CN101284815B - Pyrazolyloxyacetic acid compounds, preparation method and application - Google Patents

Abstract

The invention discloses a pyrazole oxyacetic acid compound, a preparation method and an application thereof. The compound of the general structural formula (I), wherein, X or Y are hydrogen, C _1-4 alkyl, C _1-4 alkoxy Base, substituted or unsubstituted phenoxy, halogen, nitro or trifluoromethyl; R is hydrogen or C _1-4 alkyl. The invention also discloses a preparation method of the compound and its application in the preparation of fungicides.

Description

Pyrazole oxyacetic acid compound, preparation method and use

technical field

The invention belongs to the field of organic chemistry, and in particular relates to a pyrazole oxyacetic acid compound, a preparation method, and the application of the compound in fungicides.

Background technique

Nitrogen-containing heterocycles are a class of compounds with important application value and good biological activity. Many heterocycles have been developed into new medicines and pesticides, which play an important role in human health and agricultural production. At present, many research groups at home and abroad are engaged in research and development in this field. With my country's accession to WTO and implementation of intellectual property protection, there is an urgent need to strengthen research in the field of heterocycles and release new drugs with their own intellectual property rights. At present, the research on new heterocycles is very active. Pyrazole heterocycles have attracted much attention because of their wide range of biological activities. Many pyrazole fungicides, insecticides, herbicides, plant growth regulators and medicines have been found.

Yoshioka Koichi reported that some pyrazolidinone compounds have bactericidal properties [Koichi Y, Norikazu T. Preparation of 2-(3-oxo-2-pyrazolidinyl)-5-oxo-2-tetrahydrofurancarboxylic acid derivatives antibaceterial agents[P]. JP 6221558, 1987, 09]. This kind of compound shows good bactericidal activity, has contact killing and systemic activity in field tests, and shows good protective and therapeutic activity, especially has good activity against downy mildew and blight caused by oomycetes. However, most of the plant diseases caused by oomycetes are difficult to control, especially downy mildew and blight with a short incubation period and many re-infection times, which can develop rapidly within a plant growing season and cause disease epidemics. The research on its bactericidal action mechanism shows that it is a new type of mitochondrial respiration inhibitor, which has attracted much attention due to its unique mode of action, wide bactericidal spectrum, and especially effective against resistant strains. The energy required by the bacteria comes from the oxidation and decomposition of carbohydrates, fats, proteins and other nutrients in the body, and finally produces carbon dioxide and water, which is accompanied by a series of redox reactions of dehydrogenation and electron transfer, that is, biological respiration. It is the unique mechanism of action of mitochondrial respiration inhibitors to play a bactericidal effect by inhibiting the mitochondrial respiration of bacteria and thereby inhibiting energy production. Zhao Yanlai and others also reported some pyrazole compounds with bactericidal properties [Zhao Yanlai, He Linquan. Introduction to Heterocyclic Chemistry [M]. Beijing. Higher Education Press. 1992: 229]. At the same time, the derivatives of phenoxyacetic acid also have strong antibacterial activity, and are usually used in herbicides, and can also be used as plant growth regulators, and are often used as blood lipid-lowering drugs in the medical field.

Contents of the invention

The object of the present invention is to provide a pyrazole oxyacetic acid compound with pharmacodynamic activity.

Another object of the present invention is to provide a preparation method of the above compound.

Another object of the present invention is to provide a use of the above compound.

The purpose of the present invention can be achieved through the following measures:

A compound of general structural formula (I) or a salt thereof,

in,

X or Y are hydrogen, C _1-4 alkyl, C _1-4 alkoxy, substituted or unsubstituted phenoxy, halogen, nitro or trifluoromethyl, preferably hydrogen, C _1-4 alkyl , methoxy, phenoxy, fluorine, chlorine, bromine, nitro or trifluoromethyl;

R is hydrogen or C _1-4 alkyl, preferably hydrogen or ethyl.

In the substituted or unsubstituted phenoxy group described in the present invention, the substituents are C _1-4 alkyl, nitro or halogen, preferably unsubstituted phenoxy groups.

A kind of preparation method of the compound of structural general formula (I), its synthetic route is as follows:

Substituted cinnamic acid reacts with methanol or ethanol in the presence of p-toluenesulfonic acid to generate substituted cinnamate; add n-butanol and substituted cinnamate to sodium methoxide solution, and react at 0-100°C for 1-24 hours , then add phenylhydrazine or substituted phenylhydrazine, react for 0-24h to get 1,5-diaryl-3-pyrazolidinone; put 1,5-diaryl-3-pyrazolidinone in N,N - In dimethylformamide solution, blow air into it, react at 0-100°C, cool and filter to obtain 1,5-diaryl-3-hydroxypyrazole; then react with haloalkanoic acid or haloalkanoate to form Compound (I). The concept of the substituent X in the substituted cinnamic acid is as above, and the concept of the substituent Y in the substituted phenylhydrazine is as above.

Under stirring, add substituted cinnamic acid and p-toluenesulfonic acid to anhydrous ethanol and anhydrous methanol, and reflux for 0-24 hours to generate substituted cinnamate; add n-butyl to the newly prepared sodium methoxide solution under stirring Alcohol, then add substituted cinnamate, reflux reaction for 0~24h, then add appropriate amount of phenylhydrazine or substituted phenylhydrazine, continue heating and reflux reaction for 0~24h, after cooling, filter to obtain 1,5-diaryl-3 - pyrazolidinone. Dissolve the compound in N,N-dimethylformamide solution, blow in air, react at 10-100°C for 0-24 hours, cool to room temperature, pour into a beaker filled with water, and filter after cooling to obtain 1,5-diaryl-3-hydroxypyrazole; then in dioxane, acetonitrile, N, N-dimethylformamide, acetone, dichloromethane, chloroform and other solvents or aqueous solutions, in Triethylamine, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide react with bromoacetic acid, chloroacetic acid, sodium chloroacetate, ethyl bromoacetate, and ethyl chloroacetate to form the structure described in right 1 under alkaline conditions (I) type 1,5-diaryl-3-oxyacetic acid ethyl pyrazole; then hydrolyzed in aqueous sodium hydroxide solution to generate 1,5-diaryl-3-oxoacetic acid pyrazole. .

The compound of the present invention can prepare fungicides, and can be applied to rapeseed sclerotias clerotiorum, vegetable gray mold sensitive strain Botryris cinerea Pers., scab sensitive strain Gibbrellazeae (Schw.) Petch, wheat sheath blight sensitive strain Rhizoctorua A variety of diseases caused by bacteria such as solani or rice blast fungus Pyricularia oryzaeCav.

The novel pyrazole oxyacetic acid fungicide of the present invention can be used for disease control of various crops, including medicinal plants of ginseng, American ginseng, Panax notoginseng, Atractylodes macrocephala, fritillaria, amomum, chrysanthemum, wolfberry or lily; wheat, corn, Field plants of rice, potato, sugar beet, peanut or cotton; vegetable crops of cabbage, tomato, cucumber, pepper or lentils; garden crops of peaches, pears, grapes or strawberries; flowers of clivia or aloe.

Detailed ways

Example 1

Under stirring, add 50ml of anhydrous methanol and 0.3g of p-toluenesulfonic acid to 4-methoxycinnamic acid (0.05mol). After reflux reaction for 2h, methanol is distilled off under reduced pressure to obtain methyl 4-methoxycinnamate 8.82g; add methyl 4-methoxycinnamate and 50ml n-butanol to the newly prepared 28% sodium methoxide solution under stirring, react at 100°C for 4h, then add 8ml phenylhydrazine, continue to heat and reflux for 24h Afterwards, cool and filter to obtain 10.11 g of 1-phenyl-5-(4-methoxyphenyl)-3-pyrazolidinone; this compound was dissolved in N,N-dimethylformamide solution, Air was blown in, reacted at 100°C for 1 h, cooled to room temperature, and filtered to obtain 8.92 g of 1-phenyl-5-(4-methoxyphenyl)-3-hydroxypyrazole with a yield of 66.9%; Add 4.42g of hydroxypyrazole to 100ml of water, drop an equivalent amount of ethyl bromoacetate, react at 100°C for 2 hours, extract with ethyl acetate, dry over anhydrous magnesium sulfate, filter, and remove ethyl acetate to obtain 1- Phenyl-5-(4-methoxyphenyl)-3-oxyacetoxyethylpyrazole 4.91 g, yield 83.4%. ¹ H NMRδ: 1.30(t, 3H), 3.79(s, 3H), 4.27(q, 2H), 4.86(s, 2H), 5.98(s, 1H), 6.80(d, 2H), 7.13～7.29( m, 7H).

Example 2

Under stirring, add 100ml of anhydrous methanol and 0.5g of p-toluenesulfonic acid to 3,4,5-trimethoxycinnamic acid (0.1mol), after reflux for 2h, distill under reduced pressure to obtain 4-methoxycinnamic acid Methyl ester 19.68g; Add methyl 3,4,5-trimethoxycinnamate and 50ml n-butanol to the newly prepared 28% sodium methoxide solution under stirring, react at 100°C for 4h, then add 10ml phenylhydrazine , after continuing to heat and reflux for 24h, cool and filter to obtain 24.96g of 1-phenyl-5-(3,4,5-trimethoxyphenyl)-3-pyrazolidinone; this compound was dissolved in N, In N-dimethylformamide solution, air was blown in, reacted at 100°C for 1h, cooled to room temperature, and filtered to obtain 1-phenyl-5-(3,4,5-trimethoxyphenyl)- 22.61g of 3-hydroxypyrazole, yield 69.3%; take 11.31g of hydroxypyrazole and add it to 100ml of water, add dropwise the same amount of bromoacetic acid, react at 100°C for 2h, extract with ethyl acetate, anhydrous magnesium sulfate After drying, filtering and removing ethyl acetate, 10.50 g of 1-phenyl-5-(3,4,5-trimethoxyphenyl)-3-oxoacetoxypyrazole was obtained, with a yield of 79.0%. ¹ H NMRδ: 3.57(s, 6H), 3.65(s, 3H), 4.83(s, 2H), 6.26(s, 1H), 6.48(s, 2H), 7.22～7.39(m, 5H), 8.0( s, 1H).

Example 3

Under stirring, add 20ml of absolute ethanol and 0.3g of p-toluenesulfonic acid to 4-bromocinnamic acid (0.05mol), after reflux reaction for 2h, distill under reduced pressure to obtain 11.29g of ethyl 4-bromocinnamate; under stirring Add ethyl 4-bromocinnamate and 50ml of n-butanol to the newly prepared 28% sodium methoxide solution, react at 100°C for 4 hours, then add 6.55g of p-fluorophenylhydrazine, continue to heat and reflux for 24 hours, cool and filter , to obtain 1-(4-fluorophenyl)-5-(4-bromophenyl)-3-pyrazolidinone 12.1g; this compound was dissolved in N,N-dimethylformamide solution, blown into Air, reacted at 100°C for 1 hour, cooled to room temperature, and filtered to obtain 10.92 g of 1-(4-fluorophenyl)-5-(4-bromophenyl)-3-hydroxypyrazole with a yield of 65.3%; Take 5.32g of hydroxypyrazole and add it to 100ml of water, add an equivalent amount of chloroacetic acid dropwise, react at 100°C for 2 hours, extract with ethyl acetate, dry over anhydrous magnesium sulfate, filter, and get 1-( 4.98 g of 4-fluorophenyl)-5-(4-bromophenyl)-3-oxoacetoxypyrazole, yield 80.0%. ¹ H NMRδ: 4.88(s, 2H), 6.26(s, 1H), 6.88(d, 2H), 7.02(d, 2H), 7.22(d, 2H), 7.43(d, 2H), 8.5(s, 1H ).

Example 4

Under stirring, 20ml of absolute ethanol and 0.3g of p-toluenesulfonic acid were added to 4-trifluoromethylcinnamic acid (0.05mol), and after reflux reaction for 2h, vacuum distillation gave ethyl 4-trifluoromethylcinnamate 9.77g; Add ethyl 4-trifluoromethyl cinnamate and 50ml of n-butanol to the newly prepared 28% sodium methoxide solution under stirring, react at 100°C for 4h, then add 8ml of phenylhydrazine, and continue the reaction under reflux After 24h, cool and filter to obtain 1-phenyl-5-(4-trifluoromethylphenyl)-3-pyrazolidinone, 10.15g; this compound was dissolved in N,N-dimethylformamide Air was blown into the solution, reacted at 100°C for 1 h, cooled to room temperature, and filtered to obtain 1-phenyl-5-(4-trifluoromethylphenyl)-3-hydroxypyrazole, 9.40 g, harvested The yield is 70.2%; take 5.40g of hydroxypyrazole and add it to 100ml of water, add an equivalent amount of sodium chloroacetate dropwise, react at 100°C for 2h, extract with ethyl acetate, neutralize the aqueous layer with 1N hydrochloric acid solution, and then use acetic acid Extracted with ethyl ester, dried over anhydrous magnesium sulfate, filtered, and removed ethyl acetate to obtain 5.40 g of 1-phenyl-5-(4-trifluoromethylphenyl)-3-oxoacetoxypyrazole, yield 82.1% . ¹ H NMR δ: 4.83 (s, 2H), 6.16 (s, 1H), 7.10-7.31 (m, 9H), 8.5 (s, 1H).

Example 5

Under stirring, 20ml of anhydrous methanol and 0.3g of p-toluenesulfonic acid were added to 4-fluorocinnamic acid (0.05mol), and after reflux reaction for 2h, 8.28g of methyl 4-fluorocinnamate was obtained by distillation under reduced pressure; under stirring Add methyl 4-fluorocinnamate and 50ml of n-butanol to the newly prepared 28% sodium methoxide solution, react at 100°C for 4 hours, then add 9.4g of p-methylphenylhydrazine, continue to heat and reflux for 24 hours, then cool. Filtration gave 10.45 g of 1-(4-methylphenyl)-5-(4-fluorophenyl)-3-pyrazolidinone; this compound was dissolved in N,N-dimethylformamide solution, Air was blown in, reacted at 100°C for 1 h, cooled to room temperature, and filtered to obtain 8.20 g of 1-(4-methylphenyl)-5-(4-fluorophenyl)-3-hydroxypyrazole, yield 61.2%; add 4.00g of hydroxypyrazole to 100ml of water, add dropwise an equivalent amount of sodium chloroacetate, react at 100°C for 2 hours, neutralize with 1N hydrochloric acid solution, extract with ethyl acetate, dry over anhydrous magnesium sulfate, After filtering to remove ethyl acetate, 4.10 g of 1-(4-methylphenyl)-5-(4-fluorophenyl)-3-oxoacetoxypyrazole was obtained, with a yield of 84.2%. ¹ H NMR δ: 2.49 (s, 3H), 4.83 (s, 2H), 6.16 (s, 1H), 7.10-7.21 (m, 4H), 7.280-7.41 (m, 4H), 8.5 (s, 1H).

Example 6

Under stirring, 40ml of anhydrous methanol and 0.3g of p-toluenesulfonic acid were added to 3,4-dimethoxycinnamic acid (0.03mol). After reflux for 2 hours, 3,4-dimethoxycinnamic acid was distilled under reduced pressure 5.95g methyl cinnamate and 50ml n-butanol; add 3,4-dimethoxymethyl cinnamate to the newly prepared 28% sodium methoxide solution under stirring, react at 100°C for 4 hours, then add 3.75g For p-fluorophenylhydrazine, continue to heat and reflux for 24 hours, then cool and filter to obtain 7.28g of 1-(4-fluorophenyl)-5-(3,4-dimethoxyphenyl)-3-pyrazolidinone ; The compound was dissolved in N,N-dimethylformamide solution, air was blown in, and after reacting for 1h at 100°C, it was cooled to room temperature and filtered to obtain 1-(4-fluorophenyl)-5-( 6.50 g of 3,4-dimethoxyphenyl)-3-hydroxypyrazole, yield 72.8%; 3.50 g of hydroxypyrazole was added to 100 ml of water, and an equivalent amount of ethyl bromoacetate was added dropwise, at 100° C. After reacting for 2 hours, extract with ethyl acetate, dry over anhydrous magnesium sulfate, filter, and remove ethyl acetate to obtain 1-(4-fluorophenyl)-5-(3,4-dimethoxyphenyl)-3 - 3.40 g of ethyl oxyacetate pyrazole, yield 74.8%. ¹ H NMRδ: 1.30(t, 3H), 3.73(s, 6H), 4.27(q, 2H), 4.83(s, 2H), 6.09(s, 1H), 6.80～7.08(m, 5H), 7.20～ 7.29 (d, 2H)

Example 7

Under stirring, in cinnamic acid (0.05mol), add anhydrous methanol 50ml, p-toluenesulfonic acid 0.3g, after reflux reaction 2h, underpressure distillation obtains methyl cinnamate 7.85g; Add methyl cinnamate and 50ml of n-butanol to the sodium solution, react at 100°C for 4 hours, then add 9.8g of p-tert-butylphenylhydrazine, continue to heat and reflux for 24 hours, cool and filter to obtain 1-(4- tert-butylphenyl)-5-phenyl-3-pyrazolidinone 14.55g; this compound was dissolved in N,N-dimethylformamide solution, blown in air, and reacted at 100°C for 1h, Cool to room temperature and filter to obtain 1-(4-tert-butylphenyl)-5-phenyl-3-hydroxypyrazole, 14.65g, yield 89.9%; 7.65g of hydroxypyrazole was added to 100ml of water, Add an equal amount of ethyl bromoacetate dropwise, react at 100°C for 2 hours, extract with ethyl acetate, dry over anhydrous magnesium sulfate, filter, and remove ethyl acetate to obtain 1-(4-tert-butylphenyl)-5 -Phenyl-3-oxyacetate ethylpyrazole 9.1 g, yield 94.0%. ¹ H NMR δ: 1.32 (s, 9H), 4.25 (q, 2H), 4.80 (s, 2H), 6.12 (s, 1H), 7.26-7.49 (m, 9H).

Example 8

Under stirring, in 4-methylcinnamic acid (0.05mol), add anhydrous methanol 40ml, p-toluenesulfonic acid 0.3g, after reflux reaction 2h, underpressure distillation obtains 4-methylcinnamic acid methyl ester 8.00g; Add methyl 4-methyl cinnamate and 50ml n-butanol to the newly prepared 28% sodium methoxide solution under stirring, react at 100°C for 4 hours, then add 9.8g of 2,4-dichlorophenylhydrazine, and continue heating to reflux After reacting for 24h, cool and filter to obtain 10.95g of 1-(2,4-dichlorophenyl)-5-(4-methylphenyl)-3-pyrazolidinone; this compound was dissolved in N,N - in dimethylformamide solution, bubbled with air, reacted at 100°C for 2h, cooled to room temperature, and filtered to obtain 1-(2,4-dichlorophenyl)-5-(4-methylphenyl )-3-hydroxypyrazole, 8.90g, yield 55.2%; 4.90g of hydroxypyrazole was added to 100ml of water, and an equivalent amount of ethyl bromoacetate was added dropwise. After reacting at 100°C for 2h, ethyl acetate extracted , dried over anhydrous magnesium sulfate, filtered to obtain 5.20 g of 1-(2,4-dichlorophenyl)-5-(4-methylphenyl)-3-oxyacetate ethyl pyrazole after removing ethyl acetate, Yield 83.2%. ¹ H NMR δ: 1.30 (t, 3H), 2.35 (s, 3H), 4.12 (q, 2H), 4.90 (s, 2H), 6.12 (s, 1H), 7.12-7.36 (m, 7H).

Example 9

Under stirring, 80ml of anhydrous methanol and 0.3g of p-toluenesulfonic acid were added to 3-phenoxycinnamic acid (0.05mol), and after reflux reaction for 2h, 10.50g of methyl 4-phenoxycinnamate was obtained by distillation under reduced pressure Add methyl 3-phenoxycinnamate and 50ml n-butanol to the newly prepared 28% sodium methoxide solution under stirring, react at 100°C for 4h, then add 9.8g of 2,4-dichlorophenylhydrazine, After continuing to heat and reflux for 24 hours, cool and filter to obtain 15.60 g of 1-(2,4-dichlorophenyl)-5-(3-phenoxyphenyl)-3-pyrazolidinone; In N,N-dimethylformamide solution, blow air into it, react at 100°C for 3h, cool to room temperature, and filter to obtain 1-(2,4-dichlorophenyl)-5-(3- Phenoxyphenyl)-3-hydroxypyrazole 11.90g, yield 59.3%; 6.90g of hydroxypyrazole was added to a 100ml four-necked flask, 3.0g of potassium carbonate and 100ml of acetone were added, and an equivalent amount of After reflux for 2 hours, remove acetone, add 100ml of water, extract with ethyl acetate, dry over anhydrous magnesium sulfate, filter, and obtain 1-(2,4-dichlorophenyl) after removing ethyl acetate - 5-(4-phenoxyphenyl)-3-oxoacetate ethyl pyrazole 6.10 g, yield 72.5%. ¹ H NMR δ: 1.32 (t, 3H), 4.25 (q, 2H), 4.80 (s, 2H), 6.12 (s, 1H), 6.86-7.20 (m, 10H), 7.40-7.47 (d, 2H).

Example 10

Under stirring, add 50ml of anhydrous methanol and 0.3g of p-toluenesulfonic acid to 4-chlorocinnamic acid (0.05mol), and after reflux reaction for 2h, distill under reduced pressure to obtain 8.85g of methyl 4-chlorocinnamate; Add methyl 4-chlorocinnamate and 50ml n-butanol to the freshly prepared 28% sodium methoxide solution, react at 100°C for 4h, then add 11.0g of 2,4-dinitrophenylhydrazine, and continue heating to reflux for 24h After cooling and filtering, 12.0 g of 1-(2,4-dinitrophenyl)-5-(4-chlorophenyl)-3-pyrazolidinone was obtained; the compound was dissolved in N,N-dinitrophenyl Methylformamide solution, bubbled with air, reacted at 100°C for 4h, cooled to room temperature, and filtered to obtain 1-(2,4-dinitrophenyl)-5-(4-chlorophenyl)- 9.70g of 3-hydroxypyrazole, yield 53.5%; 6.70g of hydroxypyrazole was added to a 100ml four-neck flask, 0.8g of sodium hydroxide and 100ml of anhydrous methanol were added, and an equivalent amount of ethyl bromoacetate was slowly added dropwise After reflux for 2 hours, remove methanol, add 100ml of water, extract with ethyl acetate, dry over anhydrous magnesium sulfate, filter, and remove ethyl acetate to obtain 1-(2,4-dinitrophenyl)-5- (4-Chlorophenyl)-3-oxyacetoxyethylpyrazole 6.10 g, yield 73.1%. ¹ H NMRδ: 1.32(t, 3H), 4.25(q, 2H), 4.80(s, 2H), 6.12(s, 1H), 7.30～7.33(d, 2H), 7.42～7.47(d, 2H), 7.80 (d, 1H), 8.62 (d, 1H), 8.99 (s, 1H).

Example 11

Under stirring, add 20ml of anhydrous methanol to 4-chlorocinnamic acid (0.03mol), p-toluenesulfonic acid 0.2g, after reflux reaction for 2h, decompression distillation removes methanol to obtain 5.55g of 4-chlorocinnamic acid methyl ester; Next, add methyl 4-chlorocinnamate and 50ml of n-butanol to the newly prepared 28% sodium methoxide solution, react at 100°C for 4 hours, then add 4.9g of p-tert-butylphenylhydrazine, and continue heating under reflux for 24 hours. Cool and filter to obtain 8.10 g of 1-(4-tert-butylphenyl)-5-(4-chlorophenyl)-3-pyrazolidinone; this compound was dissolved in N,N-dimethylformamide Bubble air into the solution, react at 100°C for 1 h, cool to room temperature, and filter to obtain 1-(4-tert-butylphenyl)-5-(4-chlorophenyl)-3-hydroxypyrazole 6.18 g, yield 62.3%; add 4.00 g of hydroxypyrazole to 100 ml of water, drop an equivalent amount of ethyl chloroacetate, react at 100 ° C for 2 h, extract with ethyl acetate, dry over anhydrous magnesium sulfate, filter, After removal of ethyl acetate, 3.84 g of ethyl 1-(4-tert-butylphenyl)-5-(4-chlorophenyl)-3-oxoacetate pyrazole was obtained, with a yield of 75.8%. ¹ H NMRδ: 1.29 (t, 3H), 1.32 (s, 9H), 4.23 (q, 2H), 4.89 (s, 2H), 6.02 (s, 1H), 7.16-7.33 (m, 8H).

Example 12

Under stirring, in 4-methylcinnamic acid (0.05mol), add anhydrous methanol 40ml, p-toluenesulfonic acid 0.3g, after reflux reaction 2h, underpressure distillation obtains 4-methylcinnamic acid methyl ester 8.10g; Add methyl 4-methylcinnamate and 50ml of n-butanol to the newly prepared 28% sodium methoxide solution under stirring, react at 100°C for 4 hours, then add 6.5g of p-fluorophenylhydrazine, and continue heating under reflux for 24 hours. Cool and filter to obtain 10.65 g of 1-(p-fluorophenyl)-5-(4-methylphenyl)-3-pyrazolidinone; this compound was dissolved in N,N-dimethylformamide solution , bubbling air, reacting at 100°C for 2h, cooling to room temperature, and filtering to obtain 1-(p-fluorophenyl)-5-(4-methylphenyl)-3-hydroxypyrazole, 9.50g, harvested The yield is 70.4%; take 5.50g of hydroxypyrazole and add it to 100ml of water, add an equivalent amount of ethyl bromoacetate dropwise, react at 100°C for 2h, extract with ethyl acetate, dry over anhydrous magnesium sulfate, filter, and remove ethyl acetate After esterification, 5.53 g of ethyl 1-(p-fluorophenyl)-5-(4-methylphenyl)-3-oxoacetate pyrazole was obtained, with a yield of 75.6%. ¹ H NMRδ: 1.29 (t, 3H), 2.45 (s, 3H), 4.26 (q, 2H), 4.83 (s, 2H), 6.12 (s, 1H), 7.16-7.33 (m, 8H).

Example 13

Under stirring, in cinnamic acid (0.05mol), add anhydrous methanol 50ml, p-toluenesulfonic acid 0.3g, after reflux reaction 2h, underpressure distillation obtains methyl cinnamate 7.55g; Add methyl cinnamate and 50ml of n-butanol to the sodium solution, react at 100°C for 4h, then add 8.9g of 2,4-dichlorophenylhydrazine, continue to heat and reflux for 24h, cool, and filter to obtain 1-( 2,4-dichlorophenyl)-5-phenyl-3-pyrazolidinone 12.78g; this compound was dissolved in N,N-dimethylformamide solution, blown into air, and reacted at 100°C After 2h, cool to room temperature and filter to obtain 1-(2,4-dichlorophenyl)-5-phenyl-3-hydroxypyrazole, 10.85g, yield 70.2%; take 5.85g of hydroxypyrazole and add Add an equivalent amount of chloroacetic acid dropwise to 100ml of water, react at 100°C for 2 hours, extract with ethyl acetate, dry over anhydrous magnesium sulfate, filter, and remove ethyl acetate to obtain 1-(2,4-dichlorophenyl )-5-phenyl-3-oxoacetic acid pyrazole 4.12g, yield 60.0%. ¹ H NMR δ: 4.69 (s, 2H), 6.22 (s, 1H), 7.26-7.43 (m, 8H), 10.0 (s, 1H).

Example 14

Under stirring, add 20ml of anhydrous methanol and 0.3g of p-toluenesulfonic acid to 4-methoxycinnamic acid (0.05mol), after reflux reaction for 2h, remove methanol by distillation under reduced pressure to obtain methyl 4-methoxycinnamate 8.90g; Add methyl 4-methoxycinnamate and 50ml n-butanol to the newly prepared 28% sodium methoxide solution under stirring, react at 100°C for 4h, then add 6.5g p-fluorophenylhydrazine and continue heating After reflux for 24 hours, cool and filter to obtain 11.38 g of 1-(4-fluorophenyl)-5-(4-methoxyphenyl)-3-pyrazolidinone; this compound was dissolved in N,N- In dimethylformamide solution, air was blown in, reacted at 100°C for 1h, cooled to room temperature, filtered to obtain 1-(4-fluorophenyl)-5-(4-methoxyphenyl)-3 -Hydroxypyrazole 9.42g, yield 65.9%; take 5.00g of hydroxypyrazole and add it to 100ml of water, add dropwise an equivalent amount of chloroacetic acid, react at 100°C for 2h, extract with ethyl acetate, dry over anhydrous magnesium sulfate , filtered, and ethyl acetate was removed to obtain 4.81 g of 1-(4-fluorophenyl)-5-(4-methoxyphenyl)-3-oxoacetoxypyrazole, with a yield of 80.1%. ¹ H NMR δ: 3.89 (s, 3H), 4.89 (s, 2H), 6.12 (s, 1H), 7.22-7.43 (m, 8H), 8.0 (s, 1H).

Example 15

Under stirring, 40ml of anhydrous methanol and 0.3g of p-toluenesulfonic acid were added to 3,4-dimethoxycinnamic acid (0.03mol). After reflux for 2 hours, 3,4-dimethoxycinnamic acid was distilled under reduced pressure 6.00g methyl cinnamate and 50ml n-butanol; add 3,4-dimethoxymethyl cinnamate to the newly prepared 28% sodium methoxide solution under stirring, react at 100°C for 4 hours, then add 4.9g For p-tert-butylphenylhydrazine, continue to heat and reflux for 24 hours, then cool and filter to obtain 1-(4-tert-butylphenyl)-5-(3,4-dimethoxyphenyl)-3-pyrazole Alkanone 8.55g; Dissolve this compound in N,N-dimethylformamide solution, blow in air, react at 100°C for 1h, cool to room temperature, and filter to obtain 1-(4-tert-butylbenzene base)-5-(3,4-dimethoxyphenyl)-3-hydroxypyrazole 7.70g, yield 72.3%; 4.70g of hydroxypyrazole was added to 100ml water, and an equivalent amount of chloroacetic acid was added dropwise , after reacting at 100°C for 2h, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and removed ethyl acetate to obtain 1-(4-tert-butylphenyl)-5-(4-trifluoromethylbenzene Base)-3-oxoacetic acid pyrazole 4.30g, yield 78.9%. ¹ H NMR δ: 1.32 (s, 9H), 4.89 (s, 2H), 6.12 (s, 1H), 7.02-7.23 (m, 4H), 7.32-7.48 (m, 4H), 8.0 (s, 1H).

Example 16

Under stirring, add 40ml of anhydrous methanol and 0.5g of p-toluenesulfonic acid to 3,4,5-trimethoxycinnamic acid (0.05mol), and after reflux for 2h, distill under reduced pressure to obtain 4-methoxycinnamic acid Methyl ester 10.90g; Add methyl 3,4,5-trimethoxycinnamate and 50ml n-butanol to the newly prepared 28% sodium methoxide solution under stirring, react at 100°C for 4h, then add 6.5g of Methylphenylhydrazine, continue to heat and reflux for 24h, then cool and filter to obtain 1-(4-methylphenyl)-5-(3,4,5-trimethoxyphenyl)-3-pyrazolidinone 13.80g; the compound was dissolved in N,N-dimethylformamide solution, blown into air, reacted at 100°C for 1h, cooled to room temperature, and filtered to obtain 1-(4-methylphenyl)- 10.75g of 5-(3,4,5-trimethoxyphenyl)-3-hydroxypyrazole, yield 63.3%; 6.45g of hydroxypyrazole was added to 100ml of water, and an equivalent amount of ethyl bromoacetate was added dropwise , after reacting at 100°C for 2h, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and obtained 1-(4-methylphenyl)-5-(3,4,5-trimethoxy phenyl)-3-oxoacetate ethylpyrazole 6.63g, yield 81.5%. ¹ H NMRδ: 1.30(t, 3H), 2.32(s, 3H), 3.56(s, 6H), 3.65(s, 3H), 4.26(q, 2H), 4.89(s, 2H), 6.11(s, 1H), 7.12-7.23 (m, 4H), 7.48 (d, 2H).

Example 17

Under stirring, add 40ml of absolute ethanol and 0.3g of p-toluenesulfonic acid to 4-bromocinnamic acid (0.05mol), after reflux reaction for 2h, distill under reduced pressure to obtain 11.10g of ethyl 4-bromocinnamate; under stirring Add ethyl 4-bromocinnamate and 50ml of n-butanol to the newly prepared 28% sodium methoxide solution, react at 100°C for 4 hours, then add 6.5g of p-methylphenylhydrazine, continue to heat and reflux for 24 hours, then cool. Filtration gave 12.10 g of 1-(4-methylphenyl)-5-(4-bromophenyl)-3-pyrazolidinone; this compound was dissolved in N,N-dimethylformamide solution, Bubble air, react at 100°C for 1 h, cool to room temperature, and filter to obtain 10.87 g of 1-(4-methylphenyl)-5-(4-bromophenyl)-3-hydroxypyrazole, yield 65.9%; take 5.87g of hydroxypyrazole and add it to 100ml of anhydrous acetone solution, add an equivalent amount of ethyl bromoacetate dropwise, after reflux for 2 hours, remove the acetone, add water, extract with ethyl acetate, dry over anhydrous magnesium sulfate, After filtering to remove ethyl acetate, 5.87 g of ethyl 1-(4-methylphenyl)-5-(4-bromophenyl)-3-oxoacetate pyrazole was obtained, with a yield of 78.8%. ¹ H NMRδ: 1.30(t, 3H), 2.32(s, 3H), 4.26(t, 2H), 4.89(s, 2H), 6.08(s, 1H), 6.82～7.03(d, 2H), 7.08～ 7.23 (m, 4H), 7.32~7.43 (d, 2H).

Example 18

Under stirring, in 4-chlorocinnamic acid (0.05mol), add anhydrous methanol 50ml, p-toluenesulfonic acid 0.3g, after reflux reaction 2h, underpressure distillation removes methyl alcohol to obtain 4-chlorocinnamic acid methyl ester 8.90g; Next, add methyl 4-chlorocinnamate and 50ml n-butanol to the newly prepared 28% sodium methoxide solution, react at 100°C for 4h, then add 8.9g of 2,4-dichlorophenylhydrazine, and continue to heat and reflux for 24h After cooling and filtering, 13.30g of 1-(4-2,4-dichlorophenyl)-5-(4-chlorophenyl)-3-pyrazolidinone was obtained; the compound was dissolved in N,N- Dimethylformamide solution, bubbled with air, reacted at 100°C for 5h, cooled to room temperature, filtered to obtain 1-(4-2,4-dichlorophenyl)-5-(4-chlorophenyl )-3-hydroxypyrazole 12.49g, yield 72.7%; 6.00g of hydroxypyrazole was added to 100ml of water, and an equivalent amount of sodium chloroacetate was added dropwise, and reacted at 100°C for 2h, then neutralized with 6N hydrochloric acid solution, Extract with ethyl acetate, dry over anhydrous magnesium sulfate, filter, and get 1-(4-2,4-dichlorophenyl)-5-(4-chlorophenyl)-3-oxoacetoxypyridine after removing ethyl acetate azole 5.76g, yield 82.2%. ¹ H NMR δ: , 4.86 (s, 2H), 6.18 (s, 1H), 6.89-7.23 (m, 4H), 7.38-7.43 (m, 2H), 7.52-7.53 (s, 1H).

Example 19

Under stirring, add 40ml of anhydrous methanol and 0.3g of p-toluenesulfonic acid to 4-fluorocinnamic acid (0.05mol). Add methyl 4-fluorocinnamate and 50ml of n-butanol to the newly prepared 28% sodium methoxide solution, react at 100°C for 4 hours, then add 6.5g of p-fluorophenylhydrazine, continue to heat and reflux for 24 hours, then cool and filter , to obtain 1-(4-fluorophenyl)-5-(4-fluorophenyl)-3-pyrazolidinone 11.25g; this compound was dissolved in N,N-dimethylformamide solution, blown into Air, react at 100°C for 1 hour, cool to room temperature, and filter to obtain 9.91 g of 1-(4-fluorophenyl)-5-(4-fluorophenyl)-3-hydroxypyrazole with a yield of 72.3%; Add 5.91g of hydroxypyrazole to 100ml of water, add an equivalent amount of sodium chloroacetate dropwise, react at 100°C for 2 hours, neutralize with 6N hydrochloric acid solution, extract with ethyl acetate, dry over anhydrous magnesium sulfate, filter to remove acetic acid After ethyl ester, 5.01 g of 1-(4-fluorophenyl)-5-(4-fluorophenyl)-3-oxoacetoxypyrazole was obtained with a yield of 70.0%. ¹ H NMR δ: 4.69 (s, 2H), 5.98 (s, 1H), 6.82 (d, 2H), 7.15-7.23 (m, 4H), 7.43 (m, 2H).

Example 20

Under stirring, add 80ml of anhydrous methanol and 0.3g of p-toluenesulfonic acid to 3-phenoxycinnamic acid (0.05mol), and after reflux reaction for 2h, distill under reduced pressure to obtain 9.50g of methyl 4-phenoxycinnamate and 50ml of n-butanol; under stirring, add methyl 3-phenoxycinnamate to the newly prepared 28% sodium methoxide solution, react at 100°C for 4h, then add 6.5g of p-fluorophenylhydrazine, and continue the reaction under reflux After 24h, cool and filter to obtain 13.60 g of 1-(4-fluorophenyl)-5-(3-phenoxyphenyl)-3-pyrazolidinone; this compound was dissolved in N,N-dimethyl In the base formamide solution, air was blown in, reacted at 100°C for 3h, cooled to room temperature, and filtered to obtain 1-(4-fluorophenyl)-5-(3-phenoxyphenyl)-3-hydroxyl Pyrazole 10.84g, yield 62.1%; take 5.84g of hydroxypyrazole and add it to a 100ml four-neck flask, add 0.7g sodium hydroxide and 100ml acetone, slowly add an equal amount of ethyl bromoacetate dropwise, and reflux for 2h Finally, remove acetone, add 100ml of water, extract with ethyl acetate, dry over anhydrous magnesium sulfate, filter, remove ethyl acetate to obtain 1-(4-fluorophenyl)-5-(4-phenoxyphenyl) - 5.76 g of ethyl 3-oxoacetate pyrazole, yield 78.6%. ¹ H NMRδ: 1.30 (t, 3H), 4.26 (q, 2H), 4.79 (s, 2H), 6.08 (s, 1H), 6.98-7.22 (m, 11H), 7.44 (d, 2H).

Carry out the bactericidal experiment of 21 pyrazole oxyacetic acid fungicides

The final product obtained in Example 1 was used to evaluate the bactericidal effect, and at the same time, carbendazim and procymidone were selected as comparisons. Rapeseed Sclerotinia sclerotiorum, Botryris cinerea Pers., Botryris cinerea Pers., Gibbrella zeae (Schw.) Petch, Rhizoctorua solani, Pyricularia oryzae Cav. For the target, potted cucumber seedlings at the cotyledon stage were used as test crops, and the treatment dose was: in vitro: 10ug/ml and in vivo: 1000ug/ml, and the bactericidal activity test was carried out with clean water as a control.

1 In vitro test method:

1.1 Preparation of drug-containing medium: the treatment agent was dissolved in acetone to make a mother solution; the control drug carbendazim was made into a mother solution with 0.02mol/L dilute HCl. According to a certain concentration gradient, add the test agent and the control agent respectively into the culture medium which has been sterilized and cooled to about 45°C, mix evenly, pour it into a plate, and make a drug-containing plate.

1.2 Toxicity determination: the colony diameter method was used. Connect a bacteria plate in the center of the drug-containing plate with the mycelium facing down. Cultivate at 25°C until the blank control colonies cover more than 2/3 of the culture dish, then measure the colony diameter of each treatment. Each colony was measured twice by the cross method, and the average number represented the size of the colony. Calculate the inhibition of the drug on the growth rate of the bacteria.

2 In vivo test method:

2.1 Crop cultivation: After the cucumbers are accelerated to germination, sow them on demand in plastic pots with d=6cm, absorb enough water, and place them in a net room for cultivation until the cotyledon stage for later use.

2.2 Application method: In the indoor fume hood, use a throat sprayer to evenly apply to the whole plant of cucumber seedlings.

2.3 Inoculation method: pre-transfer Sclerotinia sclerotiorum and Botrytis cinerea, grow to three quarters of a dish for later use. After 24 hours of spraying, use a puncher of d=5mm to punch the fungus cake at the edge of the colony, and connect the mycelia of the fungus cake to the front of the blade downward.

2.4 Cultivation: Cucumbers with good bacteria are placed in a humidity box for constant temperature and moisture cultivation. The cultivation temperature is 25°C, the humidity is 100%, and light/dark = 16/8:

In the in vitro test, the diameter of the colony is measured when the colony grows to more than 2/3 of the plate; in the in vivo test, the investigation results after moisturizing and culturing for 3 days, the specific results are shown in Table 1 and Table 2 below

                                                                   

                                                  

Grading standards: Grade A: inhibition rate ≥ 90%; Grade B: 90% > inhibition rate ≥ 70%; Grade C: 70% > inhibition rate ≥ 50%; Grade D: 50% > inhibition rate.

Claims (5)

1. A compound or a salt thereof as described below, selected from the group consisting of: 1-Phenyl-5-(4-methoxyphenyl)-3-oxyacetoxyethylpyrazole 1-phenyl-5-(3,4,5-trimethoxyphenyl)-3-oxoacetoxypyrazole 1-(4-fluorophenyl)-5-(4-bromophenyl)-3-oxoacetoxypyrazole 1-Phenyl-5-(4-trifluoromethylphenyl)-3-oxoacetoxypyrazole 1-(4-methylphenyl)-5-(4-fluorophenyl)-3-oxoacetoxypyrazole 1-(4-Fluorophenyl)-5-(3,4-dimethoxyphenyl)-3-oxoacetate ethylpyrazole 1-(4-tert-butylphenyl)-5-phenyl-3-oxyacetoxyethylpyrazole 1-(2,4-Dichlorophenyl)-5-(4-methylphenyl)-3-oxoacetate ethyl pyrazole 1-(2,4-Dinitrophenyl)-5-(4-chlorophenyl)-3-oxoacetoxyethylpyrazole 1-(4-tert-butylphenyl)-5-(4-chlorophenyl)-3-oxoacetate ethyl pyrazole 1-(p-Fluorophenyl)-5-(4-methylphenyl)-3-oxoacetate ethyl pyrazole 1-(2,4-Dichlorophenyl)-5-phenyl-3-oxoacetic acid pyrazole 1-(4-fluorophenyl)-5-(4-methoxyphenyl)-3-oxoacetoxypyrazole 1-(4-methylphenyl)-5-(3,4,5-trimethoxyphenyl)-3-oxoacetoxyethylpyrazole 1-(4-methylphenyl)-5-(4-bromophenyl)-3-oxoacetate ethyl pyrazole 1-(2,4-Dichlorophenyl)-5-(4-chlorophenyl)-3-oxoacetoxypyrazole 1-(4-fluorophenyl)-5-(4-fluorophenyl)-3-oxoacetoxypyrazole. 2. A preparation method of a compound of general structural formula (I), reacting A with methanol or ethanol in the presence of p-toluenesulfonic acid, generating B; React at ℃ for 1~24h, then add C, react for 0~24h to get D; put D in N,N-dimethylformamide solution, blow in air, react at 0~100℃, cool and filter to get E; then react with haloalkanoic acid or haloalkanoate to generate compound (I), and the reaction formula is as follows:

Wherein, X or Y are hydrogen, C _1-4 alkyl, methoxy, phenoxy, fluorine, chlorine, bromine, nitro or trifluoromethyl, respectively, and R is hydrogen or ethyl. 3. the preparation method of the compound of structural general formula (I) according to claim 2 is characterized in that: when preparing bactericide (I), E and halogenated alkanoic acid or halogenated alkanoic acid ester, used organic solvent is dioxygen Hexacyclic, acetonitrile, N, N-dimethylformamide, acetone, methylene chloride or chloroform, the basic catalyst used is triethylamine, potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide. 4. the application of the compound described in claim 1 in the preparation of bactericide. 5. The application according to claim 4, wherein said bacterium is a sclerotinia-susceptible strain of rapeseed, a vegetable botrytis-susceptible strain, a head blight-susceptible strain, a wheat sheath blight-susceptible strain or a rice blast fungus. the