An isopropanolamine-modified coumarin analogue, and a preparation method and application thereof
By preparing isopropanolamine-modified coumarin analogs, the problem of insufficient application of coumarin in the agricultural field has been solved, and a new type of agricultural fungicide with inhibitory effects on a variety of plant pathogenic fungi has been developed, expanding its application in the agricultural field.
Patent Information
- Application Number
- CN202510011378.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-03
- Publication Date
- 2025-12-19
- Estimated Expiration
- 2045-01-03
AI Technical Summary
Existing isopropanolamine-modified coumarin analogs are mainly used in the medical field, and have not been applied in the agricultural field, especially in the control of plant pathogenic fungi.
Using 7-hydroxy-coumarin as the parent nucleus, coumarin derivatives containing an isopropanolamine backbone were prepared by reacting propylene oxide with various substituted primary or secondary amines. Their activity against plant pathogenic fungi was then tested, leading to the development of novel agricultural fungicides.
The prepared compounds showed moderate to high inhibitory effects on a variety of plant pathogenic fungi, such as rice blast, rapeseed sclerotinia rot, cotton damping-off, pepper blight, and wheat scab, thus broadening the application of coumarin analogs in the agricultural field.
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Figure CN119751400B_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of pesticides, in particular to a coumarin analogue modified by isopropanolamine and a preparation method and application thereof. BACKGROUND
[0002] Pesticides are an important part of agricultural production. Proper use of fungicides can effectively prevent yield reduction or fruit quality decline caused by plant pathogenic fungi, and avoid causing serious economic losses. However, due to the unreasonable use of traditional fungicides and the long-term application of single formulations, many common pathogenic fungi have developed serious drug resistance. Therefore, it is still of great significance to continuously optimize the lead compounds and develop fungicides with new action mechanisms, high efficiency, low toxicity and environmental friendliness.
[0003] Natural products play a very important role in the field of pesticide development. Many important commercial pesticides are developed based on natural products, such as methoxy acrylate fungicides. The coumarin skeleton structure of natural products includes a benzene ring and an α-pyrone ring, which has a wide range of pharmacological activities, such as anticancer, antioxidant, anti-insect, herbicidal and fungicidal activities. For example, in the previous work of developing new fungicides, Liu Changling et al. successfully developed a new fungicide coumoxystrobin with independent intellectual property rights by combining the coumarin skeleton fragment with the methoxy acrylate active structure. The compound shows superior control effect on crop powdery mildew, downy mildew and anthracnose.
[0004] The existing isopropanolamine-modified coumarin analogues are all applied in the medical field, mainly for preparing anticancer, antifungal and antipsychotic drugs. There is no related report on their application in the agricultural field. SUMMARY
[0005] In view of the problem that the existing isopropanolamine-modified coumarin analogues have not been applied in the agricultural field, the present application provides an isopropanolamine-modified coumarin analogue and a preparation method and application thereof, so as to solve the above problem. The present application mainly takes 7-hydroxy-coumarin as the mother nucleus, connects propylene oxide, reacts with various substituted primary amines or secondary amines to obtain coumarin derivatives containing isopropanolamine skeleton structure, and tests the anti-plant pathogenic fungal activity of the compounds. The present application aims to develop new agricultural fungicides and provide important scientific basis for the development of new pesticides.
[0006] In the first aspect, the present application provides an isopropanolamine-modified coumarin analogue, as shown in the following formula I:
[0007] ;
[0008] or an agriculturally acceptable salt or stereoisomer thereof.
[0009] wherein
[0010] R3 is hydrogen, fluoromethyl, C1-C3 alkyl;
[0011] R4 is , , , , or a compound of formula II; the compound of formula II is shown below:
[0012] ;
[0013] wherein
[0014] R1 is C1-C4 alkyl, C3-C5 cycloalkyl, phenyl, benzyl, p-tolyl, p-tolyl, p-fluorobenzyl, p-methoxybenzyl, 2-pyridyl, 5-fluoro-2-pyridyl, 5-methyl-2-pyridyl, fluorinated ethyl;
[0015] R2 is hydrogen or C1-C3 alkyl;
[0016] and
[0017] (1) when R3 is methyl, R4 is not or ;
[0018] (2) when R3 is hydrogen, R4 is not ;
[0019] (3) when R2 and R3 are both hydrogen, R1 is not isopropyl, n-butyl, cyclopropyl or benzyl;
[0020] (4) when R2 and R3 are both methyl, R1 is not phenyl;
[0021] (5) when R2 is hydrogen and R3 is methyl, R1 is not isopropyl, phenyl, cyclopropyl, n-butyl, p-tolyl, 2-pyridyl or benzyl.
[0022] Preferably, in the compound of formula I,
[0023] R3 is hydrogen, methyl, isopropyl, difluoromethyl or trifluoromethyl;
[0024] R4 is , , or .
[0025] Preferably, in the compound of formula I,
[0026] R3 is hydrogen, methyl, isopropyl, difluoromethyl or trifluoromethyl;
[0027] R4 is a compound of formula II, wherein,
[0028] R1 is methyl, ethyl, phenyl, benzyl, 2-piperidinyl, 5-fluoro-2-pyridyl, 5-methyl-2-pyridyl or 1,1,1-trifluoroethyl;
[0029] R2 is hydrogen or methyl.
[0030] More preferably, the compound is selected from the group consisting of:
[0031] , , , , , , , , , , .
[0032] Most preferably, the compound of formula I is selected from the group consisting of:
[0033] , , , , .
[0034] In a second aspect, the present application provides a method for preparing a compound of formula I, the reaction scheme of which is as follows:
[0035] ;
[0036] wherein R3 and R4 are as defined in formula I;
[0037] comprising the following steps:
[0038] (1) reacting a compound of formula V with epibromohydrin in the presence of potassium carbonate in acetone to obtain a compound of formula IV;
[0039] (2) heating a compound of formula IV with a compound of formula III in methanol to obtain a compound of formula I.
[0040] In a third aspect, the present application provides an agricultural preparation comprising a compound of formula I.
[0041] Further, the preparation comprises an emulsifiable concentrate, a wettable powder, a granule, a suspension concentrate, a soluble powder, a smoke agent, an aqueous agent, a water dispersible granule or an aqueous emulsion.
[0042] In a fourth aspect, the present application provides a use of a compound of formula I in the prevention and treatment of agricultural pests and diseases.
[0043] Further, the agricultural plant diseases and insect pests are plant fungal diseases.
[0044] Further, the plant fungal diseases include rice sheath blight, cabbage soft rot, tomato early blight, melon and fruit rot, cucumber downy mildew, pepper downy mildew, potato late blight, cotton damping-off, apple rot, grape downy mildew, rice blast, rice false smut, wheat scab, wheat rust, rape sclerotinia rot, corn smut, apple anthracnose, apple ring rot.
[0045] The present application has the following advantages:
[0046] The compound of formula I has good antifungal effect, and can be applied to prevent and treat the plant diseases and insect pests caused by fungi, especially has good fungicidal activity on rice blast, rape sclerotinia rot, cotton damping-off, apple ring rot, pepper downy mildew and wheat scab, and widens the application of coumarin analogs in the agricultural field. DETAILED DESCRIPTION
[0047] In order to make the person skilled in the art better understand the technical solutions in the present application, the technical solutions in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all the other embodiments obtained by the person skilled in the art without creative labor should belong to the protection scope of the present application.
[0048] Embodiment 1
[0049] Preparation of compound 1 (7-(2-hydroxy-3-isopropylaminopropoxy)-chromen-2-one)
[0050] ;
[0051] (1) 7-hydroxychromen-2-one 1.62 g (0.01 mol) was taken, 10 ml of acetone was added, and after dissolution, 5.53 g (0.04 mol) of potassium carbonate was added, and after stirring uniformly, 5.48 g (0.04 mol) of epoxy bromopropane was slowly added dropwise, and heated to 80℃ for reaction; after TLC detection of complete reaction, the reaction liquid was reduced to room temperature, and then the reaction liquid was poured into water, and the water phase was extracted with 10 ml of ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate and evaporated to dryness, and the concentrate was column chromatographed (V petroleum ether: V ethyl acetate = 3:1) to obtain the intermediate 7-oxirane methoxy-chromen-2-one.
[0052] (2) Take 7-oxirane methoxy-chromen-2-one 218 mg (1.0 mmol), add 5 ml methanol to stir and dissolve, then slowly add isopropylamine 177 mg (3.0 mmol) in methanol solution, after dropwise addition, warm to 50°C for reaction; TLC test reaction complete, add water to quench the reaction, ethyl acetate 10 ml x 3 times to extract the reaction liquid three times, combined organic phase, saturated brine wash organic phase, anhydrous sodium sulfate drying, concentrated after column chromatography (V dichloromethane: V methanol = 20: 1) to get white solid 236 mg (85%).
[0053] The compounds 2-48 were prepared according to the above method in turn. The structures and NMR detection results of the compounds are shown in Table 1, and the physicochemical properties of the compounds are shown in Table 2:
[0054] Table 1 - NMR hydrogen spectrum and carbon spectrum data of part of the compounds
[0055]
[0056] Table 2 - Physicochemical properties of part of the compounds
[0057]
[0058] Example 2
[0059] In vitro toxicity determination of target compounds on plant pathogenic fungi
[0060] The mycelial growth rate method was used to determine the in vitro toxicity activity of the target compounds on various plant pathogenic fungi, and the specific process was as follows:
[0061] The target compound was dissolved in acetone or dichloromethane or DMSO to prepare a 2000 µM stock solution. Under sterile operating conditions, the prepared 2000 µM was diluted with culture medium to prepare a 50 µM toxic culture medium plate, and a blank control without drug treatment was set up, and each was repeated 3 times.
[0062] According to the agricultural industry standard of the People's Republic of China (NY / T 1156.2-2006), the mycelial growth rate method was used for determination. The cultured pathogenic fungi were cut into 5 mm diameter sterile punchers from the edge of the colony, and the punchers were inoculated into the center of the plate containing the drug using an inoculator, with the mycelium facing down, covered with a culture dish cover, and placed in a 25°C incubator.
[0063] According to the growth of the mycelium in the blank control plate, the growth of the mycelium was investigated, and after the mycelium in the blank control plate grew fully, the diameter of each treatment mycelium was measured by the cross method, and the following formula was used to calculate the mycelial growth diameter, and the average value was taken.
[0064] Mycelial growth diameter = colony diameter - puncher diameter
[0065] The determination results were calculated using the following formula, and the inhibition rate of each drug treatment on the mycelial growth of various pathogenic fungi was calculated based on the mycelial growth diameter of the blank control and the mycelial growth diameter of the drug treatment
[0066] Mycelial growth inhibition rate (%) = [(control mycelial growth diameter-drug treatment mycelial growth diameter) / blank control mycelial growth diameter] x 100
[0067] The test results of some compounds are shown in Table 3:
[0068] Table 3 - In vitro fungicidal activity determination results (%) of some compounds
[0069]
[0070] As shown in Table 3, some target compounds showed moderate or above inhibition effect on rice blast, cabbage sclerotinia, cotton damping-off, pepper late blight, and wheat scab, and had broad-spectrum fungicidal activity, such as compounds 27, 40, 44, 46, 47, etc. In addition, at the same concentration, compounds 40 and 47 showed extremely excellent inhibition activity on the five kinds of pathogenic fungi tested. In summary, compounds 40 and 47 have high application potential and development value.
[0071] Although the present application has been described in detail with reference to the preferred embodiments, the application is not limited to such but encompasses any modifications or alternatives within the scope of the application as disclosed in the appended claims.
Claims
1. A compound of formula I: ###0001### or an agriculturally acceptable salt thereof; wherein, R1 is methyl, phenyl, benzyl or 1,1,1-trifluoroethyl; R2 is hydrogen or methyl; R3 is difluoromethyl or trifluoromethyl; and R4 is hydrogen or methyl. ； 2. A compound of formula I according to claim 1, selected from the group consisting of: ###0002### ###0003### ###0004### ###0005### ###0006### ###0007### ###0008### ###0009### ###0010### ###0011### ###0012### ###0013### ###0014### ###0015### ###0016### ###0017### ###0018### ###0019### ###0020### ###0021### ###0022### ###0023### ###0024### ###0025### ###0026### ###0027### ###0028### ###0029### ###0030### ###0031### ###0032### ###0033### ###0034### ###0035### ###0036### ###0037### ###0038### ###0039### ###0040### ###0041### ###0042### ###0043### ###0044### ###0045### ###0046### ###0047### ###0048### ###0049### ###0050### ###0051### ###0052### ###0053### ###0054### ###0055### ###0056### ###0057### ###0058### ###0059### ###0060### ###0061### ###0062### ###0063### ###0064### ###0065### ###0066### ###0067### ###0068### ###0069### ###0070### ###0071### ###0072### ###0073### ###0074### ###0075### ###0076### ###0077### ###0078### ###0079### ###0080### ###0081### ###0082### ###0083### ###0084### ###0085### ###0086### ###0087### ###0088### ###0089### ###0090### ###0091### ###0092### ###0093### ###0094### ###0095### ###0096### ###0097### ###0098### ###0099### ###0100### ###0101### ###0102### ###0103### ###0104### ###0105### ###0106### ###0107### ###0108### ###0109### ###0110### ###0111### ###0112### ###0113### ###0114### ###0115### ###0116### ###0117### ###0118### ###0119### ###0120### ###0121### ###0122### ### R4 is , or a compound of formula II; the compound of formula II is shown below: ； 2. The compound of claim 1 of formula I, wherein 、 、 、 、 、 。 3. The compound of formula I according to claim 1, wherein 、 、 、 、 。 4. A process for the preparation of a compound of formula I according to claim 1, characterized in that ； 5. An agricultural formulation comprising a compound of formula I according to claim 1, characterized in that,