CN109776368B

CN109776368B - Novel thiol-pyrethrin chemical modifier and preparation method and application thereof

Info

Publication number: CN109776368B
Application number: CN201910088511.6A
Authority: CN
Inventors: 赵肃清; 张炳杰; 高美婷; 梁汉英; 方颖琳; 冯冬燕; 钟颖颖; 江政云; 杨洋; 朱秋雁; 洪为谦
Original assignee: Guangdong University of Technology
Current assignee: Guangdong University of Technology
Priority date: 2019-01-18
Filing date: 2019-01-18
Publication date: 2021-05-28
Anticipated expiration: 2039-01-18
Also published as: CN109776368A

Abstract

The invention discloses a novel thiol-pyrethrin chemical modifier and a preparation method and application thereof. The invention mainly modifies a terminal chlorine atom and an ester group on transfluthrin, replaces the terminal chlorine atom with trifluoromethyl for substitution, and replaces the ester group with a thiol ester group structure to form a series of novel thiol pyrethroid compound structures containing thiol structures. The novel thiopyrethroid chemical modifier can improve metabolic stability and reduce environmental toxicity, has a certain insecticidal effect on larvae, has insecticidal activity on adult mosquitoes in the same concentration level as bifenthrin, shows a mosquito killing effect similar to bifenthrin, and can effectively solve the serious problem of outstanding drug resistance of the existing pyrethroid insecticides. In addition, the method has the advantages of simple reaction process, few reaction steps, higher synthetic yield, short reaction period, good repeatability and the like.

Description

Novel thiol-pyrethrin chemical modifier and preparation method and application thereof

Technical Field

The invention belongs to the technical field of pesticide modified by a medicine small molecular structure. More particularly, relates to a novel thiol-pyrethrin chemical modifier, a preparation method and application thereof.

Background

The damp and hot environment in summer brings good conditions for the breeding and the emergence of mosquitoes. The mosquito which is one of the four pests brings great trouble to the daily life of people, the humming sound of the mosquito can influence the daily rest, work and study of people, and the people are very easy to be bitten by adult female mosquitoes indoors or outdoors at ordinary times, so that the skin is very easy to be inflamed, painful and itchy. More serious problems are that mosquitoes can transmit more than 80 diseases such as dengue fever, epidemic encephalitis B, yellow fever, malaria and filariasis. Therefore, mosquito killing and avoiding is an important measure for preventing mosquito-borne infectious diseases, and the research and development of an effective insecticide or a product with a mosquito repelling effect is very necessary in summer. Such a product not only needs to play a good role in killing or repelling mosquitoes, but also needs to have little or no harm to human bodies, and does not have long-term residue and any pollution to the environment.

Pyrethroid insecticides are biomimetic synthetic insecticides, such as transfluthrin and the like, can be used for preventing and treating mosquito hazards, and have the advantages of strong specificity, high insecticidal activity, small toxicity and the like, and are widely applied in the field of mosquito prevention and treatment work. Pyrethroids were originally discovered when the chrysanthemum extract was studied by the National Research and Development Company (NRDC) in the uk for its natural insecticidal properties. The research team firstly synthesizes a pyrethroid compound which is stable to light, and the prior chrysanthemum extract has unstable property and loses insecticidal activity after being exposed to light. Early synthetic pyrethroid compounds were racemic mixtures of many isomers, not all of which had insecticidal activity. Traditionally, pyrethroid insecticides have been considered to have a broad spectrum of highly effective biological activity, low environmental and food residue levels, and relatively low mammalian toxicity. However, more and more studies have found that pyrethroids interfere with the normal functioning of the organism, posing considerable threat to the health of humans and animals. Studies have shown that long term exposure to pyrethroid containing environments can have adverse effects on the health of humans, particularly children. Furthermore, with the long-term use of a large number of conventional pyrethroid insecticides, mosquitoes, flies and other pests develop significant resistance to pesticides, and thus there is a need for a new class of structural insecticide compounds with improved metabolic stability and reduced environmental toxicity.

Disclosure of Invention

The technical problem to be solved by the invention is to overcome the defects and shortcomings of the prior art and provide a novel thiol-pyrethrin chemical modifier with a novel structure, which improves the metabolic stability and reduces the environmental toxicity.

The invention also aims to provide a preparation method of the novel thiol pyrethroid chemical modifier.

The invention further aims to provide the application of the thiothrin chemical modification substance or the thiothrin chemical modification substance prepared by the method in serving as or preparing pesticides.

The above purpose of the invention is realized by the following technical scheme:

a novel chemical modifier of thiol-chrysanthemic ester is shown in the following formula (I):

wherein R is a mono-substituted or poly-substituted aromatic ring group.

Further, in a preferred embodiment of the present invention, the aromatic ring group is an aromatic ring group containing a benzene ring and/or a thiophene ring, or an aromatic ring group containing a furan ring.

Further, in a preferred embodiment of the present invention, R is-CH₃、F、Cl、-CH₃O or-CF₃。

Further, in a preferred embodiment of the present invention, the aromatic ring group is

The invention mainly modifies a terminal chlorine atom and an ester group on transfluthrin, replaces the terminal chlorine atom with trifluoromethyl for substitution, and replaces the ester group with a thiol ester group structure to form a series of novel thiol pyrethroid compound structures containing thiol structures. The novel compounds can improve metabolic stability and reduce environmental toxicity, have a certain insecticidal effect on larvae, have the insecticidal activity of part of novel thioethrin chemical modifiers on adult mosquitoes and the bifenthrin with a complex structure, have the insecticidal effect similar to bifenthrin, and have excellent modification potential.

The invention also relates to a preparation method of the novel thiol-pyrethrin chemical modifier, which comprises the following steps:

s1, adding an ultra-dry dichloromethane solvent into trifluoro-chloro-chrysanthemic acid in a protective gas atmosphere, stirring and dissolving at room temperature, adding oxalyl chloride, stirring at room temperature for 30-35 min, adding N, N-dimethylformamide, and reacting at room temperature for 0.8-1 h under stirring;

s2, drying the product under a vacuum condition, adding an ultra-dry dichloromethane solvent in a protective gas atmosphere, stirring and dissolving at room temperature, adding anhydrous pyridine, stirring and reacting for 25-30 min, then adding cyclic methyl mercaptan, and carrying out esterification reaction for 2-3 h;

and S3, after the reaction is finished, washing, extracting and drying to obtain a crude product, and purifying by silica gel column chromatography to obtain the novel thiol-chrysanthester chemical modifier.

Further, in a preferred embodiment of the present invention, in step S1, the ratio of the amounts of the materials of the trifluoro-chloro chrysanthemic acid and oxalyl chloride is 1: 2 to 4.

Further, in a preferred embodiment of the present invention, in step S2, the ratio of the amounts of the substances of chlorotrifluoro chrysanthemic acid and anhydrous pyridine is 1: 1-2; the quantitative ratio of the materials of the trifluoro-chloro chrysanthemic acid and the cyclic methyl mercaptan is 1: 1 to 2.

Further, in a preferred embodiment of the present invention, the cyclic methanethiol is selected from cyclic thiols such as p-methylbenzenethiol, p-chlorobenzenethiol, 2-furanmethanethiol, 3-trifluoromethylbenzylthiol, 4-fluorobenzenethiol, 2-chlorobenzenethiol, 4-methoxybenzenethiol, benzylthiol, and 2-thiophenemethanethiol.

Further, in a preferred embodiment of the present invention, the amount of N, N-dimethylformamide added is 0.1 mL.

Further, in a preferred embodiment of the present invention, the protective gas is nitrogen.

The application of the novel benzylthiothrin chemical modifier or the novel thiothrin chemical modifier prepared by the method in the preparation of the pesticide is also within the protection scope of the invention.

The novel thiol-pyrethrin chemical modifier has good application prospect in preparing drugs for resisting mosquitoes, repelling mosquitoes, and preventing and/or controlling malaria, encephalitis B, yellow fever, malaria, filariasis and other diseases. In addition, the novel thiol-pyrethrin chemical modifier can also be applied to pesticide chemicals and/or daily hygiene.

Further, in a preferred embodiment of the invention, the insecticide is an anti-mosquito or mosquito repellent.

Further, in a preferred embodiment of the present invention, the mosquito killing or repelling agent is Aedes albopictus and/or Culex fatigues.

Compared with the prior art, the invention has the following beneficial effects:

(1) the structure of the methothrin is chemically modified to obtain a series of novel chemical modifications of the thioethrin, the novel compounds show certain insecticidal activity, can improve metabolic stability and reduce environmental toxicity, can be widely applied to the field of insect killing and mosquito killing, provide novel safe, efficient and stable compounds for insect killing, and effectively solve the problem of drug resistance.

(2) The method has the advantages of simple reaction process, few reaction steps, high synthetic yield, short reaction period, good repeatability and the like, and has good application prospect and wide development space in the field of pesticides.

Drawings

FIG. 1 is a graph showing the results of the insecticidal and mosquito eradication kinetics test on female adult mosquitoes for the sample derivatives of example 5 of the present invention.

FIG. 2 shows the oxidative stability of thiothrin derivatives LCA-COS-01 and transfluthrin.

FIG. 3 is a graph showing the appearance of Aedes albopictus larvae after treatment with the drug; wherein, a is the normal culture of 1 instar larva for 24h, and b is the treatment of drug LCA-COS-05 for 24 h.

Detailed Description

The present invention is further illustrated by the following specific examples, which are not intended to limit the invention in any way. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.

Unless otherwise indicated, reagents and materials used in the following examples are commercially available.

EXAMPLE 1 preparation of novel thiolathrin chemical modification (LCA-COS-01)

1. The preparation of the novel thiol pyrethroid chemical modifier (LCA-COS-01) comprises the following steps:

(1) weighing 200mg (0.824mmol) of trifluoro-chloro chrysanthemic acid in a 50mL round-bottom flask, measuring 15mL of ultra-dry anhydrous dichloromethane in the flask by using a syringe under the protection of nitrogen, stirring to completely dissolve the trifluoro-chloro chrysanthemic acid, adding 0.210mL (2.473mmol) of oxalyl chloride in three times amount, stirring for about 30min, adding 0.1mL of anhydrous N, N-Dimethylformamide (DMF) by using a 1mL syringe, reacting for 1h at room temperature, and reacting for 1 h;

(2) carrying out rotary evaporation drying on a product activated by the reaction in a round-bottom flask after 1 hour of reaction in a vacuum rotary evaporation evaporator, reducing external air to enter the round-bottom flask as far as possible in the operation process, then using nitrogen as a protective gas, adding an ultra-dry dichloromethane solvent, placing the round-bottom flask on a stirrer to be stirred and dissolved at room temperature, then adding 0.133mL (1.645mmol) of anhydrous pyridine with twice amount, stirring and reacting for 30 minutes, finally adding 227mg (1.645mmol) of p-methyl mercaptan with twice amount, and stirring and reacting for 2 hours at room temperature under the protection of nitrogen;

(3) detecting reaction endpoint by TLC (developing agent: petroleum ether: ethyl acetate: 50: 1), washing, extracting, drying to obtain crude product of compound LCA-COS-01, and purifying by silica gel column chromatography (eluent: petroleum ether: ethyl acetate: 100: 1) to obtain compound LCA-COS-01, colorless transparent viscous liquid, R_f0.45 (developing solvent: petroleum ether: ethyl acetate: 50: 1), yield: 75 percent.

2. Results

(1) The compound LCA-COS-01 has a molecular structural formula shown in a formula (1):

(2) by nuclear magnetic resonance¹H NMR、¹³C NMR analysis, high resolution mass spectrometry andmelting point, etc. for structural identification.¹H NMR(400MHz,Chloroform-d)δ7.16(d,J＝8.1Hz,2H),7.11(d,J＝7.9Hz,2H),6.97–6.88(m,1H),4.17–4.05(m,2H),2.31(d,J＝12.5Hz,5H),1.30(d,J＝7.2Hz,6H).¹³C NMR(101MHz,CDCl₃) Delta 194.14,137.06,134.29,129.66,129.37,128.65,122.02,119.07,41.69,33.79,33.43,31.34,28.33,21.09,14.86 high resolution mass spectrum HRMS (APCI): C₁₇H₁₈ClF₃OSNa(385.06112)[M+Na]⁺＝385.06113。

EXAMPLE 2 preparation of novel thiolathrin chemical modification (LCA-COS-02)

1. The preparation of the novel thiol pyrethroid chemical modifier (LCA-COS-02) comprises the following steps:

(2) carrying out rotary evaporation drying on a product activated by the reaction in a round-bottom flask after 1 hour of reaction in a vacuum rotary evaporation evaporator, reducing external air to enter the round-bottom flask as far as possible in the operation process, then using nitrogen as a protective gas, adding an ultra-dry dichloromethane solvent, placing the round-bottom flask on a stirrer to be stirred and dissolved at room temperature, then adding 0.133mL (1.645mmol) of anhydrous pyridine with twice amount, stirring and reacting for 30 minutes, finally adding 205mg (1.645mmol) of p-chlorobenzenethiol with twice amount, and stirring and reacting for 2 hours at room temperature under the protection of nitrogen;

(3) detecting reaction endpoint by TLC (developing agent: petroleum ether: ethyl acetate: 50: 1), washing, extracting, drying to obtain crude product of compound LCA-COS-02, and purifying by silica gel column chromatography (eluent: petroleum ether: ethyl acetate: 100: 1) to obtain compound LCA-COS-02 as colorless transparent viscous liquid, R_f0.48 (developing solvent: petroleum ether: ethyl acetate: 50: 1), yield: 70 percent.

2. Results

(1) The compound LCA-COS-02 has a molecular structural formula shown in a formula (2):

(2) by nuclear magnetic resonance¹H NMR、¹³C NMR analysis, high-resolution mass spectrum, melting point and the like.¹H NMR(400MHz,Chloroform-d)δ7.26–7.22(m,2H),7.22–7.14(m,2H),6.88(d,J＝8.3Hz,1H),4.13–4.01(m,2H),2.34–2.25(m,2H),1.28(d,J＝14.4Hz,6H).¹³C NMR(101MHz,CDCl₃) Delta 193.91,136.26,133.32,130.26,129.63,128.94,122.35,119.18,41.83,34.04,33.10,31.64,28.44,14.98 high resolution mass spectrum HRMS (APCI): C₁₆H₁₆Cl₂F₃OSNa(383.02455)[M+H]⁺＝383.02396。

EXAMPLE 3 preparation of novel thiolathrin chemical modification (LCA-COS-03)

1. The preparation of the novel thiol pyrethroid chemical modifier (LCA-COS-03) comprises the following steps:

(2) carrying out rotary evaporation drying on a product activated by the previous reaction in a round-bottom flask after reacting for 1h in a vacuum rotary evaporation evaporator, reducing external air to enter the round-bottom flask as much as possible in the operation process, then using nitrogen as a protective gas, adding an ultra-dry dichloromethane solvent, placing the round-bottom flask on a stirrer to stir and dissolve at room temperature, then adding 0.133mL (1.645mmol) of anhydrous pyridine with twice amount, stirring and reacting for 30min, finally adding 187mg (1.645mmol) of 2-furanmethanethiol with twice amount, and stirring and reacting for 2h at room temperature under the protection of nitrogen;

(3) detecting reaction endpoint by TLC (developing agent: petroleum ether: ethyl acetate: 50: 1), washing, extracting, drying to obtain crude product of compound LCA-COS-03, and purifying by silica gel column chromatography (eluent: petroleum ether: ethyl acetate: 100: 1) to obtain compound LCA-COS-03 as colorless transparent viscous liquid, R_f0.42 (developing solvent: petroleum ether: ethyl acetate: 50: 1), yield: 72 percent.

2. Results

(1) The compound LCA-COS-03 has a molecular structural formula shown in a formula (3):

(2) by nuclear magnetic resonance¹H NMR、¹³C NMR analysis, high-resolution mass spectrum, melting point and the like.¹H NMR(400MHz,Chloroform-d)δ7.32(dd,J＝1.9,0.9Hz,1H),6.90(d,J＝8.5Hz,1H),6.29(dd,J＝3.3,1.9Hz,1H),6.20(d,J＝3.2Hz,1H),4.22–4.09(m,2H),2.35–2.25(m,2H),1.31(s,3H),1.28(s,3H).¹³C NMR(101MHz,CDCl₃) Delta 193.44,150.32,142.22,129.50,122.17,119.03,110.63,107.93,41.72,33.90,31.49,28.29,26.11,14.84 high resolution mass spectrum HRMS (APCI): C₁₄H₁₅ClF₃O₂SNa(339.04279)[M+H]⁺＝339.04285。

EXAMPLE 4 preparation of novel thiolathrin chemical modification (LCA-COS-04)

1. The preparation of the novel thiol pyrethroid chemical modifier (LCA-COS-04) comprises the following steps:

(2) carrying out rotary evaporation drying on a product activated by the reaction in a round-bottom flask after 1 hour of reaction in a vacuum rotary evaporation evaporator, reducing external air into the round-bottom flask as much as possible in the operation process, then using nitrogen as a protective gas, adding an ultra-dry dichloromethane solvent, placing the round-bottom flask on a stirrer to be stirred and dissolved at room temperature, then adding 0.133mL (1.645mmol) of anhydrous pyridine with twice amount, stirring the mixture for reaction for 30 minutes, finally adding 316mg (1.645mmol) of 3-trifluoromethyl benzyl mercaptan with twice amount, and stirring the mixture for reaction for 2 hours at room temperature under the nitrogen protective gas;

(3) detecting reaction endpoint by TLC (developing agent: petroleum ether: ethyl acetate: 50: 1), washing, extracting, drying to obtain crude product of compound LCA-COS-04, and purifying by silica gel column chromatography (eluent: petroleum ether: ethyl acetate: 100: 1) to obtain compound LCA-COS-04 as colorless transparent viscous liquid_f0.43 (developing solvent: petroleum ether: ethyl acetate: 50: 1), yield: 70 percent.

2. Results

(1) The compound LCA-COS-04 has a molecular structural formula shown in formula (4):

(2) by nuclear magnetic resonance¹H NMR、¹³C NMR analysis, high-resolution mass spectrum, melting point and the like.¹H NMR(400MHz,Chloroform-d)δ7.57–7.48(m,2H),7.43(dt,J＝15.2,7.7Hz,2H),6.93–6.85(m,1H),4.16(q,J＝14.1Hz,2H),2.38–2.27(m,2H),1.32(s,3H),1.28(s,3H).¹³C NMR(101MHz,CDCl₃) Delta 193.58,138.72,132.13,131.02,129.38,129.10,125.52,124.15,122.44,121.81,119.02,41.69,33.99,33.12,31.61,28.27,14.77 high resolution mass spectrum HRMS (APCI): C₁₇H₁₆ClF₆OS(417.05090)[M+H]⁺＝417.05096。

EXAMPLE 5 preparation of novel thiolathrin chemical modification (LCA-COS-05)

1. The preparation of the novel thiol pyrethroid chemical modifier (LCA-COS-05) comprises the following steps:

(2) carrying out rotary evaporation drying on a product activated by the reaction in a round-bottom flask after 1 hour of reaction in a vacuum rotary evaporation evaporator, reducing external air to enter the round-bottom flask as far as possible in the operation process, then using nitrogen as a protective gas, adding an ultra-dry dichloromethane solvent, placing the round-bottom flask on a stirrer to be stirred and dissolved at room temperature, then adding 0.133mL (1.645mmol) of anhydrous pyridine with twice amount, stirring and reacting for 30 minutes, finally adding 316mg (1.645mmol) of 4-fluorobenzylmercaptan with twice amount, and stirring and reacting for 2 hours at room temperature under the protection of nitrogen;

(3) detecting reaction endpoint by TLC (developing agent: petroleum ether: ethyl acetate: 50: 1), washing, extracting, drying to obtain crude product of compound LCA-COS-05, and purifying by silica gel column chromatography (eluent: petroleum ether: ethyl acetate: 100: 1) to obtain compound LCA-COS-05 as colorless transparent viscous liquid, R_f0.45 (developing solvent: petroleum ether: ethyl acetate: 50: 1), yield: 65 percent.

2. Results

(1) The compound LCA-COS-05 has a molecular structural formula shown in formula (5):

(2) by nuclear magnetic resonance¹H NMR、¹³C NMR analysis, high-resolution mass spectrum, melting point and the like.¹H NMR(400MHz,Chloroform-d)δ7.24(dd,J＝8.5,5.4Hz,2H),6.98(t,J＝8.6Hz,2H),6.93–6.87(m,1H),4.10(d,J＝5.0Hz,2H),2.31(d,J＝8.2Hz,2H),1.31(s,3H),1.28(s,3H).¹³C NMR(101MHz,CDCl₃) Delta 194.04,162.18,133.45,130.56,130.48,129.69,121.89,120.745,115.76,115.54,41.83,34.00,33.05,31.58,28.43,14.97 high resolution mass spectrum HRMS (APCI): C₁₆H₁₆ClF₄OS(367.05410)[M+H]⁺＝367.05423。

EXAMPLE 6 preparation of novel thiolathrin chemical modification (LCA-COS-06)

1. The preparation of the novel thiol pyrethroid chemical modifier (LCA-COS-06) comprises the following steps:

(2) carrying out rotary evaporation drying on a product activated by the reaction in a round-bottom flask after 1 hour of reaction in a vacuum rotary evaporation evaporator, reducing external air to enter the round-bottom flask as far as possible in the operation process, then using nitrogen as a protective gas, adding an ultra-dry dichloromethane solvent, placing the round-bottom flask on a stirrer to be stirred and dissolved at room temperature, then adding 0.133mL (1.645mmol) of anhydrous pyridine with twice amount, stirring and reacting for 30 minutes, finally adding 261mg (1.645mmol) of 2-chlorobenzyl mercaptan with twice amount, and stirring and reacting for 2 hours at room temperature under the protection of nitrogen;

(3) detecting reaction end point by TLC (developing agent: petroleum ether: ethyl acetate: 50: 1), washing, extracting, drying to obtain crude product of compound LCA-COS-06, purifying by silica gel column chromatography (eluent: petroleum ether: ethyl acetate: 100: 1) to obtain compound LCA-COS-06, colorless transparent viscous liquid, R_f0.45 (developing solvent: petroleum ether: ethyl acetate: 50: 1), yield: 68 percent.

2. Results

(1) The compound LCA-COS-06 has a molecular structural formula shown in formula (6):

(2) by nuclear magnetic resonance¹H NMR、¹³C NMR analysis, high-resolution mass spectrum, melting point and the like.¹H NMR(400MHz,Chloroform-d)δ7.40(dt,J＝7.5,3.9Hz,1H),7.36(dt,J＝7.4,3.7Hz,1H),7.21(td,J＝5.8,2.7Hz,2H),6.96–6.87(m,1H),4.32–4.17(m,2H),2.31(d,J＝7.5Hz,2H),1.30(s,3H),1.28(s,3H).¹³C NMR(101MHz,CDCl₃) Delta 193.92,135.47,134.21,131.17,129.70,128.99,127.19,121.87,120.71,41.82,34.00,31.70,31.59,28.42,14.96 high resolution mass spectrum HRMS (APCI): C₁₆H₁₆Cl₂F₃OS(383.02455)[M+H]⁺＝383.02478。

EXAMPLE 7 preparation of novel thiolathrin chemical modification (LCA-COS-07)

1. The preparation of the novel thiol pyrethroid chemical modifier (LCA-COS-07) comprises the following steps:

(2) carrying out rotary evaporation drying on a product activated by the reaction in a round-bottom flask after 1 hour of reaction in a vacuum rotary evaporation evaporator, reducing external air to enter the round-bottom flask as far as possible in the operation process, then using nitrogen as a protective gas, adding an ultra-dry dichloromethane solvent, placing the round-bottom flask on a stirrer to be stirred and dissolved at room temperature, then adding 0.133mL (1.645mmol) of anhydrous pyridine with twice amount, stirring and reacting for 30 minutes, finally adding 254mg (1.645mmol) of 4-methoxybenzyl mercaptan with twice amount, and stirring and reacting for 2 hours at room temperature under the protection of nitrogen;

(3) the end point of the reaction was checked by TLC (developer: petroleum ether: acetic acid)Ethyl ester 50: 1) the crude product of compound LCA-COS-07 was obtained by washing, extraction, drying and the like, and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate 100: 1) to obtain compound LCA-COS-07 as colorless transparent viscous liquid, R_f0.45 (developing solvent: petroleum ether: ethyl acetate: 50: 1), yield: 66 percent.

2. Results

(1) The compound LCA-COS-07 has a molecular structural formula shown in formula (7):

(2) by nuclear magnetic resonance¹H NMR、¹³C NMR analysis, high-resolution mass spectrum, melting point and the like.¹H NMR(400MHz,Chloroform-d)δ7.22–7.14(m,2H),6.96–6.89(m,1H),6.87–6.79(m,2H),4.15–4.04(m,2H),3.79(s,3H),2.34–2.26(m,2H),1.31(s,3H),1.29(s,3H).¹³C NMR(101MHz,CDCl₃) Delta 194.22,158.88,129.90,129.68,129.37,121,71,1200.54,114.09,55.26,41.71,33.78,33.19,31.32,28.31,14.85 high resolution mass spectrum HRMS (APCI): C₁₇H₁₈ClF₃O₂SK(417.02997)[M+K]⁺＝417.02961。

EXAMPLE 8 preparation of novel thiolathrin chemical modification (LCA-COS-08)

1. The preparation of the novel thiol pyrethroid chemical modifier (LCA-COS-08) comprises the following steps:

(2) carrying out rotary evaporation drying on a product activated by the reaction in a round-bottom flask after 1 hour of reaction in a vacuum rotary evaporation evaporator, reducing external air to enter the round-bottom flask as far as possible in the operation process, then using nitrogen as a protective gas, adding an ultra-dry dichloromethane solvent, placing the round-bottom flask on a stirrer to be stirred and dissolved at room temperature, then adding 0.133mL (1.645mmol) of anhydrous pyridine with twice amount, stirring and reacting for 30 minutes, finally adding 204mg (1.645mmol) of benzyl mercaptan with twice amount, and stirring and reacting for 2 hours at room temperature under the nitrogen protective condition;

(3) detecting reaction end point by TLC (developing agent: petroleum ether: ethyl acetate: 50: 1), washing, extracting, drying to obtain crude product of compound LCA-COS-08, and purifying by silica gel column chromatography (eluent: petroleum ether: ethyl acetate: 100: 1) to obtain compound LCA-COS-08 as colorless transparent viscous liquid, R_f0.48 (developing solvent: petroleum ether: ethyl acetate: 50: 1), yield: 72 percent.

2. Results

(1) The compound LCA-COS-08 has a molecular structural formula shown in a formula (8):

(2) by nuclear magnetic resonance¹H NMR、¹³C NMR analysis, high-resolution mass spectrum, melting point and the like.¹H NMR(400MHz,Chloroform-d)δ7.38–7.32(m,1H),7.32–7.26(m,4H),7.00–6.90(m,1H),4.24–4.09(m,2H),2.38–2.29(m,2H),1.34(s,3H),1.31(s,3H).¹³C NMR(101MHz,CDCl₃) Delta 194.03,137.39,129.62,128.77,128.68,127.33,121.73,120.56,41.69,33.83,33.67,31.40,28.32,14.86 high resolution mass spectrum HRMS (APCI): C₁₆H₁₇ClF₃OS(349.06352)[M+H]⁺＝349.06354。

EXAMPLE 9 preparation of novel thiolathrin chemical modification (LCA-COS-09)

1. The preparation of the novel thiol pyrethroid chemical modifier (LCA-COS-09) comprises the following steps:

(2) carrying out rotary evaporation drying on a product activated by the reaction in a round-bottom flask after 1 hour of reaction in a vacuum rotary evaporation evaporator, reducing external air to enter the round-bottom flask as far as possible in the operation process, then using nitrogen as a protective gas, adding an ultra-dry dichloromethane solvent, placing the round-bottom flask on a stirrer to be stirred and dissolved at room temperature, then adding 0.133mL (1.645mmol) of anhydrous pyridine with twice amount, stirring and reacting for 30 minutes, finally adding 214mg (1.645mmol) of 2-thiophenemethylmercaptan with twice amount, and stirring and reacting for 2 hours at room temperature under the protection of nitrogen;

(3) detecting reaction endpoint by TLC (developing agent: petroleum ether: ethyl acetate: 50: 1), washing, extracting, drying to obtain crude product of compound LCA-COS-09, and purifying by silica gel column chromatography (eluent: petroleum ether: ethyl acetate: 100: 1) to obtain compound LCA-COS-09 as colorless transparent viscous liquid_f0.45 (developing solvent: petroleum ether: ethyl acetate: 50: 1), yield: 70 percent.

2. Results

(1) The compound LCA-COS-09 has a molecular structural formula shown in formula (9):

(2) by nuclear magnetic resonance¹H NMR、¹³C NMR analysis, high-resolution mass spectrum, melting point and the like.¹H NMR(400MHz,Chloroform-d)δ7.18(dd,J＝5.1,1.3Hz,1H),6.98–6.87(m,3H),4.34(q,J＝14.7Hz,2H),2.37–2.25(m,2H),1.32(s,3H),1.30(s,3H).¹³C NMR(151MHz,CDCl₃) Delta 193.78,140.09,129.68,126.96,126.74,125.37,122.05,121.41,41.82,34.07,31.70,28.39,28.32,14.98 high resolution mass spectrum HRMS (APCI): C₁₄H₁₅ClF₃OS₂(355.01995)[M+H]⁺＝355.01993。

Example 10 insecticidal and mosquito eradication Activity test on larvae

The compounds of examples 1 to 9 were tested for insecticidal activity against Aedes albopictus larvae (Aedes albopictus lava) using a 24-well plate assay.

Larval semi-lethal concentration test: this experiment has carried out the activity test to the semi-lethal concentration of aedes albopictus larva to novel mercaptan pyrethrin and chemical modification through aseptic 24 orifice plates.

Experiment 12 gradients of diluted sample compounds were first obtained by two-fold dilution using acetone (Aceton) solvent, then 985. mu.L of dechlorinated water and 5. mu.L of food solution (13mg/mL of fish meal powder food solution) were added to each well plate using a pipette gun, and 5 or more larvae of 1 year old (5-10) were added to each well plate. To each well plate 10 μ L of 8 concentration gradients of sample compounds were added, each sample concentration being repeated in triplicate; after culturing at 26-28 ℃ for 24h, the mortality or lethality of each well plate was recorded. And counting the half-lethality LC of all novel thiothrin derivatives on 1 instar larvae₅₀The values, statistics of which are shown in table 1 below.

TABLE 1 insecticidal activity of novel thioethrin derivatives against 1-instar mosquito larvae

Note: each set of experiments was repeated 3 times and the data in the table represent the mean (n-3) ± standard deviation. LC (liquid Crystal)₅₀At half lethal concentration. The mosquito is selected to be the aedes albopictus of sensitive strain, and the compound number can be simplified to be No. 01-09. The larval mortality rate for the blank group was within 5%.

The result of the insecticidal activity test of Aedes albopictus larvae (Aedes albopictus lava) performed in examples 1-9 by using a 24-well plate method for determination shows that the novel thioethrin derivative structure of the present invention has a killing effect on the larvae of Aedes albopictus, and particularly, the three groups of derivatives in examples 05, 06, and 08 show excellent insecticidal activity on the larvae, that is, the structure substituted at the ortho position of part of the benzene ring of the novel thioethrin derivative has a highly effective insecticidal effect on the larvae of Aedes albopictus.

Example 11 adult mosquito insecticidal and mosquito eradication Activity test

Insecticidal activity tests of Aedes albopictus female adult mosquitoes (Aedes albopictus male mosquitoes) were performed on the compounds of examples 1-9 using the CDC bottle bioassay experiment. The insecticidal activity of the novel thioethrin derivatives against female adult mosquitoes was experimentally tested and the results are shown in table 2 below. Table 3 shows insecticidal activity tests of two positive groups of bifenthrin and transfluthrin against female adult mosquitoes. The mortality rate of adult mosquitoes in the blank group is generally controlled within 2 percent.

Activity test of female adult mosquitoes: in a female adult mosquito experiment, all pupated adult mosquitoes are cultured for about 3-5 days by using 10% sugar water and dechlorinated water, and then female mosquitoes are separated by utilizing the blood sucking property of the female adult mosquitoes. The adult mosquito experiment adopts a standard CDC bottle bioassay (contact method), wherein 10 gradient diluted sample compounds are obtained by using acetone (Aceton) solvent through a double dilution method, then 3 groups of different concentrations of high, medium and low are made for each sample compound, each concentration is repeated in parallel for 3 times, 1mL of sample solution is added into each Wheatstone bottle, the sample solution is uniformly coated on the inner bottle wall of the whole Wheatstone bottle, the Wheatstone bottle is placed in a dark and ventilated shade place for drying for about 2-3 hours, after the Wheatstone bottle is completely dried, 15-25 or more female adult mosquitoes are added into each Wheatstone bottle, the death number of the mosquitoes is recorded every 15 minutes, the lethality rate of the novel thiothrin derivatives to the female adult mosquitoes in 3 different time periods such as 30min, 60min and 120min is finally counted, and the statistical results are shown in tables 2 and 3.

TABLE 2 CDC bottle bioassay experiments on novel thiolathrin derivatives against female adult mosquitoes

Note: each set of experiments was repeated 3 times and the data in the table represent the mean (n-3) ± standard deviation. μ g/bottle represents the amount added per Wheatstone bottle. Then 1600, 200 and 12.5 mug/bottle high and low three different concentrations of each group of samples are counted to obtain the corresponding concentrations and the lethality rate of the corresponding time points.

TABLE 3 Positive group CDC bottle bioassay experiment on Aedes albopictus female adult mosquitoes

Note: each set of experiments was repeated 3 times and the data in the table represent the mean (n-3) ± standard deviation. μ g/bottle represents the amount added per Wheatstone bottle. Then taking bifenthrin and transfluthrin as control groups, taking 1600, 12.5 and 1.56 mu g/bottle of three different concentrations and counting corresponding concentrations and lethality of corresponding time points.

Tests on the insecticidal activity of Aedes albopictus female adult mosquitoes (Aedes albopictus femal adult mosquitoes) by using CDC (CDC) bottle bioassay experiments and results show that the novel thioethrin derivative still has quite excellent killing activity on the female adult mosquitoes under the condition of low concentration of 12.5 mu g/botle, and the insecticidal effect of the novel thioethrin derivative is gradually increased with the time. And can be at approximately the same level as compared to the two positive control groups. The structure of the pyrethrin thiol derivative has the advantages of simple structure, convenient and easy synthesis, low synthesis cost and the like.

Example 12 experiment of dynamics test of mosquito killing and killing by adult mosquito

According to the result of the test for mosquito killing activity of adult mosquitoes of example 5, the sample derivative of example 5 with the best mosquito killing effect is selected, and the kinetic experiment test is carried out on the compounds with 4 different concentration gradients, all the operations are the same as example 11, the survival/death number of the female adult mosquitoes in the Wheatstone bottle is measured once every 15 minutes, and finally, the mortality rate of the corresponding time point is made, and the test is continuously carried out for 120 minutes. And by calculation and statistics, the mortality of female adult mosquitoes was plotted against time as shown in fig. 1.

The experimental results of the dynamics test of the obtained No. 05 derivative on the insect killing and mosquito killing of female adult mosquitoes are shown in figure 1. As can be seen from figure 1, the novel thioethrin LCA-COS-05 sample has excellent insecticidal and mosquito killing activity on female adult mosquitoes, and the insecticidal activity is gradually enhanced along with the increase of the sample concentration. In addition, the mortality rate of the female adult mosquitoes is increased gradually with the passage of time under the condition of the same concentration, and the insecticidal and mosquito killing activity of the novel thioethrin derivative on the female adult mosquitoes is enhanced with the passage of time. In conclusion, the novel thiol-pyrethrin chemical modifier has low toxicity to larvae, but has excellent insecticidal activity to adult mosquitoes, and can be basically in a level close to that of a positive group.

Example 13 metabolic stability test

1. Method for testing oxidation stability of drug

One LCA-COS-01 number of the synthetic thiol-pyrethroid derivative is arbitrarily selected as a, and transfluthrin is selected as a standard control group number as b; weighing 20mg of the raw materials respectively, dissolving the raw materials in 2mL of methanol solvent, and stirring for 15min to fully dissolve the raw materials; then 200 mul of 30 percent hydrogen peroxide H is respectively taken by a pipette₂O₂And the time is counted once every 15min, the time is stopped after 60min, and the blank control group is dissolved in 2mL of methanol solvent by using LCA-COS-01 and is numbered as c. The stability of the compounds was checked by TLC (developing solvent: petroleum ether: ethyl acetate: 50: 1) and then three groups of samples tested under numbers a, b and c were subjected to TLC to check the stability of the compounds.

2. Results

As shown in figure 2, when the sample LCA-COS-01 is dissolved in 2mL of methanol and 200 μ L of hydrogen peroxide is added, a large amount of white bubbles are generated immediately by LCA-COS-01, and a trace amount of white bubbles are generated by transfluthrin control groupHowever, after 15min of hydrogen peroxide oxidation, when the TLC plate is spotted (developing solvent: petroleum ether: ethyl acetate: 50: 1), the blank control group c is basically kept unchanged and is the only spot, R is_f0.45; at the moment, original raw material points are basically not seen in the group a point plate, namely LCA-COS-01 of the group a is completely oxidized and disappears; b, the group point plate sample has raw material points and also has other impurity points, which indicates that the transfluthrin control group is partially oxidized by hydrogen peroxide; the effect is basically consistent with that of the 15min test after the measurement is carried out once again after 60 min.

In combination, transfluthrin has a greater oxidative stability than transfluthrin; meanwhile, according to the anti-mosquito activity in the embodiment 10 and the embodiment 11, the thiothrin is possibly inferior to the positive control group of bifenthrin and transfluthrin in larval insecticidal activity, but basically can reach the same level in adult mosquito activity (which shows that the action systems are different, so that the action effects are different), which shows that the thiothrin chemical modifier of the invention tends to the insecticidal activity of adult mosquitoes, has good killing effect on adult mosquitoes in practical application, and has high practical application and popularization value.

Example 14 cytotoxicity pretreatment experiments

1. Cytotoxicity detection method

Cells (selected from the human hepatoma cell model HepG2) were seeded into 96-well plates at a cell density of 3000 cells/80 μ L per well. After 24 hours of inoculation, 20. mu.L of transfluthrin and LCA-COS-05 compound solutions (sample concentrations were 100. mu.g/mL) were added. Cell activity was tested 48 hours after compound treatment. Staurosporicae (MCE) was used as an internal control in the plate, and after incubation, 10. mu.L/well of MTT (5mg/mL, Yeasen) was added to each well of the cell plate, and the cell plate was incubated at 37 ℃ for 4 h. The supernatant of the cell liquid plate was discarded, and 120. mu.L/well of DMSO was added to each well of the cell plate. The plates were shaken for 10min and the OD was determined using an envision (Pekinelmer) with an absorption wavelength of 570 nm.

2. Results

Experiments show that the cell model can basically grow normally in a 96-well plate, and the sample LCA-COS-05 compound has less toxicity to HepG 2; the cell survival rate is higher, and the survival rate of the LCA-COS-05 compound sample on the cell model is more than 85%. The thiol pyrethrin chemical modifier can reduce the environmental toxicity, can be widely applied to the field of insect killing and mosquito killing, and provides a new safe, efficient and stable compound for insect killing.

EXAMPLE 15 Experimental preliminary experiments on the drug resistance Activity against Aedes albopictus

1. Drug resistance testing method for mosquitoes

And (3) bifenthrin treatment: 1mg/mL bifenthrin as a positive group (150 μ L) is used to act on 3-instar larvae in 300mL of aqueous solution for about 15min (0.5mg/L), then the larvae are filtered out and put into fresh dechlorinated water for culture, the death rate is about 50-60%, and the remaining surviving larvae are cultured. The insecticidal activity test of Aedes albopictus female adult mosquitoes (Aedes albopictus femaleadult mosquitos) is carried out by adopting a CDC bottle bioassay experiment to obtain the cultured female adult mosquitoes; namely, a bifenthrin resistant female adult mosquito was tested for drug resistance using the method of example 11. Bifenthrin and sample set LCA-COS-05 were selected for testing and were tested at a concentration of 100 μ g/bottle, simultaneously.

2. Results

After 120min of test, the experiment shows that the lethality rate of the thiothrin LCA-COS-05 drug group to the resistant adult mosquitoes is over 90 percent, and the death rate is very high; however, bifenthrin at this concentration is within 5% lethal to the drug-resistant female adult mosquitoes, and the mortality rate is very low. The thioethrin LCA-COS-05 sample still has high insecticidal activity to the cultured drug-resistant mosquitoes, but bifenthrin has high drug resistance to the drug-resistant female adult mosquitoes under the same condition. The thiol pyrethroid chemical modifier can effectively solve the problem of drug resistance of the prior pyrethroid insecticides.

EXAMPLE 16 appearance characteristics of drug treated Aedes albopictus larvae

1. Method of producing a composite material

And selecting a group of concentrations (2 mu mol/mL) and amplifying by a fluorescence microscope for 20 times after the toxicity test of the chemical modifier LCA-COS-05 thioethrin for 1-instar larvae is finished for 24 hours (by adopting the method of example 10), photographing and observing the growth and living forms of the larvae, and observing the growth forms of the larvae after the action of the drugs.

2. Results

As can be seen from figure 3, the larvae added with the acetone blank control group had normal body types and very active growth activities, but the larvae after the action of the chemical modifier of the drug LCA-COS-05 thiolanthrin had teratogenic phenomena, the body length of the larvae was shortened, the head was large, the lower body was small, the larvae were malformed, the growth activities were low, and the activities were relatively lazy in the growing aqueous system. The thiol pyrethrin chemical modifier has certain lethal or teratogenic effect on larvae, and can be widely applied to the field of killing insects and mosquitoes.

The above detailed description is of the preferred embodiment for the convenience of understanding the present invention, but the present invention is not limited to the above embodiment, that is, it is not intended that the present invention necessarily depends on the above embodiment for implementation. It will be apparent to those skilled in the art that any modification of the present invention, equivalent substitutions of selected materials and additions of auxiliary components, selection of specific modes and the like, which are within the scope and disclosure of the present invention, are contemplated by the present invention.

Claims

1. The chemical modifier of the thioethrin is characterized in that the structural formula is shown as the following formula (I):

2. the method for preparing the thiolathrin chemical modification compound as claimed in claim 1, characterized by comprising the following steps:

s1, adding an ultra-dry dichloromethane solvent into trifluoro-chloro-chrysanthemic acid in a protective gas atmosphere, stirring and dissolving at room temperature, adding oxalyl chloride, stirring at room temperature for 30min, adding N, N-dimethylformamide, and reacting at room temperature for 1h under stirring;

the mass ratio of the trifluoro-chloro-chrysanthemic acid to the oxalyl chloride is 1: 3;

s2, drying the product under a vacuum condition, adding an ultra-dry dichloromethane solvent in a protective gas atmosphere, stirring and dissolving at room temperature, adding anhydrous pyridine, stirring and reacting for 30min, then adding cyclic methyl mercaptan, and carrying out esterification reaction for 2 h;

the ratio of the amounts of the substances of the trifluoro-chloro chrysanthemic acid and the anhydrous pyridine is 1: 2; the quantitative ratio of the materials of the trifluoro-chloro chrysanthemic acid and the cyclic methyl mercaptan is 1: 2;

and S3, after the reaction is finished, washing, extracting and drying to obtain a crude product, and purifying by silica gel column chromatography to obtain the thioethrin chemical modifier.

3. The use of a chemical modification of thiothrin as claimed in claim 1 as or in the preparation of a pesticide.

4. Use according to claim 3, wherein the insecticide is an anti-mosquito or mosquito repellent.

5. Use according to claim 4, wherein the mosquito in the anti-mosquito or mosquito repellent is Aedes albopictus and/or Culex fatigold.