Isopropanolamine modified coumarin analogue as well as preparation method and application thereof

Abstract

The invention relates to an isopropanolamine modified coumarin analogue as well as a preparation method and application thereof, and belongs to the technical field of pesticides. The isopropanolamine modified coumarin analogue is as shown in the following formula I: # imgabs0 #. The compound shown in the formula I is applied to prevention and treatment of agricultural diseases and insect pests, especially plant fungal diseases. The compound shown in the formula I has a very good antifungal effect, can be applied to prevention and treatment of crop diseases caused by fungi, and particularly shows relatively good bactericidal activity on rice blast, sclerotinia rot of colza, cotton damping off, apple ring spot, phytophthora capsici, wheat scab and the like; the application of the coumarin analogue in the field of agriculture is widened.

Description

Technical Field

[0001] The invention relates to the technical field of pesticides, and in particular to an isopropanolamine-modified coumarin analogue, a preparation method and application thereof. Background Art

[0002] Pesticides are an important part of agricultural production. The proper use of pesticide fungicides can effectively prevent the reduction of yield or the decline of fruit quality caused by plant pathogenic fungi, and avoid serious economic losses. However, due to the irrational use of traditional fungicides and the long-term application of single preparations, many common pathogenic fungi have developed serious drug resistance. Therefore, it is still of great significance to continuously optimize lead compounds and develop fungicides with new mechanisms of action, high efficiency, low toxicity and environmental friendliness.

[0003] Natural products play a very important role in the development of pesticides. Many important commercial pesticides are developed based on natural products, such as methoxyacrylate fungicides. The natural product coumarin skeleton structure includes a benzene ring and an α-pyrone ring, which has a wide range of pharmacological activities, such as anti-cancer, antioxidant, insecticide, herbicide and fungicide activities. For example, in the early development of new fungicides, Liu Changling and others successfully developed a new fungicide with independent intellectual property rights, coumoxystrobin, by superimposing the coumarin skeleton fragment with the methoxyacrylate active structure. This compound shows excellent control effects on crop powdery mildew, downy mildew and anthracnose.

[0004] Existing isopropanolamine-modified coumarin analogs are all used in the medical field, mainly for the preparation of anticancer, antifungal, and antipsychotic drugs, but there are no reports on their application in the agricultural field. Summary of the invention

[0005] In view of the problem that the existing isopropanolamine-modified coumarin analogs have not been applied to the agricultural field, the present invention provides an isopropanolamine-modified coumarin analog and its preparation method and application to solve the above problems. The present invention mainly uses 7-hydroxy-coumarin as the parent nucleus, connects propylene oxide, and reacts with various substituted primary amines or secondary amines to obtain coumarin derivatives containing an isopropanolamine skeleton structure, and tests the anti-plant pathogenic fungi activity of these compounds. The present invention aims to develop new agricultural fungicides and provide important scientific basis for the development of new pesticides.

[0006] In a first aspect, the present invention provides an isopropanolamine-modified coumarin analogue, as shown in the following formula I: ; or agriculturally acceptable salts or stereoisomers thereof; in, R3 is hydrogen, fluoromethyl, or C1-C3 alkyl; R4 is , , , , Or a compound of formula II; the compound of formula II is shown below: ; in, R1 is C1-C4 alkyl, C3-C5 cycloalkyl, phenyl, benzyl, p-tolyl, p-methylbenzyl, p-fluorobenzyl, p-methoxybenzyl, 2-pyridyl, 5-fluoro-2-pyridyl, 5-methyl-2-pyridyl, or fluoroethyl; R2 is hydrogen or a C1~C3 alkyl group; and, (1) When R3 is methyl, R4 is not or ; (2) When R3 is hydrogen, R4 is not ; (3) When R2 and R3 are both hydrogen, R1 is not isopropyl, n-butyl, cyclopropyl or benzyl; (4) When R2 and R3 are both methyl groups, R1 is not phenyl; (5) When R2 is hydrogen and R3 is methyl, R1 is not isopropyl, phenyl, cyclopropyl, n-butyl, p-tolyl, 2-pyridyl or benzyl.

[0007] Preferably, in the compound of formula I, R3 is hydrogen, methyl, isopropyl, difluoromethyl or trifluoromethyl; R4 is , , or .

[0008] Preferably, in the compound of formula I, R3 is hydrogen, methyl, isopropyl, difluoromethyl or trifluoromethyl; R4 is a compound II, wherein R1 is methyl, ethyl, phenyl, benzyl, 2-piperidinyl, 5-fluoro-2-pyridinyl, 5-methyl-2-pyridinyl or 1,1,1-trifluoroethyl; R2 is hydrogen or methyl.

[0009] More preferably, it is selected from the following compounds: , , , , , , , , , , .

[0010] Most preferably, Formula I is selected from the following compounds: , , , , .

[0011] In a second aspect, the present invention provides a method for preparing a compound of formula I, the reaction formula is as follows: ; wherein R3 and R4 are as defined in Formula I; The following steps are involved: (1) reacting a compound of formula V with epibromopropane in acetone under the catalysis of potassium carbonate to obtain a compound of formula IV; (2) The compound of formula IV and the compound of formula III are heated in methanol to react to obtain the compound of formula I.

[0012] In a third aspect, the present invention provides an agricultural formulation comprising a compound of formula I.

[0013] Furthermore, the preparation includes emulsifiable concentrate, wettable powder, granule, suspension, soluble powder, smoke concentrate, water, water dispersant or water emulsion.

[0014] In a fourth aspect, the present invention provides an application of a compound of formula I in preventing and controlling agricultural pests and diseases.

[0015] Furthermore, the agricultural pests and diseases are plant fungal diseases.

[0016] Furthermore, the plant fungal diseases include rice sheath blight, cabbage soft rot, tomato early blight, citrus fruit rot, cucumber downy mildew, pepper blight, potato late blight, cotton damping-off, apple rot, grape downy mildew, rice blast, rice seedling blight, wheat fusarium rust, wheat rust, rapeseed sclerotinia, corn smut, corn leaf spot, apple anthracnose, and apple ring rot.

[0017] The beneficial effects of the present invention are: The compound of formula I provided by the present invention has a good antifungal effect and can be used to prevent and treat diseases and insect pests on crops caused by fungi, especially showing good fungicidal activity against rice blast, rapeseed sclerotinia, cotton damping-off, apple ring rot, pepper blight and wheat fusarium head blight, thereby broadening the application of coumarin analogs in the agricultural field. DETAILED DESCRIPTION

[0018] In order to enable those skilled in the art to better understand the technical solutions in the present invention, the technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work should fall within the scope of protection of the present invention.

[0019] Example 1 Preparation of compound 1 (7-(2-hydroxy-3-isopropylaminopropoxy)-chromen-2-one) ; (1) Take 1.62 g (0.01 mol) of 7-hydroxychromen-2-one, add 10 ml of acetone, dissolve it, add 5.53 g (0.04 mol) of potassium carbonate, stir evenly, slowly add 5.48 g (0.04 mol) of epibromopropane, heat to 80°C for reaction; after TLC detection, cool the reaction solution to room temperature, then pour the reaction solution into water, extract the aqueous phase with 10 ml of ethyl acetate, dry the organic phase with anhydrous sodium sulfate and evaporate to dryness, and purify the concentrate by column chromatography (V petroleum ether: V ethyl acetate = 3:1) to obtain the intermediate 7-oxiranemethoxy-chromen-2-one.

[0020] (2) Take 218 mg (1.0 mmol) of 7-oxiranemethoxy-chromen-2-one, add 5 ml of methanol, stir and dissolve, then slowly add a methanol solution containing 177 mg (3.0 mmol) of isopropylamine. After the addition is complete, heat to 50°C for reaction. After TLC detection, add water to quench the reaction. Extract the reaction solution three times with 10 ml of ethyl acetate. Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate and perform column chromatography (V dichloromethane: V methanol = 20:1) to obtain 236 mg (85%) of white solid.

[0021] Compounds 2 to 48 were prepared in sequence according to the above method. The compound structures and NMR detection results are shown in Table 1 below. The physicochemical properties of the compounds are shown in Table 2: Table 1-NMR hydrogen and carbon spectrum data of some compounds

[0022] Table 2-Physical and chemical properties of some compounds

[0023] Example 2 Indoor toxicity assay of target compounds against plant pathogenic fungi The mycelium growth rate method was used to determine the indoor toxicity activity of the target compounds against a variety of plant pathogenic fungi. The specific process is as follows: Dissolve the target compound in acetone or dichloromethane or DMSO to prepare a 2000µM stock solution. Under sterile operating conditions, dilute the prepared 2000µM with culture medium to a 50µM toxic medium plate. Set up a blank control without drug treatment in the experiment, and repeat 3 times.

[0024] According to the agricultural industry standard of the People's Republic of China (NY / T 1156.2-2006), the mycelium growth rate method was used for determination. The cultured pathogens were cut from the edge of the colony using a sterile puncher with a diameter of 5 mm under aseptic operation conditions, and the cakes were inoculated into the center of the plate containing the agent using an inoculator, with the mycelium facing downward, and the culture dish was covered with a lid and placed in a 25°C incubator for culture.

[0025] The growth of pathogenic hyphae was investigated according to the growth of colonies in the blank control culture dish. After the colonies in the blank control were fully grown, the diameter of each treated colony was measured by the cross method. The colony growth diameter was calculated using the following formula and the average value was taken.

[0026] Colony growth diameter = colony diameter - cake diameter The results were calculated using the following formula: the growth diameter of the blank control colony and the growth diameter of the drug-treated colony were used to calculate the inhibition rate of hyphae growth of various pathogenic fungi by each drug treatment. Mycelial growth inhibition rate (%) = [(control colony growth diameter - agent-treated colony growth diameter) / blank control colony growth diameter] × 100 The test results of some compounds are shown in Table 3: Table 3 - In vitro bactericidal activity test results of some compounds (%)

[0027] As shown in Table 3, some target compounds showed moderate or above inhibitory effects on multiple pathogenic fungi such as rice blast, rapeseed sclerotinia, cotton damping-off, pepper phytophthora and wheat fusarium, and had broad-spectrum antifungal activity, such as compounds 27, 40, 44, 46, 47, etc. In addition, at the same concentration, compounds 40 and 47 showed extremely excellent inhibitory effects on the five pathogenic fungi tested. In summary, compounds 40 and 47 have high application potential and development value.

[0028] Although the present invention has been described in detail by way of preferred embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, a person of ordinary skill in the art may make various equivalent modifications or substitutions to the embodiments of the present invention, and such modifications or substitutions shall be within the scope of the present invention. Any person of ordinary skill in the art may easily conceive of changes or substitutions within the technical scope disclosed by the present invention, and such changes or substitutions shall be within the scope of protection of the present invention.

Claims

1. Compounds of formula I: ； or agriculturally acceptable salts or stereoisomers thereof; in, R3 is hydrogen, fluoromethyl, or C1-C3 alkyl; R4 is , , , , Or a compound of formula II; the compound of formula II is shown below: ； in, R1 is C1-C4 alkyl, C3-C5 cycloalkyl, phenyl, benzyl, p-tolyl, p-methylbenzyl, p-fluorobenzyl, p-methoxybenzyl, 2-pyridyl, 5-fluoro-2-pyridyl, 5-methyl-2-pyridyl, or fluoroethyl; R2 is hydrogen or a C1~C3 alkyl group; and, (1) When R3 is methyl, R4 is not or ; (2) When R3 is hydrogen, R4 is not ; (3) When R2 and R3 are both hydrogen, R1 is not isopropyl, n-butyl, cyclopropyl or benzyl; (4) When R2 and R3 are both methyl groups, R1 is not phenyl; (5) When R2 is hydrogen and R3 is methyl, R1 is not isopropyl, phenyl, cyclopropyl, n-butyl, p-tolyl, 2-pyridyl or benzyl.

2. The compound of formula I according to claim 1, characterized in that In the compound of formula I, R3 is hydrogen, methyl, isopropyl, difluoromethyl or trifluoromethyl; R4 is , , or .

3. The compound of formula I according to claim 1, characterized in that In the compound of formula I, R3 is hydrogen, methyl, isopropyl, difluoromethyl or trifluoromethyl; R4 is a compound of formula II, wherein R1 is methyl, ethyl, phenyl, benzyl, 2-piperidinyl, 5-fluoro-2-pyridinyl, 5-methyl-2-pyridinyl or 1,1,1-trifluoroethyl; R2 is hydrogen or methyl.

4. The compound of formula I according to claim 1, characterized in that Selected from the following compounds: 、 、 、 、 、 、 、 、 、 、 。 5. The compound of formula I according to claim 1, characterized in that Selected from the following compounds: 、 、 、 、 。 6. A method for preparing the compound of formula I as claimed in claim 1, characterized in that: The reaction formula is as follows: ； wherein R3 and R4 are as defined in Formula I; The following steps are involved: (1) reacting a compound of formula V with epibromopropane in acetone under the catalysis of potassium carbonate to obtain a compound of formula IV; (2) The compound of formula IV and the compound of formula III are heated in methanol to react to obtain the compound of formula I.

7. An agricultural formulation comprising a compound of formula I as claimed in claim 1, characterized in that The agricultural preparations include emulsifiable concentrates, wettable powders, granules, suspensions, soluble powders, smoke concentrates, aqueous concentrates, water dispersants or aqueous emulsions.

8. Use of the compound of formula I as claimed in claim 1 in preventing and controlling agricultural pests and diseases.

9. The use according to claim 8, characterized in that The agricultural pests and diseases are plant fungal diseases.

10. The use according to claim 9, characterized in that The plant fungal diseases include rice sheath blight, cabbage soft rot, tomato early blight, citrus fruit rot, cucumber downy mildew, pepper blight, potato late blight, cotton damping-off, apple rot, grape downy mildew, rice blast, rice seedling blight, wheat fusarium rust, wheat rust, rapeseed sclerotinia, corn smut, corn leaf spot, apple anthracnose, and apple ring rot.

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