A class of (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives containing bishydrazide and preparation method and application thereof

Abstract

The present invention relates to a class of (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives containing dihydrazide having fungicidal activity as shown in general formula (I), as well as preparation methods and applications thereof. A pesticide molecule design method of splicing active fragments is used to connect differently substituted (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acids with differently substituted benzoylhydrazides, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 As defined in the specification. The technical effect of the present invention is: a class of (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives containing dihydrazide with broad-spectrum fungicidal activity has been discovered, which is a fungicide with broad application prospects.

Description

Technical Field

[0001] The present invention relates to a synthesis technology of agricultural chemical fungicides, in particular to a class of (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives containing dihydrazide and a preparation method and application thereof. Background Art

[0002] With the rapid development of agriculture and the widespread use of pesticides, people are increasingly concerned about the adverse effects of pesticides on the human living environment, physical health, and even the entire ecosystem. Therefore, there is a need to continuously develop new fungicides that are green, efficient, low-toxic, low-cost, and have unique mechanisms of action.

[0003] 4,5-Dihydrothiazole is a very important class of non-aromatic heterocycles containing nitrogen and sulfur atoms. It can interact with a variety of receptors and enzymes in the body and has a wide range of biological activities, including anti-tumor and anti-HIV activities, as an iron ion chelator, bactericidal and anti-inflammatory activities, and as a β-lactamase inhibitor. The bisacylhydrazide structure is widely present in pesticide molecules such as fungicides, insecticides, and herbicides, playing a crucial role in their biological activity.

[0004] Based on this, in order to discover a new type of fungicide that is green, efficient, low-toxic, low-cost and has a unique mechanism of action, a class of (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives containing dihydrazide that have not been reported in the literature were designed and synthesized. Biological activity tests showed that these derivatives have high fungicidal activity. Summary of the Invention

[0005] The present invention provides a class of (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives containing bishydrazide, their preparation methods, and applications. These derivatives can be widely used in the preparation of agricultural chemical fungicides and are fungicides with broad application prospects. These derivatives exhibit high fungicidal activity against pathogens such as peanut brown spot pathogen, tomato early blight pathogen, rapeseed sclerotinia pathogen, Rhizoctonia graminearum, and apple ring rot pathogen, and can be used as fungicides for the prevention and control of these pathogens.

[0006] The (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives containing dihydrazide provided by the present invention have the following general formula (I):

[0007]

[0008] Where:

[0009] R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10is hydrogen, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, trifluoromethyl, substituted amide, substituted amino acid ester, substituted thiourea, C1-C6 alkylurea, substituted N-cyanosulfoxide, substituted N-cyanoimino, substituted N-trifluoroacetylsulfoxide, and substituted N-trifluoroacetylimino;

[0010] In the above definition of derivatives, the terms used, whether used alone or in compound words, represent the following substituents:

[0011] Halogen is fluorine, chlorine, bromine or iodine;

[0012] Alkyl is a straight chain or branched chain alkyl;

[0013] A haloalkyl group is a straight-chain or branched-chain alkyl group, in which the hydrogen atoms may be partially or completely replaced by halogen atoms;

[0014] Alkenyl is a straight or branched chain having 2 to 6 carbon atoms and may have a double bond at any position;

[0015] The alkynyl group is a straight or branched chain group having 2 to 6 carbon atoms and may have a triple bond at any position.

[0016] A method for synthesizing a class of (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives containing bishydrazide is as follows:

[0017]

[0018] The preparation steps are as follows:

[0019] Step (1): Compound 1 and Compound 2 are dissolved in an organic solvent and water at a molar ratio of 1:1.5, and a base is added with stirring, followed by reaction at room temperature for 1-48 hours. After filtration under reduced pressure, the organic solvent is removed, and the mixture is alkalized to pH 11 with an alkaline solution. Organic impurities are extracted with an organic solvent, and the aqueous phase is acidified to pH 2 to obtain Compound 3.

[0020] Step (2): Dissolve the above compound 3 in an organic solvent, add a condensing agent at 0°C, allow the reaction to slowly warm to room temperature, stir for 0.5h, and then return the temperature to below 0°C. Add 1-1.1 equivalents of compound 4 and 1.2-1.5 equivalents of a base to the above reaction system in sequence. After the addition is complete, slowly warm to room temperature. After the reaction is complete, add an organic solvent, wash with water, aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution in sequence, discard the aqueous layer, combine the organic phases, add anhydrous sodium sulfate, and dry. Filter under reduced pressure, concentrate, and purify by column chromatography to obtain the compound of formula I. The groups in the reaction formula are shown above.

[0021] The organic solvent is anhydrous methanol, anhydrous ethanol, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, and 1,4-dioxane.

[0022] The condensing agents are EDCI and HOBt, EDCI and DMAP, DIC and DMAP, DIC and HOBt, DCC and DMAP, DCC and HOBt, CDI, HATU, HBTU, and PyBOP.

[0023] The base is N,N-diisopropylethylamine, pyridine, triethylamine, N-methylpyridine, 1,8-diaza-bicyclo(5,4,0)undec-7-ene, N,N-dimethylaniline, sodium bicarbonate, potassium bicarbonate.

[0024] The (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives containing dihydrazide described in the present invention are used to prepare agricultural chemical fungicides, especially for the prevention and control of pathogens such as peanut brown spot pathogen, tomato early blight pathogen, rapeseed sclerotinia pathogen, cereal root fungus and apple ring rot pathogen.

[0025] The pesticide composition provided by the present invention is composed of (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives containing bishydrazide as active ingredients and agriculturally acceptable adjuvants for the prevention and treatment of pathogens.

[0026] The technical effect of the present invention is: a class of dihydrazide-containing (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives with broad-spectrum fungicidal activity is discovered, which can be widely used in the preparation of agricultural chemical fungicides and is a fungicide with broad application prospects. DETAILED DESCRIPTION

[0027] The present invention is further described below with reference to the following examples, the purpose of which is to provide a better understanding of the content of the present invention and to embody the essential features of the present invention. Therefore, the examples given should not be regarded as limiting the scope of protection of the present invention.

[0028] Example 1:

[0029] Synthesis of (R)-N′-benzoyl-2-(p-tolyl)-4,5-dihydrothiazole-4-carboxylic acid hydrazide (derivative 07)

[0030] 1) Step A: Preparation of (R)-2-(p-methylphenyl)-4,5-dihydrothiazole-4-carboxylic acid

[0031] To a 100 mL round-bottom flask, p-toluonitrile (1.17 g, 10.0 mmol) and L-cysteine ​​2 (1.815 g, 15.0 mmol) were added, and then 30 mL of methanol aqueous solution (V 甲醇 ∶V 水=1:1) for dissolution, 1.260 g of sodium bicarbonate and 0.5 mL of 1 mol / L aqueous sodium hydroxide solution were added portionwise to the stirred reaction system, stirred at room temperature, and monitored by TLC. After the reaction was complete, most of the solvent was removed under reduced pressure, 1 mol / L sodium hydroxide solution was slowly added dropwise to a pH of 11, and then extracted with ethyl acetate (3×15 mL). The organic layer was discarded, and the aqueous phase was retained. 1 mol / L hydrochloric acid solution was slowly added dropwise with stirring to a pH of 1. Ethyl acetate was extracted (3×15 mL), and the phase was washed with saturated sodium chloride solution (3×15 mL). The aqueous phase was discarded, and the organic phases were combined and dried over anhydrous sodium sulfate. Filtered under reduced pressure and concentrated to obtain compound (R)-2-(4-nitrophenyl)-4,5-dihydrothiazole-4-carboxylic acid as a yellow solid with a yield of 67.8% and mp of 140-141°C.

[0032] 2) Step B: Preparation of (R)-N′-benzoyl-2-(p-tolyl)-4,5-dihydrothiazole-4-carboxylic acid hydrazide

[0033] (R)-2-(p-Methylphenyl)-4,5-dihydrothiazole-4-carboxylic acid (1.0 mmol) was added to a 50 mL three-necked round-bottom flask, and 15.0 mL of dry dichloromethane was added to dissolve the mixture. The temperature was monitored by a thermometer. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 2.304 g, 1.20 mmol) and 1-hydroxybenzotriazole (HOBt, 1.431 g, 1.06 mmol) were added in sequence under ice bath. After the addition was completed, the reaction mixture was slowly heated to room temperature and stirred for 0.5 h. The mixture was then weighed. The reaction mixture was cooled to below 0°C, and benzohydrazide (0.136 g, 1.0 mmol) and triethylamine (0.121 g, 1.2 mmol) were added dropwise to the reaction system. After the addition was completed, the temperature was slowly raised to room temperature. The reaction was monitored by TLC. After the reaction was completed, 20.0 mL of dichloroethane was added, and the mixture was washed with water, 1 mol / L aqueous hydrochloric acid solution (3×15 mL), saturated aqueous sodium bicarbonate solution (3×15 mL), and saturated aqueous sodium chloride solution (3×15 mL) in sequence. The aqueous phase was discarded, the organic phases were combined, and anhydrous sodium sulfate was added for drying. The mixture was filtered under reduced pressure, concentrated, and purified by column chromatography (V 乙酸乙酯 ∶V 石油醚 =1:3) to give (R)-N′-benzoyl-2-(p-tolyl)-4,5-dihydrothiazole-4-carboxylic acid hydrazide (derivative 07) as a pale yellow solid in a yield of 76.5% with an mp of 172-173°C.

[0034] The derivatives 01-289 prepared according to the preparation method of Example 1 but using different raw materials are listed in Table 1. 1H NMR (Bruker AV400 spectrometer using tetramethylsilane as the internal standard) data are listed in Table 2.

[0035] Table 1

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042] Table 2

[0043]

[0044]

[0045] Example 2:

[0046] The derivatives (01-289) provided by the present invention were used to conduct tests to verify the biological activity evaluation against pathogens:

[0047] Any derivative (01-289) provided by the present invention is dissolved in a solvent, water and a surfactant, and mixed to form a uniform aqueous phase. When used, it can be diluted with water to any desired concentration. The test objects and test methods are as follows:

[0048] Table 3 Test strains in the experiment

[0049] name Latin name code name Sclerotinia sclerotiorum Sclerotinia sclerotiorum SS Apple ring rot Physalospora piricola PP Rhizoctonia graminearum Rhizoctonia cerealis RC Cucumber gray mold Botrytis cinerea BC Potato late blight Phytophthora infestans(Mont.)de Bary PI Tomato early blight Alternaria solani AS Wheat Gibberella Gibberella zeae GZ Rice sheath blight pathogen Pellicularia sasakii PS Peanut brown spot pathogen Cercospora Arachidicola CA

[0050] The test method uses the bacterial growth rate determination method, and the specific steps are as follows: first, weigh 3 mg of the test sample and dissolve it with an appropriate amount of N,N-dimethylformamide. Add an aqueous solution containing a small amount of Tween 20 emulsifier to dilute the N,N-dimethylformamide solution to 500 μg / mL. Then, under sterile conditions, transfer 1 mL of the test sample solution to the culture medium. Then add 9 mL of culture medium and gently shake the culture plate to obtain a 50 μg / mL plate of the test sample. The blank control is a plate with 1 mL of sterile water. Then, use a 4 mm punch to cut the bacteria along the edge of the hyphae. The cut bacteria are placed in an equilateral triangle on the plate. Each test is repeated 3 times. Then, place the culture plate in a constant temperature incubator at 24±1°C. When the hyphae on the blank control plate grow to 2.0-3.0 cm, measure the diameter of the hyphae with a vernier ruler, calculate the average value, and calculate the relative in vitro antibacterial inhibition rate according to the following formula:

[0051]

[0052] The test results of the above experiments are shown in Table 4. The fungicidal activities of some compounds are equivalent to or exceed those of the control drugs chlorothalonil and azoxystrobin.

[0053] Table 4 In vitro antibacterial activity of compound I

[0054] NO. CA PP BC SS RC PS PI AS GZ 01 55.00 60.00 53.60 68.80 63.64 54.39 33.33 78.89 54.55 02 58.30 45.30 50.00 43.80 54.55 68.42 87.50 66.67 81.82 03 70.00 68.60 42.90 81.30 45.27 73.68 37.50 38.89 9.09 04 64.44 49.58 22.73 70.14 54.55 43.16 33.33 42.22 72.73 05 50.43 66.70 57.14 62.50 56.09 63.16 45.83 62.22 63.64 07 65.00 82.90 32.10 56.30 66.36 57.89 33.33 66.67 100 14 50.77 83.68 15.38 50.00 54.55 64.91 29.17 44.44 57.70 16 58.00 86.59 23.81 79.14 36.36 54.39 29.17 57.78 63.64 20 50.78 76.67 31.82 21.43 54.55 66.67 45.83 44.44 55.07 21 66.70 74.30 42.90 56.30 45.45 43.86 33.33 38.89 9.09 22 40.43 83.81 33.33 31.25 27.27 66.67 33.33 71.11 63.64 23 50.43 78.57 47.62 49.25 83.33 52.27 7.41 25.00 20.00 23 60.00 84.39 57.14 70.56 43.48 40.74 10.53 54.29 33.33 25 40.90 74.39 14.29 57.14 75.86 76.25 5.00 63.33 50.77 32 34.78 93.81 38.10 43.75 76.67 52.27 3.70 60.00 24.00 34 76.49 98.41 43.12 86.12 56.47 51.02 45.34 85.12 42.67 Chlorothalonil 59.01 88.13 95.24 41.23 56.36 94.31 80.69 62.86 40.23 Azoxystrobin 55.56 91.18 71.43 87.03 88.10 84.06 80.77 46.88 75.00

Claims

1. A method for synthesizing a (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivative containing a dihydrazide, characterized in that: It has the following general formula (I): wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are selected from any one of hydrogen, alkyl, alkenyl, alkynyl, halogen, nitro, cyano and trifluoromethyl; In the above definition of derivatives, halogen is fluorine, chlorine, bromine or iodine; alkyl is a straight-chain or branched alkyl; Alkenyl is a straight or branched chain having 2 to 6 carbon atoms and may have a double bond at any position; Alkynyl is a straight or branched chain having 2 to 6 carbon atoms and may have a triple bond at any position; The synthesis method of the (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives containing dihydrazide is as follows: The preparation steps are as follows: Step (1): Compound 1 and Compound 2 are dissolved in a mixture of an organic solvent and water at a molar ratio of 1:1.5, a base is added under stirring, and then the mixture is reacted at room temperature for 1-48 hours. After filtration under reduced pressure, the organic solvent is removed, and the mixture is alkalized to a pH of 11 with an alkaline solution. Organic impurities are extracted with an organic solvent, and the aqueous phase is acidified to a pH of 2 to obtain Compound 3; Step (2): Compound 3 is dissolved in an organic solvent, and a condensing agent is added at 0°C. After the addition is complete, the reaction is slowly warmed to room temperature and stirred for 0.5h. The reaction temperature is then lowered to below 0°C. 1-1.1 equivalents of compound 4 and 1.2-1.5 equivalents of a base are sequentially added to the reaction system. After the addition is complete, the reaction is slowly warmed to room temperature. After the reaction is complete, an organic solvent is added, and the mixture is washed with water, aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution in sequence. The aqueous layer is discarded, the organic phases are combined, anhydrous sodium sulfate is added for drying, filtered under reduced pressure, concentrated, and purified by column chromatography to obtain a compound of formula I; The condensing agent is any one of EDCI and HOBt, EDCI and DMAP, DIC and DMAP, DIC and HOBt, DCC and DMAP, DCC and HOBt, CDI, HATU, HBTU, and PyBOP; The base in step (2) is any one of N,N-diisopropylethylamine, pyridine, triethylamine, N-methylpyridine, 1,8-diazabicyclo(5,4,0)undec-7-ene, N,N-dimethylaniline, sodium bicarbonate, and potassium bicarbonate.

2. The method for synthesizing a (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivative containing a dihydrazide according to claim 1, wherein: In step (2), compound 3 is dissolved in an organic solvent, and the organic solvent is any one of anhydrous methanol, anhydrous ethanol, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, and 1,4-dioxane.

3. An application of a (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivative containing a dihydrazide, characterized in that: Used in the preparation of agricultural chemical fungicides; Or, a pesticide composition comprising an active ingredient and an agriculturally acceptable adjuvant for use in the prevention and treatment of pathogens; The (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives containing dihydrazide have the following general formula (I): wherein R3 and R8 are selected from any one of hydrogen, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, and trifluoromethyl; R1, R2, R4, R5, R6, R7, R9, and R10 are hydrogen; halogen is fluorine, chlorine, bromine, or iodine; alkyl is a straight or branched chain alkyl; alkenyl is a straight or branched chain having 2 to 6 carbon atoms and may have a double bond at any position; alkynyl is a straight or branched chain having 2 to 6 carbon atoms and may have a triple bond at any position; The pathogen is any one of peanut brown spot pathogen, tomato early blight pathogen, rapeseed sclerotinia pathogen, graminearum Rhizoctonia graminearum and apple ring rot pathogen.

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