin drying. Silica gel was added to mix the sample. A pale yellow solid was obtained by column chromatography (the mobile phase solvents were dichloromethane and methanol). mp182.4-183.3℃. ¹ H NMR (500MHz, CDCl ₃ )δ18.30(s,1H,OH),8.86(s,1H,Ar-H),8.01(d,J＝8.0Hz,1H,Ar-H),7.96-7.88(m,2H,Ar-H),7.76-7.71(m,1H,Ar-H),

7.60-7.53(m,2H,Ar-H),7.51-7.45(m,1H,Ar-H),7.41-7.33(m,1H,Ar-H).

Example 10 Preparation of 3-(Benzo[b]thiophen-2-yl)-2-((4-bromophenyl)(hydroxy)methyl)-3-oxopropionitrile

Step A: Preparation of benzothiophene-2-yl chloride

Stir benzothiophene-2-carboxylic acid (10 mmol) and tetrahydrofuran (40 mL) in a dry three-necked flask, heat to 80°C, add thionyl chloride (23 mmol) and 1 mmol N-methylpyrrolidone after the benzothiophene-2-carboxylic acid is completely dissolved, and reflux for 12 hours. After the reaction is completed, remove the solvent by rotary evaporation, and use it directly for the next step without purification.

Step B: Preparation of 3-(Benzo[b]thiophen-2-yl)-2-((4-bromophenyl)(hydroxy)methyl)-3-oxopropionitrile

In a 100 mL round-bottom flask, add 20 mL of tetrahydrofuran, then add 4-bromo-benzoylacetonitrile (1.2 mmol), and then add sodium hydride solid (3.5 mmol) in batches. In a low-temperature stirrer at -5 ° C, stir and react for 10-20 min. Then, dissolve the acyl chloride (2 mmol) obtained in the previous step in 5 mL of tetrahydrofuran, and slowly drip it into the tetrahydrofuran solution of benzoylacetonitrile using a constant pressure dropping funnel. React at -5 ° C for 5 min, and then transfer the reaction system to room temperature 25 ° C for 24 h.

After the reaction, citric acid was added to the reaction system to acidify to pH=2, and then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was dried by spin drying. Silica gel was added to mix the sample. A pale yellow solid was obtained by column chromatography (the mobile phase solvents were dichloromethane and methanol). mp129.1-130.6℃. ¹ H NMR (400MHz, CDCl ₃ )δ18.22(s,1H,OH),8.84(s,1H,Ar-H),8.12(d,J＝1.9Hz,1H,Ar-H),8.04-7.96(m,2H,Ar-H),7.92(d,J＝8.2Hz,1H,Ar-H),7.80-7.75(m,1H,Ar-H),7.57-7.51(m,1H,Ar-H),7.49-7.41(m,2H,Ar-H).

Example 11 Preparation of 3-(Benzo[b]thiophen-2-yl)-2-((4-trifluoromethylphenyl)(hydroxy)methyl)-3-oxopropionitrile

Step A: Preparation of benzothiophene-2-yl chloride

Stir benzothiophene-2-carboxylic acid (10 mmol) and tetrahydrofuran (40 mL) in a dry three-necked flask, heat to 80°C, add thionyl chloride (23 mmol) and 1 mmol N-methylpyrrolidone after the benzothiophene-2-carboxylic acid is completely dissolved, and reflux for 4 hours. After the reaction is completed, remove the solvent by rotary evaporation, and use it directly for the next step without purification.

Step B: Preparation of 3-(Benzo[b]thiophen-2-yl)-2-((4-trifluoromethylphenyl)(hydroxy)methyl)-3-oxopropionitrile

In a 100 mL round-bottom flask, add 20 mL of tetrahydrofuran, then add 4-trifluoromethyl-benzoylacetonitrile (1.0 mmol), and then add sodium hydride solid (4.0 mmol) in batches. In a low-temperature stirrer at -5 ° C, stir and react for 10-20 min. Then, dissolve the acyl chloride (2 mmol) obtained in the previous step in 5 mL of tetrahydrofuran, and slowly drip it into the tetrahydrofuran solution of benzoylacetonitrile using a constant pressure dropping funnel. React at -5 ° C for 5 min, and then transfer the reaction system to room temperature 25 ° C for 14 h.

After the reaction, citric acid was added to the reaction system to acidify to pH=2, and then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was dried by spin drying. Silica gel was added to mix the sample. A pale yellow solid was obtained by column chromatography (the mobile phase solvents were dichloromethane and methanol). mp172.5-172.7℃. ¹ H NMR (600MHz, CDCl ₃ )δ18.24(s,1H,OH),8.85(s,1H,Ar-H),8.28-8.24(m,2H,Ar-H),7.97(d,J＝8.1Hz,1H,Ar-H),7.90(t,J＝7.6Hz,2H,Ar-H),7.70(t,J＝8.1Hz,1H,Ar-H),7.56-7.51(m,1H,Ar-H),7.45(t,J＝7.5Hz,1H,Ar-H).

Example 12 Preparation of 2-(Benzofuran-2-carbonyl)-3-(2-chlorophenyl)-3-hydroxypropionitrile

Step A: Preparation of benzofuran-2-yl chloride

Stir benzofuran-2-carboxylic acid (10 mmol) and acetonitrile (40 mL) in a dry three-necked flask, heat to 80°C, add thionyl chloride (20 mmol) and 1 mmol N,N-dimethylformamide after the benzofuran-2-carboxylic acid is completely dissolved, and reflux for 6 hours. After the reaction is completed, remove the solvent by rotary evaporation, and use it directly for the next step without purification.

Step B: Preparation of 2-(Benzofuran-2-carbonyl)-3-(2-chlorophenyl)-3-hydroxypropionitrile

In a 100 mL round-bottom flask, add 20 mL of tetrahydrofuran, then add 2-chloro-benzoylacetonitrile (1.1 mmol), and then add sodium hydride solid (3.0 mmol) in batches. In a low-temperature stirrer at -5 ° C, stir and react for 10-20 min. Then, dissolve the acyl chloride (2 mmol) obtained in the previous step in 5 mL of tetrahydrofuran, and slowly drip it into the tetrahydrofuran solution of benzoylacetonitrile using a constant pressure dropping funnel. React at -5 ° C for 5 min, and then transfer the reaction system to room temperature 25 ° C for 14 h.

After the reaction, citric acid was added to the reaction system to acidify to pH=2, and then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was dried by spin drying. Silica gel was added to mix the sample. A pale yellow solid was obtained by column chromatography (the mobile phase solvents were dichloromethane and methanol). mp179.0-180.4℃. ¹ H NMR (500MHz, CDCl ₃ )δ17.65(s,1H,OH),8.37(s,1H,Ar-H),8.29(d,J＝0.9Hz,1H,Ar-H),7.80-7.75(m,1H,Ar-H),7.71-7.65(m,1H,Ar-H),7.64-7.52(m,3H,Ar-H),7.52-7.47(m,1H,Ar-H),7.47-7.41(m,1H,Ar-H).

Example 13 Preparation of 2-(Benzofuran-2-carbonyl)-3-(3-chlorophenyl)-3-hydroxypropionitrile

Step A: Preparation of benzofuran-2-yl chloride

Stir benzofuran-2-carboxylic acid (10 mmol) and acetonitrile (40 mL) in a dry three-necked flask, heat to 70°C, add thionyl chloride (20 mmol) and 1 mmol dimethylaniline after the benzofuran-2-carboxylic acid is completely dissolved, and reflux for 8 hours. After the reaction is completed, remove the solvent by rotary evaporation, and use it directly in the next step without purification.

Step B: Preparation of 2-(Benzofuran-2-carbonyl)-3-(3-chlorophenyl)-3-hydroxypropionitrile

In a 100 mL round-bottom flask, add 20 mL of tetrahydrofuran, then add 3-chloro-benzoylacetonitrile (1.5 mmol), and then add sodium hydride solid (3.5 mmol) in batches. In a low-temperature stirrer at -5 ° C, stir and react for 10-20 min. Then, dissolve the acyl chloride (2 mmol) obtained in the previous step in 5 mL of tetrahydrofuran, and slowly drip it into the tetrahydrofuran solution of benzoylacetonitrile using a constant pressure dropping funnel. React at -5 ° C for 5 min, and then transfer the reaction system to room temperature 25 ° C for 14 h.

After the reaction, citric acid was added to the reaction system to acidify to pH=2, extracted with ethyl acetate, dried over anhydrous sodium sulfate, the solvent was dried by spin drying, silica gel was added and mixed, and a light yellow solid was obtained by column chromatography (mobile phase solvents were dichloromethane and methanol). mp185.4-187.2℃. ¹ H NMR (600MHz, CDCl ₃ ) δ18.33(s,1H,OH),8.32(d,J＝1.1Hz,1H,Ar-H),8.19-8.11(m,2H,Ar-H),7.79(d,J＝7.9Hz,1H,Ar-H),7.68(d,J＝8. 4Hz,1H,Ar-H),7.61-7.54(m,1H,Ar-H),7.39(t,J=7.5Hz,1H,Ar-H),7.30-7.22(m,2H,Ar-H).

Example 14 Preparation of 2-(Benzofuran-2-carbonyl)-3-(3-fluorophenyl)-3-hydroxypropionitrile

Step A: Preparation of benzofuran-2-yl chloride

Stir benzofuran-2-carboxylic acid (10 mmol) and tetrahydrofuran (40 mL) in a dry three-necked flask, heat to 65°C, add thionyl chloride (20 mmol) and 1 mmol N,N-dimethylformamide after the benzofuran-2-carboxylic acid is completely dissolved, and reflux for 2 hours. After the reaction is completed, remove the solvent by rotary evaporation, and use it directly for the next step without purification.

Step B: Preparation of 2-(Benzofuran-2-carbonyl)-3-(3-fluorophenyl)-3-hydroxypropionitrile

In a 100 mL round-bottom flask, add 20 mL of tetrahydrofuran, then add 3-fluoro-benzoylacetonitrile (1.0 mmol), and then add sodium hydride solid (2.5 mmol) in batches. In a low-temperature stirrer at -5 ° C, stir and react for 10-20 min. Then, dissolve the acyl chloride (2 mmol) obtained in the previous step in 5 mL of tetrahydrofuran, and slowly drip it into the tetrahydrofuran solution of benzoylacetonitrile using a constant pressure dropping funnel. React at -5 ° C for 5 min, and then transfer the reaction system to room temperature 25 ° C for 8 h.

After the reaction, citric acid was added to the reaction system to acidify to pH=2, and then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was dried by spin drying. Silica gel was added to mix the sample. A light yellow solid was obtained by column chromatography (the mobile phase solvents were dichloromethane and methanol). mp179.9-180.2℃. ¹ H NMR (600MHz, CDCl ₃ )δ18.29(s,1H,OH),8.32(d,J＝1.0Hz,1H,Ar-H),8.07-8.00(m,2H,Ar-H),7.79(d,J＝7.9Hz,1H,Ar-H),7.68(d,J＝8.5Hz,1H,Ar-H),7.61-7.52(m,3H,Ar-H),7.39(t,J＝7.5Hz,1H,Ar-H).

Example 15 Preparation of 2-(Benzofuran-2-carbonyl)-3-(3-bromophenyl)-3-hydroxypropionitrile

Step A: Preparation of benzofuran-2-yl chloride

Stir benzofuran-2-carboxylic acid (10 mmol) and toluene (40 mL) in a dry three-necked flask, heat to 100°C, add thionyl chloride (20 mmol) and 1 mmol N,N-dimethylformamide after the benzofuran-2-carboxylic acid is completely dissolved, and reflux for 2 hours. After the reaction is completed, remove the solvent by rotary evaporation, and use it directly in the next step without purification.

Step B: Preparation of 2-(Benzofuran-2-carbonyl)-3-(3-bromophenyl)-3-hydroxypropionitrile

In a 100 mL round-bottom flask, add 20 mL of tetrahydrofuran, then add 3-bromo-benzoylacetonitrile (1.4 mmol), and then add sodium hydride solid (3.5 mmol) in batches. In a low-temperature stirrer at -5 ° C, stir and react for 10-20 min. Then, dissolve the acyl chloride (2 mmol) obtained in the previous step in 5 mL of tetrahydrofuran, and slowly drip it into the tetrahydrofuran solution of benzoylacetonitrile using a constant pressure dropping funnel. React at -5 ° C for 5 min, and then transfer the reaction system to room temperature 25 ° C for 16 h.

After the reaction, citric acid was added to the reaction system to acidify to pH=2, extracted with ethyl acetate, dried over anhydrous sodium sulfate, the solvent was dried by spin drying, silica gel was added and mixed, and a light yellow solid was obtained by column chromatography (mobile phase solvents were dichloromethane and methanol). mp176.7-177.1℃. ¹ H NMR (600MHz, CDCl ₃ ) δ18.08 (s, 1H, OH), 8.28 (d, J = 1.0Hz, 1H, Ar-H), 8.13 (t, J = 1.9Hz, 1H, Ar-H), 8.04-8.00 (m, 1H, Ar-H), 7.80-7.75 (m ,2H,Ar-H),7.68-7.64(m,1H,Ar-H),7.59-7.53(m,1H,Ar-H),7.43(t,J＝7.9Hz,1H,Ar-H),7.40-7.34(m,1H,Ar-H).

Example 16 Preparation of 2-(Benzofuran-2-carbonyl)-3-(4-trifluoromethylphenyl)-3-hydroxypropionitrile

Step A: Preparation of benzofuran-2-yl chloride

Stir benzofuran-2-carboxylic acid (10 mmol) and toluene (40 mL) in a dry three-necked flask, heat to 100°C, add thionyl chloride (30 mmol) and 1 mmol N,N-dimethylformamide after the benzofuran-2-carboxylic acid is completely dissolved, and reflux for 4 hours. After the reaction is completed, remove the solvent by rotary evaporation, and use it directly in the next step without purification.

Step B: Preparation of 2-(Benzofuran-2-carbonyl)-3-(4-trifluoromethylphenyl)-3-hydroxypropionitrile

In a 100 mL round-bottom flask, add 20 mL of tetrahydrofuran, then add 4-trifluoromethyl-benzoylacetonitrile (1.0 mmol), and then add sodium hydride solid (4.0 mmol) in batches. In a low-temperature stirrer at -5 ° C, stir and react for 10-20 min. Then, dissolve the acyl chloride (2 mmol) obtained in the previous step in 5 mL of tetrahydrofuran, and slowly drip it into the tetrahydrofuran solution of benzoylacetonitrile using a constant pressure dropping funnel. React at -5 ° C for 5 min, and then transfer the reaction system to room temperature 25 ° C for 24 h.

After the reaction, citric acid was added to the reaction system to acidify to pH=2, and then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was dried by spin drying. Silica gel was added to mix the sample. A light yellow solid was obtained by column chromatography (the mobile phase solvents were dichloromethane and methanol). mp181.2-181.4℃. ¹ H NMR (600MHz, CDCl ₃ )δ18.13(s,1H,OH),8.33(s,1H,Ar-H),8.17(d,J＝8.1Hz,2H,Ar-H),7.85(d,J＝8.1Hz,2H,Ar-H),7.83-7.79(m,1H,Ar-H),7.70(d,J＝8.5Hz,1H,Ar-H),7.63-7.58(m,1H,Ar-H),7.41(t,J＝7.5Hz,1H,Ar-H).

Example 17 Preparation of 3-hydroxy-3-phenyl-2-(quinoxaline-2-carbonyl)propionitrile

Step A: Preparation of quinoxaline-2-yl chloride

Quinoxaline-2-carboxylic acid (10 mmol) and toluene (40 mL) were stirred in a dry three-necked flask, heated to 100°C, and after the quinoxaline-2-carboxylic acid was completely dissolved, thionyl chloride (30 mmol) and 1 mmol N,N-dimethylformamide were added and refluxed for 8 h. After the reaction was completed, the solvent was removed by rotary evaporation and the mixture was directly used for the next step without purification.

Step B: Preparation of 3-hydroxy-3-phenyl-2-(quinoxaline-2-carbonyl)propionitrile

In a 100 mL round-bottom flask, add 20 mL of tetrahydrofuran, then add benzoylacetonitrile (2.0 mmol), and then add sodium hydride solid (4.0 mmol) in batches. In a low-temperature stirrer at -5 ° C, stir and react for 10-20 min. Then, dissolve the acyl chloride (2 mmol) obtained in the previous step in 5 mL of tetrahydrofuran, and slowly drip it into the tetrahydrofuran solution of benzoylacetonitrile using a constant pressure dropping funnel. React at -5 ° C for 5 min, and then transfer the reaction system to room temperature 25 ° C for 12 h.

After the reaction, citric acid was added to the reaction system to acidify to pH=2, and then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was dried by spin drying. Silica gel was added to mix the sample. A pale yellow solid was obtained by column chromatography (the mobile phase solvents were dichloromethane and methanol). mp126.1-126.4℃. ¹ H NMR (600MHz, CDCl ₃ )δ17.94-17.91(m,1H,OH),9.47(s,1H,Ar-H),8.35-8.30(m,1H,Ar-H),8.23-8.18(m,1H,Ar-H),8.18-8.14(m,2H,Ar-H),7.95-7.90(m,2H,Ar-H),7.70-7.64(m,1H,Ar-H),7.64-7.54(m,2H,Ar-H).

Example 18 Preparation of 3-(3-chlorophenyl)-3-hydroxy-2-(quinoxaline-2-carbonyl)propionitrile

Step A: Preparation of quinoxaline-2-yl chloride

Quinoxaline-2-carboxylic acid (10 mmol) and toluene (40 mL) were stirred in a dry three-necked flask, heated to 100°C, and after the quinoxaline-2-carboxylic acid was completely dissolved, thionyl chloride (30 mmol) and 1 mmol dimethylaniline were added and refluxed for 4 h. After the reaction was completed, the solvent was removed by rotary evaporation and the mixture was directly used for the next step without purification.

Step B: Preparation of 3-(3-chlorophenyl)-3-hydroxy-2-(quinoxaline-2-carbonyl)propionitrile

In a 100mL round-bottom flask, add 20mL tetrahydrofuran, then add 3-chloro-benzoyl acetonitrile (2.0mmol), then add sodium hydride solid (3.5mmol) in batches, stir and react for 10-20min in a low-temperature stirrer at -5℃, then dissolve the acyl chloride (2mmol) obtained in the previous step in 5mL tetrahydrofuran, slowly drip into the tetrahydrofuran solution of benzoyl acetonitrile with a constant pressure dropping funnel, react at -5℃ for 5min, and then transfer the reaction system to room temperature 25℃ for 13h. After the reaction is completed, add citric acid to the reaction system to acidify to pH=2, extract with ethyl acetate, dry with anhydrous sodium sulfate, spin dry the solvent, add silica gel and mix. Use column chromatography (mobile phase solvents are dichloromethane and methanol) to obtain a light yellow solid. mp167.6-169.5℃. ¹ H NMR (600MHz, CDCl ₃ ) δ17.96(s,1H,OH),9.48(s,1H,Ar-H),8.35-8.30(m,1H,Ar-H),8.28-8.19(m,3H,Ar-H),7.99-7.95(m,1H,Ar-H), 7.94-7.89(m,1H,Ar-H),7.26(t,J＝8.5Hz,2H,Ar-H).

Example 19 Preparation of 3-(4-fluorophenyl)-3-hydroxy-2-(quinoxaline-2-carbonyl)propionitrile

Step A: Preparation of quinoxaline-2-yl chloride

Quinoxaline-2-carboxylic acid (10 mmol) and toluene (40 mL) were stirred in a dry three-necked flask, and the temperature was raised to 100°C. After the quinoxaline-2-carboxylic acid was completely dissolved, thionyl chloride (30 mmol) and 1 mmol dimethylaniline were added and refluxed for 10 h. After the reaction was completed, the solvent was removed by rotary evaporation, and the mixture was directly used for the next step without purification.

Step B: Preparation of 3-(4-fluorophenyl)-3-hydroxy-2-(quinoxaline-2-carbonyl)propionitrile

In a 100 mL round-bottom flask, add 20 mL of tetrahydrofuran, then add 4-fluoro-benzoylacetonitrile (1.6 mmol), and then add sodium hydride solid (3.0 mmol) in batches. In a low-temperature stirrer at -5 ° C, stir and react for 10-20 min. Then, dissolve the acyl chloride (2 mmol) obtained in the previous step in 5 mL of tetrahydrofuran, and slowly drip it into the tetrahydrofuran solution of benzoylacetonitrile using a constant pressure dropping funnel. React at -5 ° C for 5 min, and then transfer the reaction system to room temperature 25 ° C for 20 h.

After the reaction, citric acid was added to the reaction system to acidify to pH=2, and then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was dried by spin drying. Silica gel was added to mix the sample. A pale yellow solid was obtained by column chromatography (the mobile phase solvents were dichloromethane and methanol). mp176.9-177.2℃. ¹ H NMR (600MHz, CDCl ₃ )δ17.85(s,1H,OH),9.49(s,1H,Ar-H),8.35-8.30(m,1H,Ar-H),8.11-8.06(m,2H,Ar-H),8.00-7.92(m,3H,Ar-H),7.67-7.61(m,1H,Ar-H),7.52(t,J＝7.8Hz,1H,Ar-H).

Example 20 Preparation of 3-(4-methylbenzene)-3-hydroxy-2-(quinoxaline-2-carbonyl)propionitrile

Step A: Preparation of quinoxaline-2-yl chloride

Quinoxaline-2-carboxylic acid (10 mmol) and toluene (40 mL) were stirred in a dry three-necked flask, heated to 100°C, and after the quinoxaline-2-carboxylic acid was completely dissolved, thionyl chloride (30 mmol) and 1 mmol N,N-dimethylformamide were added and refluxed for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation and the mixture was directly used for the next step without purification.

Step B: Preparation of 3-(4-methylbenzene)-3-hydroxy-2-(quinoxaline-2-carbonyl)propionitrile

In a 100 mL round-bottom flask, add 20 mL of tetrahydrofuran, then add 4-methyl-benzoylacetonitrile (1.0 mmol), and then add sodium hydride solid (3.0 mmol) in batches. In a low-temperature stirrer at -5 ° C, stir and react for 10-20 min. Then, dissolve the acyl chloride (2 mmol) obtained in the previous step in 5 mL of tetrahydrofuran, and slowly drip it into the tetrahydrofuran solution of benzoylacetonitrile using a constant pressure dropping funnel. React at -5 ° C for 5 min, and then transfer the reaction system to room temperature 25 ° C for 18 h.

After the reaction, citric acid was added to the reaction system to acidify to pH=2, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was dried by spin drying. Silica gel was added to mix the sample. A pale yellow solid was obtained by column chromatography (the mobile phase solvents were dichloromethane and methanol). mp122.9-123.3℃. ¹ H NMR (600MHz, CDCl ₃ )δ17.96(s,1H,OH),9.46(s,1H,Ar-H),8.35-8.30(m,1H,Ar-H),8.23-8.19(m,1H,Ar-H),8.10(d,J＝8.2Hz,2H,Ar-H),

7.95-7.89(m,2H,Ar-H),7.37(d,J＝8.0Hz,2H,Ar-H),2.47(s,3H,CH ₃ ).

Example 21 Preparation of 2-(Benzofuran-2-carbonyl)-3-cyclopropyl-3-hydroxyacrylonitrile

Stir benzofuran-2-carboxylic acid (10 mmol) and toluene (40 mL) in a dry three-necked flask, heat to 100°C, add thionyl chloride (30 mmol) and 1 mmol N,N-dimethylformamide after the benzofuran-2-carboxylic acid is completely dissolved, and reflux for 4 hours. After the reaction is completed, remove the solvent by rotary evaporation, and use it directly in the next step without purification.

In a 100 mL round-bottom flask, add 20 mL of tetrahydrofuran, then add 3-cyclopropyl-3-oxopropionitrile (1.0 mmol), and then add sodium hydride solid (3.0 mmol) in batches. In a low-temperature stirrer at -5 ° C, stir and react for 10-20 min. Then, dissolve the acyl chloride (2 mmol) obtained in the previous step in 5 mL of tetrahydrofuran, and slowly drip it into the tetrahydrofuran solution of benzoylacetonitrile using a constant pressure dropping funnel. React at -5 ° C for 5 min, and then transfer the reaction system to room temperature 25 ° C for 18 h.

After the reaction, citric acid was added to the reaction system to acidify to pH=2, extracted with ethyl acetate, dried over anhydrous sodium sulfate, the solvent was dried by spin drying, silica gel was added and mixed, and a light yellow solid was obtained by column chromatography (mobile phase solvents were dichloromethane and methanol). mp148.8-149.2℃. ¹ H NMR (500MHz, CDCl ₃ ) δ17.89 (s, 1H, OH), 8.13 (s, 1H, Ar-H), 7.74 (d, J = 7.9Hz, 1H, Ar-H), 7.65 (d, J = 8.4Hz, 1H, Ar-H), 7.53 (t, J = 7.8Hz, 1H ,Ar-H),7.35(t,J＝7.5Hz,1H,Ar-H),2.53-2.49(m,1H,CH),1.42(d,J＝4.2Hz,2H,CH ₂ ),1.30-1.26(m,2H,CH ₂ ).

A series of compounds shown in the following table were synthesized using similar methods as described above, and all compounds were confirmed by NMR and high-resolution mass spectrometry.

The groups represented by R ₁ and R ₂ in the structural formula are shown in Table 1:

Table 1:

Note: The yield is the yield after the last step of purification. Example 21 Test of the inhibitory activity of substituted aryl diketone nitrile compounds on 4-HPPD

The inhibitory activity of substituted aromatic diketonitrile compounds against 4-HPPD was tested by treating barnyard grass with stems and leaves using the small cup method.

Greenhouse small cup method: take a certain amount of soil that has passed through a 5mm sieve into a paper cup, soak the selected crop seeds in warm water for 12 hours, and place them in a 25℃ incubator for germination for 24 hours. Select 5-8 uniform and well-germinated crop seeds, place them evenly on the soil surface with the navel facing down, cover them with 1cm thick dry soil, and culture them at a temperature of 26.5℃, a humidity of 75%, and a 12h light and dark cycle.

Herbicide concentration screening: different concentrations of commercial herbicides mesotrione and isoxathiapiprolin and substituted aromatic diketone nitrile compounds (0g ai/hm ² , 30g ai/hm ² , 60g ai/hm ² , 90g ai/hm ² , 120g ai./hm ² , 150g ai/hm ² , 180g ai/hm ² ) were selected and sprayed on barnyard grass (from seedlings to 2-3 leaves and 1 heart stage). After 5 days of treatment, the concentration that caused certain phytotoxicity to barnyard grass was screened. Among them, the barnyard grass damage was more obvious when it was treated with 150g ai/ha.

Three days after emergence, the synthesized compounds were sprayed on the stems and leaves of barnyard grass, and the same amount of clean water was sprayed as a blank control. Three days after the drug spraying, the activity of HPPD enzyme in the leaves was measured. It was determined that at a dosage of 150g ai/ha, most of the compounds had good post-emergence herbicidal activity against barnyard grass. Therefore, the results of the effects of each compound on the HPPD enzyme activity in barnyard grass at 150g ai/ha are shown in Table 2:

Table 2: Inhibitory activity of substituted aryl diketone nitrile compounds and control compounds on 4-HPPD

Enzyme activity inhibition rate = [(control group activity - experimental group activity) / control group activity] × 100%

From the results shown in Table 2, it can be seen that the above compounds have good inhibitory activity against 4-HPPD, and I-18, I-29, I-30, I-33, and I-34 show excellent activity.

Example 22 Herbicidal Activity Test

This example is used to illustrate the herbicidal activity inhibition rate (%) of the substituted aryl diketone nitrile compounds of the present invention (dosage is 150 g/hectare).

Herbicidal activity inhibition rate = [(average growth index of the control group - average growth index of the treatment group)] / average growth index of the control group × 100%

In order to explore the control effect of the compounds on weeds, five common grass weeds in the field were selected for experiments under greenhouse conditions: barnyard grass, foxtail grass, ryegrass, winter grazing and broad-leaved weeds: velvetleaf. Commercial herbicides mesotrione and isoxathiapiprolin were selected as controls, and an aqueous solution containing only adjuvants was used as a blank control. After 7 days of application at a dosage of 150 g ai/ha, visual judgment was made according to the standards in Table 3 based on the damage of the plants. The results are shown in Table 4.

Table 3 Visual evaluation criteria for bioassay activity experiments

Table 4: Herbicidal activity results of compound I (150 g ai/ha)

Note: Inhibition rate rating scale compared with untreated control: A: 100-90%; B: 89-70%; C: 69-60; D: 59-50%; E: 49-30%; F: 29-10%; G: 9-0%

As can be seen from the table, at a dosage of 150 g ai/ha, most of the synthesized compounds had lower control effects on the five weeds tested under greenhouse potted conditions than the control agents mesotrione and isoxaflutole. Only a few compounds showed good control effects on some of the weeds tested. Among them, compound I-33 showed similar or even better post-emergence herbicidal activity than mesotrione and isoxaflutole. For example, the control effect of compound I-33 on velvetleaf can reach more than 90%, which is higher than the control effect of mesotrione and isoxaflutole of 80%. It is worth noting that when the intermediate is cyclopropyl, it is more conducive to the improvement of herbicidal activity. For example, the control effect of compound I-33 on barnyard grass and velvetleaf can reach more than 90%. In most cases, the electron-withdrawing group on the benzene ring is more conducive to the improvement of herbicidal activity, and the stronger the electron-withdrawing ability, the higher the herbicidal activity. For ryegrass, specifically: 7 days after application, the inhibition rate of ryegrass sprayed with isoxaflutole reached more than 90%, while only mesotrione and compound I-33 treated ryegrass had an inhibition rate of more than 70%, and the activity of the remaining compounds was low or not obvious. For winter grazing, specifically: 7 days after application, the inhibition rate of winter grazing sprayed with mesotrione reached more than 90%, while only isoxaflutole and compound I-33 treated winter grazing had an inhibition rate of more than 70%, and the activity of the remaining compounds was low or not obvious.

Example 23 Safety Experiment

This example is used to illustrate the safety of the substituted aryl diketone nitrile compounds of the present invention. Test target crops: wheat, rice, rapeseed, sorghum, soybean, peanut and corn.

Greenhouse cup method: Take a certain amount of soil that has passed through a 5mm sieve, soak the selected crop seeds in warm water for 12 hours, and place them in a 25℃ incubator for germination for 24 hours. Select 5-8 uniform and well-germinated crop seeds, evenly place them on the soil surface, with the navel facing down, and cover them with about 10g of dry soil. The temperature is 26.5℃, the humidity is 75%, and the light and dark cycles are 12 hours each. All treatments were paralleled three times, and different concentrations of newly synthesized compounds were sprayed at the 3-4 leaf stage. The agent was treated by leaf spraying. After application, the seeds were placed in a greenhouse for cultivation and observation. After one week, the chlorophyll content of the crop stems and leaves was measured to determine the safety activity of the crop. The chlorophyll content in the determined crops is shown in Table 5.

Table 5: Effects of mesotrione, isoxathiapiprolin and compound I-33 on chlorophyll content of weeds (150 g ai/ha)

Note: “±” represents the average standard deviation of three parallel experiments; CK is the blank control experiment

From the results shown in Table 4, it can be seen that mesotrione, isoxaflutole and compound I-33 all showed excellent crop safety for wheat, corn, peanuts, sorghum and soybeans, but mesotrione and isoxaflutole had poor crop safety for rapeseed and rice, among which the inhibition rate for rapeseed reached more than 70%, and showed certain crop toxicity for rapeseed and rice. Compared with mesotrione and isoxaflutole, compound I-33 also had certain toxicity for rapeseed and rice, among which the inhibition rate for rapeseed reached more than 60%, slightly lower than mesotrione and isoxaflutole, and the inhibition rate for rice reached more than 50%, which was similar to mesotrione.

It can be seen from the above data that the substituted aromatic diketone nitrile compounds prepared in the present invention have a weeding effect, especially have an excellent effect in controlling grass weeds, and are generally safe.

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 and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. The substituted aryl diketone nitrile compound is characterized in that the structural general formula of the substituted aryl diketone nitrile compound is shown as the following formula (I):

Wherein: the R ₁ is selected from one of cyclopropane, thiophene and substituted or unsubstituted phenyl;

said R ₂ is selected from

One of the following; wherein R ₃ represents any one of H, halogen and CF ₃,C₁～C₆ alkyl.

2. The synthetic route for pyrazole derivative compounds according to claim 1, characterized in that the synthetic route is as follows:

Wherein the compound (I) is a compound of formula (I) as claimed in claim 1.

3. The process for producing a substituted aryldiketone nitrile compound as claimed in claim 1, wherein: the method comprises the following steps:

Step one: dissolving the compound 1 in an organic solvent I, adding an acyl halide reagent and a catalyst, uniformly mixing, and reacting the obtained mixed reaction solution 1 at the temperature of between room temperature and 100 ℃ for 2 to 12 hours to obtain a compound 2;

Step two: mixing the compound 3 with an organic solvent II, adding sodium hydride in batches, and uniformly mixing to obtain a mixed reaction solution 2; dissolving the compound 2 in an organic solvent II to obtain a compound 2 solution; slowly dripping the compound 2 solution into the mixed reaction liquid 2 at the temperature of-5 ℃; after the dripping is finished, continuing to react for 2-10min at the temperature of minus 5 ℃, and then transferring the reaction system to the room temperature for reacting for 8-24 h to obtain the compound (I).

4. A method of preparation according to claim 3, characterized in that: the molar ratio of the compound 1 to the acid halide reagent in the first step is 1.0:1.0 to 3.0.

5. The method of claim 4, wherein: the preferred molar ratio of compound 1 to the acid halide reagent in step one is 1.0:1.5.

6. A method of preparation according to claim 3, characterized in that: in the second step, the molar ratio of the compound 3 to the compound 2 to sodium hydride in the sodium hydride solution is 0.5-1.5: 1.0:1.0 to 3.0.

7. The method of manufacturing according to claim 6, wherein: the preferred molar ratio of compound 3 to compound 2, sodium hydride in sodium hydride solution in step two is 0.8:1:1.5.

8. Use of a substituted aryl diketopyrrolopyrrole nitrile compound according to claim 1 or a substituted aryl diketopyrrolopyrrole nitrile compound prepared by a method according to any one of claims 3 to 7 as a 4-hydroxyphenylpyruvate dioxygenase inhibitor.

9. Use of a substituted aryl diketo nitrile compound according to claim 1 or a substituted aryl diketo nitrile compound prepared by a process according to any one of claims 3 to 7 for the control of weeds or for the preparation of a weed control agent.

10. The use according to claim 9, characterized in that: the weeds are at least one of abutilon, winter pasture, ryegrass, green bristlegrass or barnyard grass.