A flavonol derivative containing triazolopyridine and its preparation method and application

Abstract

The present invention discloses a flavonol derivative containing triazolopyridine, which is characterized by a structural formula as shown in Formula S: #imgabs0#, wherein: R1 is hydrogen, alkyl or alkoxy; R2 contains one or more halogens, alkyl or alkoxy groups at the ortho, meta or para position on the benzene ring; and n is 3 or 4. The present invention conducts a plant fungus inhibition activity test on the disclosed flavonol derivative containing triazolopyridine, and proves that the disclosed flavonol derivative containing triazolopyridine has good fungus inhibition activity and can be used in the preparation of a plant pathogen inhibition agent.

Description

Technical Field

[0001] The present invention relates to the technical field of pesticide synthesis, and in particular to a method for preparing a flavonol derivative containing triazolopyridine and its application in antibacterial properties. Background Art

[0002] Natural products and their biomimetic pesticides are increasingly important in controlling plant diseases due to their environmentally friendly properties, unique action sites, and high selectivity. Flavonols, a class of plant secondary metabolites representing flavonoids, are widely found in plants such as angiosperms, gymnosperms, mosses, and Alliums, and play important ecological roles. Pharmacological studies have shown that flavonols possess a wide range of biological activities, including antibacterial, antiviral, antitumor, and antioxidant properties. However, research on the effects of flavonols on common plant diseases in agricultural and commercial crops is currently limited. Therefore, using these compounds as a starting point and modifying their structures has great potential to yield organic active molecules with excellent antibacterial activity against plant pathogens. This suggests that flavonols hold great potential for further research and application.

[0003] In 2017, Huang et al. (Huang Minguo, Ruan Xianghui, Zhang Juping, Li Qin, Wang Yihui, Chen Lijuan, Zhang Cheng, Li Pu, Xue Wei. Synthesis and antibacterial activity of substituted flavonoid phosphates [J]. Journal of Organic Chemistry, 2017, 37(08): 2145-2152.)

[0004] A series of flavonol derivatives containing phosphate groups were synthesized. Bioassay results showed that the target compounds had good inhibitory activity against citrus canker and rice bacterial blight.

[0005] In 2015, Han et al. (Han, Y.; Ding, Y.; Xie, DD; Hu, DY; Li, P.; Li, XT; moiety[J].Eur.J.Med.Chem.2015,92:732-737.)

[0006] A series of flavonols containing 1,4-pentadien-3-one groups were synthesized and their antiviral activities were evaluated. Bioactivity assays showed that most of the compounds had strong antiviral activity against cucumber mosaic virus.

[0007] Flavonols are derived from natural products. So far, there have been no reports on flavonol derivatives containing triazolopyridine and their application in pesticides. There have also been no reports on their activity against nine plant fungi, including rice sheath blight (Rs), blueberry gray mold (Bc), rapeseed disk (Ss), pepper phytophthora (Pc), Fusarium graminearum (Fg), Colletotrichum gloeosporioides (Cg), pepper wilt (Fc), cabbage black spot (Ab) and Phomopsis sclerotiorum (Ps). Summary of the Invention

[0008] The purpose of the present invention is to provide a preparation method and application of flavonol derivatives containing triazolopyridine. By introducing active triazolopyridine into the structure of flavonol, a series of flavonol derivatives containing triazolopyridine with antifungal properties are synthesized.

[0009] To achieve the above object, the present invention provides the following technical solutions:

[0010] A flavonol derivative containing triazolopyridine, the general structural formula of which is shown below:

[0011]

[0012] Wherein: R1 is hydrogen, alkyl or alkoxy; R2 is hydrogen, halogen, alkyl or alkoxy. R1 is hydrogen, C1-C6 alkyl or C1-C6 alkoxy; the R2 group is one or more methyl, methoxy, tert-butyl, fluorine, chlorine or bromine at the o-, m- or p-position of the benzene ring.

[0013] Furthermore, the R1 group is hydrogen, C1-C6 alkyl or C1-C6 alkoxy; the R2 group contains one or more methyl, methoxy, tert-butyl, fluorine, chlorine or bromine at the ortho, meta or para position on the benzene ring.

[0014] A method for preparing a flavonol derivative containing triazolopyridine, the synthesis route of which is as follows:

[0015] (1) Using 2,3-dichloropyridine and hydrazine hydrate as raw materials, heating under reflux to obtain 3-chloro-2-hydrazinopyridine (intermediate 1):

[0016]

[0017] (2) In the presence of a base (sodium hydroxide), the reaction is heated under reflux with carbon disulfide in ethanol, and then acidified with hydrochloric acid to obtain 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (intermediate 2):

[0018]

[0019] (3) Substituted o-hydroxyacetophenone and substituted benzaldehyde undergo aldol condensation reaction to obtain 3-(substituted phenyl)-1-(2-hydroxy-4-substituted phenyl)-2-propen-1-one (intermediate 3):

[0020]

[0021] (4) 2-(Substituted phenyl)-3-hydroxy-7-substituted-4H-chromene-4-one (Intermediate 4) was prepared from 3-(substituted phenyl)-1-(2-hydroxy-4-substituted phenyl)-2-propen-1-one, sodium hydroxide, and hydrogen peroxide in ethanol as solvent at room temperature:

[0022]

[0023] (5) 2-(substituted phenyl)-3-hydroxy-7-substituted-4H-chromen-4-one and 1,3-dibromopropane or 1,4-dibromobutane are used in the presence of potassium carbonate as a catalyst and N,N-dimethylformamide as a solvent to prepare 3-(3-bromopropoxy)-7-substituted-2-(substituted phenyl)-4H-bromo-4-one (Intermediate 5) or 3-(4-bromobutoxy)-7-substituted-2-(substituted phenyl)-4H-bromo-4-one (Intermediate 5):

[0024]

[0025] (6) the 2-(substituted phenyl)-3-hydroxy-7-substituted-4H-chromen-4-one and 1,3-dibromopropane or 1,4-dibromobutane are reacted with 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol in the presence of K2CO3 as an acid-binding agent and acetonitrile as a solvent to produce a flavonol derivative (S) containing a triazolopyridine;

[0026]

[0027] Application of triazolopyridine-containing flavonol derivatives in inhibiting plant fungi.

[0028] The plant fungi are rice sheath blight (Rs), blueberry gray mold (Bc), rapeseed sclerotinia (Ss), pepper phytophthora (Pc), Fusarium graminearum (Fg), gloeosporioides (Cg), pepper wilt (Fc), cabbage black spot (Ab) and Phomopsis sclerotiorum (Ps).

[0029] The beneficial technical effects of the present invention are as follows: This application introduces the highly active 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol group into the structure of a flavonol, namely, the 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol structure is attached to the 3-hydroxyl group of the flavonol. A series of triazolopyridine-containing flavonol derivatives were synthesized. Testing of the synthesized triazolopyridine-containing flavonol derivatives for antifungal activity revealed that the compounds of the present invention have excellent antifungal activity and can be used to prepare agents for inhibiting plant pathogens. DETAILED DESCRIPTION

[0030] Various exemplary embodiments of the present invention are now described in detail. This detailed description should not be considered as a limitation of the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention. It should be understood that the terms used in the present invention are only for describing specific embodiments and are not intended to limit the present invention.

[0031] In addition, for numerical ranges in the present invention, it is understood that each intervening value between the upper and lower limits of the range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated value or intervening value in the stated range is also included in the present invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention.

[0033] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0034] Example 1

[0035] The preparation method of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-2-(4-methoxyphenyl)-4H-chromen-4-one (target compound S1) comprises the following steps:

[0036] (1) Preparation of 3-chloro-2-hydrazinopyridine (Intermediate 1):

[0037] To a 100 mL three-necked flask, add 4.00 g of 2,3-dichloropyridine (27.03 mmol) and 10.83 mL of hydrazine hydrate (216.24 mmol), followed by 40 mL of ethanol. Reflux at 90°C with magnetic stirring for 6-8 h until the reaction is complete. After TLC monitoring until the starting material spots disappear, the reaction system is cooled to room temperature. A large amount of white needle-like solid precipitates at the bottom of the flask, representing Intermediate 1. Filter, dry, and set aside. Yield: 85%.

[0038] (2) Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate 2):

[0039] In a 100 mL three-necked flask, 3.00 g of intermediate 1 (20.90 mmol) and 2.51 g of sodium hydroxide (62.69 mmol) were added, followed by 50 mL (18.50 mmol) of ethanol. Magnetic stirring was started, and 2.53 mL of carbon disulfide (41.79 mmol) was slowly added dropwise at room temperature. After the addition was complete, the reaction was controlled at 90° C. and heated for 8-10 h until the reactants were completely reacted. After monitoring by TLC until the starting material point disappeared, the reaction system in the flask was cooled to room temperature and poured into a 500 mL beaker containing 300 mL of ice water. 5% HCl solution was added dropwise with a rubber dropper until the pH value in the beaker was about 3 as measured by pH paper. A large amount of white solid precipitated at the bottom of the beaker as intermediate 2, which was filtered, dried, and set aside. Yield: 77%.

[0040] (3) Preparation of 3-(4-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propen-1-one (Intermediate 3):

[0041] 3.00 g of o-hydroxyacetophenone (22.03 mmol) and 3.30 g of p-anisaldehyde (24.24 mmol) were placed in a 500 mL round-bottom flask. 300 mL of ethanol was added until the compound was completely dissolved. 20-30 mL of 10% sodium hydroxide solution was slowly added dropwise. Stir at room temperature for 4 days. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 4:1, v / v). After stopping the reaction, the reaction mixture was poured into a 500 mL beaker containing 400 mL of ice water. 5% HCl solution was added dropwise using a rubber-tipped pipette until the pH value in the beaker reached approximately 6 using pH paper. A large amount of yellow solid, Intermediate 3, precipitated at the bottom of the beaker. The solid was filtered, dried, and set aside. Yield: 71%.

[0042] (4) Preparation of 2-(4-methoxyphenyl)-3-hydroxy-4H-chromene-4-one (Intermediate 4):

[0043] 3.00 g of intermediate 3 (11.80 mmol) was placed in a 500 mL round-bottom flask. 300 mL of ethanol was added until the compound was completely dissolved. 20-30 mL of 10% sodium hydroxide solution and 2.17 mL of hydrogen peroxide (70.79 mmol) were slowly added. The mixture was stirred at room temperature for 3 days. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 4:1, v / v). After stopping the reaction, the reaction mixture was poured into a 500 mL beaker containing 400 mL of ice water. 5% HCl solution was added dropwise using a rubber-tipped pipette until the pH value in the beaker reached approximately 6 using pH paper. A large amount of yellow solid, intermediate 4, precipitated at the bottom of the beaker. The solid was filtered, dried, and set aside. Yield: 63%.

[0044] (5) Preparation of 3-(3-bromopropoxy)-2-(4-methoxyphenyl)-4H-bromo-4-one (Intermediate 5):

[0045] 1.00 g of intermediate 4 (3.73 mmol) was placed in a 50 mL round-bottom flask. 20 mL of N,N-dimethylformamide was added until the intermediate 4 was completely dissolved. 1.13 mL of 1,3-dibromopropane (11.18 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 6 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 4:1, v / v). After stopping the reaction, the reaction mixture was poured into a 250 mL beaker containing 100 mL of water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 5 in a 62% yield.

[0046] (6) Preparation of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-2-(4-methoxyphenyl)-4H-chromen-4-one (target compound S1):

[0047] 0.86 g of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (4.62 mmol), 1.07 g of K2CO3 (7.71 mmol), and 50 mL of acetonitrile solution were added to a 100 mL round-bottom flask. After stirring at room temperature for 30 min, 1.00 g of 3-(3-bromopropoxy)-2-(4-methoxyphenyl)-4H-bromo-4-one (2.57 mmol) was added to the reaction system. The reaction was continued at room temperature for 18 h. The reaction system was concentrated under reduced pressure to remove part of the solvent and poured into 100 mL of ice water. The mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target compound S1 in a yield of 44%.

[0048] Example 2

[0049] The preparation method of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-2-(p-tolyl)-4H-chromen-4-one (target compound S2) comprises the following steps:

[0050] (1) Preparation of 3-chloro-2-hydrazinopyridine (Intermediate 1):

[0051] As in step (1) of Example 1.

[0052] (2) Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate 2):

[0053] As in step (2) of Example 1.

[0054] (3) Preparation of 3-(4-methylphenyl)-1-(2-hydroxyphenyl)-2-propene-1-one (Intermediate 3):

[0055] As in step (3) of Example 1, except that p-methoxybenzaldehyde is replaced by an equimolar amount of p-tolualdehyde.

[0056] (4) Preparation of 2-(4-methylphenyl)-3-hydroxy-4H-chromen-4-one (Intermediate 4):

[0057] As in step (4) of Example 1, except that 3-(4-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propen-1-one is replaced by an equimolar amount of 3-(4-tolyl)-1-(2-hydroxyphenyl)-2-propen-1-one.

[0058] (5) Preparation of 3-(3-bromopropoxy)-2-(4-methylphenyl)-4H-bromo-4-one (Intermediate 5):

[0059] As in step (5) of Example 1, except that 2-(4-methoxyphenyl)-3-hydroxy-4H-chromen-4-one is replaced by an equimolar amount of 2-(4-methylphenyl)-3-hydroxy-4H-chromen-4-one.

[0060] (6) Preparation of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-2-(4-methylphenyl)-4H-chromen-4-one (target compound S2):

[0061] As in step (5) of Example 1, except that 3-(3-bromopropoxy)-2-(4-methoxyphenyl)-4H-bromo-4-one is replaced with an equimolar amount of 3-(3-bromopropoxy)-2-(4-methylphenyl)-4H-bromo-4-one, yield: 31%.

[0062] Example 3

[0063] The preparation method of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-2-(4-fluorophenyl)-4H-chromen-4-one (target compound S3) comprises the following steps:

[0064] (1) Preparation of 3-chloro-2-hydrazinopyridine (Intermediate 1):

[0065] As in step (1) of Example 1.

[0066] (2) Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate 2):

[0067] As in step (2) of Example 1.

[0068] (3) Preparation of 3-(4-fluorophenyl)-1-(2-hydroxyphenyl)-2-propen-1-one (Intermediate 3):

[0069] As in step (3) of Example 1, except that p-methoxybenzaldehyde is replaced by an equimolar amount of p-fluorobenzaldehyde.

[0070] (4) Preparation of 2-(4-fluorophenyl)-3-hydroxy-4H-chromen-4-one (Intermediate 4):

[0071] As in step (4) of Example 1, except that 3-(4-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propen-1-one is replaced by an equimolar amount of 3-(4-fluorophenyl)-1-(2-hydroxyphenyl)-2-propen-1-one.

[0072] (5) Preparation of 3-(3-bromopropoxy)-2-(4-fluorophenyl)-4H-bromo-4-one (Intermediate 5):

[0073] As in step (5) of Example 1, except that 2-(4-methoxyphenyl)-3-hydroxy-4H-chromen-4-one is replaced by an equimolar amount of 2-(4-fluorophenyl)-3-hydroxy-4H-chromen-4-one.

[0074] (6) Preparation of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-2-(4-fluorophenyl)-4H-chromen-4-one (target compound S3):

[0075] As in step (5) of Example 1, except that 3-(3-bromopropoxy)-2-(4-methoxyphenyl)-4H-bromo-4-one was replaced with an equimolar amount of 3-(3-bromopropoxy)-2-(4-fluorophenyl)-4H-bromo-4-one, yield: 19%.

[0076] Example 4

[0077] The preparation method of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-2-(4-chlorophenyl)-4H-chromen-4-one (target compound S4) comprises the following steps:

[0078] (1) Preparation of 3-chloro-2-hydrazinopyridine (Intermediate 1):

[0079] As in step (1) of Example 1.

[0080] (2) Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate 2):

[0081] As in step (2) of Example 1.

[0082] (3) Preparation of 3-(4-chlorophenyl)-1-(2-hydroxyphenyl)-2-propen-1-one (Intermediate 3):

[0083] As in step (3) of Example 1, except that p-methoxybenzaldehyde is replaced by an equimolar amount of p-chlorobenzaldehyde.

[0084] (4) Preparation of 2-(4-chlorophenyl)-3-hydroxy-4H-chromene-4-one (Intermediate 4):

[0085] As in step (4) of Example 1, except that 3-(4-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propen-1-one is replaced by an equimolar amount of 3-(4-chlorophenyl)-1-(2-hydroxyphenyl)-2-propen-1-one.

[0086] (5) Preparation of 3-(3-bromopropoxy)-2-(4-chlorophenyl)-4H-bromo-4-one (Intermediate 5):

[0087] As in step (5) of Example 1, except that 2-(4-methoxyphenyl)-3-hydroxy-4H-chromen-4-one is replaced by an equimolar amount of 2-(4-chlorophenyl)-3-hydroxy-4H-chromen-4-one.

[0088] (6) Preparation of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-2-(4-chlorophenyl)-4H-chromen-4-one (target compound S4):

[0089] As in step (5) of Example 1, except that 3-(3-bromopropoxy)-2-(4-methoxyphenyl)-4H-bromo-4-one is replaced with an equimolar amount of 3-(3-bromopropoxy)-2-(4-chlorophenyl)-4H-bromo-4-one, yield: 49%.

[0090] Example 5

[0091] The preparation method of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-2-(4-bromophenyl)-4H-chromen-4-one (target compound S5) comprises the following steps:

[0092] (1) Preparation of 3-chloro-2-hydrazinopyridine (Intermediate 1):

[0093] As in step (1) of Example 1.

[0094] (2) Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate 2):

[0095] As in step (2) of Example 1.

[0096] (3) Preparation of 3-(4-bromophenyl)-1-(2-hydroxyphenyl)-2-propen-1-one (Intermediate 3):

[0097] As in step (3) of Example 1, except that p-methoxybenzaldehyde is replaced by an equimolar amount of p-bromobenzaldehyde.

[0098] (4) Preparation of 2-(4-bromophenyl)-3-hydroxy-4H-chromen-4-one (Intermediate 4):

[0099] As in step (4) of Example 1, except that 3-(4-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propen-1-one is replaced by an equimolar amount of 3-(4-bromophenyl)-1-(2-hydroxyphenyl)-2-propen-1-one.

[0100] (5) Preparation of 3-(3-bromopropoxy)-2-(4-bromophenyl)-4H-bromo-4-one (Intermediate 5):

[0101] As in step (5) of Example 1, except that 2-(4-methoxyphenyl)-3-hydroxy-4H-chromen-4-one is replaced by an equimolar amount of 2-(4-bromophenyl)-3-hydroxy-4H-chromen-4-one.

[0102] (6) Preparation of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-2-(4-bromophenyl)-4H-chromen-4-one (target compound S5):

[0103] As in step (5) of Example 1, except that 3-(3-bromopropoxy)-2-(4-methoxyphenyl)-4H-bromo-4-one is replaced with an equimolar amount of 3-(3-bromopropoxy)-2-(4-bromophenyl)-4H-bromo-4-one, yield: 45%.

[0104] Example 6

[0105] The preparation method of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-7-methoxy-2-(4-methylphenyl)-4H-chromen-4-one (target compound S6) comprises the following steps:

[0106] (1) Preparation of 3-chloro-2-hydrazinopyridine (Intermediate 1):

[0107] As in step (1) of Example 1.

[0108] (2) Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate 2):

[0109] As in step (2) of Example 1.

[0110] (3) Preparation of 3-(4-methylphenyl)-1-(2-hydroxy-4-methoxyphenyl)-2-propene-1-one (Intermediate 3):

[0111] As in step (3) of Example 1, except that p-methoxybenzaldehyde is replaced by an equimolar amount of p-methylbenzaldehyde, and o-hydroxyacetophenone is replaced by an equimolar amount of 2-hydroxy-4-methoxyacetophenone.

[0112] (4) Preparation of 2-(4-methylphenyl)-3-hydroxy-7-methoxy-4H-chromen-4-one (Intermediate 4):

[0113] As in step (4) of Example 1, except that 3-(4-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propene-1-one is replaced by an equimolar amount of 3-(4-methylphenyl)-1-(2-hydroxy-4-methoxyphenyl)-2-propene-1-one.

[0114] (5) Preparation of 3-(3-bromopropoxy)-7-methoxy-2-(4-methylphenyl)-4H-chromen-4-one (Intermediate 5):

[0115] As in step (5) of Example 1, except that 2-(4-methoxyphenyl)-3-hydroxy-4H-chromen-4-one is replaced by an equimolar amount of 2-(4-methylphenyl)-3-hydroxy-7-methoxy-4H-chromen-4-one.

[0116] (6) Preparation of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-7-methoxy-2-(4-methylphenyl)-4H-chromen-4-one (target compound S6):

[0117] As in step (5) of Example 1, except that 3-(3-bromopropoxy)-2-(4-methoxyphenyl)-4H-bromo-4-one is replaced by an equimolar amount of 3-(3-bromopropoxy)-7-methoxy-2-(4-methylphenyl)-4H-chromen-4-one, yield: 46%.

[0118] Example 7

[0119] The preparation method of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-7-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one (target compound S7) comprises the following steps:

[0120] (1) Preparation of 3-chloro-2-hydrazinopyridine (Intermediate 1):

[0121] As in step (1) of Example 1.

[0122] (2) Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate 2):

[0123] As in step (2) of Example 1.

[0124] (3) Preparation of 3-(4-methoxyphenyl)-1-(2-hydroxy-4-methoxyphenyl)-2-propene-1-one (Intermediate 3):

[0125] The same as step (3) of Example 1, except that o-hydroxyacetophenone is replaced by an equimolar amount of 2-hydroxy-4-methoxyacetophenone.

[0126] (4) Preparation of 2-(4-methoxyphenyl)-3-hydroxy-7-methoxy-4H-chromen-4-one (Intermediate 4):

[0127] As in step (4) of Example 1, except that 3-(4-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propen-1-one is replaced by an equimolar amount of 3-(4-methoxyphenyl)-1-(2-hydroxy-4-methoxyphenyl)-2-propen-1-one.

[0128] (5) Preparation of 3-(3-bromopropoxy)-7-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one (Intermediate 5):

[0129] As in step (5) of Example 1, except that 2-(4-methoxyphenyl)-3-hydroxy-4H-chromen-4-one is replaced by an equimolar amount of 2-(4-methoxyphenyl)-3-hydroxy-7-methoxy-4H-chromen-4-one.

[0130] (6) Preparation of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-7-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one (target compound S7):

[0131] As in step (5) of Example 1, except that 3-(3-bromopropoxy)-2-(4-methoxyphenyl)-4H-bromo-4-one is replaced by an equimolar amount of 3-(3-bromopropoxy)-7-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one, yield: 46%.

[0132] Example 8

[0133] The preparation method of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-7-methoxy-2-(4-fluorophenyl)-4H-chromen-4-one (target compound S8) comprises the following steps:

[0134] (1) Preparation of 3-chloro-2-hydrazinopyridine (Intermediate 1):

[0135] As in step (1) of Example 1.

[0136] (2) Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate 2):

[0137] As in step (2) of Example 1.

[0138] (3) Preparation of 3-(4-fluorophenyl)-1-(2-hydroxy-4-methoxyphenyl)-2-propen-1-one (Intermediate 3):

[0139] As in step (3) of Example 1, except that p-methoxybenzaldehyde is replaced by an equimolar amount of p-fluorobenzaldehyde, and o-hydroxyacetophenone is replaced by an equimolar amount of 2-hydroxy-4-methoxyacetophenone.

[0140] (4) Preparation of 2-(4-fluorophenyl)-3-hydroxy-7-methoxy-4H-chromen-4-one (Intermediate 4):

[0141] As in step (4) of Example 1, except that 3-(4-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propen-1-one is replaced by an equimolar amount of 3-(4-fluorophenyl)-1-(2-hydroxy-4-methoxyphenyl)-2-propen-1-one.

[0142] (5) Preparation of 3-(3-bromopropoxy)-7-methoxy-2-(4-fluorophenyl)-4H-chromen-4-one (Intermediate 5):

[0143] As in step (5) of Example 1, except that 2-(4-methoxyphenyl)-3-hydroxy-4H-chromen-4-one is replaced by an equimolar amount of 2-(4-fluorophenyl)-3-hydroxy-7-methoxy-4H-chromen-4-one.

[0144] (6) Preparation of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-7-methoxy-2-(4-fluorophenyl)-4H-chromen-4-one (target compound S8):

[0145] As in step (5) of Example 1, except that 3-(3-bromopropoxy)-2-(4-methoxyphenyl)-4H-bromo-4-one was replaced with an equimolar amount of 3-(3-bromopropoxy)-7-methoxy-2-(4-fluorophenyl)-4H-chromen-4-one, yield: 22%.

[0146] Example 9

[0147] The preparation method of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-7-methoxy-2-(4-chlorophenyl)-4H-chromen-4-one (target compound S9) comprises the following steps:

[0148] (1) Preparation of 3-chloro-2-hydrazinopyridine (Intermediate 1):

[0149] As in step (1) of Example 1.

[0150] (2) Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate 2):

[0151] As in step (2) of Example 1.

[0152] (3) Preparation of 3-(4-chlorophenyl)-1-(2-hydroxy-4-methoxyphenyl)-2-propen-1-one (Intermediate 3):

[0153] As in step (3) of Example 1, except that p-methoxybenzaldehyde is replaced by an equal molar amount of p-chlorobenzaldehyde, and o-hydroxyacetophenone is replaced by an equal molar amount of 2-hydroxy-4-methoxyacetophenone.

[0154] (4) Preparation of 2-(4-chlorophenyl)-3-hydroxy-7-methoxy-4H-chromen-4-one (Intermediate 4):

[0155] As in step (4) of Example 1, except that 3-(4-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propen-1-one is replaced by an equimolar amount of 3-(4-chlorophenyl)-1-(2-hydroxy-4-methoxyphenyl)-2-propen-1-one.

[0156] (5) Preparation of 3-(3-bromopropoxy)-7-methoxy-2-(4-chlorophenyl)-4H-chromen-4-one (Intermediate 5):

[0157] As in step (5) of Example 1, except that 2-(4-methoxyphenyl)-3-hydroxy-4H-chromen-4-one is replaced by an equimolar amount of 2-(4-chlorophenyl)-3-hydroxy-7-methoxy-4H-chromen-4-one.

[0158] (6) Preparation of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-7-methoxy-2-(4-chlorophenyl)-4H-chromen-4-one (target compound S9):

[0159] As in step (5) of Example 1, except that 3-(3-bromopropoxy)-2-(4-methoxyphenyl)-4H-bromo-4-one is replaced by an equimolar amount of 3-(3-bromopropoxy)-7-methoxy-2-(4-chlorophenyl)-4H-chromen-4-one, yield: 59%.

[0160] Example 10

[0161] The preparation method of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-7-methoxy-2-(4-bromophenyl)-4H-chromen-4-one (target compound S10) comprises the following steps:

[0162] (1) Preparation of 3-chloro-2-hydrazinopyridine (Intermediate 1):

[0163] As in step (1) of Example 1.

[0164] (2) Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate 2):

[0165] As in step (2) of Example 1.

[0166] (3) Preparation of 3-(4-bromophenyl)-1-(2-hydroxy-4-methoxyphenyl)-2-propen-1-one (Intermediate 3):

[0167] As in step (3) of Example 1, except that p-methoxybenzaldehyde is replaced by an equimolar amount of p-bromobenzaldehyde, and o-hydroxyacetophenone is replaced by an equimolar amount of 2-hydroxy-4-methoxyacetophenone.

[0168] (4) Preparation of 2-(4-bromophenyl)-3-hydroxy-7-methoxy-4H-chromen-4-one (Intermediate 4):

[0169] As in step (4) of Example 1, except that 3-(4-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propen-1-one is replaced by an equimolar amount of 3-(4-bromophenyl)-1-(2-hydroxy-4-methoxyphenyl)-2-propen-1-one.

[0170] (5) Preparation of 3-(3-bromopropoxy)-7-methoxy-2-(4-bromophenyl)-4H-chromen-4-one (Intermediate 5):

[0171] As in step (5) of Example 1, except that 2-(4-methoxyphenyl)-3-hydroxy-4H-chromen-4-one is replaced by an equimolar amount of 2-(4-bromophenyl)-3-hydroxy-7-methoxy-4H-chromen-4-one.

[0172] (6) Preparation of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-7-methoxy-2-(4-bromophenyl)-4H-chromen-4-one (target compound S10):

[0173] As in step (5) of Example 1, except that 3-(3-bromopropoxy)-2-(4-methoxyphenyl)-4H-bromo-4-one is replaced by an equimolar amount of 3-(3-bromopropoxy)-7-methoxy-2-(4-bromophenyl)-4H-chromen-4-one, yield: 54%.

[0174] Example 11

[0175] The preparation method of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-2-(3-fluorophenyl)-4H-chromen-4-one (target compound S11) comprises the following steps:

[0176] (1) Preparation of 3-chloro-2-hydrazinopyridine (Intermediate 1):

[0177] As in step (1) of Example 1.

[0178] (2) Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate 2):

[0179] As in step (2) of Example 1.

[0180] (3) Preparation of 3-(3-fluorophenyl)-1-(2-hydroxyphenyl)-2-propen-1-one (Intermediate 3):

[0181] As in step (3) of Example 1, except that p-anisaldehyde is replaced by an equimolar amount of m-fluorobenzaldehyde.

[0182] (4) Preparation of 2-(3-fluorophenyl)-3-hydroxy-4H-chromene-4-one (Intermediate 4):

[0183] As in step (4) of Example 1, except that 3-(4-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propen-1-one is replaced by an equimolar amount of 3-(3-fluorophenyl)-1-(2-hydroxyphenyl)-2-propen-1-one.

[0184] (5) Preparation of 3-(3-bromopropoxy)-2-(3-fluorophenyl)-4H-bromo-4-one (Intermediate 5):

[0185] As in step (5) of Example 1, except that 2-(4-methoxyphenyl)-3-hydroxy-4H-chromen-4-one is replaced by an equimolar amount of 2-(3-fluorophenyl)-3-hydroxy-4H-chromen-4-one.

[0186] (6) Preparation of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-2-(3-fluorophenyl)-4H-chromen-4-one (target compound S11):

[0187] As in step (5) of Example 1, except that 3-(3-bromopropoxy)-2-(4-methoxyphenyl)-4H-bromo-4-one is replaced with an equimolar amount of 3-(3-bromopropoxy)-2-(3-fluorophenyl)-4H-bromo-4-one, yield: 40%.

[0188] Example 12

[0189] The preparation method of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-2-(2-methoxyphenyl)-4H-chromen-4-one (target compound S12) comprises the following steps:

[0190] (1) Preparation of 3-chloro-2-hydrazinopyridine (Intermediate 1):

[0191] As in step (1) of Example 1.

[0192] (2) Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate 2):

[0193] As in step (2) of Example 1.

[0194] (3) Preparation of 3-(2-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propen-1-one (Intermediate 3):

[0195] As in step (3) of Example 1, except that p-anisaldehyde is replaced by an equimolar amount of o-anisaldehyde.

[0196] (4) Preparation of 2-(2-methoxyphenyl)-3-hydroxy-4H-chromen-4-one (Intermediate 4):

[0197] As in step (4) of Example 1, except that 3-(4-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propen-1-one is replaced by an equimolar amount of 3-(2-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propen-1-one.

[0198] (5) Preparation of 3-(3-bromopropoxy)-2-(2-methoxyphenyl)-4H-bromo-4-one (Intermediate 5):

[0199] As in step (5) of Example 1, except that 2-(4-methoxyphenyl)-3-hydroxy-4H-chromen-4-one is replaced by an equimolar amount of 2-(2-methoxyphenyl)-3-hydroxy-4H-chromen-4-one.

[0200] (6) Preparation of 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)propoxy)-2-(2-methoxyphenyl)-4H-chromen-4-one (target compound S12):

[0201] As in step (5) of Example 1, except that 3-(3-bromopropoxy)-2-(4-methoxyphenyl)-4H-bromo-4-one is replaced with an equimolar amount of 3-(3-bromopropoxy)-2-(2-methoxyphenyl)-4H-bromo-4-one, yield: 55%.

[0202] Example 13

[0203] The preparation method of 3-(4-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)butoxy)-2-(4-methoxyphenyl)-4H-chromen-4-one (target compound S13) comprises the following steps:

[0204] (1) Preparation of 3-chloro-2-hydrazinopyridine (Intermediate 1):

[0205] As in step (1) of Example 1.

[0206] (2) Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate 2):

[0207] As in step (2) of Example 1.

[0208] (3) Preparation of 3-(4-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propen-1-one (Intermediate 3):

[0209] As in step (3) of Example 1.

[0210] (4) Preparation of 2-(4-methoxyphenyl)-3-hydroxy-4H-chromene-4-one (Intermediate 4):

[0211] As in step (4) of Example 1.

[0212] (5) Preparation of 3-(4-bromobutoxy)-2-(4-methoxyphenyl)-4H-bromo-4-one (Intermediate 5):

[0213] As in step (5) of Example 1, except that 1,3-dibromopropane is replaced by an equimolar amount of 1,4-dibromobutane.

[0214] (6) Preparation of 3-(4-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)butoxy)-2-(4-methoxyphenyl)-4H-chromen-4-one (target compound S13):

[0215] As in step (5) of Example 1, except that 3-(3-bromopropoxy)-2-(4-methoxyphenyl)-4H-bromo-4-one is replaced by an equimolar amount of 3-(4-bromobutoxy)-2-(4-methoxyphenyl)-4H-bromo-4-one, yield: 52%.

[0216] Example 14

[0217] The preparation method of 3-(4-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)butoxy)-2-(4-methylphenyl)-4H-chromen-4-one (target compound S14) comprises the following steps:

[0218] (1) Preparation of 3-chloro-2-hydrazinopyridine (Intermediate 1):

[0219] As in step (1) of Example 1.

[0220] (2) Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate 2):

[0221] As in step (2) of Example 1.

[0222] (3) Preparation of 3-(4-methylphenyl)-1-(2-hydroxyphenyl)-2-propene-1-one (Intermediate 3):

[0223] As in step (3) of Example 1, except that p-methoxybenzaldehyde is replaced by an equimolar amount of p-tolualdehyde.

[0224] (4) Preparation of 2-(4-methylphenyl)-3-hydroxy-4H-chromen-4-one (Intermediate 4):

[0225] As in step (4) of Example 1, except that 3-(4-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propen-1-one is replaced by an equimolar amount of 3-(4-tolyl)-1-(2-hydroxyphenyl)-2-propen-1-one.

[0226] (5) Preparation of 3-(4-bromobutoxy)-2-(4-methylphenyl)-4H-bromo-4-one (Intermediate 5):

[0227] As in step (5) of Example 1, except that 1,3-dibromopropane is replaced by an equimolar amount of 1,4-dibromobutane, and 2-(4-methoxyphenyl)-3-hydroxy-4H-chromen-4-one is replaced by an equimolar amount of 2-(4-methylphenyl)-3-hydroxy-4H-chromen-4-one.

[0228] (6) Preparation of 3-(4-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)butoxy)-2-(4-methylphenyl)-4H-chromen-4-one (target compound S14):

[0229] As in step (5) of Example 1, except that 3-(3-bromopropyloxy)-2-(4-methoxyphenyl)-4H-bromo-4-one is replaced by an equimolar amount of 3-(4-bromobutyloxy)-2-(4-methylphenyl)-4H-bromo-4-one, yield: 42%.

[0230] Example 15

[0231] The preparation method of 3-(4-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)butoxy)-2-(4-fluorophenyl)-4H-chromen-4-one (target compound S15) comprises the following steps:

[0232] (1) Preparation of 3-chloro-2-hydrazinopyridine (Intermediate 1):

[0233] As in step (1) of Example 1.

[0234] (2) Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate 2):

[0235] As in step (2) of Example 1.

[0236] (3) Preparation of 3-(4-fluorophenyl)-1-(2-hydroxyphenyl)-2-propen-1-one (Intermediate 3):

[0237] As in step (3) of Example 1, except that p-methoxybenzaldehyde is replaced by an equimolar amount of p-fluorobenzaldehyde.

[0238] (4) Preparation of 2-(4-fluorophenyl)-3-hydroxy-4H-chromen-4-one (Intermediate 4):

[0239] As in step (4) of Example 1, except that 3-(4-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propen-1-one is replaced by an equimolar amount of 3-(4-fluorophenyl)-1-(2-hydroxyphenyl)-2-propen-1-one.

[0240] (5) Preparation of 3-(4-bromobutoxy)-2-(4-fluorophenyl)-4H-bromo-4-one (Intermediate 5):

[0241] The same as step (5) of Example 1, except that 1,3-dibromopropane is replaced by an equal molar amount of 1,4-dibromobutane, and 2-(4-methoxyphenyl)-3-hydroxy-4H-chromen-4-one is replaced by an equal molar amount of 2-(4-fluorophenyl)-3-hydroxy-4H-chromen-4-one.

[0242] (6) Preparation of 3-(4-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)butoxy)-2-(4-fluorophenyl)-4H-chromen-4-one (target compound S15):

[0243] As in step (5) of Example 1, except that 3-(3-bromopropyloxy)-2-(4-methoxyphenyl)-4H-bromo-4-one is replaced by an equimolar amount of 3-(4-bromobutoxy)-2-(4-fluorophenyl)-4H-bromo-4-one, yield: 33%.

[0244] Example 16

[0245] The preparation method of 3-(4-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)butoxy)-2-(4-chlorophenyl)-4H-chromen-4-one (target compound S16) comprises the following steps:

[0246] (1) Preparation of 3-chloro-2-hydrazinopyridine (Intermediate 1):

[0247] As in step (1) of Example 1.

[0248] (2) Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate 2):

[0249] As in step (2) of Example 1.

[0250] (3) Preparation of 3-(4-chlorophenyl)-1-(2-hydroxyphenyl)-2-propen-1-one (Intermediate 3):

[0251] As in step (3) of Example 1, except that p-methoxybenzaldehyde is replaced by an equimolar amount of p-chlorobenzaldehyde.

[0252] (4) Preparation of 2-(4-chlorophenyl)-3-hydroxy-4H-chromene-4-one (Intermediate 4):

[0253] As in step (4) of Example 1, except that 3-(4-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propen-1-one is replaced by an equimolar amount of 3-(4-chlorophenyl)-1-(2-hydroxyphenyl)-2-propen-1-one.

[0254] (5) Preparation of 3-(4-bromobutoxy)-2-(4-chlorophenyl)-4H-bromo-4-one (Intermediate 5):

[0255] As in step (5) of Example 1, except that 1,3-dibromopropane is replaced by an equal molar amount of 1,4-dibromobutane, and 2-(4-methoxyphenyl)-3-hydroxy-4H-chromen-4-one is replaced by an equal molar amount of 2-(4-chlorophenyl)-3-hydroxy-4H-chromen-4-one.

[0256] (6) Preparation of 3-(4-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)butoxy)-2-(4-chlorophenyl)-4H-chromen-4-one (target compound S16):

[0257] As in step (5) of Example 1, except that 3-(3-bromopropyloxy)-2-(4-methoxyphenyl)-4H-bromo-4-one is replaced by an equimolar amount of 3-(4-bromobutoxy)-2-(4-chlorophenyl)-4H-bromo-4-one, yield: 53%.

[0258] Example 17

[0259] The preparation method of 3-(4-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)butoxy)-2-(4-bromophenyl)-4H-chromen-4-one (target compound S17) comprises the following steps:

[0260] (1) Preparation of 3-chloro-2-hydrazinopyridine (Intermediate 1):

[0261] As in step (1) of Example 1.

[0262] (2) Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate 2):

[0263] As in step (2) of Example 1.

[0264] (3) Preparation of 3-(4-bromophenyl)-1-(2-hydroxyphenyl)-2-propen-1-one (Intermediate 3):

[0265] As in step (3) of Example 1, except that p-methoxybenzaldehyde is replaced by an equimolar amount of p-bromobenzaldehyde.

[0266] (4) Preparation of 2-(4-bromophenyl)-3-hydroxy-4H-chromen-4-one (Intermediate 4):

[0267] As in step (4) of Example 1, except that 3-(4-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propen-1-one is replaced by an equimolar amount of 3-(4-bromophenyl)-1-(2-hydroxyphenyl)-2-propen-1-one.

[0268] (5) Preparation of 3-(4-bromobutoxy)-2-(4-bromophenyl)-4H-bromo-4-one (Intermediate 5):

[0269] As in step (5) of Example 1, except that 1,3-dibromopropane is replaced by an equimolar amount of 1,4-dibromobutane, and 2-(4-methoxyphenyl)-3-hydroxy-4H-chromen-4-one is replaced by an equimolar amount of 2-(4-bromophenyl)-3-hydroxy-4H-chromen-4-one.

[0270] (6) Preparation of 3-(4-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)butoxy)-2-(4-bromophenyl)-4H-chromen-4-one (target compound S17):

[0271] As in step (5) of Example 1, except that 3-(3-bromopropyloxy)-2-(4-methoxyphenyl)-4H-bromo-4-one is replaced by an equimolar amount of 3-(4-bromobutoxy)-2-(4-bromophenyl)-4H-bromo-4-one, yield: 56%.

[0272] Example 18

[0273] The preparation method of 3-(4-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)butoxy)-7-methoxy-2-(4-methylphenyl)-4H-chromen-4-one (target compound S18) comprises the following steps:

[0274] (1) Preparation of 3-chloro-2-hydrazinopyridine (Intermediate 1):

[0275] As in step (1) of Example 1.

[0276] (2) Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate 2):

[0277] As in step (2) of Example 1.

[0278] (3) Preparation of 3-(4-methylphenyl)-1-(2-hydroxy-4-methoxyphenyl)-2-propene-1-one (Intermediate 3):

[0279] As in step (3) of Example 1, except that p-methoxybenzaldehyde is replaced by an equimolar amount of p-methylbenzaldehyde, and o-hydroxyacetophenone is replaced by an equimolar amount of 2-hydroxy-4-methoxyacetophenone.

[0280] (4) Preparation of 2-(4-methylphenyl)-3-hydroxy-7-methoxy-4H-chromen-4-one (Intermediate 4):

[0281] As in step (4) of Example 1, except that 3-(4-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propene-1-one is replaced by an equimolar amount of 3-(4-methylphenyl)-1-(2-hydroxy-4-methoxyphenyl)-2-propene-1-one.

[0282] (5) Preparation of 3-(4-bromobutoxy)-7-methoxy-2-(4-methylphenyl)-4H-chromen-4-one (Intermediate 5):

[0283] As in step (5) of Example 1, except that 2-(4-methoxyphenyl)-3-hydroxy-4H-chromene-4-one is replaced by an equimolar amount of 2-(4-methylphenyl)-3-hydroxy-7-methoxy-4H-chromene-4-one, and 1,3-dibromopropane is replaced by an equimolar amount of 1,4-dibromobutane.

[0284] (6) Preparation of 3-(4-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)butoxy)-7-methoxy-2-(4-methylphenyl)-4H-chromen-4-one (target compound S18):

[0285] As in step (5) of Example 1, except that 3-(3-bromopropoxy)-2-(4-methoxyphenyl)-4H-bromo-4-one is replaced by an equimolar amount of 3-(4-bromobutoxy)-7-methoxy-2-(4-methylphenyl)-4H-chromen-4-one, yield: 53%.

[0286] Example 19

[0287] The preparation method of 3-(4-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)butoxy)-7-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one (target compound S19) comprises the following steps:

[0288] (1) Preparation of 3-chloro-2-hydrazinopyridine (Intermediate 1):

[0289] As in step (1) of Example 1.

[0290] (2) Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate 2):

[0291] As in step (2) of Example 1.

[0292] (3) Preparation of 3-(4-methoxyphenyl)-1-(2-hydroxy-4-methoxyphenyl)-2-propene-1-one (Intermediate 3):

[0293] The same as step (3) of Example 1, except that o-hydroxyacetophenone is replaced by an equimolar amount of 2-hydroxy-4-methoxyacetophenone.

[0294] (4) Preparation of 2-(4-methoxyphenyl)-3-hydroxy-7-methoxy-4H-chromen-4-one (Intermediate 4):

[0295] As in step (4) of Example 1, except that 3-(4-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propen-1-one is replaced by an equimolar amount of 3-(4-methoxyphenyl)-1-(2-hydroxy-4-methoxyphenyl)-2-propen-1-one.

[0296] (5) Preparation of 3-(4-bromobutoxy)-7-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one (Intermediate 5):

[0297] As in step (5) of Example 1, except that 2-(4-methoxyphenyl)-3-hydroxy-4H-chromene-4-one is replaced by an equimolar amount of 2-(4-methoxyphenyl)-3-hydroxy-7-methoxy-4H-chromene-4-one, and 1,3-dibromopropane is replaced by an equimolar amount of 1,4-dibromobutane.

[0298] (6) Preparation of 3-(4-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)butoxy)-7-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one (target compound S19):

[0299] As in step (5) of Example 1, except that 3-(3-bromopropoxy)-2-(4-methoxyphenyl)-4H-bromo-4-one is replaced by an equimolar amount of 3-(4-bromobutoxy)-7-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one, yield: 61%.

[0300] Example 20

[0301] The preparation method of 3-(4-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)butoxy)-7-methoxy-2-(4-fluorophenyl)-4H-chromen-4-one (target compound S20) comprises the following steps:

[0302] (1) Preparation of 3-chloro-2-hydrazinopyridine (Intermediate 1):

[0303] As in step (1) of Example 1.

[0304] (2) Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate 2):

[0305] As in step (2) of Example 1.

[0306] (3) Preparation of 3-(4-fluorophenyl)-1-(2-hydroxy-4-methoxyphenyl)-2-propen-1-one (Intermediate 3):

[0307] As in step (3) of Example 1, except that p-methoxybenzaldehyde is replaced by an equimolar amount of p-fluorobenzaldehyde, and o-hydroxyacetophenone is replaced by an equimolar amount of 2-hydroxy-4-methoxyacetophenone.

[0308] (4) Preparation of 2-(4-fluorophenyl)-3-hydroxy-7-methoxy-4H-chromen-4-one (Intermediate 4):

[0309] As in step (4) of Example 1, except that 3-(4-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propen-1-one is replaced by an equimolar amount of 3-(4-fluorophenyl)-1-(2-hydroxy-4-methoxyphenyl)-2-propen-1-one.

[0310] (5) Preparation of 3-(4-bromobutoxy)-7-methoxy-2-(4-fluorophenyl)-4H-chromen-4-one (Intermediate 5):

[0311] As in step (5) of Example 1, except that 2-(4-methoxyphenyl)-3-hydroxy-4H-chromene-4-one is replaced by an equimolar amount of 2-(4-fluorophenyl)-3-hydroxy-7-methoxy-4H-chromene-4-one, and 1,3-dibromopropane is replaced by an equimolar amount of 1,4-dibromobutane.

[0312] (6) Preparation of 3-(4-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)butoxy)-7-methoxy-2-(4-fluorophenyl)-4H-chromen-4-one (target compound S20):

[0313] As in step (5) of Example 1, except that 3-(3-bromopropoxy)-2-(4-methoxyphenyl)-4H-bromo-4-one is replaced by an equimolar amount of 3-(4-bromobutoxy)-7-methoxy-2-(4-fluorophenyl)-4H-chromen-4-one, yield: 64%.

[0314] Example 21

[0315] The preparation method of 3-(4-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)butoxy)-7-methoxy-2-(4-chlorophenyl)-4H-chromen-4-one (target compound S21) comprises the following steps:

[0316] (1) Preparation of 3-chloro-2-hydrazinopyridine (Intermediate 1):

[0317] As in step (1) of Example 1.

[0318] (2) Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate 2):

[0319] As in step (2) of Example 1.

[0320] (3) Preparation of 3-(4-chlorophenyl)-1-(2-hydroxy-4-methoxyphenyl)-2-propen-1-one (Intermediate 3):

[0321] As in step (3) of Example 1, except that p-methoxybenzaldehyde is replaced by an equal molar amount of p-chlorobenzaldehyde, and o-hydroxyacetophenone is replaced by an equal molar amount of 2-hydroxy-4-methoxyacetophenone.

[0322] (4) Preparation of 2-(4-chlorophenyl)-3-hydroxy-7-methoxy-4H-chromen-4-one (Intermediate 4):

[0323] As in step (4) of Example 1, except that 3-(4-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propen-1-one is replaced by an equimolar amount of 3-(4-chlorophenyl)-1-(2-hydroxy-4-methoxyphenyl)-2-propen-1-one.

[0324] (5) Preparation of 3-(4-bromobutoxy)-7-methoxy-2-(4-chlorophenyl)-4H-chromen-4-one (Intermediate 5):

[0325] As in step (5) of Example 1, except that 2-(4-methoxyphenyl)-3-hydroxy-4H-chromene-4-one is replaced by an equimolar amount of 2-(4-chlorophenyl)-3-hydroxy-7-methoxy-4H-chromene-4-one, and 1,3-dibromopropane is replaced by an equimolar amount of 1,4-dibromobutane.

[0326] (6) Preparation of 3-(4-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)butoxy)-7-methoxy-2-(4-chlorophenyl)-4H-chromen-4-one (target compound S21):

[0327] As in step (5) of Example 1, except that 3-(3-bromopropoxy)-2-(4-methoxyphenyl)-4H-bromo-4-one is replaced by an equimolar amount of 3-(4-bromobutoxy)-7-methoxy-2-(4-chlorophenyl)-4H-chromen-4-one, yield: 55%.

[0328] Example 22

[0329] The preparation method of 3-(4-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)butoxy)-7-methoxy-2-(4-bromophenyl)-4H-chromen-4-one (target compound S22) comprises the following steps:

[0330] (1) Preparation of 3-chloro-2-hydrazinopyridine (Intermediate 1):

[0331] As in step (1) of Example 1.

[0332] (2) Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate 2):

[0333] As in step (2) of Example 1.

[0334] (3) Preparation of 3-(4-bromophenyl)-1-(2-hydroxy-4-methoxyphenyl)-2-propen-1-one (Intermediate 3):

[0335] As in step (3) of Example 1, except that p-methoxybenzaldehyde is replaced by an equimolar amount of p-bromobenzaldehyde, and o-hydroxyacetophenone is replaced by an equimolar amount of 2-hydroxy-4-methoxyacetophenone.

[0336] (4) Preparation of 2-(4-bromophenyl)-3-hydroxy-7-methoxy-4H-chromen-4-one (Intermediate 4):

[0337] As in step (4) of Example 1, except that 3-(4-methoxyphenyl)-1-(2-hydroxyphenyl)-2-propen-1-one is replaced by an equimolar amount of 3-(4-bromophenyl)-1-(2-hydroxy-4-methoxyphenyl)-2-propen-1-one.

[0338] (5) Preparation of 3-(4-bromobutoxy)-7-methoxy-2-(4-bromophenyl)-4H-chromen-4-one (Intermediate 5):

[0339] As in step (5) of Example 1, except that 2-(4-methoxyphenyl)-3-hydroxy-4H-chromene-4-one is replaced by an equimolar amount of 2-(4-bromophenyl)-3-hydroxy-7-methoxy-4H-chromene-4-one, and 1,3-dibromopropane is replaced by an equimolar amount of 1,4-dibromobutane.

[0340] (6) Preparation of 3-(4-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)butoxy)-7-methoxy-2-(4-bromophenyl)-4H-chromen-4-one (target compound S22):

[0341] As in step (5) of Example 1, except that 3-(3-bromopropoxy)-2-(4-methoxyphenyl)-4H-bromo-4-one is replaced by an equimolar amount of 3-(4-bromobutoxy)-7-methoxy-2-(4-bromophenyl)-4H-chromen-4-one, yield: 61%.

[0342] The physicochemical properties of the triazolopyridine-containing flavonol derivatives prepared in Examples 1 to 22 are shown in Table 1. 1 H NMR), carbon spectrum ( 13 C NMR) and fluorine spectra ( 19 F NMR) data are shown in Table 2.

[0343] Table 1 Physicochemical properties of target compounds obtained in Examples 1-22

[0344]

[0345]

[0346] Table 2 Nuclear magnetic resonance spectrum data of flavonol derivatives containing triazolopyridine prepared in Examples 1 to 22

[0347]

[0348]

[0349]

[0350]

[0351]

[0352] Test Example 1

[0353] Plant fungistatic activity test:

[0354] 1. Test Method

[0355] The antifungal activity of the target compounds was tested by the mycelial growth rate method, with the commercial agent azoxystrobin (ASB) as the positive control drug. The test strains included: rice sheath blight (Rs), blueberry gray mold (Bc), rapeseed sclerotinia (Ss), pepper phytophthora (Pc), Fusarium graminearum (Fg), Colletotrichum gloeosporioides (Cg), pepper wilt (Fc), cabbage black spot (Ab) and Phomopsis sclerotiorum (Ps).

[0356] (1) Preparation of potato dextrose agar medium

[0357] Potato dextrose agar (PDA) medium: Add 40 g of potato dextrose agar to 1000 mL of boiling distilled water and place in a 2000 mL beaker. Measure 20.0 mL of the medium with a graduated cylinder and dispense into 50 mL conical flasks. Seal with a breathable sealing film and place in an autoclave at 121°C for 20 min. Set aside.

[0358] (2) Fungal activation

[0359] Place the culture dish in a clean bench and sterilize it with UV for 1 hour. Pour about 20.0 mL of sterilized PDA culture medium evenly into the culture dish. After cooling, place the frozen bacteria in a 28°C incubator for 2 hours. Use a sterilized needle to pick up the activated mycelium and place it in the center of the cooled culture medium. Seal it with sealing film, turn it upside down and place it in a 28°C constant temperature incubator for activation for 3-5 days. Set aside.

[0360] (3) Treatment of drugs

[0361] Weigh 10.0 mg of the target compound and dissolve it in 1000 μL of DMSO to a concentration of 100 μg / mL.

[0362] (4) Antifungal activity experimental operation

[0363] In a sterile clean bench, take 200 μL of the drug solution and add it to the sterilized warm PDA culture medium. Shake it thoroughly to mix it evenly. At this time, the drug concentration is 100 μg / mL. Take 200 μL of DMSO and add it to the sterilized PDA culture medium as the blank control group. After shaking, add it evenly to 3 culture dishes with a diameter of 6 cm. Use a 5 mm diameter puncher to pick up the bacterial cake from the activated culture dish containing mycelium, turn it upside down in the center of the culture dish containing the drug solution and the blank control group, seal it with a sealing film, and place it together in a 28 ° C constant temperature incubator for 3-5 days. After the colony in the blank control group grows to a diameter of 4.0-5.0 cm, remove the culture dish and measure the colony diameter using the cross method. Repeat for each group of experiments. The inhibition rate formula is as follows:

[0364] Corrected diameter = colony diameter of culture medium containing drug solution - inoculated cake diameter (5mm)

[0365] Inhibition rate = (corrected diameter of colonies in the blank control group - corrected diameter of colonies in the drug-containing medium) / corrected diameter of colonies in the blank control group × 100%

[0366] 2. The results of the bioactivity test on plant fungi are shown in Table 3.

[0367] Table 3 Antibacterial activity of the compounds prepared in Examples 1 to 22 against 9 test pathogens at a concentration of 100

[0368]

[0369]

[0370] a Average of three replicates; b Commercial agent azoxystrobin.

[0371] As can be seen from Table 3, some compounds have certain inhibitory activity against blueberry gray mold, rapeseed sclerotinia, and phomopsis. At a concentration of 100 μg / mL, the inhibition rates of compounds S2, S3, S4, S11, and S17 against rapeseed sclerotinia were 79.2, 76.7, 71.7, 75.0, and 71.7%, respectively, which were superior to azoxystrobin (70.0%). The inhibitory activities of compounds S1, S2, S6, and S7 against blueberry gray mold were 79.5, 85.8, 79.9, and 81.2%, respectively, which were superior to azoxystrobin (79.1%). The inhibition rates of S11 and S12 against phomopsis were 65.3 and 71.3%, respectively, which were superior to azoxystrobin (59.6%).

[0372] The above experimental activity data show that flavonol derivatives containing triazolopyridine have certain inhibitory effects on plant pathogens (blueberry gray mold, rapeseed sclerotinia, and Phomopsis spp.). Among them, some target compounds show excellent activity in inhibiting plant pathogens and can be used as potential antibacterial drugs with good application prospects.

[0373] Among them, the flavonol derivatives containing triazolopyridine have excellent inhibitory activity against Sclerotinia sclerotiorum, and the prepared compounds are preferably protective against Sclerotinia sclerotiorum.

[0374] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Any simple modifications, equivalent changes, and modifications made to the above embodiments based on the technical essence of the present invention without departing from the technical solution of the present invention shall fall within the scope of protection determined by the claims of the present invention.

Claims

1. A flavonol derivative containing a triazolopyridine, characterized in that: The structural formula is shown in Formula S: Wherein: R1 is hydrogen, alkyl or alkoxy; R2 contains one or more halogen, alkyl or alkoxy groups at the ortho, meta or para position on the benzene ring; n is 3 or 4.

2. The triazolopyridine-containing flavonol derivative according to claim 1, characterized in that: R1 is hydrogen, C1-C6 alkyl or C1-C6 alkoxy; R2 is one or more methyl, methoxy, tert-butyl, fluorine, chlorine or bromine at the ortho, meta or para position on the benzene ring.

3. A method for preparing a triazolopyridine-containing flavonol derivative according to claim 1, characterized in that: The specific steps include: (1) Using 2,3-dichloropyridine and hydrazine hydrate as raw materials, heating and refluxing to obtain 3-chloro-2-hydrazinylpyridine; (2) In the presence of a base, react with carbon disulfide in ethanol under heating and reflux, and acidify with hydrochloric acid to obtain 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol; (3) performing an aldol condensation reaction of substituted o-hydroxyacetophenone and substituted benzaldehyde to obtain 3-(substituted phenyl)-1-(2-hydroxy-4-substituted phenyl)-2-propen-1-one; (4) 2-(Substituted phenyl)-3-hydroxy-7-substituted-4H-chromen-4-one was prepared from 3-(substituted phenyl)-1-(2-hydroxy-4-substituted phenyl)-2-propen-1-one, sodium hydroxide, and hydrogen peroxide in ethanol as solvent at room temperature; (5) 2-(substituted phenyl)-3-hydroxy-7-substituted-4H-chromen-4-one and 1,3-dibromopropane or 1,4-dibromobutane, using potassium carbonate as a catalyst and N,N-dimethylformamide as a solvent, to prepare 3-(3-bromopropoxy)-7-substituted-2-(substituted phenyl)-4H-bromo-4-one or 3-(4-bromobutoxy)-7-substituted-2-(substituted phenyl)-4H-bromo-4-one; (6) The 3-(3-bromopropoxy)-7-substituted-2-(substituted phenyl)-4H-bromo-4-one or 3-(4-bromobutoxy)-7-substituted-2-(substituted phenyl)-4H-bromo-4-one is reacted with 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol using K2CO3 as an acid binding agent and acetonitrile as a solvent to generate a flavonol derivative containing a triazolopyridine; 4. Use of the triazolopyridine-containing flavonol derivative according to claim 1 or 2 in the preparation of a plant fungus inhibitory drug.

5. The use according to claim 4, characterized in that: The plant fungi are rice sheath blight (Rs), blueberry gray mold (Bc), rapeseed sclerotinia (Ss), gloeosporioides (Cg), pepper wilt (Fc), cabbage black spot (Ab) and phomopsis (Ps).

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