Pyrazole-containing chalcone derivative as well as preparation method and application thereof

Abstract

The invention discloses a pyrazole-containing chalcone derivative as well as a preparation method and application thereof, and belongs to the technical field of pesticide synthesis. A series of pyrazol-containing chalcone derivatives are synthesized by taking chalcone as a leading structure and introducing a pyrazol skeleton with excellent agricultural activity into the structure of chalcone, and plant pathogenic fungus activity inhibition tests are carried out on the synthesized pyrazol-containing chalcone derivatives, so that the activity of the pyrazol-containing chalcone derivatives is shown in the description. The synthesized pyrazole-containing chalcone derivative can effectively inhibit plant pathogenic fungi, and especially has relatively good inhibitory activity on phomopsis, phytophthora capsici and capsicum oxysporum.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pesticide synthesis, in particular to a chalcone derivative containing pyrazole and a preparation method and application thereof. BACKGROUND

[0002] With the growth of global population, plant diseases have exacerbated the threat of food shortages. Among plant diseases, most diseases are caused by pathogenic fungi. The use of pesticides can effectively prevent the infection of plant fungal pathogens, but traditional pesticides are harmful to the human body, not environmentally friendly, and frequently cross-used, making the plant diseases, insect pests and weeds gradually resistant, drug-resistant, and rampant again. Green pesticides have the characteristics of high activity, low dosage, no residue, etc., and natural products are an important source of green pesticide lead compounds.

[0003] Natural products are the result of nature's exploration of the chemical space related to biology through evolution, and are a valuable source of small molecules with biological activity in chemical biology and medicinal chemistry. Natural products are often used as lead compounds for drug design and synthesis due to their low toxicity to humans and animals, environmental friendliness, unique target points, and good biological activity.

[0004] Chalcone is a class of flavonoids produced by natural plants or chemical synthesis. The biological activity of chalcone derivatives has been found in many application fields. The most natural chalcones are isolated from leguminous plants, compositae and moraceae. Studies have shown that their derivatives have antibacterial, antiviral, anti-inflammatory and anticancer biological activities. In 2015, Koneni V. Sashidhara et al. found that a chalcone derivative containing thiazole had an MIC of 1.4 μM against Staphylococcus aureus, and hemolysis and toxicity data showed that the compound had no hemolysis and no toxicity to mammalian cells. In 2019, Yang et al. found that a trimethoxyphenyl chalcone-benzimidazole salt could induce G1 phase arrest and apoptosis of hepatoma (SMMC-7721) cells. In 2022, Zhou et al. found that a chalcone derivative containing a piperazine fragment had the best inhibitory effect on Alternaria brassicae (Ab) and Capsicum capsicum (Cc), with EC 50 all 9.9 μg / mL, which were better than azoxystrobin (14.9, 19.3 μg / mL). In 2024, Mao found that a chalcone derivative containing phenoxy pyridine had an EC 5090.7 mu g / mL, which is superior to the control drug ningnanmycin (NNM, 148.3 mu g / mL). In 2024, Chen et al. found that a chalcone derivative can inhibit viral replication in the SARS-CoV-2 replicon system. It can be seen that chalcone derivatives have various biological activities and significant application effects. Therefore, structural modification and transformation of the site of chalcone are expected to obtain compounds with more diverse product types, more abundant functional groups and better biological activities, so as to realize the application value in medicine and pesticides.

[0005] Pyrazole is a kind of five-membered nitrogen-containing heterocycle, which has insecticidal, antibacterial, herbicidal and other biological activities, and plays an important role in the field of pharmacy. At present, there are many pesticides containing pyrazole structure on the market, such as insecticide fipronil, herbicide pyraflufen-ethyl and fungicide pyraclostrobin.

[0006] At present, there is no report on introducing pyrazole small molecule groups into chalcone structure and testing the inhibitory activity of chalcone derivatives containing pyrazole on plant pathogenic fungi. SUMMARY

[0007] The purpose of the present application is to provide a chalcone derivative containing pyrazole and a preparation method and application for inhibiting plant pathogenic fungi thereof.

[0008] In order to achieve the above purpose, the present application provides the following technical solutions:

[0009] One of the technical solutions of the present application: a chalcone derivative containing pyrazole, the structural formula of which is as follows:

[0010]

[0011] In the formula, R1 is CHF2 or CF3, and R2 is hydrogen, methyl or halogen.

[0012] The R2 is a benzene ring para position containing a methyl group; or the benzene ring ortho, meta, para position contains one or more halogens.

[0013] Preferably, the halogen is F, Cl or Br.

[0014] The second technical solution of the application: a preparation method of the above-mentioned chalcone derivative containing pyrazole, the steps of which include:

[0015] (1) taking substituted 1-methyl-1H-pyrazole-4-carboxylic acid and thionyl chloride as raw materials, heating and reacting, and then distilling under reduced pressure after the reaction is completed to obtain intermediate 1;

[0016] The structural formula of the intermediate 1 is as follows:

[0017] (2) using p-hydroxyacetophenone and substituted benzaldehyde as raw materials, reacting in a solvent containing an alkaline catalyst at room temperature, after the reaction, pouring into ice water, adjusting pH, precipitating the product, filtering, and removing impurities from the filter residue to obtain the intermediate 2;

[0018] The intermediate 2 has the following structural formula:

[0019] (3) using the intermediate 2 and 1,3-dibromopropane as raw materials, heating and reacting in a solvent under alkaline conditions, after the reaction, adding ice water to precipitate the product, filtering, washing, and drying to obtain the intermediate 3;

[0020] The intermediate 3 has the following structural formula:

[0021] (4) using the intermediate 3 and N-Boc-piperazine as raw materials, heating and reacting in a solvent under alkaline conditions, after the reaction, adding ice water to precipitate the product, filtering, washing, and drying to obtain the intermediate 4;

[0022] The intermediate 4 has the following structural formula:

[0023] (5) using the intermediate 4 and 10-37% HCl solution as raw materials, heating to remove Boc to obtain the intermediate 5;

[0024] The intermediate 5 has the following structural formula:

[0025] (6) using the intermediate 1 and the intermediate 5 as raw materials, reacting under ice bath conditions, after the reaction, purifying the crude product to obtain the pyrazole-containing chalcone derivative.

[0026] Preferably, in step (1), the molar ratio of the 1-methyl-1H-pyrazole-4-carboxylic acid and the thionyl chloride is 10.0:(3.0-5.0); the heating reaction temperature is 60-90°C, and the time is 4-10h.

[0027] Preferably, in step (2), the molar ratio of the p-hydroxyacetophenone, the substituted benzaldehyde, and the sodium hydroxide is 1:(1.1-1.3):(5.0-8.0); the time is 3-7d, and the pH is 5-6.

[0028] Preferably, in step (3), the molar ratio of the intermediate 2, the 1,3-dibromopropane, and the potassium carbonate is 1:(5.0-7.0):(3.0-5.0); the heating reaction temperature is 60-90°C, and the time is 6-10h.

[0029] Preferably, in step (4), the molar ratio of the intermediate 3, N-Boc-piperazine and potassium carbonate is 1.0:(5.0-7.0):(6.0-8.0); the heating reaction is carried out at a temperature of 60-90℃ for 6-10 hours.

[0030] Preferably, in step (5), the Boc-removing step comprises: dissolving the intermediate 4 in methanol, stirring at room temperature for 10-30 minutes, adding dropwise a 10-37% HCl solution, heating to 50-80℃, and reacting for 1-5 hours to remove the Boc protection; the molar ratio of the intermediate 4 and the 10-37% HCl solution is 1.0:(10.0-30.0).

[0031] Preferably, in step (6), the molar ratio of the intermediate 5, the intermediate 1 and potassium carbonate is 1.0:(3.0-5.0):(3.0-5.0); after the reaction, the purification step specifically comprises: dispersing the reaction system into water, extracting with dichloromethane, evaporating the extract, and purifying through silica gel column chromatography; the column chromatography uses a mixture of dichloromethane and methanol in a volume ratio of 20:1.

[0032] The third technical scheme of the present application provides a use of the above-mentioned pyrazole-containing chalcone derivative in the preparation of a plant pathogenic fungus inhibiting drug.

[0033] Preferably, the plant pathogenic bacteria include Ps, Pc, Rs, Ss, Bc, Fo, Foc and Bd.

[0034] Preferably, the plant pathogenic bacteria are Ps, Pc and Fo.

[0035] The present application has the following beneficial technical effects:

[0036] The present application provides a pyrazole-containing chalcone derivative, a preparation method and application thereof, introduces pyrazole with excellent biological activity into the structure of chalcone, synthesizes a series of pyrazole-containing chalcone derivatives, and finds that the synthesized pyrazole-containing chalcone derivatives can effectively inhibit plant pathogenic fungi, especially Ps, Pc and Fo, through the activity test of the synthesized pyrazole-containing chalcone derivatives on plant pathogenic fungi. DETAILED DESCRIPTION

[0037] The following detailed description of various exemplary embodiments of the application should not be considered to be limiting of the application, but rather a description of certain specific aspects, features, and embodiments of the application. It is understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the application.

[0038] In addition, for numerical ranges of values recited herein, it is contemplated that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically contemplated. Each smaller range that falls between any stated range, as well as each end point

[0039] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Although preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application.

[0040] As used herein, the terms "comprise", "comprising", "include", "including", "have", "having" and the like are open-ended terms that are intended to mean including, but not limited to.

[0041] One of the technical purposes of the present application is to provide a pyrazole-containing chalcone derivative, which has the following structure:

[0042]

[0043] In the formula, R1 is CHF2 or CF3, and R2 is independently selected from unsubstituted or optionally substituted methyl, halogen.

[0044] In some embodiments, the optionally substituted methyl is a methyl group at the para position of a benzene ring, and the optionally substituted halogen is one or more halogen groups at the ortho, meta, or para position of a benzene ring.

[0045] Another technical purpose of the present application is to provide a method for preparing the above-mentioned pyrazole-containing chalcone derivative, which comprises the following steps:

[0046] (1) Using substituted 1-methyl-1H-pyrazole-4-carboxylic acid and thionyl chloride as raw materials, heating at 60-90°C for 6-10 hours, and then distilling under reduced pressure to obtain intermediate 1.

[0047] The reaction equation is as follows:

[0048]

[0049] The substituted 1-methyl-1H-pyrazole-4-carboxylic acid and the amount of substance of sulfurous acid chloride are 10.0:(3.0-5.0).

[0050] (2) The intermediate 2 is obtained by using p-hydroxyacetophenone and substituted benzaldehyde as raw materials, reacting at room temperature in a solvent containing an alkaline catalyst for 3-7 days, pouring into ice water after the reaction is completed, adjusting pH, precipitating the product, filtering, and removing impurities from the filter residue.

[0051] The reaction equation is as follows:

[0052]

[0053] The amount of substance of the p-hydroxyacetophenone, the substituted benzaldehyde, and the sodium hydroxide is 1:(1.1-1.3):(5.0-8.0), and the pH is 5-6;

[0054] (3) The intermediate 3 is obtained by using the intermediate 2 and 1,3-dibromopropane as raw materials, heating at 60-90°C in a solvent under alkaline conditions for 6-10 hours, adding ice water after the reaction is completed to precipitate the product, and filtering, washing, and drying.

[0055] The reaction equation is as follows:

[0056]

[0057] The amount of substance of the intermediate 2, the 1,3-dibromopropane, and the potassium carbonate is 1:(5.0-7.0):(3.0-5.0);

[0058] (4) The intermediate 4 is obtained by using the intermediate 3 and N-Boc-piperazine as raw materials, heating at 60-90°C in a solvent under alkaline conditions for 6-10 hours, adding ice water after the reaction is completed to precipitate the product, and filtering, washing, and drying.

[0059] The reaction equation is as follows:

[0060]

[0061] In some embodiments, the reaction system is also dispersed into water, and then extraction, drying, and rotary evaporation under reduced pressure are performed;

[0062] The amount of substance of the intermediate 3, the N-Boc-piperazine, and the potassium carbonate is 1.0:(5.0-7.0):(6.0-8.0);

[0063] (5) The intermediate 5 is obtained by using the intermediate 4 and a 10-37% HCl solution as raw materials, heating at 50-80°C for 1-5 hours.

[0064] The reaction equation is as follows:

[0065]

[0066] The molar ratio of the intermediate 4 and 10-37% HCl solution is 1.0:(10.0-30.0).

[0067] (6) Intermediate 5 and intermediate 1 are used as raw materials, and the reaction is carried out under ice bath condition, and the pyrazole-containing chalcone derivative is obtained after purification.

[0068] The reaction equation is as follows:

[0069]

[0070] The molar ratio of the intermediate 5, the intermediate 1 and potassium carbonate is 1.0:(3.0-5.0):(3.0-5.0); the purification step after the reaction is completed specifically includes: dispersing the reaction system into water, extracting with dichloromethane, evaporating the extract, and purifying through silica gel column chromatography; the solution used in the column chromatography is a mixture of dichloromethane and methanol with a volume ratio of 20:1.

[0071] The third technical purpose of the present application is to provide an application of the above-mentioned pyrazole-containing chalcone derivative in preparing a medicine for inhibiting plant pathogenic fungi.

[0072] To achieve the above technical purposes, the present application provides the following embodiments.

[0073] Embodiment 1

[0074] (E)-1-(4-(3-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)propoxy)phenyl)-3-phenylpropen-2-yl-1-ketone (compound No. Z1) comprises the following steps:

[0075] (1) Synthesis of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (intermediate 1): 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (3.52 g, 20.0 mmol) is added into a 100 mL round-bottom flask, and thionyl chloride (10 mL) is slowly dropped, and then slowly warmed to 80°C for 8 h, and the reaction progress is monitored by TLC. After the reaction is completed, the excess thionyl chloride is removed by distillation under reduced pressure to obtain the intermediate 1 with a yield of 90%.

[0076] (2) Synthesis of (E)-l-(4-phenyl)-3-phenylpropen-2-en-l-one (Intermediate 2): 4-Hydroxybenzaldehyde (3.00 g, 22.0 mmol) and solvent ethanol (80 mL) were added into a 250 mL three-necked round-bottom flask, stirred at room temperature for 10 min, then benzaldehyde (2.81 g, 26.4 mmol) was added slowly, stirred at room temperature for 30 min, then sodium hydroxide (4.41 g, 110.0 mmol) in water was added slowly, the reaction was carried out for 3-7 d, TLC was used to monitor the reaction progress. After the reaction was completed, the reaction system was poured into ice water, the pH was adjusted to 5-6, a large amount of yellow solid was precipitated, suction filtration, and oven drying to obtain Intermediate 2, the yield was 92%.

[0077] (3) Synthesis of (E)-l-(4-(3-bromopropoxy)phenyl)-3-phenylpropen-2-en-l-one (Intermediate 3): Intermediate 2 (2.00 g, 8.9 mmol), potassium carbonate (3.70 g, 26.7 mmol) and 100 mL acetonitrile were sequentially added into a 250 mL three-necked round-bottom flask, stirred at 80°C for 3 h, then 1,3-dibromopropane (4.55 mL, 44.5 mmol) was added slowly dropwise, the reaction was carried out for 6-10 h, TLC was used to monitor the reaction progress. After the reaction was completed, the reaction system was poured into ice water, a large amount of yellow solid was precipitated, suction filtration, and oven drying to obtain Intermediate 3, the yield was 76%.

[0078] (4) Synthesis of 4-(3-(4-cinnamoylphenoxy)propyl)piperazine-l-carboxylic acid tert-butyl ester (Intermediate 4): Intermediate 3 (2.00 g, 5.8 mmol), potassium carbonate (4.80 g, 34.8 mmol) and 100 mL acetonitrile were sequentially added into a 250 mL three-necked round-bottom flask, stirred at 80°C for 30 min, then N-Boc-piperazine (5.40 g, 29.0 mmol) was added, the reaction was carried out for 6-10 h under reflux, TLC was used to monitor the reaction progress. After the reaction was completed, the reaction system was poured into ice water, a large amount of yellow solid was precipitated, suction filtration, and oven drying to obtain Intermediate 4, the yield was 82%.

[0079] (5) Synthesis of (E)-3-phenyl-l-(4-(3-(piperazin-l-yl)propoxy)phenyl)-2-en-l-one hydrochloride (Intermediate 5): Intermediate 4 (2.00 g, 4.4 mmol) and 10 mL methanol were sequentially added into a 100 mL round-bottom flask, stirred at room temperature for 10 min, then 8 mL of 37% HCl solution was added dropwise, the reaction was carried out for 2 h at 70°C, TLC was used to monitor the reaction progress. After the reaction was completed, suction filtration, and oven drying to obtain Intermediate 5, the yield was 90%.

[0080] (6) Synthesis of (E)-1-(4-(3-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazole-4- carbonyl)piperazin-1-yl)propoxy)phenyl)-3-phenylprop-2-en-1-one (Z1): Intermediate 5 (1.00 g, 2.6 mmol), potassium carbonate (1.07 g, 7.8 mmol) and 40 mL of dichloromethane were added into a 100 mL round bottom flask successively, after stirring for 30 min at room temperature, Intermediate 1 (1.51 g, 7.8 mmol) was added dropwise under ice bath condition, the reaction was carried out for 1 h, TLC was used to monitor the reaction progress. After the reaction was completed, the system was dispersed into 100 mL ice water, dichloromethane was used to extract three times (3 x 25 mL), the combined organic phase was dried over anhydrous Na2SO4, and rotary evaporation under reduced pressure was performed to obtain the crude product. Finally, the obtained crude product was subjected to column chromatography (dichloromethane / methanol = 20:1, V / V) to obtain compound Z1, and the yield was 54%.

[0081] Example 2

[0082] Synthesis of (E)-1-(4-(3-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazole-4- carbonyl)piperazin-1-yl)propoxy)phenyl)-3-(2-fluorophenyl)prop-2-en-1-one (compound number Z2), the steps were the same as in Example 1, except that the benzaldehyde in step (2) was replaced with an equal amount of 2-fluorobenzaldehyde. Yield: 52%.

[0083] Example 3

[0084] Synthesis of (E)-1-(4-(3-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazole-4- carbonyl)piperazin-1-yl)propoxy)phenyl)-3-(3-fluorophenyl)prop-2-en-1-one (compound number Z3), the steps were the same as in Example 1, except that the benzaldehyde in step (2) was replaced with an equal amount of 3-fluorobenzaldehyde. Yield: 34%.

[0085] Example 4

[0086] Synthesis of (E)-1-(4-(3-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazole-4- carbonyl)piperazin-1-yl)propoxy)phenyl)-3-(4-fluorophenyl)prop-2-en-1-one (compound number Z4), the steps were the same as in Example 1, except that the benzaldehyde in step (2) was replaced with an equal amount of 4-fluorobenzaldehyde. Yield: 53%.

[0087] Example 5

[0088] Synthesis of (E)-3-(2-chlorophenyl)-l-(4-(3-(4-(3-(difluoromethyl)-l- methyl-lH-pyrazole-4-carbonyl)piperazin-l-yl)propoxy)phenyl)prop-2-en-l-one (Compound No. Z5) following the procedure of Example 1 except that benzaldehyde in Step (2) was replaced with an equivalent amount of 2-chlorobenzaldehyde. Yield: 37%.

[0089] Example 6

[0090] Synthesis of (E)-3-(3-chlorophenyl)-l-(4-(3-(4-(3-(difluoromethyl)-l- methyl-lH-pyrazole-4-carbonyl)piperazin-l-yl)propoxy)phenyl)prop-2-en-l-one (Compound No. Z6) following the procedure of Example 1 except that benzaldehyde in Step (2) was replaced with an equivalent amount of 3-chlorobenzaldehyde. Yield: 45%.

[0091] Example 7

[0092] Synthesis of (E)-3-(3-bromophenyl)-l-(4-(3-(4-(3-(difluoromethyl)-l- methyl-lH-pyrazole-4-carbonyl)piperazin-l-yl)propoxy)phenyl)prop-2-en-l-one (Compound No. Z7) following the procedure of Example 1 except that benzaldehyde in Step (2) was replaced with an equivalent amount of 3-bromobenzaldehyde. Yield: 54%.

[0093] Example 8

[0094] Synthesis of (E)-3-(4-bromophenyl)-l-(4-(3-(4-(3-(difluoromethyl)-l- methyl-lH-pyrazole-4-carbonyl)piperazin-l-yl)propoxy)phenyl)prop-2-en-l-one (Compound No. Z8) following the procedure of Example 1 except that benzaldehyde in Step (2) was replaced with an equivalent amount of 4-bromobenzaldehyde. Yield: 60%.

[0095] Example 9

[0096] Synthesis of (E)-l-(4-(3-(4-(3-(difluoromethyl)-l-methyl-lH-pyrazole-4- carbonyl)piperazin-l-yl)propoxy)phenyl)-3-(p-tolyl)prop-2-en-l-one (Compound No. Z9) following the procedure of Example 1 except that benzaldehyde in Step (2) was replaced with an equivalent amount of 4-methylbenzaldehyde. Yield: 63%.

[0097] Example 10

[0098] Synthesis of (E)-3-(2,4-dichlorophenyl)-1-(4-(3-(4-(3-(difluoromethyl)-1-methyl- 1H-pyrazole-4-carbonyl)piperazin-1-yl)propoxy)phenyl)prop-2-en-1-one (Compound No. Z10) following the procedure of Example 1 except that in step (2) benzaldehyde was replaced by an equivalent amount of 2,4-dichlorobenzaldehyde. Yield: 67%.

[0099] Example 11

[0100] Synthesis of (E)-3-(3-fluorophenyl)-1-(4-(3-(4-(1-methyl-3-(trifluoromethyl)-1H- pyrazole-4-carbonyl)piperazin-1-yl)propoxy)phenyl)prop-2-en-1-one (Compound No. Z11) following the procedure of Example 1 except that in step (1) 3-(difluoromethyl)-1- methyl-1H-pyrazole-4-carboxylic acid was replaced by an equivalent amount of 3- (trifluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid and in step (2) benzaldehyde was replaced by an equivalent amount of 3-fluorobenzaldehyde. Yield: 55%.

[0101] Example 12

[0102] Synthesis of (E)-3-(4-fluorophenyl)-1-(4-(3-(4-(1-methyl-3-(trifluoromethyl)-1H- pyrazole-4-carbonyl)piperazin-1-yl)propoxy)phenyl)prop-2-en-1-one (Compound No. Z12) following the procedure of Example 1 except that in step (1) 3-(difluoromethyl)-1- methyl-1H-pyrazole-4-carboxylic acid was replaced by an equivalent amount of 3- (trifluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid and in step (2) benzaldehyde was replaced by an equivalent amount of 4-fluorobenzaldehyde. Yield: 53%.

[0103] Example 13

[0104] Synthesis of (E)-3-(2-chlorophenyl)-1-(4-(3-(4-(1-methyl-3-(trifluoromethyl)-1H- pyrazole-4-carbonyl)piperazin-1-yl)propoxy)phenyl)prop-2-en-1-one (Compound No. Z13) following the procedure of Example 1 except that in step (1) 3-(difluoromethyl)-1- methyl-1H-pyrazole-4-carboxylic acid was replaced by an equivalent amount of 3- (trifluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid and in step (2) benzaldehyde was replaced by an equivalent amount of 2-chlorobenzaldehyde. Yield: 42%.

[0105] Example 14

[0106] Synthesis of (E)-3-(3-chlorophenyl)-l-(4-(3-(4-(l-methyl-3-(trifluoromethyl)-lH- pyrazole-4-carbonyl)piperazin-l-yl)propoxy)phenyl)prop-2-en-l-one (Compound No. Z14) following the procedure of Example 1 except that 3-(difluoromethyl)-l-methyl-lH-pyrazole-4- carboxylic acid in Step (1) was replaced with an equivalent amount of 3-(trifluoromethyl)-l- methyl-lH-pyrazole-4-carboxylic acid and benzaldehyde in Step (2) was replaced with an equivalent amount of 3-chlorobenzaldehyde. Yield: 71%.

[0107] Example 15

[0108] Synthesis of (E)-3-(3-bromophenyl)-l-(4-(3-(4-(l-methyl-3-(trifluoromethyl)-lH-pyrazole-4- carbonyl)piperazin-l-yl)propoxy)phenyl)prop-2-en-l-one (Compound No. Z15) following the procedure of Example 1 except that 3-(difluoromethyl)-l-methyl-lH-pyrazole-4- carboxylic acid in Step (1) was replaced with an equivalent amount of 3-(trifluoromethyl)-l- methyl-lH-pyrazole-4-carboxylic acid and benzaldehyde in Step (2) was replaced with an equivalent amount of 3-bromobenzaldehyde. Yield: 74%.

[0109] Example 16

[0110] Synthesis of (E)-3-(2,4-dichlorophenyl)-l-(4-(3-(4-(l-methyl-3-(trifluoromethyl)-lH-pyrazole-4- carbonyl)piperazin-l-yl)propoxy)phenyl)prop-2-en-l-one (Compound No. Z16) following the procedure of Example 1 except that 3-(difluoromethyl)-l-methyl-lH-pyrazole-4- carboxylic acid in Step (1) was replaced with an equivalent amount of 3-(trifluoromethyl)-l- methyl-lH-pyrazole-4-carboxylic acid and benzaldehyde in Step (2) was replaced with an equivalent amount of 2,4-dichlorobenzaldehyde. Yield: 96%.

[0111] The physicochemical properties and mass spectrometry data of the pyrazole-containing chalcone derivatives synthesized in Examples Z1 to Z16 are shown in Table 1, and the nuclear magnetic resonance (NMR) data are shown in Table 2.

[0112] Table 1. Physicochemical properties of target compounds and their mass spectrometry data.

[0113] Compound Yield / % Property Melting point (°C) HRMS, m / z (calcd.) Z1 54 White solid 113.2-114.5 509.23392 (509.23587) [M+H] + ]] Z2 52 Pink solid 118.8-119.2 527.22473 (527.22645) [M+H] + ]] Z3 34 Yellow oil - 527.22461 (527.22645) [M+H] + ]] Z4 53 White solid 122.4-124.3 527.22479 (527.22645) [M+H] + ]] Z5 37 White solid 218.0-219.6 543.19519 (543.19690) [M+H] + ]] Z6 45 Red oil - 543.19525 (543.19690) [M+H] + <!-- 8 -->]] Z7 31 White solid 164.4-165.9 587.14508 (587.14639) [M+H] + ]] Z8 60 White solid 144.2-144.6 587.14520 (587.14639) [M+H] + ]] Z9 63 White solid 144.9-145.9 523.25024 (523.25152) [M+H] + ]] Z10 67 White solid 101.9-102.8 577.15686 (577.15793) [M+H] + ]] Z11 55 White solid 215.0-216.8 545.21545 (545.21703) [M+H] + ]] Z12 53 White solid 144.6-145.9 545.21503 (545.21703) [M+H] + ]] Z13 42 White solid 270.1-271.9 561.18579 (561.18748) [M+H] + ]] Z14 71 White solid 262.6-264.0 561.18903 (561.18748) [M+H] + ]] Z15 74 White solid 267.9-269.3 605.13531 (605.13696) [M+H] + ]] Z16 96 Yellow oil - 595.14679 (595.14851) [M+H] + ]]

[0114] Table 2. Nuclear magnetic resonance (NMR) data of target compounds.

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121] Test Example 1 Anti-plant pathogenic fungal activity test

[0122] Test method:

[0123] The mycelial growth rate method was used to evaluate the in vitro activity of common plant diseases such as Phomopsis sp. (Ps), Phytophthora capsici (Pc), Rhizoctonia solani (Rs), Sclerotinia sclerotiorum (Ss), Botrytis cinerea (Bc), Fusarium oxysporum (Fo), Fusarium oxysporum f. sp. cucumeris (Foc), and Botryosphaeria dothidea (Bd). The commercial pesticide azoxystrobin (Az) was used as a positive control. The specific steps are as follows:

[0124] (1) Using a 90 mm petri dish, the test plant pathogenic fungi were inoculated in PDA medium, then placed in a constant temperature incubator at 28°C and incubated in reverse to the usable state for standby.

[0125] (2) The sample and control pesticide were respectively prepared into PDA medium containing 100 μg / mL of drug concentration, poured into a 60 mm petri dish, and cooled. A 5 mm sterile puncher was used to punch out a fungus cake along the outermost periphery of the mycelium, and then a sterile needle was used to pick up the fungus cake and place it in the middle of the medium. The mycelium was attached to the medium, wrapped with a breathable wrapping film, and placed in a 28°C incubator for several days. When the mycelium diameter of the blank control group was 45-50 mm, the mycelium diameter of each group was measured, and the inhibition rate of the measured compound was calculated according to the following formula. The results are shown in Table 3.

[0126]

[0127] I: Inhibition rate

[0128] C: Mycelium diameter of the blank control group

[0129] T: Mycelium diameter of the drug treatment group

[0130] (3) The results of the anti-plant pathogenic fungal bioactivity test are shown in Table 3.

[0131] Table 3. In vitro inhibition activity of Z1-Z16 at 100 μg / mL against 8 plant fungi.

[0132]

[0133] From Table 3, it can be seen that the inhibition rates of compounds Z6, Z10 and Z16 on Ps were 82.3, 81.9 and 83.7% respectively at 100 μg / mL, which were better than the control drug Az (75.0%); the inhibition rates of compounds Z3, Z5, Z6, Z9, Z14 and Z15 on Pc were 71.3, 71.7, 85.7, 75.1, 72.2 and 72.2% respectively at 100 μg / mL, which were significantly better than Az (59.2%); the inhibition rate of compound Z6 on Bc was 84.8% at 100 μg / mL, which was equivalent to Az (81.1%); the inhibition rate of compound Z16 on Ss was 77.4% at 100 μg / mL, which was equivalent to Az (75.8%), the inhibition rate on Fo was 73.1%, which was significantly better than Az (61.1%), and the inhibition rate on Foc was 53.4%, which was equivalent to Az (48.6%).

[0134] The above experimental activity data show that the pyrazole-containing chalcone derivatives have good inhibitory effect on plant pathogenic fungi, and some of the target compounds exhibit excellent activity against plant pathogens, and can be used as potential anti-plant pathogen drugs, and have good application prospect.

[0135] The above only describes the preferred embodiments of the present application, and it should be noted that for those skilled in the art, without departing from the principles of the present application, a number of improvements and refinements can be made, and these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. A chalcone derivative containing pyrazole, characterized in that: The derivative has the following structural formula: In the formula, R1 is CH2F or CF3, and R2 is hydrogen, methyl or halogen.

2. The pyrazole-containing chalcone derivative according to claim 1, characterized in that, The R2 is a methyl group at the para position of the benzene ring, or one or more halogen groups at the ortho, meta or para position of the benzene ring.

3. A process for the preparation of a pyrazole-containing chalcone derivative according to claim 1 or 2, characterized by: The method comprises the following steps: (1) using substituted 1-methyl-1H-pyrazole-4-carboxylic acid and sulfurous acid chloride as raw materials, heating to react, and then distilling under reduced pressure to obtain intermediate 1; The structural formula of the intermediate 1 is: wherein R1 is CHF2 or CF3; (2) using p-hydroxyacetophenone and substituted benzaldehyde as raw materials, reacting at room temperature in a solvent containing an alkaline catalyst, adding ice water after the reaction is completed, adjusting the pH, precipitating the product, filtering, and removing impurities from the filter residue to obtain intermediate 2; The structural formula of the intermediate 2 is: (3) using intermediate 2 and 1,3-dibromopropane as raw materials, heating to react in a solvent under alkaline conditions, adding ice water after the reaction is completed to precipitate the product, and filtering, washing and drying to obtain intermediate 3; The structural formula of the intermediate 3 is: (4) using intermediate 3 and N-Boc-piperazine as raw materials, heating to react in a solvent under alkaline conditions, adding ice water after the reaction is completed to precipitate the product, and filtering, washing and drying to obtain intermediate 4; The structural formula of the intermediate 4 is: (5) using intermediate 4 and 10-37% HCl solution as raw materials, heating to remove the Boc to obtain intermediate 5; The structural formula of the intermediate 5 is: (6) using intermediate 1 and intermediate 5 as raw materials, reacting under ice bath conditions, and then purifying the crude product to obtain the pyrazole-containing chalcone derivative.

4. The method of claim 3, wherein: In step (1), the molar ratio of 1-methyl-1H-pyrazole-4-carboxylic acid to sulfurous acid chloride is 10.0:(3.0-5.0); the heating reaction is performed at a temperature of 60-90°C for 4-10 hours; in step (2), the molar ratio of p-hydroxyacetophenone to substituted benzaldehyde to sodium hydroxide is 1:(1.1-1.3):(5.0-8.0); the reaction is performed for 3-7 days at a pH of 5-6.

5. The method of claim 3, wherein: In step (3), the molar ratio of intermediate 2 to 1,3-dibromopropane to potassium carbonate is 1:(5.0-7.0):(3.0-5.0); the heating reaction is performed at a temperature of 60-90°C for 6-10 hours.

6. The method of claim 3, wherein: In step (4), the molar ratio of intermediate 3 to N-Boc-piperazine to potassium carbonate is 1.0:(5.0-7.0):(6.0-8.0); the heating reaction is performed at a temperature of 60-90°C for 6-10 hours.

7. The method of claim 3, wherein: In step (5), the Boc removal step comprises: dissolving intermediate 4 in methanol, stirring at room temperature for 10-30 minutes, then adding 10-37% HCl solution dropwise, heating to 50-80°C, and reacting for 1-5 hours to remove the Boc; the molar ratio of intermediate 4 to 10-37% HCl solution is 1.0:(10.0-30.0).

8. The method of claim 3, wherein: In step (6), the molar ratio of intermediate 5 to intermediate 1 to potassium carbonate is 1.0:(3.0-5.0):(3.0-5.0); the purification step is silica gel column chromatography, and the solution used is a mixture of dichloromethane and methanol in a volume ratio of 20:

1.

9. The use of the pyrazole-containing chalcone derivatives according to claims 1 and 2 in the preparation of agents for inhibiting plant pathogenic fungi.

10. Use according to claim 9, characterized in that: The plant pathogenic fungi include *Pseudomonas stenophylla*, *Phytophthora capsici*, *Rhizoctonia solani*, *Sclerotinia sclerotiorum*, *Gray mold*, *Fusarium wilt*, *Fusarium wilt*, and *Vitis vinifera*.

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