CN107646855B - Application of thiazole compound containing piperidine in preparation of bactericide and preparation method thereof - Google Patents

Abstract

The invention discloses and provides an application of a piperidinethiazole-containing compound as a fungicide in preventing and treating cucumber downy mildew and rice sheath blight, and a preparation method of the piperidinethiazole-containing compound. The invention provides a new application of the piperidinethiazole-containing compound, which is a new compound with bactericidal activity and provides a basis for the research and development of the piperidinethiazole pesticide, and the preparation method of the invention provides the preparation of the fungicide. raw material base.

Description

Application of a kind of piperidine thiazole compound in the preparation of bactericide and preparation thereof method

technical field

The invention relates to an application of a piperidine thiazole compound in preparing a bactericide and a preparation method thereof.

Background technique

Piperidinethiazoles were originally used as microsomal triglyceride transfer protein (MTP) inhibitors and are an important class of drug intermediates. Piperidine thiazole compounds have innovative chemical structures and mechanisms of action, low toxicity and high efficiency, so their research and development are increasingly active, attracting more and more attention of workers.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is to provide an application of a piperidinethiazole-containing compound in the preparation of a bactericide and a preparation method thereof.

In order to solve the above-mentioned technical problems, the technical scheme adopted in the present invention is as follows:

An application of the piperidine thiazole-containing compound represented by the formula (I) in the preparation of a fungicide, characterized in that the piperidine thiazole-containing compound is used in the prevention and control of rice sheath blight and cucumber downy mildew;

In formula (I): R is one of methyl, halogen, trifluoromethyl and tert-butyl; R ₁ is 4-chlorophenyl, 4-methylphenyl, 4-nitrophenyl, diamond One of alkyl and 4-trifluoromethylphenyl; G is selected from one of the following groups (a1) and (a2);

。

.

Further, the piperidinthiazole-containing compound represented by the formula (I) is used as a fungicide in inhibiting downy mildew of cucumber and sheath blight of rice.

A preparation method of a piperidine thiazole compound as shown in formula (I), characterized in that it comprises the following steps:

Step A: diazotization reaction occurs with the compound shown in formula (II) and sodium nitrite in concentrated hydrochloric acid solution, under -5～5 ℃ condition, add 40～50% fluoroboric acid, obtain fluoroboric acid diazonium salt , catalyzed by cuprous oxide, reacted with isopropenyl acetate in the presence of anhydrous sodium acetate, and distilled to obtain the compound shown in formula (III);

Step B: compound (III) and sulfonyl chloride obtained in step A are added to methylene chloride, react at a temperature of 10~40 ° C, and after tracking detection to complete the reaction, the reaction solution is post-treated to obtain formula (IV) shown in compound of;

Step C: dissolving N-boc-4-cyanopiperidine in dimethylformamide, adding sodium hydrosulfide and ammonium chloride, tracking and detecting to after complete hydrolysis, the reaction solution is obtained by post-processing formula (V). compound shown;

Step D: Dissolve compound (IV) obtained in step B and compound (V) obtained in step C in an organic solvent, add sodium acetate, react at 80~100 ° C, after the reaction is complete, adjust pH=3~8, extract , rotary evaporation to obtain the compound shown in formula (VI);

Step E: The compound (VI) obtained in step D is acidly hydrolyzed in the solution, and after tracking and detection to complete reaction, the reaction solution is post-treated to obtain the compound of formula (VII);

Step F: The compound (VII) obtained in the step E and the acid chloride or sulfonyl chloride are tracked and detected to complete the reaction under the condition that triethylamine is used as a base and dichloromethane is used as a solvent. Crystallization obtains the target product shown in formula (I);

Its reaction equation is as follows:

。

.

Further, in the step A, the substance ratio of compound (II): sodium nitrite: concentrated hydrochloric acid = 1.0: 1.0: 3.0~3.5: 3.0~4.0, anhydrous sodium acetate: isopropenyl acetate: cuprous oxide The quantity ratio of substances = 1:3~3.5:0.01~0.05.

Further, in the step B, the substance ratio of compound (III):dichloromethane:sulfonyl chloride=1.0:2.0~4.0:1.0~1.2.

Further, in described step C, sodium hydrosulfide: ammonium chloride: N-boc-4-cyanopiperidine substance ratio=1.5～2.5:1.5～2.5:1.0.

Further, in the described step D, the organic solvent is one of glacial acetic acid, 20～80% acetic acid methanol solution and 20～80% acetic acid ethanol solution, preferably glacial acetic acid; compound (IV): compound (V): anhydrous The quantity ratio of sodium acetate substance = 1.0~1.1: 1.0: 2.0~2.5.

Further, the acid hydrolysis reagent in the step E is a dioxane solution containing 20-40% hydrogen chloride or an ethyl acetate solution containing 20-40% hydrogen chloride.

Further, in the described step F, compound (VI): acyl chloride or sulfonyl chloride: the substance amount ratio of triethylamine=1.0:0.9～1.0:2.5～3.0, and the recrystallization reagent is methanol, ethyl acetate and petroleum ether. one or several mixtures.

The present invention has the following beneficial effects:

(1) The present invention provides a new application of piperidinethiazole-containing compounds, which are new compounds with bactericidal activity and provide a basis for the research and development of piperidinethiazole-type pesticides;

(2) The present invention provides a method for preparing a piperidinethiazole-containing compound, which provides a raw material basis for the preparation of a fungicide.

Detailed ways

The technical solutions of the present invention are described below with specific embodiments, but the protection scope of the present invention is not limited thereto.

The piperidine thiazole-containing compound (I) of the present invention can be prepared according to the following method:

(1) Synthesis of p-chloroaniline target compound (I):

A) Synthesis of 1-(4-chlorophenyl)-2-propanone,

4-Chloroaniline (0.15mol) and concentrated hydrochloric acid were added to a 250ml three-necked flask equipped with mechanical stirring. Under the condition of 0°C, NaNO ₂ (0.15mol) was added dropwise with a constant pressure dropping funnel. For 30 min, 40% HBF ₄ (0.19 mol) was added dropwise with a constant pressure dropping funnel at 0°C, kept for 3 h, filtered under reduced pressure to obtain diazonium fluoroborate, washed with glacial ethanol, and dried to remove water;

Add sodium acetate (0.25mol), isopropenyl acetate (0.80mol), cuprous oxide (0.02mol) to a 250ml four-neck flask equipped with mechanical stirring, and slowly add the dry diazonium fluoroborate in batches. In a four-necked flask, control the temperature at 35~40°C, react for 8 hours, remove the salt by suction filtration, wash the filter cake with petroleum ether, collect the filtrate, distill under reduced pressure, collect the fractions at 70~75°C to obtain 1-(4-chloro phenyl)-2-propanone;

B) Synthesis of 1-(4-Chlorophenyl)-2-chloro-acetone,

Add 1-(4-chlorophenyl)-2-acetone and dichloromethane to a 50ml three-necked flask, use magnetic stirring, add sulfonyl chloride dropwise with a constant pressure dropping funnel, react for 2h, adjust with saturated sodium bicarbonate solution pH=8~9, extracted with dichloromethane, dried over anhydrous sodium sulfate, and rotary-evaporated to obtain 1-(4-chlorophenyl)-2-chloro-acetone;

C) Synthesis of N-boc-4-thioamide piperidine,

Add 70% NaSH (100g), NH ₄ Cl (100g), 1200ml DMF, N-boc-4-cyanopiperidine (86g) to a 2L four-necked flask with mechanical stirring, stir at room temperature for 72h, the reaction is complete Then, add 6L of ice water to a 10L beaker, slowly add the contents of the 2L four-necked flask to the ice water during stirring, and after stirring for 1h, a large amount of white solids appear, filter with suction, and extract the filtrate with 500ml×3 ethyl acetate , rotary steam, combined with filter cake and dried to obtain N-boc-4-thioamide piperidine;

D) Synthesis of 4-methyl-5-(4-chlorophenyl)-(N-boc-4-piperidin-4-yl)-2-thiazole

Add 1-(4-chlorophenyl)-2-chloro-acetone and N-boc-4-thioamide piperidine, glacial acetic acid, and anhydrous sodium acetate into a 100ml three-necked flask, at 100°C under magnetic stirring conditions Then, react overnight, adjust Ph=8~9 with saturated aqueous solution of NaHCO3, extract with ethyl acetate 30ml x 3, rotary evaporate to obtain crude product, and recrystallize to obtain 4-methyl-5(4-chlorophenyl)-2 -(N-boc-4-piperidin-4-yl)thiazole;

E) Synthesis of 4-methyl-5-(4-chlorophenyl)-2-(piperidine hydrochloride-4-yl)thiazole,

Add 4-methyl-5(4-chlorophenyl)-2-(N-boc-4-piperidin-4-yl)thiazole and 2NHCl dioxane solution into a 100ml three-necked flask, and react at room temperature 4h, filter under reduced pressure to obtain white 4-methyl-5-(4-chlorophenyl)-2-(piperidine hydrochloride-4-yl)thiazole;

F) Synthesis of 4-methyl-5phenyl-(p-chlorobenzoylpiperidin-4-yl)-2-thiazole,

In a sealed tube, add 0.100g 4-methyl-5-(4-chlorophenyl)-2-(piperidine hydrochloride-4-yl)thiazole, 0.1g triethylamine, 1ml dichloromethane, p- Nitrobenzoyl chloride, reacted for 2h, washed with water, washed with acid, extracted with dichloromethane 10ml×3, and rotary evaporated to obtain the target compound 4-methyl-5-(4-chlorophenyl)-2-(p-nitro) Benzoylpiperidin-4-yl) thiazole, other amide/sulfonamide compounds were prepared in the same way.

Example 1

According to the synthetic method of above-mentioned p-chloroaniline target compound (I), obtained:

4-methyl-5-(4-chlorophenyl)-2-(p-nitrobenzenesulfonylpiperidin-4-yl)thiazole, white crystal, melting point yield 95%;

¹ H NMR (500 MHz, Chloroform- d ) δ 8.33 (d, J = 8.4 Hz, 2H, Ph-H), 7.91 (d, J = 8.4 Hz, 2H, Ph-H), 7.35 – 7.15 (m, 4H, Ph-H), 3.86 (dt, J = 12.0, 3.4Hz, 2H, Pip-H), 2.88 (ddt, J = 11.3, 7.0, 3.6 Hz, 1H, Pip-H), 2.59 – 2.43 (m , 2H, Pip-H), 2.35 (s, 3H, -CH ₃ ), 2.21 – 2.09 (m, 2H, Pip-H), 1.87 (qd, J =11.7, 3.8 Hz, 2H, Pip-H).

Example 2

According to the synthetic method of above-mentioned p-chloroaniline target compound (I), obtained:

4-Methyl-5-(4-chlorophenyl)-2-(3,4,5-trimethoxybenzoylpiperidin-4-yl)thiazole white crystal, yield 92%;

¹ H NMR (500 MHz, Chloroform- d ) δ 7.44 – 7.16 (m, 4H, Ph-H), 6.62 (s, 2H, Ph-H), 4.74 (s, 1H, Pip-H), 3.83 (d , J = 9.9 Hz, 9H, -OCH3), 3.08 (s, 4H, Pip-H), 2.46 (s, 3H, -CH3), 2.18 (s, 2H, Pip-H), 1.82 (s, 2H, Pip-H).

Example 3

According to the synthetic method of above-mentioned p-chloroaniline target compound (I), obtained:

4-Methyl-5-(4-chlorophenyl)-2-(2-naphthoylpiperidin-4-yl)thiazole white crystal, yield 92%;

¹ H NMR (500 MHz, Chloroform- d ) δ 7.95 (s, 1H, Ph-H), 7.92 – 7.82 (m, 3H, Ph-H), 7.70 (d, J = 7.8 Hz, 2H, Ph-H ), 7.61 – 7.46 (m, 5H, Ph-H), 4.89(s, 1H, Pip-H), 3.99 (s, 1H, Pip-H), 3.39 (d, J = 11.7 Hz, 1H, Pip- H), 3.17(d, J = 61.6 Hz, 2H, Pip-H), 2.53 (s, 3H, -CH3), 2.41 – 2.07 (m, 2H, Pip-H), 2.08 – 1.71 (m, 2H, Pip-H).

(2) Synthesis of 3-methylaniline target compound (I)

A) Synthesis of 1-(3-methylphenyl)-2-propanone,

Add 3-methylaniline (0.15mol) and concentrated hydrochloric acid to a 250ml there-necked flask equipped with mechanical stirring, and at 0°C, add NaNO ₂ (0.15mol) dropwise with a constant pressure dropping funnel. For 30 min, 40% HBF ₄ (0.19 mol) was added dropwise with a constant pressure dropping funnel at 0°C, kept for 3 h, and filtered under reduced pressure to obtain fluoroborate diazonium salt, which was washed with glacial ethanol and dried to remove water;

Add sodium acetate (0.25mol), isopropenyl acetate (0.80mol), cuprous oxide (0.02mol) to a 250ml four-neck flask equipped with mechanical stirring, and slowly add the dry diazonium fluoroborate in batches. In a four-necked flask, control the temperature at 35~40°C, react for 8 hours, remove the salt by suction filtration, wash the filter cake with petroleum ether, collect the filtrate, distill under reduced pressure, collect the fractions at 63~65°C to obtain 1-(3-methylmethane) phenyl)-2-propanone;

B) Synthesis of 1-(3-methylphenyl)-2-chloro-acetone,

In a 50ml three-necked flask, add 1-phenyl-2-acetone, dichloromethane, use magnetic stirring, add sulfonyl chloride dropwise with a constant pressure dropping funnel, react for 2h, adjust pH=8~9 with saturated sodium bicarbonate solution, Extraction with dichloromethane, drying over anhydrous sodium sulfate, and rotary evaporation to obtain 1-(3-methylphenyl)-2-chloro-acetone;

C) Synthesis of N-boc-4-thioamide piperidine,

Add 70% NaSH (100g), NH ₄ Cl (100g), 1200ml DMF, N-boc-4-cyanopiperidine (86g) to a 2L four-necked flask with mechanical stirring, stir at room temperature for 72h, the reaction is complete Then, add 6L of ice water to a 10L beaker, slowly add the contents of the 2L four-necked flask to the ice water during stirring, and after stirring for 1h, a large amount of white solids appear, filter with suction, and extract the filtrate with 500ml×3 ethyl acetate , rotary steam, combined with filter cake and dried to obtain N-boc-4-thioamide piperidine;

D) Synthesis of 4-methyl-5-(3-methylphenyl)-(N-boc-4-piperidin-4-yl)-2-thiazole,

In a 100ml three-necked flask, add the compound N-boc-4-thioamide piperidine, 1-(3-methylphenyl)-2-chloro-acetone, glacial acetic acid and anhydrous sodium acetate, and stir magnetically at 100°C Condition, react overnight, adjust Ph=8~9 with saturated NaHCO3 aqueous solution, extract with ethyl acetate 30ml x 3, rotary evaporation, the crude product is gray-brown, and recrystallized to obtain 4-methyl-5-(3-methyl) phenyl)-(N-boc-4-piperidin-4-yl)-2-thiazole;

E) Synthesis of 4-methyl-5-(4-chlorophenyl)-2-(piperidine hydrochloride-4-yl)thiazole,

Add 4-methyl-5-(3-methylphenyl)-(N-boc-4-piperidin-4-yl)-2-thiazole, 2NHCl dioxane solution into a 100ml three-necked flask, at room temperature The reaction was continued for 4 h, and filtered under reduced pressure to obtain white 4-methyl-5-(3-methylphenyl)-2-(piperidine hydrochloride-4-yl)thiazole;

F) Synthesis of 4-methyl-5-(3-methylphenyl)-2-(p-nitrobenzoylpiperidin-4-yl)thiazole,

Add 0.100g 4-methyl-5-(3-methylphenyl)-2-(piperidine hydrochloride-4-yl)thiazole, 0.1g triethylamine, 1ml dichloromethane, p- Nitrobenzoyl chloride, reacted for 2h, washed with water, washed with acid, extracted with 1 methylene chloride 10ml×3, and rotary evaporated to obtain the target compound 4-methyl-5-(3-methylphenyl)-(p-nitroacyl) Piperidin-4-yl)-2-thiazole, other amide/sulfonamide compounds were prepared in the same way.

Example 4

According to the synthetic method of above-mentioned 3-methylaniline target compound (I), obtained:

4-Methyl-5-(3-methylphenyl)-2-(p-nitrobenzenesulfonylpiperidin-4-yl)thiazole, white crystal, melting point, yield 96%;

¹ H NMR (500 MHz, Chloroform- d ) δ 8.54 – 8.31 (m, 2H, Ph-H), 8.11 – 7.86 (m, 2H, Ph-H), 7.59 – 7.32 (m, 4H, Ph-H) , 3.96 (dt, J = 12.0, 3.2 Hz, 2H, Pip-H), 3.06 (s, 1H, Pip-H), 2.67 – 2.53 (m, 2H, Pip-H), 2.47 (s, 6H, 3 -CH3,3-CH3), 2.26 (d, J = 13.2 Hz, 2H, Pip-H), 1.97 (td, J = 11.7, 8.0 Hz, 2H, Pip-H).

Example 5

According to the synthetic method of above-mentioned 3-methylaniline target compound (I), obtained:

4-Methyl-5-(3-methylphenyl)-2-(2-naphthoylpiperidin-4-yl)thiazole white crystal, yield 96%;

¹ H NMR (500 MHz, Chloroform- d ) δ 7.95 (s, 1H, Ph-H), 7.92 – 7.82 (m, 3H, Ph-H), 7.70 (d, J = 7.8 Hz, 2H, Ph-H ), 7.61 – 7.46 (m, 5H, Ph-H), 4.89(s, 1H, Pip-H), 3.99 (s, 1H, Pip-H), 3.39 (d, J = 11.7 Hz, 1H, Pip- H), 3.17(d, J = 61.6 Hz, 2H, Pip-H), 2.53 (s, 6H-CH3), 2.41 – 2.07 (m, 2H, Pip-H), 2.08 – 1.71 (m, 2H, Pip-H) -H).

Example 6

According to the synthetic method of above-mentioned 3-methylaniline target compound (I), obtained:

4-Methyl-5-(3-methylphenyl)-2-(p-trifluoromethylbenzoylpiperidin-4-yl)thiazole white crystal, yield 94%;

¹ H NMR (500 MHz, Chloroform- d ) δ 8.47 – 8.37 (m, 2H, Ph-H), 8.03 – 7.94 (m, 2H Ph-H), 7.43 (d, J = 8.2 Hz, 2H, Ph- H), 7.34 (d, J = 8.5 Hz, 1H, Ph-H), 3.97 (d, J = 11.4 Hz, 1H, Pip-H), 3.18 (s, 1H, Pip-H), 2.58 (t, J =11.7 Hz, 2H, Pip-H), 2.49 (s, 6H, -CH3), 2.29 (d, J = 12.9 Hz, 2H, Pip-H), 1.96(q, J = 11.9, 11.5 Hz, 2H , Pip-H).

(3) Synthesis of p-bromoaniline target compound (I)

A) Synthesis of 1-(4-bromophenyl)-2-propanone,

In a 250ml three-necked flask equipped with mechanical stirring, add p-bromoaniline (0.15mol), concentrated hydrochloric acid, and at ₀ °C, add NaNO (0.15mol) dropwise with a constant pressure dropping funnel, and after the addition is completed, keep the temperature for 30min, 40% HBF ₄ (0.19mol) was added dropwise with a constant pressure dropping funnel at 0°C, incubated for 3 hours, and filtered under reduced pressure to obtain diazonium fluoroborate salt, which was washed with ice ethanol and dried to remove water;

Add sodium acetate (0.25mol), isopropenyl acetate (0.80mol), cuprous oxide (0.02mol) to a 250ml four-neck flask equipped with mechanical stirring, and slowly add the dry diazonium fluoroborate in batches. In a four-necked flask, control the temperature at 35~40°C, react for 8h, remove the salt by suction filtration, wash the filter cake with petroleum ether, collect the filtrate, distill under reduced pressure, collect the fractions at 100~102°C to obtain 1-(4-bromo phenyl)-2-propanone;

B) Synthesis of 1-(4-bromophenyl)-2-chloro-acetone,

Add 1-(4-bromophenyl)-2-acetone and dichloromethane to a 50ml three-necked flask, use magnetic stirring, add sulfonyl chloride dropwise with a constant pressure dropping funnel, react for 2h, and adjust pH with saturated sodium bicarbonate solution = 8~9, extracted with dichloromethane, dried over anhydrous sodium sulfate, and rotary evaporated to obtain 1-(4-bromophenyl)-2-chloro-acetone;

C) Synthesis of N-boc-4-thioamide piperidine,

Add 70% NaSH (100g), NH ₄ Cl (100g), 1200ml DMF, N-boc-4-cyanopiperidine (86g) to a 2L four-necked flask with mechanical stirring, stir at room temperature for 72h, the reaction is complete Then, add 6L of ice water to a 10L beaker, slowly add the contents of the 2L four-necked flask to the ice water during stirring, and after stirring for 1h, a large amount of white solids appear, filter with suction, and extract the filtrate with 500ml×3 ethyl acetate , rotary steam, combined with filter cake and dried to obtain N-boc-4-thioamide piperidine;

D) Synthesis of 4-methyl-5-(4-bromophenyl)-(N-boc-4-piperidin-4-yl)-2-thiazole,

In a 100ml three-necked flask, add 1-(4-bromophenyl)-2-chloro-acetone, N-boc-4-thioamide piperazine glacial acetic acid, anhydrous sodium acetate, and react at 100°C under magnetic stirring conditions. Overnight, adjusted to Ph=8~9 with saturated aqueous NaHCO3 solution, extracted with ethyl acetate 30ml x 3, rotary-evaporated, the crude product was gray-brown, and recrystallized to obtain 4-methyl-5-(4-bromophenyl)-( N-boc-4-piperidin-4-yl)-2-thiazole;

E) Synthesis of 4-methyl-5-(4-bromophenyl)-2-(piperidine hydrochloride-4-yl)thiazole,

In a 100ml three-necked flask, add 4-methyl-5-(4-bromophenyl)-(N-boc-4-piperidin-4-yl)-2-thiazole, 2NHCl dioxane solution, at room temperature The reaction was carried out for 4 h, and suction filtration was performed under reduced pressure to obtain white 4-methyl-5-(3-methylphenyl)-2-(piperidine hydrochloride-4-yl)thiazole;

F) Synthesis of 4-methyl-5-(4-bromophenyl)-(p-nitrobenzoylpiperidin-4-yl)-2-thiazole,

Add 0.100g 4-methyl-5-(3-methylphenyl)-2-(piperidine hydrochloride-4-yl)thiazole, 0.1g triethylamine, 1ml dichloromethane, 2 - Naphthoyl chloride, reacted for 2h, washed with water, washed with acid, extracted with 1 dichloromethane 10ml×3, and rotary evaporated to obtain the target compound 4-methyl-5-(3-methylphenyl)-2-(2-naphthalene) Acylpiperidin-4-yl) thiazole, other amide/sulfonamide compounds were prepared in the same way.

Example 7

According to the synthetic method of above-mentioned p-bromoaniline target compound (I), obtained:

4-Methyl-5-(4-bromophenyl)-2-(2-naphthoylpiperidin-4-yl)thiazole, white crystal, yield 95%;

¹ H NMR (500 MHz, Chloroform- d ) δ 7.95 (s, 1H, Ph-H), 7.92 – 7.82 (m, 3H, Ph-H), 7.70 (d, J = 7.8 Hz, 2H, Ph-H ), 7.61 – 7.46 (m, 5H, Ph-H), 4.89(s, 1H,), 3.99 (s, 1H, Pip-H), 3.39 (d, J = 11.7 Hz, 1H, Pip-H), 3.17 (d, J =61.6 Hz, 2H, Pip-H), 2.53 (s, 3H, -CH3), 2.41 – 2.07 (m, 2H, Pip-H), 2.08 – 1.71(m, 2H, Pip-H ).

Example 8

According to the synthetic method of above-mentioned p-bromoaniline target compound (I), obtained:

4-methyl-5-(4-bromophenyl)-2-(adamantanoylpiperidin-4-yl)thiazole white crystal, yield 93%;

¹ H NMR (500 MHz, Chloroform- d ) δ 7.60 (d, J = 8.0 Hz, 2H, Ph-H), 7.29 (d, J = 9.5 Hz, 2H, Ph-H), 4.67 (d, J = 13.3 Hz, 2H, Pip-H), 3.55 (s, 1H, Pip-H), 3.00 (t, J = 12.7 Hz, 2H, Pip-H), 2.57 (s, 3H, -CH3), 2.27 (dd , J = 39.2, 10.1 Hz, 2H, Pip-H), 2.13 – 1.91 (m, 9H, 7-NA-H, 2- Pip-H), 1.83 – 1.59 (m, 8H, 7-NA-H) .

Example 9

According to the synthetic method of above-mentioned p-bromoaniline target compound (I), obtained:

4-Methyl-5-(4-bromophenyl)-2-(p-nitrobenzenesulfonylpiperidin-4-yl)thiazole white crystal, yield 95%;

¹ H NMR (500 MHz, Chloroform- d ) δ 7.67 (d, J = 8.1 Hz, 2H, Ph-H), 7.57 (d, J = 8.2 Hz, 2H, Ph-H), 7.36 (d, J = 8.0 Hz, 2H, Ph-H), 7.27 (d, J = 7.7Hz, 2H, Ph-H), 3.96 (dt, J = 12.0, 3.2 Hz, 2H, Pip-H), 3.06 (s, 1H, Pip-H), 2.67 – 2.53 (m, 2H, Pip-H), 2.47 (s, 3H, -CH3), 2.26 (d, J = 13.2 Hz, 2H, Pip-H), 1.97 (td, J = 11.7, 8.0 Hz, 2H, Pip-H).

Example 10

According to the synthetic method of above-mentioned p-bromoaniline target compound (I), obtained:

4-Methyl-5-(4-bromophenyl)-2-(p-trifluoromethylbenzoylpiperidin-4-yl)thiazole White crystal, yield 93%

¹ H NMR (500 MHz, Chloroform- d ) δ 8.47 – 8.37 (m, 2H, Ph-H), 8.03 – 7.94 (m, 2H, Ph-H), 7.43 (d, J = 8.2 Hz, 2H, Ph -H), 7.34 (d, J = 8.5 Hz, 2H, Ph-H), 3.97 (d, J = 11.4 Hz, 1H), 3.18 (s, 1H, Pip-H), 2.58 (t, J = 11.7 Hz, 2H Pip-H), 2.49 (s, 3H, -CH3), 2.29 (d, J = 12.9 Hz, 2H Pip-H), 1.96 (q, J =11.9, 11.5 Hz, 2H Pip-H).

(IV) Synthesis of 3-Chloroaniline Target Compound (I)

A) Synthesis of 1-(3-chlorophenyl)-2-propanone,

Add 3-chloroaniline (0.15mol) and concentrated hydrochloric acid to a 250ml three-necked flask equipped with mechanical stirring. Under the condition of 0°C, NaNO ₂ (0.15mol) was added dropwise with a constant pressure dropping funnel, the addition was completed, and the temperature was kept for 30min. , 40% HBF ₄ (0.19 mol) was added dropwise with a constant pressure dropping funnel at 0°C, kept for 3 h, filtered under reduced pressure to obtain diazonium fluoroborate, washed with glacial ethanol, and dried to remove water;

Add sodium acetate (0.25mol), isopropenyl acetate (0.80mol), cuprous oxide (0.02mol) to a 250ml four-neck flask equipped with mechanical stirring, and slowly add the dry diazonium fluoroborate in batches. In a four-necked flask, control the temperature at 35~40°C, react for 8 hours, remove the salt by suction filtration, wash the filter cake with petroleum ether, collect the filtrate, distill under reduced pressure, collect the fractions at 75~77°C, and obtain 1-(3-chlorine phenyl)-2-propanone;

B) Synthesis of 1-(3-chlorophenyl)-2-chloro-acetone,

Add 1-(3-chlorophenyl)-2-acetone and dichloromethane to a 50ml three-necked flask, use magnetic stirring, add sulfonyl chloride dropwise with a constant pressure dropping funnel, react for 2h, and adjust pH with saturated sodium bicarbonate solution = 8~9, extracted with dichloromethane, dried over anhydrous sodium sulfate, and rotary-evaporated to obtain 1-(3-chlorophenyl)-2-chloro-acetone;

C) Synthesis of N-boc-4-thioamide piperidine,

Add 70% NaSH (100g), NH ₄ Cl (100g), 1200ml DMF, N-boc-4-cyanopiperidine (86g) to a 2L four-necked flask with mechanical stirring, stir at room temperature for 72h, the reaction is complete Then, add 6L of ice water to a 10L beaker, slowly add the contents of the 2L four-necked flask to the ice water during stirring, and after stirring for 1h, a large amount of white solids appear, filter with suction, and extract the filtrate with 500ml×3 ethyl acetate , rotary steam, combined with filter cake and dried to obtain N-boc-4-thioamide piperidine;

D) Synthesis of 4-methyl-5-(3-chlorophenyl)-(N-boc-4-piperidin-4-yl)-2-thiazole,

Add 1-(3-chlorophenyl)-2-chloro-acetone and N-boc-4-thioamide piperidine, glacial acetic acid, and anhydrous sodium acetate to a 100ml three-necked flask, at 100°C, under the condition of magnetic stirring , reacted overnight, adjusted Ph=8~9 with saturated NaHCO3 aqueous solution, extracted with ethyl acetate 30ml x 3, and rotary evaporated to obtain the crude compound of formula (V) in gray-brown color, which was recrystallized to obtain 4-methyl-5-(3 -chlorophenyl)-(N-boc-4-piperidin-4-yl)-2-thiazole;

E) Synthesis of 4-methyl-5-(3-chlorophenyl)-2-(piperidine hydrochloride-4-yl)thiazole,

In a 100ml three-necked flask, add 4-methyl-5-(3-chlorophenyl)-(N-boc-4-piperidin-4-yl)-2-thiazole, 2NHCl dioxane solution, at room temperature The reaction was carried out for 4 h and filtered under reduced pressure to obtain white 4-methyl-5-(3-chlorophenyl)-2-(piperidine hydrochloride-4-yl)thiazole;

F) Synthesis of 4-methyl-5-(3-chlorophenyl)-(p-nitrobenzoylpiperidin-4-yl)-2-thiazole,

Add 0.100g 4-methyl-5-(3-chlorophenyl)-2-(piperidine hydrochloride-4-yl)thiazole, 0.1g triethylamine, 1ml dichloromethane, p-methyl into the sealed tube sulfonyl chloride, reacted for 2h, washed with water, washed with acid, extracted with 1 methylene chloride 10ml×3, and rotary evaporated to obtain the target compound 4-methyl-5-(3-methylphenyl)-2-(2-naphthoyl) Piperidin-4-yl) thiazole, other amide/sulfonamide compounds were prepared in the same way.

Example 11

According to the synthetic method of above-mentioned 3-chloroaniline target compound (I), obtained:

4-Methyl-5-(3-chlorophenyl)-2-(p-methylbenzenesulfonylpiperidin-4-yl)thiazole white crystal, yield 96%;

¹ H NMR (500 MHz, Chloroform- d ) δ 7.69 – 7.60 (m, 2H, Ph-H), 7.40 – 7.30 (m, 5H, Ph-H), 7.28 – 7.23 (m, 1H, Ph-H) , 3.88 (dt, J = 12.1, 3.3 Hz, 2H, Pip-H), 3.00 (td, J = 9.9, 8.1, 5.8 Hz, 1H, Pip-H), 2.52 – 2.36 (m, 8H, 6-CH3 , 2-Pip-H), 2.27 – 2.13 (m, 2H, Pip-H), 1.90 (qd, J = 12.1, 4.0 Hz, 2H, Pip-H).

Embodiment 1～11 bactericidal activity test:

1. Reagent: the piperidine thiazole compounds prepared in Examples 1 to 11;

2. Screening method

2.1 Screening targets: cucumber powdery mildew ( Sphaerotheca fuliginea ); cucumber downy mildew ( Pseudoperoniospora cubensis ); cucumber gray mold ( Botrytis cinerea ); rice sheath blight ( Rhizoctonia solani ).

2.2 Experimental method

With reference to the creation of the SOP (Fungicide Volume) for the evaluation of biological activity of pesticides, the living potted method was adopted;

The inoculation method is spore suspension inoculation and inoculation of mycelium block method, and the in vitro mycelium inhibition method is used for wheat scab.

Indoor living targets are shown in Table 1

Table 1 Screening results of bactericidal activity of compound (I)

The assay results (Table 1) showed that some compounds had a certain inhibitory effect on cucumber downy mildew and rice sheath blight, and some target compounds had a certain inhibitory effect on cucumber downy mildew at 200 mg/L, among which compound I-1. I-2, I-3 works better.

Finally, it should be noted that the above implementations are only used to illustrate the technical solutions of the present invention and not to limit the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should The solution can be modified or equivalently replaced without departing from the spirit and scope of the technical solution of the present invention, and it should be covered within the scope of the claims of the present invention.

Claims (10)

1. the application of a piperidinethiazole-containing compound in the preparation of a fungicide for preventing and treating cucumber powdery mildew, it is characterized in that the structural formula of the piperidinethiazole-containing compound is shown in formula (I);

In formula (I): R is 4-chloro, R ₁ is 4-nitrophenyl, and G is represented by formula (a2); Or R is 4-chloro, R ₁ is 3,4,5-trimethoxyphenyl, and G is represented by formula (a1); Or R is 3-methyl, R ₁ is 4-nitrophenyl, and G is represented by formula (a2); Or R is 3-methyl, R ₁ is 2-naphthyl, and G is represented by formula (a1); Or R is 3-methyl, R ₁ is 4-trifluoromethyl phenyl, and G is represented by formula (a1); Or R is 4-bromo, R ₁ is 2-naphthyl, and G is represented by formula (a1); Or R is 4-bromo, R ₁ is adamantyl, and G is represented by formula (a1); Or R is 4-bromo, R ₁ is 4-nitrophenyl, and G is represented by formula (a2);

. 2. The application of a piperidinethiazole-containing compound in the preparation of a fungicide for preventing and treating rice sheath blight, characterized in that the structural formula of the piperidinethiazole-containing compound is shown in formula (I);

In formula (I): R is 4-chloro, R ₁ is 2-naphthyl, and G is represented by formula (a1); Or R is 3-methyl, R ₁ is 2-naphthyl, and G is represented by formula (a1); Or R is 3-chloro, R ₁ is 4-methylphenyl, and G is represented by formula (a2);

. 3. a preparation method containing piperidine thiazole compounds, is characterized in that comprising the following steps: Step A: diazotization reaction occurs with the compound shown in formula (II) and sodium nitrite in concentrated hydrochloric acid solution, under -5～5 ℃ condition, add 40～50% fluoroboric acid, obtain fluoroboric acid diazonium salt , catalyzed by cuprous oxide, reacted with isopropenyl acetate in the presence of anhydrous sodium acetate, and distilled to obtain the compound shown in formula (III); Step B: compound (III) and sulfonyl chloride obtained in step A are added to methylene chloride, react at a temperature of 10~40 ° C, and after tracking detection to complete the reaction, the reaction solution is post-treated to obtain formula (IV) shown in compound of; Step C: dissolving N-boc-4-cyanopiperidine in dimethylformamide, adding sodium hydrosulfide and ammonium chloride, tracking and detecting to after complete hydrolysis, the reaction solution is obtained by post-processing formula (V). the compound shown; Step D: Dissolve the compound (IV) obtained in step B and the compound (V) obtained in step C in an organic solvent, add sodium acetate, react at 80~100 ° C, after the reaction is complete, adjust pH=3~8, extract , rotary evaporation to obtain the compound shown in formula (VI); Step E: The compound (VI) obtained in step D is acidly hydrolyzed in the solution, and after the complete acid hydrolysis is detected by tracking, the reaction solution is subjected to post-treatment to obtain the compound represented by the formula (VII); Step F: The compound (VII) obtained in the step E and the acid chloride or sulfonyl chloride are tracked and detected to complete the reaction under the condition that triethylamine is used as a base and dichloromethane is used as a solvent. Crystallization obtains the target product shown in formula (I); Its reaction equation is as follows:

; Wherein: R is 4-chloro, R ₁ is 2-naphthyl, and G is represented by formula (a1); Or R is 3-methyl, R ₁ is 2-naphthyl, and G is represented by formula (a1); Or R is 3-chloro, R ₁ is 4-methylphenyl, and G is represented by formula (a2);

. 4. the preparation method of containing piperidine thiazole compounds according to claim 3 is characterized in that in described step A, anhydrous sodium acetate: isopropenyl acetate: the amount ratio of cuprous oxide substance=1:3～3.5 : 0.01~0.05. 5. The preparation method of piperidine thiazole compounds according to claim 3, characterized in that in the step B, compound (III): methylene chloride: sulfonyl chloride substance amount ratio=1.0:2.0～4.0:1.0 ~1.2. 6. the preparation method containing piperidine thiazole compounds according to claim 3 is characterized in that in described step C, sodium hydrosulfide: ammonium chloride: the amount ratio of N-boc-4-cyano piperidine substance= 1.5~2.5: 1.5~2.5: 1.0. 7. the preparation method of containing piperidine thiazole compounds according to claim 3, is characterized in that in described step D, organic solvent is glacial acetic acid, 20～80% acetic acid methanol solution and 20～80% acetic acid ethanol solution. One; compound (IV): compound (V): sodium acetate substance ratio=1.0~1.1:1.0:2.0~2.5. 8. the preparation method containing piperidine thiazole compounds according to claim 3 is characterized in that described step E acidolysis reagent is the dioxane solution containing 20～40% hydrogen chloride or the dioxane solution containing 20～40% hydrogen chloride. ethyl acetate solution. 9. The preparation method of piperidine thiazole-containing compound according to claim 3, characterized in that in the step F, compound (VII): acid chloride or sulfonyl chloride: the substance amount ratio of triethylamine=1.0:0.9～ 1.0: 2.5~3.0, the recrystallization reagent is one or several mixtures of methanol, ethyl acetate and petroleum ether. 10. The preparation method of piperidinethiazole-containing compounds according to claim 3, wherein the organic solvent in the step D is glacial acetic acid.