CN107721997B

CN107721997B - Thiadiazole thiazolinone compound and preparation method and application thereof

Info

Publication number: CN107721997B
Application number: CN201710932057.9A
Authority: CN
Inventors: 甘春芳; 董新; 黄燕敏; 崔建国; 展军颜
Original assignee: Nanning Normal University
Priority date: 2017-10-10
Filing date: 2017-10-10
Publication date: 2020-09-22
Anticipated expiration: 2037-10-10
Also published as: CN107721997A

Abstract

The invention discloses a thiadiazole thiazolinone compound, which has a chemical structure shown as the following formula:

wherein the content of the first and second substances,

Description

Thiadiazole thiazolinone compound and preparation method and application thereof

Technical Field

The invention relates to the field of pesticide bactericides, in particular to a thiadiazole thiazolinone compound.

Background

In recent years, heterocyclic compounds generally have good biological activity and play an irreparable role in the creation and development processes of new pesticides. The 4-thiazolinone compounds are five-membered heterocyclic compounds containing nitrogen atoms and sulfur atoms, and the 4-thiazolinone compounds have better biological activities, such as biological activities of antibiosis, antiphlogosis, antitumor, antivirus and the like. Due to the good biological activity of the 4-thiazolinone compounds, the compounds have wide research and application values, are widely researched and applied in the fields of chemistry, medicines and pesticides, and are an indispensable part in the development and creation processes of new pesticides.

Thiazole rings are also an important structure in heterocyclic compounds, and are widely applied to the fields of pesticide research and plant protection. The 1,3, 4-thiadiazole derivative is also widely concerned about biological activities of weeding, sterilizing, killing insects, regulating plant growth and the like, and is a hot spot of green pesticide research. Thiazole pesticides reported at home and abroad, such as thiamethoxam and Fluensulfone, are emerging continuously; the bactericides ethaboxam, thifluzamide, probenazole and thiazole diclofop-methyl; the herbicide benthiavalicarb isopropyl and the herbicide safener metolachlor and the like.

The synthesis and biological activity research of diheterocyclic compounds has become an important direction of heterocyclic pesticides. Such as thiabendazole, the herbicides oxadiazon, pyrazosulfuron-ethyl, pyraflufen-ethyl, and the insecticide imidacloprid are all diheterocyclic pesticides which are used on the market. Bis-heterocyclic pesticides can increase their biological activity through the combined action of two heterocycles.

Disclosure of Invention

An object of the present invention is to solve at least the above problems and to provide at least the advantages described later.

It is still another object of the present invention to provide a thiadiazole-type thiazolinone compound.

Another object of the present invention is to provide a process for the preparation of the above compounds.

It is a further object of the present invention to provide the use of the above compounds in fungicides and insecticides.

To achieve these objects and other advantages in accordance with the present invention, there is provided a thiadiazole-thiazolinone compound characterized in that its chemical structure is as shown in the following formula:

wherein the content of the first and second substances,

preferably, the preparation method comprises the steps of taking thiosemicarbazide as a raw material, dehydrating and cyclizing the thiosemicarbazide with formic acid under the catalysis of concentrated sulfuric acid to synthesize a first intermediate product, then synthesizing a second intermediate product with chloroacetyl chloride, cyclizing the second intermediate product with thiocyanamide to synthesize a third intermediate product, and finally reacting the third compound with R1 through Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound, wherein,

the first intermediate product is 2-amino-1, 3, 4-thiadiazole, and the structural formula is as follows:

the second intermediate product is 2-chloroacetamido-1, 3, 4-thiadiazole-2-acetimide, and the structural formula is as follows:

the third intermediate product is 2- (1,3, 4-thiadiazole-2-imino) -4-thiazolinone, and the structural formula is as follows:

preferably, the preparation of the first intermediate product by using thiosemicarbazide as a raw material specifically comprises the following steps: weighing 4.98-5.08 g of thiosemicarbazide, adding 2.7-3.3 mL of formic acid into a round two-neck flask, stirring at room temperature to form slurry, dropwise adding 5.6-6.4 mL of concentrated hydrochloric acid into the round two-neck flask by using a constant-pressure separating funnel, continuously stirring uniformly, transferring the round two-neck flask to an oil bath heating magnetic stirrer, reacting at 105-115 ℃ for 4-5 h, detecting by TLC (thin layer chromatography) until no raw material is present, stopping the reaction, cooling to room temperature to obtain a cooling liquid, pouring the cooling liquid into ice water, adjusting the pH of the system to 7-8 by using concentrated ammonia water in the ice water, standing at low temperature for at least 12h, and performing suction filtration and washing on separated white powder to obtain a first intermediate product, wherein detection tracking reagents used by TLC are dichloromethane and methanol, and the volume ratio of the detection tracking reagents is 10: 1;

the synthesis of the second intermediate product with chloroacetyl chloride specifically comprises: weighing 0.95-1.05 g of a first intermediate product, adding the first intermediate product into a round two-necked flask, adding 20-30 mL of redistilled dimethylformamide, adding 1.5-1.65 mL of dried triethylamine after the first intermediate product is completely dissolved, transferring to an ice bath condition, measuring 1-1.2 mL of chloroacetyl chloride, dropwise adding the chloroacetyl chloride into the reaction by using a constant-pressure dropping funnel, finishing dropping for 25-35 min, stirring at room temperature and normal pressure for reaction for 3.5-4.5 h, detecting by TLC until no raw material exists, stopping the reaction, pouring a reaction mixture into 48-52 mL of ice water, sealing a preservative film, standing at 2-4 ℃ for at least 12h, performing suction filtration, washing and drying to obtain a second intermediate product, wherein detection tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection tracking reagents is 10:1, and the washing is performed by using 30mL of distilled water for 3 times;

the cyclization synthesis of the third intermediate product under the action of ammonium thiocyanate specifically comprises the following steps: weighing 0.15-0.25 g of a second intermediate product, adding the second intermediate product into a round two-neck flask, adding 22-26 mL of redistilled dimethylformamide until the second intermediate product is completely dissolved, weighing 0.08-0.18 g of ammonium thiocyanate, adding the ammonium thiocyanate into the round two-neck flask, reacting for 3.5-4.5 h under an oil bath at 75-85 ℃, detecting and tracking by TLC until no raw material point exists, stopping the reaction, pouring a reaction mixture into 26-34 g of crushed ice, sealing a preservative film, standing for at least 12h at 2-4 ℃, performing suction filtration, washing and drying to obtain a third intermediate product, wherein detection and tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection and tracking reagents is 10:1, and the third intermediate product is washed by distilled water with 10mL in total for 3 times during washing.

Preferably, the step of reacting the third intermediate product with 4-cyanobenzaldehyde by Knoevenagle condensation reaction to obtain thiadiazole thiazolinone compounds specifically comprises: weighing 0.06-0.16 g of a third intermediate product, 0.11-0.21 g of 4-cyanobenzaldehyde and 0.13-0.23 g of anhydrous sodium acetate, adding the third intermediate product into a round two-neck flask, adding 2-4 mL of acetic anhydride and 3-5 mL of glacial acetic acid, stirring the mixture under the condition of an oil bath at 100-110 ℃ until the mixture is completely dissolved, continuing to react for 5.5-6.5 hours, detecting and tracking the reaction by TLC until a raw material point disappears, stopping the reaction, cooling the reaction product to room temperature, pouring the reaction product into 45-55 mL of ice water, sealing a preservative film, standing the reaction product in a refrigerator at 2-4 ℃ for at least 12 hours, and performing suction filtration, washing and drying to obtain a first compound, wherein detection and tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection and tracking reagents is 10:1, washing the first compound by using distilled water accounting for 3 times and washing by methanol accounting for 30mL, and washing the first compound by adopting a structural formula for 3:

wherein the content of the first and second substances,

preferably, the step of reacting the third intermediate product with 3-hydroxybenzaldehyde by Knoevenagle condensation reaction to obtain thiadiazole thiazolinone compounds specifically comprises: weighing 0.15-0.25 g of the third intermediate product, 0.19-0.29 g of 3-hydroxybenzaldehyde and 0.28-0.38 g of anhydrous sodium acetate, adding into a round-bottom flask, then adding 5-7 mL of acetic anhydride and 7-9 mL of glacial acetic acid, stirring under the condition of 100-110 ℃ oil bath until the acetic anhydride and the glacial acetic acid are completely dissolved, continuing to react for 5.5-6.5 h, detecting and tracking the reaction by TLC until no raw material is obtained, stopping the reaction, cooling to room temperature, then pouring the reaction mixture into 45-55 mL of ice water, sealing a preservative film, standing for at least 12h at the temperature of 2-4 ℃, carrying out suction filtration, washing and drying to obtain a second compound, wherein, detection tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection tracking reagents is 10:1, the detection tracking reagents are washed by distilled water with the total volume of 30mL for 3 times and then by methanol with the total volume of 30mL for 3 times, and the chemical structural formula of the second compound is as follows:

wherein the content of the first and second substances,

preferably, the step of reacting the third intermediate product with 4-fluorobenzaldehyde by Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound specifically comprises the following steps: weighing 0.15-0.25 g of the third intermediate product and 0.31-0.41 g of anhydrous sodium acetate, weighing 233-237 mu L of 4-fluorobenzaldehyde, adding into a round two-neck flask, then adding 5-7 mL of acetic anhydride and 7-9 mL of glacial acetic acid, stirring under the condition of 100-110 ℃ oil bath until the acetic anhydride and the glacial acetic acid are completely dissolved, continuing to react for 5.5-6.5 h, detecting and tracking the reaction by TLC until no raw material is obtained, stopping the reaction, cooling to room temperature, then pouring the reaction mixture into 45-55 mL of ice water, sealing a preservative film, standing for at least 12h at the temperature of 2-4 ℃, carrying out suction filtration, washing and drying to obtain a third compound, wherein, detection tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection tracking reagents is 10:1, the detection tracking reagents are washed by distilled water with the total volume of 30mL for 3 times and then by methanol with the total volume of 30mL for 3 times, and the chemical structural formula of the third compound is as follows:

wherein,

Preferably, the step of reacting the third intermediate product with p-chlorobenzaldehyde by Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound specifically comprises the following steps: weighing 0.16-0.26 g of third intermediate product, 0.20-0.30 g of p-chlorobenzaldehyde and 0.28-0.39 g of anhydrous sodium acetate, adding the third intermediate product into a round two-neck flask, adding 5-7 mL of acetic anhydride and 7-9 mL of glacial acetic acid, stirring the mixture under the condition of 100-110 ℃ oil bath until the mixture is completely dissolved, continuing to react for 5.5-6.5 h, detecting and tracking the reaction by TLC until no raw material point exists, stopping the reaction, cooling the reaction mixture to room temperature, then pouring the reaction mixture into 45-55 mL of ice water, standing the reaction mixture for at least 12h at 2-4 ℃, and obtaining a fourth compound through suction filtration, washing and drying, wherein detection and tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection and tracking reagents is 10:1, the third intermediate product is washed by 3 times by 30mL of distilled water and then by 3 times by 30mL of methanol, and the fourth compound has the following chemical formula:

wherein the content of the first and second substances,

preferably, the step of reacting the third intermediate product with 2, 5-dihydroxybenzaldehyde by Knoevenagle condensation reaction to obtain thiadiazole thiazolinone compounds specifically comprises: weighing 0.25-0.35 g of a third intermediate product, 0.27-0.38 g of 2, 5-dihydroxybenzaldehyde and 0.30-0.41 g of anhydrous sodium acetate, adding the anhydrous sodium acetate into a round two-neck flask, then adding 5-7 mL of acetic anhydride and 7-9 mL of glacial acetic acid, stirring the mixture under the condition of an oil bath at 100-110 ℃ until the mixture is completely dissolved, continuing to react for 5.5-6.5 h, detecting and tracking the reaction by TLC until no raw material exists, stopping the reaction, cooling the mixture to room temperature, then pouring the reaction mixture into 45-55 mL of ice water, standing the mixture for at least 12h at 2-4 ℃, and performing suction filtration, washing and drying to obtain a fifth compound, wherein detection and tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection and tracking reagents is 10:1, the third intermediate product is washed by distilled water accounting for 3 times and then by methanol accounting for 30mL, and the structural formula of the fifth compound is as follows:

wherein the content of the first and second substances,

preferably, the step of reacting the third intermediate product with 4-dimethylaminobenzaldehyde by Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound specifically comprises the following steps: weighing 0.15-0.25 g of the third intermediate product, 0.25-0.35 g of 4-dimethylaminobenzaldehyde and 0.28-0.38 g of anhydrous sodium acetate, adding into a round two-neck flask, then adding 5-7 mL of acetic anhydride and 7-9 mL of glacial acetic acid, stirring under the condition of 100-110 ℃ oil bath until the acetic anhydride and the glacial acetic acid are completely dissolved, continuing to react for 5.5-6.5 h, detecting and tracking the reaction by TLC until no raw material is obtained, stopping the reaction, cooling to room temperature, then pouring the reaction mixture into 45-55 mL of ice water, sealing a preservative film, standing for at least 12h at the temperature of 2-4 ℃, performing suction filtration, washing and drying to obtain a sixth compound, wherein, detection tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection tracking reagents is 10:1, the detection tracking reagents are washed by distilled water with the total volume of 30mL for 3 times and then by methanol with the total volume of 30mL for 3 times, and the chemical structural formula of the sixth compound is as follows:

wherein the content of the first and second substances,

preferably, the thiadiazole thiazolinone compound is applied to agricultural fungicides.

Preferably, the thiadiazole thiazolinone compound is applied to pesticides.

The invention can at least achieve the following beneficial effects:

according to the invention, by utilizing the active structure splicing principle, 1,3, 4-thiadiazole and 4-thiazolinone are structurally spliced to synthesize a diheterocyclic compound with a thiazolylo and thiazolinone, so that the diheterocyclic pesticide derivative with excellent activity is obtained, and a new green pesticide variety with high activity, low toxicity and less pollution is screened out.

The invention records six specific thiadiazole thiazolinone compounds, the preparation method has the advantages of few steps, simple operation, saving a large amount of time and cost in actual production and good economic benefit. The data show that the phenyl substituted thiadiazole thiazolinone compound has good inhibition effect on the growth and proliferation of early blight of tomato, rice blast and the like, and can be used as a pesticide intermediate for the preparation and application of different agricultural bactericides. Meanwhile, the compound can also be used as an insecticide applied to the planting of rice, rape and the like.

Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.

Detailed Description

The present invention is further described in detail below with reference to examples so that those skilled in the art can practice the invention with reference to the description.

It is to be noted that the experimental methods described in the following embodiments are all conventional methods unless otherwise specified, and the reagents and materials are commercially available unless otherwise specified.

< example 1>

The preparation method of the first intermediate product by taking the thiosemicarbazide as the raw material specifically comprises the following steps: weighing 4.98g of thiosemicarbazide, adding into a round two-neck flask, adding 2.7mL of formic acid, stirring at room temperature to be slurry, dropwise adding 5.6mL of concentrated hydrochloric acid into the round two-neck flask by using a constant-pressure separating funnel, continuously stirring uniformly, transferring the round two-neck flask to an oil bath heating magnetic stirrer, reacting for 4 hours at 105 ℃, detecting by TLC (thin layer chromatography) until no raw material point exists, stopping the reaction, cooling to room temperature to obtain a cooling liquid, and coolingPouring the solution into ice water, adjusting the pH of the system to 7-8 in the ice water by using concentrated ammonia water, standing at low temperature for at least 12 hours, and performing suction filtration and washing on separated white powder to obtain a first intermediate product, wherein detection tracking reagents used by TLC are dichloromethane and methanol in a volume ratio of 10:1, namely V_{Methylene dichloride}:V_Methanol＝10:1；

The first intermediate product is 2-amino-1, 3, 4-thiadiazole which is a colorless transparent massive crystal and has the following structural formula:

step two, synthesizing a second intermediate product with chloroacetyl chloride specifically comprises the following steps: weighing 0.95g of a first intermediate product, adding the first intermediate product into a round two-neck flask, adding 20mL of dimethylformamide subjected to redistillation treatment, after the first intermediate product is completely dissolved, adding 1.5mL of dried triethylamine, moving to an ice bath condition, measuring 1mL of chloroacetyl chloride, dropwise adding the chloroacetyl chloride into the reaction by using a constant-pressure dropping funnel, finishing dropping for 25min, stirring and reacting at room temperature and normal pressure for 3.5h, stopping the reaction when TLC detection reaction is finished until no raw material point exists, pouring the reaction mixture into 48mL of ice water, sealing a preservative film, standing at 2-4 ℃ for at least 12h, and performing suction filtration, washing and drying to obtain a second intermediate product, wherein detection tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection tracking reagents is 10:1, and the second intermediate product is washed by using distilled water accounting for 30mL for 3 times during washing;

the second intermediate product is 2-chloroacetamido-1, 3, 4-thiadiazole-2-acetimide which is white powder and has the following structural formula:

step three, the cyclizing synthesis of the third intermediate product under the action of the thiocyanate amine specifically comprises the following steps: weighing 0.15g of second intermediate product, adding the second intermediate product into a round two-neck flask, adding 22mL of redistilled dimethylformamide until the second intermediate product is completely dissolved, then weighing 0.08g of ammonium thiocyanate, adding the ammonium thiocyanate into the round two-neck flask, reacting for 3.5h under a 75 ℃ oil bath, detecting and tracking by TLC until no raw material point exists, stopping the reaction, pouring the reaction mixture into 26g of crushed ice, sealing a preservative film, standing for at least 12h at 2-4 ℃, and performing suction filtration, washing and drying to obtain a third intermediate product, wherein detection and tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection and tracking reagents is 10:1, and the third intermediate product is washed by distilled water accounting for 10mL in total for 3 times during washing.

The third intermediate product is 2- (1,3, 4-thiadiazole-2-imino) -4-thiazolinone, which is white powder and has the following structural formula:

step four, reacting the third intermediate product with 4-cyanobenzaldehyde through Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound, which specifically comprises the following steps: weighing 0.06g of third intermediate product, 0.11g of 4-cyanobenzaldehyde and 0.13g of anhydrous sodium acetate, adding the third intermediate product into a round two-neck flask, adding 2mL of acetic anhydride and 3mL of glacial acetic acid, stirring the mixture under the condition of 100 ℃ oil bath until the mixture is completely dissolved, continuing to react for 5.5 hours, detecting and tracking the reaction by TLC until the raw material point disappears, stopping the reaction, cooling the reaction to room temperature, pouring the reaction product into 45mL of ice water, sealing a preservative film, standing the reaction product in a refrigerator at 2-4 ℃ for at least 12 hours, and performing suction filtration, washing and drying to obtain a first compound, wherein detection and tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection and tracking reagents is 10:1, the detection and tracking reagents used by TLC are washed by 3 times with 30mL of distilled water and then washed by 3 times with 30mL of methanol, and the chemical structural formula:

wherein the content of the first and second substances,

< example 2>

The first step, the second step and the third step are the same as those in the example 1, and the dosage and experimental parameters of all the substances are also the same, except that:

step four, reacting the third intermediate product with 3-hydroxybenzaldehyde through Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound, which specifically comprises the following steps: weighing 0.15g of third intermediate product, 0.19g of 3-hydroxybenzaldehyde and 0.28g of anhydrous sodium acetate, adding the third intermediate product into a round-bottom flask, adding 5mL of acetic anhydride and 7mL of glacial acetic acid, stirring the mixture at 100 ℃ in an oil bath until the mixture is completely dissolved, continuing to react for 5.5h, detecting and tracking TLC (thin layer chromatography) until no raw material point exists, stopping the reaction, cooling the mixture to room temperature, pouring the reaction mixture into 45mL of ice water, sealing a preservative film, standing the mixture at 2-4 ℃ for at least 12h, and performing suction filtration, washing and drying to obtain a second compound, wherein detection and tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection and tracking reagents is 10:1, the third intermediate product is washed by 3 times of distilled water accounting for 30mL, and then washed by 3 times of methanol accounting for 30mL, and the chemical structural formula of the second compound is as follows:

wherein the content of the first and second substances,

< example 3>

step four, reacting the third intermediate product with 4-fluorobenzaldehyde through Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound, which specifically comprises the following steps: weighing 0.15g of a third intermediate product and 0.31g of anhydrous sodium acetate, weighing 233 mu L of 4-fluorobenzaldehyde, adding into a round two-necked flask, adding 5mL of acetic anhydride and 7mL of glacial acetic acid, stirring at 100 ℃ in an oil bath until the mixture is completely dissolved, continuing to react for 5.5h, detecting and tracking by TLC until no raw material point exists, stopping the reaction, cooling to room temperature, pouring the reaction mixture into 45mL of glacial water, standing at 2-4 ℃ for at least 12h, performing suction filtration, washing and drying to obtain a third compound, wherein detection and tracking reagents used by TLC are dichloromethane and methanol in a volume ratio of 10:1, washing by using 30mL of distilled water for 3 times, and then washing by using 30mL of methanol for 3 times, and the third compound has the following chemical structural formula:

wherein,

< example 4>

step four, reacting the third intermediate product with p-chlorobenzaldehyde through Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound, which specifically comprises the following steps: weighing 0.16g of a third intermediate product, 0.20g of p-chlorobenzaldehyde and 0.28g of anhydrous sodium acetate, adding the third intermediate product into a round two-necked flask, adding 5mL of acetic anhydride and 7mL of glacial acetic acid, stirring the mixture under the condition of 100 ℃ oil bath until the mixture is completely dissolved, continuing to react for 5.5h, detecting and tracking by TLC (thin layer chromatography) until no raw material point exists, stopping the reaction, cooling the mixture to room temperature, pouring the reaction mixture into 45mL of glacial water, sealing a preservative film, standing the mixture for at least 12h at 2-4 ℃, and performing suction filtration, washing and drying to obtain a fourth compound, wherein detection and tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection and tracking reagents is 10:1, the third intermediate product is washed by 3 times of distilled water accounting for 30mL in total during washing, and then washed by 3 times of methanol accounting for 30mL in total, and the chemical structural formula of the:

wherein the content of the first and second substances,

< example 5>

step four, reacting the third intermediate product with 2, 5-dihydroxybenzaldehyde through Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound, which specifically comprises the following steps: weighing 0.25g of a third intermediate product, 0.27g of 2, 5-dihydroxybenzaldehyde and 0.30g of anhydrous sodium acetate, adding the third intermediate product into a round two-necked flask, adding 5mL of acetic anhydride and 7mL of glacial acetic acid, stirring the mixture under the condition of 100 ℃ oil bath until the mixture is completely dissolved, continuing to react for 5.5h, detecting and tracking the reaction by TLC until no raw material point exists, stopping the reaction, cooling the mixture to room temperature, pouring the reaction mixture into 45mL of glacial water, standing the mixture for at least 12h at the temperature of 2-4 ℃, and performing suction filtration, washing and drying to obtain a fifth compound, wherein detection and tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection and tracking reagents is 10:1, the detection and tracking reagents used by TLC are washed by 3 times of distilled water accounting for 30mL, and then washed by 3 times of methanol accounting for 30mL, and the chemical structural formula of:

wherein the content of the first and second substances,

< example 6>

step four, reacting the third intermediate product with 4-dimethylaminobenzaldehyde through Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound, which specifically comprises the following steps: weighing 0.15g of a third intermediate product, 0.25g of 4-dimethylaminobenzaldehyde and 0.28g of anhydrous sodium acetate, adding the third intermediate product into a round two-necked flask, adding 5mL of acetic anhydride and 7mL of glacial acetic acid, stirring the mixture under the condition of 100-110 ℃ oil bath until the mixture is completely dissolved, continuing to react for 5.5h, detecting and tracking the reaction by TLC until no raw material point exists, stopping the reaction, cooling the mixture to room temperature, pouring the reaction mixture into 45mL of glacial water, standing the mixture for at least 12h at the temperature of 2-4 ℃, and performing suction filtration, washing and drying to obtain a sixth compound, wherein detection and tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection and tracking reagents is 10:1, the detection and tracking reagents used by TLC are washed by 3 times of distilled water accounting for 30mL, and then washed by 3 times of methanol accounting for 30mL, and the chemical structural formula of:

wherein the content of the first and second substances,

< example 7>

The preparation method of the first intermediate product by taking the thiosemicarbazide as the raw material specifically comprises the following steps: weighing 5.028g (55.17mmol) of white flaky thiosemicarbazide, adding 3mL (74.30mmol) of formic acid into a 50mL round two-neck flask, stirring the mixture at room temperature to form a slurry, then dropwise adding 6mL of concentrated hydrochloric acid into the round two-neck flask by using a constant-pressure separating funnel, continuously stirring the mixture uniformly, moving the round two-neck flask to an oil bath heating magnetic stirrer, reacting the mixture at 110 ℃ for 4 to 5 hours, detecting the reaction by TLC until no raw material point exists, stopping the reaction, cooling the reaction to room temperature to obtain a cooling liquid, pouring the cooling liquid into ice water, adjusting the pH of the system to 7 to 8 by using concentrated ammonia water in the ice water, standing the system at low temperature for at least 12 hours, performing suction filtration and washing on white powder separated out at a price to obtain a first intermediate product, wherein detection tracking reagents used by TLC are dichloromethane and methanol, and the volume ratio of the detection tracking reagents is 10:1, namely V_{Methylene dichloride}:V_Methanol＝10:1；

the mass of the first intermediate product was 4.286g, yield: 76.82%, the structural characterization data is as follows:

IR(KBr)ν/cm-1:3284,3102,1619,1504,1018,682；1H NMR(300MHz,DMSO-d6):7.20(2H，s，-NH2),8.56(1H，s，N＝CH-S)；13C NMR(75MHz,DMSO-d6):143.07(2-C),168.73(4-C)；HR-EI-MS m/z:102.0122[M+H]+，(calcd for C2H4N3S,102.0126)。

step two, synthesizing a second intermediate product with chloroacetyl chloride specifically comprises the following steps: weighing 1.001g (9.898mmol) of first intermediate product, adding the first intermediate product into a 100mL round two-necked flask, adding 25mL of dimethylformamide subjected to redistillation treatment, adding 1.645mL (11.878mmol) of dried triethylamine after the first intermediate product is completely dissolved, transferring the mixture to an ice bath condition, measuring 1.12mL (14.875mmol) of chloroacetyl chloride, dropwise adding the chloroacetyl chloride into the reaction by using a constant-pressure dropping funnel, stirring the mixture at room temperature and normal pressure for reaction for 4 hours, detecting the reaction by TLC until no raw material point exists, stopping the reaction, pouring the reaction mixture into 50mL of ice water, sealing a preservative film, standing the mixture at the temperature of 2-4 ℃ for at least 12 hours, and performing suction filtration, washing and drying to obtain a second intermediate product, wherein detection tracking reagents used by TLC are dichloromethane and methanol, and the volume ratio of the detection tracking reagents is 10:1, namely V_{Methylene dichloride}:V_MethanolWashing with distilled water of 30mL in total for 3 times (10: 1);

the mass of the second intermediate product was 1.212g, yield: 69.18%, the structural characterization data is as follows:

IR(KBr)ν/cm^-1:3409,3104,3070,2992,2935,2895,2818,2718,2222,1741,1711,1591, 1447,1220,1167,1135,1055,1015,908,858.¹H NMR(300MHz,DMSO-d₆):12.95(s,1H, -NH-),9.22(s,1H,N＝CH-S),4.46(s,2H,CO-CH₂-Cl).¹³C NMR(75MHz, DMSO-d₆):170.86,163.81,154.40,47.80.HR-EI-MS m/z:177.9838[M+H]⁺(calcd for C₄H₆ClN₃OS,177.9842).

step threeThe cyclization synthesis of the third intermediate product under the action of ammonium thiocyanate specifically comprises the following steps: weighing 0.203g (1.147mmol) of second intermediate product, adding the second intermediate product into a 100mL round two-neck flask, adding 25mL redistilled dimethylformamide until the second intermediate product is completely dissolved, then weighing 0.131g (1.721mmol) of ammonium thiocyanate, adding the ammonium thiocyanate into the round two-neck flask, reacting for 4 hours under an oil bath at 80 ℃, detecting and tracking by TLC until no raw material point exists, stopping the reaction, pouring the reaction mixture into 30g of crushed ice, sealing a preservative film, standing for at least 12 hours at 2-4 ℃, and performing suction filtration, washing and drying to obtain a third intermediate product, wherein detection and tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection and tracking reagents is 10:1, namely V_{Methylene dichloride}：V_MethanolWhen washing was carried out, 3 times of washing was carried out with a total of 10mL of distilled water.

mass of the third intermediate product was 0.187g, yield: 81.66%, the structural characterization data is as follows:

m.p.：194-195℃，IR(KBr)/cm^-1:3409,3104,2718,2222,1711,1591,1454,1447,1407, 1285,1167,1135,1015,908,818；¹H NMR(300MHz,DMSO-d₆):12.30(s,1H,-NH-),9.30 (s,1H,N＝CH-S),4.10(s,2H,CO-CH₂-S).¹³C NMR(75MHz,DMSO-d₆):174.55,170.72,166.45,151.64,36.02.HR-EI-MS m/z:200.9906[M+H]⁺(calcd for C₅H₅N₄OS₂,200.9905).

step four, reacting the third intermediate product with 4-cyanobenzaldehyde through Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound, which specifically comprises the following steps: 0.110g (0.550mmol) of the third intermediate, 0.155g (1.182mmol) of 4-cyanobenzaldehyde, 0.182g (2.219mmol) of anhydrous sodium acetate were weighed into a 100mL round two-necked flask, 3mL of acetic anhydride and 4mL of glacial acetic acid were added thereto, and the reaction was continued for 6 hours while stirring in an oil bath at 105 ℃ until complete dissolution was achievedPerforming TLC detection tracking reaction until the raw material point disappears, stopping the reaction, cooling to room temperature, pouring the reactant into 50mL of ice water, sealing a preservative film, placing the mixture in a refrigerator at 2-4 ℃ for standing for at least 12h, performing suction filtration, washing and drying to obtain a first compound, wherein detection tracking reagents used by TLC are dichloromethane and methanol in a volume ratio of 10:1, namely V_{Methylene dichloride}：V_MethanolWhen washing is carried out, 3 times of washing is carried out by using distilled water with the total volume of 30mL, and then 3 times of washing is carried out by using methanol with the total volume of 30mL, wherein the chemical structural formula of the first compound is as follows:

wherein the content of the first and second substances,

the first compound was a white powder with a mass of 0.065g, yield: 35.91%, the structural characterization data is as follows:

m.p.：m.p.：250-252℃；IR(KBr)ν/cm^-1:3411,3124,2918,2820,1713,1581,1486,1399,1267,1088,1008,846；¹H NMR(300MHz,DMSO-d₆)：9.37(s,1H,N＝CH-S), 7.80(s,H,NH),7.82(s,1H,HC＝C),7.82-8.02(m,4H,Ph-H).¹³C NMR(75MHz,DMSO -d₆):169.54,167.18,158.77,151.75,135.35,132.24,130.98,127.57,125.57,124.89,1 23.60.

< example 8>

The first, second and third steps are the same as those in example 7, and the amounts and experimental parameters of the respective substances are also the same, except that:

step four, reacting the third intermediate product with 3-hydroxybenzaldehyde through Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound, which specifically comprises the following steps: 0.200g (1.000mmol) of the third intermediate, 0.244g (1.998mmol) of 3-hydroxybenzaldehyde and 0.328g (3.999mmol) of anhydrous sodium acetate are weighed into a 100mL round-bottomed flask, 6mL of acetic anhydride and 7mL of glacial acetic acid are added, the mixture is stirred in an oil bath at 105 ℃ until the mixture is completely dissolved, the reaction is continued for 6h, and the reaction is followed by TLC detectionStopping the reaction until no raw material exists, cooling to room temperature, pouring the reaction mixture into 50mL of ice water, sealing a preservative film, standing at 2-4 ℃ for at least 12h, performing suction filtration, washing and drying to obtain a second compound, wherein detection tracking reagents used by TLC are dichloromethane and methanol in a volume ratio of 10:1, namely V_{Methylene dichloride}：V_MethanolWhen washing is carried out, 3 times of washing are carried out by using distilled water with the total volume of 30mL, and then 3 times of washing are carried out by using methanol with the total volume of 30mL, wherein the chemical structural formula of the second compound is as follows:

wherein the content of the first and second substances,

the second compound was 0.121g of white powder, yield: 37.81%, the structural characterization data is as follows:

m.p.：174-175℃；IR(KBr)ν/cm^-1:3434,3124,3082,2962,2915,2828,1761,1713,1576, 1481,1242,1030,1013,903,813,729,659；¹H NMR(300MHz,DMSO-d₆):9.83(s,1H, N＝CH-S),7.99(s,1H,),7.60-7.69(m,2H,Ph-H),7.49(m,1H,Ph-H),7.32-7.36(m,1H, ＝CH-Ph).¹³C NMR(75MHz,DMSO-d₆):183.64,172.52,164.18,137.67,133.66,133.54,131.45,130.99,125.08,119.08,113.05,112.43.

< example 9>

step four, reacting the third intermediate product with 4-fluorobenzaldehyde through Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound, which specifically comprises the following steps: weighing 0.201g (1.005mmol) of the third intermediate product and 0.328g (3.999mmol) of anhydrous sodium acetate, measuring 215 mu L (2.004mmol) of 4-fluorobenzaldehyde, adding into a 100mL round-bottom flask, adding 6mL of acetic anhydride and 8mL of glacial acetic acid, stirring at 105 ℃ in an oil bath until the mixture is completely dissolved, continuing to react for 6h, and detecting by TLCDetecting and tracking the reaction until no raw material point exists, stopping the reaction, cooling to room temperature, then pouring the reaction mixture into 50mL of ice water, sealing a preservative film, standing for at least 12h at the temperature of 2-4 ℃, and performing suction filtration, washing and drying to obtain a third compound, wherein detection and tracking reagents used by TLC are dichloromethane and methanol in a volume ratio of 10:1, namely V_{Methylene dichloride}：V_MethanolWhen washing is carried out, 3 times of washing are carried out by using distilled water with the total volume of 30mL, and then 3 times of washing are carried out by using methanol with the total volume of 30mL, wherein the chemical structural formula of the third compound is as follows:

wherein,

The third compound was a tan powder with a mass of 0.19g, yield: 59.94%, the structural characterization data is as follows:

m.p.：182-184℃。IR(KBr)ν/cm^-1:3411,3124,2918,2820,1713,1581,1486,1447,1399, 1329,1202,1162,1088,1053,1008,881,726,517；¹H NMR(300MHz,DMSO-d₆):9.84(s, 1H,N＝CH-S),8.03(s,1H,＝CH-Ph),7.83(dd,J＝9.0,6.0Hz,2H,Ph-H),7.48(t,J＝18,9.0 Hz,2H,Ph-H).¹³C NMR(75MHz,DMSO-d₆):183.57,164.41,163.43,162.08,159.06,156.81，133.81,133.69,130.09,117.41,117.12.

< example 10>

step four, reacting the third intermediate product with p-chlorobenzaldehyde through Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound, which specifically comprises the following steps: 0.208g (1.040mmo) of the third intermediate, 0.25g (2.047mmol) of p-chlorobenzaldehyde and 0.337g (4.108mmol) of anhydrous sodium acetate were weighed into a 100mL round-bottomed flask, and 6mL of acetic anhydride and 8mL of glacial acetic acid were added thereto, and stirred in an oil bath at 105 ℃ until completely dissolvedPerforming hydrolysis, continuing to react for 6 hours, detecting and tracking the reaction by TLC (thin layer chromatography) until no raw material point exists, stopping the reaction, cooling to room temperature, pouring the reaction mixture into 50mL of ice water, sealing a preservative film, standing for at least 12 hours at the temperature of 2-4 ℃, performing suction filtration, washing and drying to obtain a fourth compound, wherein detection and tracking reagents used by TLC are dichloromethane and methanol in a volume ratio of 10:1, namely V_{Methylene dichloride}：V_MethanolWhen washing is carried out, 3 times of washing are carried out by using distilled water with the total volume of 30mL, and then 3 times of washing are carried out by using methanol with the total volume of 30mL, wherein the chemical structural formula of the fourth compound is as follows:

wherein the content of the first and second substances,

the fourth compound was a white powder with a mass of 0.15g, yield: 43.52%, the structural characterization data is as follows:

m.p.：242-243℃。IR(KBr)ν/cm^-1:3424,3129,3082,2962,2915,1716,1579,1449,1397, 1332,1267,1212,1053,921,818,763；¹H NMR(300MHz,DMSO-d₆):9.84(s,1H,N＝CH-S), 8.00(s,1H,＝CH-Ph),7.76(m,2H,Ph-H),7.70(s,1H,Ph-H),7.62-7.64(m,2H,Ph-H).¹³C NMR(75MHz,DMSO-d₆):183.57,164.35,163.31,159.11,156.77,136.24,135.07,132.79, 130.11,129.84,122.16.

< example 11>

step four, reacting the third intermediate product with 2, 5-dihydroxybenzaldehyde through Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound, which specifically comprises the following steps: 0.202g (1.010mmol) of the third intermediate, 0.277g (1.513mmol) of 2, 5-dihydroxybenzaldehyde and 0.329g (4.011mmol) of anhydrous sodium acetate were weighed into a 100mL round two-necked flask, and 6mL of acetic anhydride, 8mL of glacial acetic acid and 105 ℃ oil were addedStirring the mixture under a bath condition until the mixture is completely dissolved, continuously reacting for 6 hours, detecting and tracking the reaction by TLC (thin layer chromatography) until no raw material point exists, stopping the reaction, cooling the reaction mixture to room temperature, pouring the reaction mixture into 50mL of ice water, sealing a preservative film, standing the reaction mixture at the temperature of 2-4 ℃ for at least 12 hours, and performing suction filtration, washing and drying to obtain a fifth compound, wherein detection and tracking reagents used by TLC are dichloromethane and methanol in a volume ratio of 10:1, namely V_{Methylene dichloride}：V_MethanolWhen washing is carried out, 3 times of washing are carried out by using distilled water with the total volume of 30mL, and then 3 times of washing are carried out by using methanol with the total volume of 30mL, and the chemical structural formula of the fifth compound is as follows:

wherein the content of the first and second substances,

the fifth compound was a white powder with a mass of 0.126g, yield: 38.99%, m.p.: 208 ℃ and 209 ℃. The structural characterization data are as follows:

IR(KBr)ν/cm^-1:3299,3096,2783,2745,2666,1614,1509,1442,1400,1376,1331,1216, 1050,1140,1018,886,785；¹H NMR(300MHz,DMSO-d₆):10.06(s,1H,-NH),9.84(s,1H,) 9.39(s,1H,N＝CH-S),7.60(s,1H,Ph-H),7.42(s,1H,Ph-H),7.39(s,1H,Ph-H),7.36(m,1H, ＝CH-Ph).¹³C NMR(75MHz,DMSO-d₆)：169.63,169.50,164.19,158.38,152.61,148.59, 147.28,128.26,127.10,125.70,125.37,121.73.

< example 12>

step four, reacting the third intermediate product with 4-dimethylaminobenzaldehyde through Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound, which specifically comprises the following steps: 0.20g (1.020mmol) of the third intermediate, 0.302g (2.024mmol) of 4-dimethylaminobenzaldehyde, 0.328g (3.999mmol) of anhydrous sodium acetate are weighed out and 100m of sodium acetate are addedAdding 6mL of acetic anhydride and 8mL of glacial acetic acid into an L round two-neck flask, stirring the mixture under the condition of 105 ℃ oil bath until the mixture is completely dissolved, continuing to react for 6 hours, detecting and tracking the reaction by TLC (thin layer chromatography) until no raw material point exists, stopping the reaction, cooling the reaction mixture to room temperature, pouring the reaction mixture into 50mL of ice water, sealing a preservative film, standing the reaction mixture at the temperature of 2-4 ℃ for at least 12 hours, and performing suction filtration, washing and drying to obtain a sixth compound, wherein detection tracking reagents used by TLC are dichloromethane and methanol in a volume ratio of 10:1, namely V_{Methylene dichloride}：V_MethanolWhen washing is carried out, 3 times of washing are carried out by using distilled water with the total volume of 30mL, and then 3 times of washing are carried out by using methanol with the total volume of 30mL, wherein the chemical structural formula of the sixth compound is as follows:

wherein the content of the first and second substances,

the sixth compound was an orange-red powder with a mass of 0.201g, yield: the content of the active carbon is 59.52%,

the structural characterization data are as follows:

m.p.：246-248℃，1H NMR(300MHz,DMSO-d6)：12.70(s,1H,-NH),7.67(s,1H, ＝CH-Ph),7.52(s,2H,Ph-H),6.84(m,2H,Ph-H),3.04(s,6H,-CH3).

< example 13>

The preparation method of the first intermediate product by taking the thiosemicarbazide as the raw material specifically comprises the following steps: weighing 5.08g of thiosemicarbazide, adding into a round two-neck flask, adding 3.3mL of formic acid, stirring at room temperature to be slurry, dropwise adding 6.4mL of concentrated hydrochloric acid into the round two-neck flask by using a constant-pressure separating funnel, continuously stirring uniformly, transferring the round two-neck flask onto an oil bath heating magnetic stirrer, reacting at 115 ℃ for 5 hours, detecting by TLC (thin layer chromatography) until no raw material point exists, stopping the reaction, cooling to room temperature to obtain a cooling liquid, pouring the cooling liquid into ice water, adjusting the pH of the system to 7-8 by using concentrated ammonia water in the ice water, standing at low temperature for at least 12 hours, carrying out suction filtration and washing on white powder separated out at price to obtain white powderTo the first intermediate product, in which the detection follow-up reagents used in TLC were dichloromethane and methanol in a volume ratio of 10:1, i.e., V_{Methylene dichloride}:V_Methanol＝10:1；

step two, synthesizing a second intermediate product with chloroacetyl chloride specifically comprises the following steps: weighing 1.05g of a first intermediate product, adding the first intermediate product into a round two-neck flask, adding 30mL of dimethylformamide subjected to redistillation treatment, after the first intermediate product is completely dissolved, adding 1.65mL of dry triethylamine, moving to an ice bath condition, measuring 1.2mL of chloroacetyl chloride, dropwise adding the chloroacetyl chloride into the reaction by using a constant-pressure dropping funnel, finishing dropping for 35min, stirring and reacting at room temperature and normal pressure for 4.5h, stopping the reaction until no raw material point exists, pouring a reaction mixture into 52mL of ice water, sealing a preservative film, standing at 2-4 ℃ for at least 12h, performing suction filtration, washing and drying to obtain a second intermediate product, wherein detection and tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection and tracking reagents is 10:1, and washing is performed 3 times by using distilled water accounting for 30mL in total;

step three, the cyclizing synthesis of the third intermediate product under the action of the thiocyanate amine specifically comprises the following steps: weighing 0.25g of second intermediate product, adding the second intermediate product into a round two-neck flask, adding 26mL of redistilled dimethylformamide until the second intermediate product is completely dissolved, then weighing 0.18g of ammonium thiocyanate, adding the ammonium thiocyanate into the round two-neck flask, reacting for 4.5h under an oil bath at 85 ℃, detecting and tracking the reaction by TLC until no raw material point exists, stopping the reaction, pouring the reaction mixture into 34g of crushed ice, sealing a preservative film, standing for at least 12h at 2-4 ℃, and performing suction filtration, washing and drying to obtain a third intermediate product, wherein detection and tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection and tracking reagents is 10:1, and the third intermediate product is washed by distilled water accounting for 10mL in total for 3 times during washing.

step four, reacting the third intermediate product with 4-cyanobenzaldehyde through Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound, which specifically comprises the following steps: weighing 0.16g of third intermediate product, 0.21g of 4-cyanobenzaldehyde and 0.23g of anhydrous sodium acetate, adding the third intermediate product into a round two-neck flask, adding 4mL of acetic anhydride and 5mL of glacial acetic acid, stirring the mixture under the condition of 110 ℃ oil bath until the mixture is completely dissolved, continuing to react for 6.5h, detecting and tracking the reaction by TLC until the raw material point disappears, stopping the reaction, cooling the reaction to room temperature, pouring the reaction product into 55mL of glacial water, standing the reaction product in a refrigerator at 2-4 ℃ for at least 12h, and performing suction filtration, washing and drying to obtain a first compound, wherein detection and tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection and tracking reagents is 10:1, the detection and tracking reagents used by TLC are washed by 3 times of distilled water accounting for 30mL, and then washed by 3 times of methanol accounting for 30mL, and the:

wherein the content of the first and second substances,

< example 14>

The first, second and third steps are the same as in example 13, and the amounts and experimental parameters of the respective substances are the same, except that:

step four, reacting the third intermediate product with 3-hydroxybenzaldehyde through Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound, which specifically comprises the following steps: weighing 0.25g of third intermediate product, 0.29g of 3-hydroxybenzaldehyde and 0.38g of anhydrous sodium acetate, adding the third intermediate product into a round-bottom flask, adding 7mL of acetic anhydride and 9mL of glacial acetic acid, stirring at 110 ℃ in an oil bath to completely dissolve, continuing to react for 6.5h, detecting and tracking by TLC to react until no raw material point exists, stopping the reaction, cooling to room temperature, pouring the reaction mixture into 55mL of glacial water, standing at 2-4 ℃ for at least 12h, performing suction filtration, washing and drying to obtain a second compound, wherein detection and tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection and tracking reagents is 10:1, the detection and tracking reagents used by TLC are washed by 3 times of distilled water with the total volume of 30mL, and then washed by 3 times of methanol with the total volume of 30mL, and the chemical structural formula of the second compound is as follows:

wherein the content of the first and second substances,

< example 15>

step four, reacting the third intermediate product with 4-fluorobenzaldehyde through Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound, which specifically comprises the following steps: weighing 0.25g of a third intermediate product and 0.41g of anhydrous sodium acetate, measuring 237 microliter of 4-fluorobenzaldehyde, adding into a round two-neck flask, adding 7mL of acetic anhydride and 9mL of glacial acetic acid, stirring at 110 ℃ in an oil bath until the mixture is completely dissolved, continuing to react for 6.5 hours, detecting and tracking by TLC until no raw material point exists, stopping the reaction, cooling to room temperature, pouring the reaction mixture into 55mL of ice water, sealing a preservative film, standing for at least 12 hours at 2-4 ℃, and performing suction filtration, washing and drying to obtain a third compound, wherein detection and tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection and tracking reagents is 10:1, the third compound is washed by 3 times with 30mL of distilled water and then 3 times with 30mL of methanol, and the chemical structural formula of the third compound is as follows:

wherein,

< example 16>

step four, reacting the third intermediate product with p-chlorobenzaldehyde through Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound, which specifically comprises the following steps: weighing 0.26g of a third intermediate product, 0.30g of p-chlorobenzaldehyde and 0.39g of anhydrous sodium acetate, adding the third intermediate product into a round two-necked flask, adding 7mL of acetic anhydride and 9mL of glacial acetic acid, stirring at 110 ℃ in an oil bath until the third intermediate product and the anhydrous sodium acetate are completely dissolved, continuing to react for 6.5h, detecting and tracking by TLC (thin layer chromatography) until no raw material point exists, stopping the reaction, cooling to room temperature, pouring the reaction mixture into 55mL of glacial water, standing at 2-4 ℃ for at least 12h, and performing suction filtration, washing and drying to obtain a fourth compound, wherein detection and tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection and tracking reagents is 10:1, the detection and tracking reagents used by TLC are washed by 3 times of distilled water with the total volume of 30mL, and then washed by 3 times of methanol with the total volume of 30mL, and:

wherein the content of the first and second substances,

< example 17>

step four, reacting the third intermediate product with 2, 5-dihydroxybenzaldehyde through Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound, which specifically comprises the following steps: weighing 0.35g of third intermediate product, 0.38g of 2, 5-dihydroxybenzaldehyde and 0.41g of anhydrous sodium acetate, adding the third intermediate product into a round two-necked flask, adding 7mL of acetic anhydride and 9mL of glacial acetic acid, stirring the mixture under the condition of 110 ℃ oil bath until the mixture is completely dissolved, continuing to react for 6.5h, detecting and tracking the reaction by TLC until no raw material point exists, stopping the reaction, cooling the mixture to room temperature, pouring the reaction mixture into 55mL of glacial water, standing the mixture for at least 12h at the temperature of 2-4 ℃, and performing suction filtration, washing and drying to obtain a fifth compound, wherein detection and tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection and tracking reagents is 10:1, the detection and tracking reagents used by TLC are washed by 3 times of distilled water of 30mL in total and then washed by 3 times of methanol of 30mL in total, and the chemical structural formula of:

wherein the content of the first and second substances,

< example 18>

step four, reacting the third intermediate product with 4-dimethylaminobenzaldehyde through Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound, which specifically comprises the following steps: weighing 0.25g of a third intermediate product, 0.35g of 4-dimethylaminobenzaldehyde and 0.38g of anhydrous sodium acetate, adding the third intermediate product into a round two-necked flask, adding 7mL of acetic anhydride and 9mL of glacial acetic acid, stirring the mixture under the condition of 110 ℃ oil bath until the mixture is completely dissolved, continuing to react for 6.5h, detecting and tracking the reaction by TLC until no raw material point exists, stopping the reaction, cooling the reaction to room temperature, pouring the reaction mixture into 55mL of glacial water, standing the reaction mixture for at least 12h at the temperature of 2-4 ℃, and performing suction filtration, washing and drying to obtain a sixth compound, wherein detection and tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection and tracking reagents is 10:1, the detection and tracking reagents used by TLC are washed by 3 times of distilled water accounting for 30mL, and then washed by 3 times of methanol accounting for 30mL, and the chemical structural:

wherein the content of the first and second substances,

< comparative test >

The phenyl-substituted thiadiazole thiazolinone compounds prepared in examples 7 to 12 of the present invention are respectively prepared into reagents for performing a sterilization test on some plant bacteria or fungi and a pest killing test on some plant diseases, and the results are shown in tables 1 and 2.

First, sterilization test

S1, adding a proper amount of methanol (analytically pure) into the first compound, the second compound, the third compound, the fourth compound, the fifth compound and the sixth compound prepared in the embodiments 7-12 of the invention respectively to completely dissolve the samples, and preparing 500g/L of solution to be detected. A blank set (i.e., test solutions without any of the compounds prepared in examples 6-10) was also set. And adding 1.5mL of the prepared 500g/L solution to be tested into 13.5mL of potato glucose agar, uniformly mixing to prepare 50g/L of PDA test agar liquid, pouring the PDA test agar liquid into a disposable sterile culture dish, cooling and solidifying at room temperature to obtain an agar culture dish for later use, wherein the agar culture dish comprises an agar culture dish formed by a first compound, a second compound, a third compound, a fourth compound, a fifth compound and an agar culture dish formed by a blank group.

S2, selecting the test strains which grow uniformly and vigorously, and setting the test strains into agar blocks with the diameter of 7mm by using a puncher for later use. The test agar block is reversely buckled in a cultured agar culture dish and is placed in a constant temperature and humidity incubator with the temperature of 28.0 ℃ and the humidity of 60 percent for culture for 72 hours.

And S3, taking out the test strains, measuring the growth diameter of the bacterial colony by using a vernier caliper (measuring for 2 times by a cross method, and taking an average value), and recording the experimental result.

Wherein, original fungus cake diameter is 7mm, and blank control colony diameter after the cultivation is the reference, and the colony diameter is less, and antibacterial effect is better, and big more then does not have bacteriostatic action.

The inhibition rate EB is ═ [ (blank colony growth diameter-agent-treated colony growth diameter)/(blank colony growth diameter) ] × 100%, and the experimental test results are the average of the 3 colony test diameters and the inhibition rate was calculated.

Meanwhile, according to the steps of S1, S2 and S3, the isoprothiolane, the bismerthiazol and the azoxystrobin are respectively prepared into solutions, corresponding agar culture dishes are obtained, and the inhibition rates of the isoprothiolane, the bismerthiazol and the azoxystrobin on the test strains are calculated.

The test strains comprise tomato early blight bacteria, banana fusarium wilt bacteria, cucumber fusarium wilt bacteria and rice blast bacteria.

TABLE 1 fungicidal Activity

As can be obtained from Table 1, the thiadiazole thiazolinone compounds prepared in examples 9-11, as thiazolinone compounds with a brand new chemical structure, have good inhibition rate on tomato early blight, and can reach 65.04% at most, which is higher than that of isoprothiolane and bismerthiazol; has better inhibition rate on banana fusarium wilt and cucumber fusarium wilt, which are higher than that of pyricularin and bismerthiazol. In addition, the inhibition rate of the third compound prepared in the embodiment 10 of the invention on rice blast germs reaches 86.96%, which is higher than that of pyricularia oryzae and bismerthiazol, although the inhibition rate is slightly lower than that of pyraclostrobin on rice blast, the method for preparing the third compound in the embodiment 10 has simple operation steps compared with the preparation of pyraclostrobin, does not involve hydrogenation reduction reaction, has low requirement on equipment, less byproducts, less three-waste discharge and environmental protection.

Second, insecticidal test

The first compound, the second compound, the third compound, the fourth compound, the fifth compound and the sixth compound prepared in examples 7 to 12 of the present invention, and the buprofezin and 1,2, 3-thiadiazole-1, 3, 4-thiadiazole compounds commonly used in the prior art are respectively prepared into reagents with concentrations of 500ppm, and a blank control without spraying any reagent is set at the same time.

And (3) performing activity determination by taking plutella xylostella, aphid, tetranychid and rice field brown planthopper as targets.

(1) The method for measuring the plutella xylostella comprises the following steps: the rape leaves were punched out into 1 cm-diameter leaves with a punch and the pressure of the spray treatment was 15psi (about 1.05 kg/cm)²) Spraying is carried out on the front side and the back side of each blade, and the liquid spraying amount is 0.5 ml. And (3) inoculating 20 2-year-old Plutella xylostella moths to each leaf after drying in the shade, then placing the leaves into an observation room with the temperature of 25 ℃ and the relative humidity of 60-70% for culture, investigating the number of the surviving moths after 72 hours, and calculating the death rate.

(2) The method for measuring aphids comprises the following steps: a culture dish with the diameter of 6cm is taken, a layer of filter paper is covered on the bottom of the culture dish, and a proper amount of tap water is dripped for moisturizing. Apple leaves with proper size (diameter about 2cm) and 20 aphids are cut from apple leaves for culturing aphids, winged aphids and the aphids on the front of the leaves are removed, and the leaves are placed in a culture dish with the back facing upwards. The pressure of the spray treatment was 15psi (about 1.05 kg/cm)²) The spraying liquid amount is 0.5ml, the treated solution is placed into an observation room at 25 ℃ and relative humidity of 6-70% for culture, the number of surviving insects is investigated after 48 hours, and the death rate is calculated.

(3) Method for assaying Tetranychus urticae: taking peanut leaves, inoculating 20 tetranychids on each leaf, and spraying under the pressure of 15psi (about 1.05 kg/cm)²) Spraying is carried out on the front side and the back side of each blade, and the liquid spraying amount is 0.5 ml. And then culturing in an observation room with the temperature of 25 ℃ and the relative humidity of 60-70%, investigating the number of the survival insects after 72 hours, and calculating the death rate.

(4) The method for determining the brown planthopper in the rice field comprises the following steps: after rice is planted in a plurality of culture rooms with the same area, 100 brown planthoppers are respectively thrown, the prepared reagents are respectively sprayed and sprayed after two days, the spraying liquid amount is 10ml, the number of surviving insects is investigated after 72 hours, and the death rate is calculated.

The results of the investigation are shown in table 2 below.

TABLE 2 insecticidal Activity

As can be seen from table 2, the thiadiazole thiazolinone compounds prepared in examples 7 to 12, as thiazolinone compounds having a completely new chemical structure, have good killing effects on diamond back moth, aphid, leaf mite and brown planthopper in rice field, and the rice seedlings grow normally without any harmful condition when the rice seedlings are observed after application of the compound to rice plants planted in a culture room.

While embodiments of the invention have been disclosed above, it is not limited to the applications listed in the description and the embodiments, which are fully applicable in all kinds of fields of application of the invention, and further modifications may readily be effected by those skilled in the art, so that the invention is not limited to the specific details without departing from the general concept defined by the claims and the scope of equivalents.

Claims

1. A thiadiazole thiazolinone compound characterized by having a chemical structure represented by the following formula:

wherein the content of the first and second substances,

2. a preparation method of thiadiazole thiazolinone compound according to claim 1, which is characterized in that thiosemicarbazide is used as raw material, and is dehydrated and cyclized with formic acid under the catalysis of concentrated sulfuric acid to synthesize a first intermediate product, then is cyclized with chloroacetyl chloride to synthesize a second intermediate product, and is cyclized with ammonium thiocyanate to synthesize a third intermediate product, and finally the third intermediate product is reacted with R1 through Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound, wherein,

3. the method for preparing a thiadiazole thiazolinone compound according to claim 2, wherein the preparation of the first intermediate product using thiosemicarbazide as a raw material specifically comprises: weighing 4.98-5.08 g of thiosemicarbazide, adding 2.7-3.3 mL of formic acid into a round two-neck flask, stirring at room temperature to form slurry, dropwise adding 5.6-6.4 mL of concentrated hydrochloric acid into the round two-neck flask by using a constant-pressure separating funnel, continuously stirring uniformly, transferring the round two-neck flask to an oil bath heating magnetic stirrer, reacting at 105-115 ℃ for 4-5 h, detecting by TLC (thin layer chromatography) until no raw material is present, stopping the reaction, cooling to room temperature to obtain a cooling liquid, pouring the cooling liquid into ice water, adjusting the pH of the system to 7-8 by using concentrated ammonia water in the ice water, standing at low temperature for at least 12h, and performing suction filtration and washing on separated white powder to obtain a first intermediate product, wherein detection tracking reagents used by TLC are dichloromethane and methanol, and the volume ratio of the detection tracking reagents is 10: 1;

4. The method for preparing thiadiazole thiazolinone compound according to claim 3, wherein the step of reacting the third intermediate with 4-cyanobenzaldehyde by Knoevenagle condensation reaction to obtain thiadiazole thiazolinone compound comprises: weighing 0.06-0.16 g of a third intermediate product, 0.11-0.21 g of 4-cyanobenzaldehyde and 0.13-0.23 g of anhydrous sodium acetate, adding the third intermediate product into a round two-neck flask, adding 2-4 mL of acetic anhydride and 3-5 mL of glacial acetic acid, stirring the mixture under the condition of an oil bath at 100-110 ℃ until the mixture is completely dissolved, continuing to react for 5.5-6.5 hours, detecting and tracking the reaction by TLC until a raw material point disappears, stopping the reaction, cooling the reaction product to room temperature, pouring the reaction product into 45-55 mL of ice water, sealing a preservative film, standing the reaction product in a refrigerator at 2-4 ℃ for at least 12 hours, and performing suction filtration, washing and drying to obtain a first compound, wherein detection and tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection and tracking reagents is 10:1, washing the first compound by using distilled water accounting for 3 times and washing by methanol accounting for 30mL, and washing the first compound by adopting a structural formula for 3:

wherein the content of the first and second substances,

5. the method for preparing a thiadiazole thiazolinone compound according to claim 3, wherein the step of reacting the third intermediate product with 4-fluorobenzaldehyde by Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound specifically comprises: weighing 0.15-0.25 g of a third intermediate product and 0.31-0.41 g of anhydrous sodium acetate, weighing 233-237 mu L of 4-fluorobenzaldehyde, adding into a round two-neck flask, adding 5-7 mL of acetic anhydride and 7-9 mL of glacial acetic acid, stirring under the condition of 100-110 ℃ oil bath until the mixture is completely dissolved, continuing to react for 5.5-6.5 h, detecting and tracking the reaction by TLC until no raw material is present, stopping the reaction, cooling to room temperature, pouring the reaction mixture into 45-55 mL of glacial water, standing for at least 12h at 2-4 ℃, performing suction filtration, washing and drying to obtain a third compound, wherein detection and tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection and tracking reagents is 10:1, washing is performed by 3 times with 30mL of distilled water and then 3 times with 30mL of methanol, and the chemical structural formula of the third compound is as follows:

wherein,

6. The method for preparing thiadiazole thiazolinone compound according to claim 3, wherein the step of reacting the third intermediate product with p-chlorobenzaldehyde by Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound comprises: weighing 0.16-0.26 g of third intermediate product, 0.20-0.30 g of p-chlorobenzaldehyde and 0.28-0.39 g of anhydrous sodium acetate, adding the third intermediate product into a round two-neck flask, adding 5-7 mL of acetic anhydride and 7-9 mL of glacial acetic acid, stirring the mixture under the condition of 100-110 ℃ oil bath until the mixture is completely dissolved, continuing to react for 5.5-6.5 h, detecting and tracking the reaction by TLC until no raw material point exists, stopping the reaction, cooling the reaction mixture to room temperature, then pouring the reaction mixture into 45-55 mL of ice water, standing the reaction mixture for at least 12h at 2-4 ℃, and obtaining a fourth compound through suction filtration, washing and drying, wherein detection and tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection and tracking reagents is 10:1, the third intermediate product is washed by 3 times by 30mL of distilled water and then by 3 times by 30mL of methanol, and the fourth compound has the following chemical formula:

wherein the content of the first and second substances,

7. the method for preparing thiadiazole thiazolinone compound according to claim 3, wherein the step of reacting the third intermediate product with 4-dimethylaminobenzaldehyde by Knoevenagle condensation reaction to obtain the thiadiazole thiazolinone compound specifically comprises: weighing 0.15-0.25 g of the third intermediate product, 0.25-0.35 g of 4-dimethylaminobenzaldehyde and 0.28-0.38 g of anhydrous sodium acetate, adding into a round two-neck flask, then adding 5-7 mL of acetic anhydride and 7-9 mL of glacial acetic acid, stirring under the condition of 100-110 ℃ oil bath until the acetic anhydride and the glacial acetic acid are completely dissolved, continuing to react for 5.5-6.5 h, detecting and tracking the reaction by TLC until no raw material is obtained, stopping the reaction, cooling to room temperature, then pouring the reaction mixture into 45-55 mL of ice water, sealing a preservative film, standing for at least 12h at the temperature of 2-4 ℃, performing suction filtration, washing and drying to obtain a sixth compound, wherein, detection tracking reagents used by TLC are dichloromethane and methanol, the volume ratio of the detection tracking reagents is 10:1, the detection tracking reagents are washed by distilled water with the total volume of 30mL for 3 times and then by methanol with the total volume of 30mL for 3 times, and the chemical structural formula of the sixth compound is as follows:

wherein the content of the first and second substances,

8. the use of the thiadiazole thiazolinone compound according to claim 1 in the preparation of an agricultural fungicide.

9. The use of the thiadiazole thiazolinone compound according to claim 1 in the preparation of an insecticide.