WO2020232742A1 - New bifenthrin derivative, preparation method therefor and use thereof - Google Patents

Abstract

Provided is a bifenthrin derivative, wherein same has a structural formula as shown in formula (I). The derivative is obtained mainly through modifying and transforming benzene rings at the ortho-position and terminal-position on an intermediate benzene ring of bifenthrin; and same has an excellent insecticidal and mosquito-killing effect on both larvae and adult mosquitoes, and has a significantly reduced toxicity.

Description

A novel bifenthrin derivative and its preparation method and application Technical field

The invention belongs to the technical field of pesticides modified by small drug molecule structures. More specifically, it relates to a novel bifenthrin derivative and its preparation method and application.

Background technique

At present, blood-sucking adult mosquitoes bite humans and animals, which can spread many diseases, such as malaria, dengue fever, filariasis, Japanese encephalitis and other intermediate hosts of more than 80 pathogens. 100% of the population on all continents outside of Antarctica can be exposed to the presence of mosquitoes. The blood-sucking mosquitoes not only have a serious impact on people’s daily life, study and work, but more importantly, mosquitoes are the spread of the above-mentioned diseases. The media can cause a series of health and safety issues. Therefore, how to carry out effective mosquito control, play a good role in killing mosquitoes or repelling mosquitoes, at the same time, the harm to the human body is minimal, or even no harm, and there will be no long-term residues and any pollution to the environment. It is always mosquitoes. The key object of vector control research.

Pyrethroid insecticides are widely used spectrum insecticides that can control a variety of pests. Their insecticidal toxicity is higher than that of the older generation insecticides such as organochlorine, organophosphorus and carbamate pesticides. 10 to 100 times. After more than 30 years of development, pyrethroid insecticides have been widely used worldwide in the past 30 years due to their broad insecticidal spectrum, good effect, low residue, and environmental friendliness. , Vegetables, fruit forest pests and other agricultural pests have a good control effect, and also has a very good killing effect on indoor mosquitoes, cockroaches, head lice and other pests.

More and more studies have found that pyrethroids can interfere with the normal functions of organisms and pose a considerable threat to human and animal health. Studies have shown that long-term exposure to an environment containing pyrethroids will adversely affect the health of the human body, especially children. The research team of the inventor of the present application previously disclosed a new type of pyrethroid chemical modification and its preparation method and application in Chinese patent document CN 109651183 A, mainly through the two terminal chlorine atoms on tetrafluthrin Modification and transformation of the ester group, that is, the two end chlorine atoms are replaced with two bromine atoms, and the above ester group is replaced with an amide group structure. At the same time, the ring substitution is mainly the substitution of the aryl ring, forming a series of A novel chrysanthemum amide derivative structure containing dibromo substitution and amide structure. These new chrysanthemum amide derivatives have certain insecticidal and mosquito killing effects on both larvae and adult mosquitoes, and can improve metabolic stability and reduce environmental toxicity, and have excellent potential for transformation.

Bifenthrin is a commonly used pyrethroid insecticide and pesticide. It is also widely used in agriculture and forestry to prevent and control termite damage, and it is more widely used in agricultural production. Bifenthrin has a low resistance barrier, and long-term application of a single agent is easy to induce resistance, and because it has been widely marketed in agriculture and life hygiene, it is easy to appear between other pyrethroid insecticides Cross-resistance, especially the metabolic resistance (metabolic resistance) in the mosquito resistance mechanism reported in the relevant literature. The metabolic resistance mechanism is more common, and it is closely related to the cross-resistance of mosquitoes to multiple insecticides, that is, metabolic resistance often causes the cross-resistance of mosquitoes to other insecticides.

Compared with other pyrethroid insecticides, bifenthrin is less toxic to mammals, humans, and aquatic organisms. Among the existing pyrethroid drugs, it is a relatively safe, low-toxicity drug, and it is more This kind of sanitary and anti-epidemic and agricultural pests have rapid paralysis and lethal effects, and the price of bifenthrin is very affordable. However, due to its own increasingly serious drug resistance problem, many researchers hope to use bifenthrin as a basis to develop bifenthrin derivatives with better anti-mosquito activity, improved metabolic stability and reduced environmental toxicity. Reduce the risk of pest resistance.

Summary of the invention

The primary purpose of the present invention is to overcome the above-mentioned defects and deficiencies of the prior art, and provide a novel bifenthrin derivative, which has better anti-mosquito activity, can improve metabolic stability and reduce environmental toxicity, and can greatly reduce pests Resistance risk.

Another object of the present invention is to provide a method for preparing the above-mentioned novel bifenthrin derivatives.

Another object of the present invention is to provide the application of the above-mentioned novel bifenthrin derivative or the novel bifenthrin derivative prepared by using the above-mentioned method as an insecticide.

The above objectives of the present invention are achieved through the following technical solutions:

A new type of bifenthrin derivative, its structural formula is shown in the following formula (I):

Wherein, when R ₁ is H, R ₂ is a Cl or CF ₃ substituted group, R ₃ is H, a substituted or unsubstituted non-heterocyclic aryl or heterocyclic aryl group; or when R ₁ is a Cl substituted group, R ₂ is H, Cl or CF ₃ substituent group, R ₃ is H, substituted or unsubstituted non-heterocyclic aryl or heterocyclic aryl; the non-heterocyclic aryl is phenyl, naphthyl, anthracenyl , Phenanthryl or pyrenyl; the heterocyclic aryl group is a 5- to 9-membered monocyclic or polycyclic heterocyclic aryl group containing one or more O or S heteroatoms.

The present invention uses bifenthrin as the reference structure of the lead compound, mainly by modifying the ortho-position H, CH ₃ and the terminal benzene ring of the middle benzene ring on the bifenthrin, that is, the ortho-position H of the middle benzene ring Or CH ₃ is replaced with atomic groups such as H, Cl and CF ₃ , and the above-mentioned terminal benzene ring is replaced with substituted or unsubstituted non-heterocyclic aryl or heterocyclic aryl, thereby forming a series of new structures The new bifenthrin derivatives. These new bifenthrin derivatives can improve metabolic stability and reduce environmental toxicity, and have excellent insecticidal effects on larvae. At the same time, bifenthrin derivatives have excellent insecticidal and mosquito killing effects on adult mosquitoes. .

Further, in a preferred embodiment of the present invention, the substituents in the non-heterocyclic aryl group and the heterocyclic aryl group are selected from halogen and/or C ₁ ～C ₆ alkyl; the substitution position is ortho position, para position Position or meta position, the number of substituents is single substitution or multiple substitution.

In the present invention, the original terminal benzene ring of bifenthrin is replaced with a non-heterocyclic aryl group containing halogens such as F, Cl, and Br, or a C ₁ -C ₆ alkyl group such as methyl and ethyl. And heterocyclic aryl groups, thereby forming a series of novel bifenthrin derivatives containing polyhalogen substituted structures, further improving its insecticidal and mosquito effect and metabolic stability.

Further, in a preferred embodiment of the present invention, the non-heterocyclic aryl group is phenyl, and the heterocyclic aryl group includes thienyl, benzothienyl, furyl or pyranyl.

The present invention finds that the original terminal benzene ring of bifenthrin is replaced with phenyl, thienyl and benzothiophene that contain halogens such as F, Cl, and Br, or alkyl groups such as methyl and ethyl. At the base, the combined effect of killing insects and mosquitoes, metabolic stability and reducing toxicity is better.

Further, in a preferred embodiment of the present invention, when R ₁ is a Cl substituted group, R ₂ is a H or Cl substituted group, and R ₃ is H, containing halogen and/or C ₁ ～C ₆ alkyl substituted Or unsubstituted phenyl, thienyl or benzothienyl.

Further, in a preferred embodiment of the present invention, the halogen is selected from F, Cl, Br or I; the C ₁ -C ₆ alkyl group is selected from methyl, ethyl, n-propyl or isopropyl .

Furthermore, in a preferred embodiment of the present invention, the C ₁ -C ₆ alkyl group is a methyl group.

The invention also discloses a preparation method of the novel bifenthrin derivative, which comprises the following steps:

S1. Under protective gas atmosphere, add n-butyl lithium solution to ultra-dry tetrahydrofuran (THF) and anhydrous diisopropylamine, stir and cool to -78～-60℃, add substituted iodobenzene, React at -78～-60℃ for 2～3h, add dry ice and react at -60～-50℃ for 2～3h to obtain intermediate B containing carboxyl group;

S2. Add the solvent to Intermediate B, then add oxalyl chloride and N,N-dimethylformamide, and react at room temperature for 0.8～1h, add anhydrous pyridine and ultra-dry methanol, and carry out the esterification reaction for 2～3h , To obtain intermediate C containing ester groups;

S3. Add solvent and reducing agent to Intermediate C, and react for 30-35 min at 100-105°C in an oil bath to obtain Intermediate D containing ester groups;

S4. Add solvent, perfluthrin, oxalyl chloride and N,N-dimethylformamide to the reactor successively, and react at room temperature for 0.8～1h; add anhydrous pyridine, stir and react for 30～35min, then add Intermediate D, undergo an esterification reaction for 2 to 3 hours to obtain a novel bifenthrin derivative in which R ₃ is a H atom;

S5. Adding a new bifenthrin derivative in which R ₃ is an H atom to the solvent, adding K ₃ PO ₄ , PdCl ₂ (dppf), Pd(OAc) ₂ and mono- or poly-substituted aryl boronic acid, the aryl boronic acid selected from non-aromatic heterocyclic group or heterocyclic aromatic boronic acid and Suzuki coupling reaction at 100 ~ 105 ℃ an oil bath at 16 ~ 24h, to give wherein R ₃ is a substituted or unsubstituted non-hybrid Novel bifenthrin derivatives of ring aryl or heterocyclic aryl.

In this application, the substituted iodobenzene can be selected from 2,6-dichloroiodobenzene (A ₁ ), 2-trifluoromethyl iodobenzene (A ₂ ), 4-chloroiodobenzene (A ₃ ) and other substituted iodobenzenes containing different halogen structures.

The present invention selects different substituted iodobenzenes, such as 2,6-dichloroiodobenzene (A ₁ ), 2-trifluoromethyl iodobenzene (A ₂ ), 4-chloroiodobenzene (A ₃ ), etc. as raw materials, through The strong base function of n-butyllithium carries out the hydrogen-lithium displacement reaction on the H on the benzene ring, and the different intermediates B (B ₁ , B ₂ , B ₃ ) containing carboxyl groups are synthesized under dry ice conditions; The carboxyl group is activated by acylation, and then esterified with methanol to obtain different intermediates C (C ₁ , C ₂ , C ₃ ) containing ester groups; then the ester group is reduced to a benzyl hydroxyl group under the action of a reducing agent , Get three different intermediates D (D ₁ , D ₂ , D ₃ ) with benzyl hydroxy groups; then esterify with the acylation activated permethrin acid and intermediate D to obtain anti-mosquito Active three novel bifenthrin derivatives in which R ₃ is H atom (see No. 1, 2 and 3 novel bifenthrin derivatives in the examples of this application); finally these three 1, 2, No. 3 novel bifenthrin derivative, Suzuki coupling reaction with corresponding mono- or poly-substituted aryl boronic acid can obtain the final target compound (such as No. 4-18 novel bifenthrin in the examples of this application). derivative).

Further, in a preferred embodiment of the present invention, the whole reaction from step S1 to step S5 is preferably carried out in a protective gas atmosphere. The protective gas is nitrogen or argon.

The synthetic route of the bifenthrin derivative of the present invention is shown in the following figure:

Among them, (a) is LiTMP, THF, -78～-60℃, 2～3h/CO ₂ , -60～-50℃, 2～3h; (b) is (COCl) ₂ , CH ₂ Cl ₂ , DMF /Pyr, CH ₃ OH, 2～3h, rt; (c) is LiBH ₄ , toluene, 100～105℃, 30～35min; (d) is (COCl) ₂ , CH ₂ Cl ₂ , DMF, 30～35min ,rt; (e) is CH ₂ Cl ₂ , Pyr, 2～3h, rt; (f) is PdCl ₂ (dppf), Pd(OAc) ₂ , K ₃ PO4, toluene, 100～105℃, 16～24h .

In this synthesis route, the key step that controls the entire reaction process is the hydrogen lithium replacement reaction in step S1 and the formation of important carboxyl groups under CO ₂ conditions. The n-butyl lithium used in this step is more active and easily interacts with the air. Water vapor and oxygen react violently, so step S1 should be carried out under ultra-dry nitrogen or argon conditions, and it needs to be reacted under anhydrous, oxygen-free and low temperature environment of -78～-60℃, otherwise it will easily affect the intermediates. The yield of B can even lead to almost no product yield. In addition, the Suzuki coupling reaction of step S5 is also the key to the success or failure of the synthesis of the entire reaction structure. Among them, the choice of catalyst, base and solvent is the key, acetic acid target (Pd(OAc) ₂ ) and 1,1'-bisdiphenyl Phosphine ferrocene palladium dichloride (PdCl ₂ (dppf)) is a preferred choice. As a palladium metal catalyst, its catalytic activity is strong and relatively stable. This step also needs to be carried out under protective gas atmosphere conditions, because the Oxygen is very easy to oxidize the palladium metal catalyst to lose its catalytic activity and ultimately affect the reaction yield.

In step S5 of the present invention, tetrakis(triphenylphosphine)palladium(0) can also be added as a more efficient catalyst.

Further, in a preferred embodiment of the present invention, in step S2 and step S4, the solvent is ultra-dry dichloromethane; in step S3 and step S5, the solvent is toluene.

Further, in a preferred embodiment of the present invention, in step S2, the molar ratio of intermediate B, oxalyl chloride, anhydrous pyridine and methanol is preferably 1:2~3:2~3:1.5-2.

Further, in a preferred embodiment of the present invention, in step S3, the molar ratio of the intermediate C and the reducing agent is preferably 1:1.2 to 1.5; the reducing agent is preferably lithium borohydride.

Further, in a preferred embodiment of the present invention, in step S4, the molar ratio of trifluthrin, oxalyl chloride, anhydrous pyridine and intermediate D is preferably 3:2~3:2~3:1.

Further, in a preferred embodiment of the present invention, in step S5, the novel bifenthrin derivative in which R ₃ is an H atom, K ₃ PO ₄ , PdCl ₂ (dppf), Pd(OAc) ₂ and aromatic The molar ratio of boronic acid is preferably 1:4-5:0.1-0.2:0.02-0.03:1.5-2.

The application of the above-mentioned novel bifenthrin derivatives or the novel bifenthrin derivatives prepared by the above-mentioned method as or preparing insecticides is also within the protection scope of the present invention.

The novel bifenthrin derivatives of the present invention have good applications in the preparation of drugs for anti-mosquito, repellent, prevention and/or control of malaria, Japanese encephalitis, yellow fever, malaria, filariasis and other diseases prospect. In addition, the novel bifenthrin derivatives can also be used in pesticide chemicals and/or daily hygiene.

In the present invention, the control objects of the insecticide include mosquitoes, flies, mites, lepidopteran larvae, whiteflies, aphids or herbivorous spider mites.

Furthermore, in a preferred embodiment of the present invention, the mosquitoes include Aedes albopictus, Culex pipiens fatigue, Aedes aegypti, and/or Culex pipiens.

The present invention also provides an insecticide containing the above-mentioned novel bifenthrin derivative or the novel bifenthrin derivative prepared by the above-mentioned method. It can be used to effectively kill various pests such as mosquitoes, flies, mites, lepidopteran larvae, whiteflies, aphids, and herbivorous spider mites, while improving metabolic stability and reducing environmental toxicity, greatly reducing the risk of pest resistance .

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

(1) The present invention chemically modifies the structure of bifenthrin to obtain a series of new bifenthrin chemical modifications. These new compounds show equivalent to bifenthrin and even higher insecticidal properties than bifenthrin It has anti-mosquito activity and can improve metabolic stability and reduce environmental toxicity. It can be widely used in the field of insecticide and mosquito killing, providing new safe, efficient and stable compounds for insecticide, effectively solving the problem of drug resistance .

(2) The present invention has the advantages of simple reaction process, few reaction steps, high yield, short reaction period, good repeatability, etc., and has good application prospects and broad development space in the field of pesticides.

Description of the drawings

Figure 1 is a fitting curve of the lethality of compounds 1, 2, 3, and 4 on the first instar larvae.

Figure 2 shows the fitting curve of the lethality of compounds 5 and 6 to the first instar larvae.

Figure 3 is a fitting curve of the lethality of compounds 7 and 8 to the first instar larvae.

Figure 4 is a fitting curve of the lethality of compounds 9, 10, 11, and 12 to the first instar larvae.

Figure 5 is a fitting curve of the lethality of compounds 14, 16, 17, and 18 to the first instar larvae.

Figure 6 is a fitting curve of the lethality rate of compound 1 and 7 to female adult mosquitoes within 30 min.

Fig. 7 is the fitting curve of the lethality rate of compound 16 and 18 to female adult mosquito within 30 min.

Fig. 8 is a fitting curve of the lethality of compounds 1, 7, 16, and 18 to female adult mosquitoes within 60 min.

Figure 9 is a fitting curve of the lethality rate of compounds 1, 7, 16, and 18 to female adult mosquitoes within 120 min.

Figure 10 shows the insecticidal and mosquito kinetic curve of compound 1 on adult female mosquitoes.

Figure 11 shows the insecticidal and mosquito kinetic curve of compound 7 on adult female mosquitoes.

Figure 12 is the insecticidal and mosquito kinetic curve of compound 16 on adult female mosquitoes

Figure 13 is the insecticidal and mosquito kinetic curve of compound 18 on adult female mosquitoes.

Figure 14 shows the insecticidal and mosquito kinetic curve of bifenthrin on adult female mosquitoes.

Figure 15 shows the insecticidal and mosquito kinetic curve of tetrafluthrin against adult female mosquitoes.

Figure 16 shows the toxic effects of bifenthrin and compound 7 on HepG2 cells.

Detailed ways

The present invention will be further described below in conjunction with specific embodiments, but the embodiments do not limit the present invention in any form. Unless otherwise specified, the technical means used in the embodiments are conventional means well known to those skilled in the art. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the technical field.

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

Example 1 Synthesis of compound intermediate B (B ₁ , B ₂ , B ₃ )

1. Synthetic route

Among them, the condition (a) is LiTMP, THF, -78～-60℃, 2～3h/CO ₂ , -60～-50℃, 2～3h.

2. Synthesis steps

(1) After the reaction vessel is cleaned and dried, use high-purity ultra-dry nitrogen as the reaction protective gas, pay attention to removing the air in the reaction vessel, and do a nitrogen ball protection;

(2) Add 60 mL of ultra-dry tetrahydrofuran (THF) containing molecular sieves under the protection of nitrogen, then take anhydrous diisopropylamine (30 mmol, 8.41 mL) under the protection of nitrogen, perform magnetic stirring, and place it in a Dewar flask. Add 300±5mL of ethyl acetate into the Dewar flask, slowly add crushed dry ice to make the reaction temperature drop below -20℃, and stir for 10min at low temperature;

(3) Under the protection of nitrogen, add n-butyllithium (2.5M, 30mmol, 12mL) to the reaction vessel, and stir for 30min at a low temperature of -20°C;

(4) Immediately add crushed dry ice to the ethyl acetate solvent in the Dewar flask until the cooling temperature drops to -78～-60℃, and add substituted iodobenzene A containing different halogen structures (such as 2,4-dichloro 1 -Iodobenzene, 2-trifluoromethyliodobenzene or 4-chloroiodobenzene, the addition amount is 2.72mL, 2.9mL or 2.4mL respectively) 20mmol, and the reaction is stirred at a low temperature of -78℃ for 2h, and then under nitrogen protection Add excess crushed dry ice to the reaction vessel under conditions, and react for 2 to 3 hours at a low temperature below -50°C. Remove the Dewar until the temperature of the reaction vessel rises to room temperature; check the end of the reaction by TLC [Developing agent: V (petroleum ether)/V (ethyl acetate) = 1/1];

(5) After the reaction is completed, remove tetrahydrofuran and other volatile solvents under reduced pressure at 45°C, slowly add 50 mL of deionized water, and slowly add a 4M HCl solution under magnetic stirring to adjust the pH of the system to 1～2. Use ethyl acetate The extraction was performed three times, dried over anhydrous MgSO ₄ , filtered and concentrated by rotary evaporation to obtain the crude product as a brown solid, which was passed through silica gel column chromatography [eluent: V (petroleum ether)/V (ethyl acetate) = 16/1 ] Purification to obtain compound intermediate B (B ₁ , B ₂ , B ₃ ), a white or light gray solid, with yields of 91%, 14% and 45%, respectively.

Example 2 Synthesis of compound intermediate C (C ₁ , C ₂ , C ₃ )

1. Synthetic route

Among them, the condition (b) is (COCl) ₂ , CH ₂ Cl ₂ , DMF/Pyr, CH ₃ OH, 2 to 3 h, rt.

2. Synthesis steps

(1) Weigh out the compound intermediate B (B ₁ , B ₂ , B ₃ ) (1 g, 3.16 mmol, 3.16 mmol, 3.54 mmol) of Example 1 after purification, and add 20 mL of ultra-dry anhydrous under the protection of nitrogen After dichloromethane (DCM) was stirred to completely dissolve it, three times the amount of oxalyl chloride (9.48mmol, 9.48mmol, 10.62mmol) was added and stirred for 20-30 min;

(2) Under the protection of nitrogen, add 0.1 mL of anhydrous N,N-dimethylformamide (DMF), and after reacting at room temperature for 1 hour, the product activated by the reaction is dried in vacuum and exhausted during the operation. It is possible to reduce outside air entering the reaction device; use nitrogen as a protective gas, add ultra-dry dichloromethane solvent, stir and dissolve at room temperature, add twice the amount of anhydrous pyridine (6.32mmol, 6.32mmol, 7.08mmol), And stir the reaction for 30min; finally add twice the amount of ultra-dry methanol (6.32mmol, 6.32mmol, 7.08mmol) under nitrogen protection at room temperature, stirring for 3h or more than 3h; the end of the reaction is detected by TLC [Developer: V (Petroleum Ether)/V(ethyl acetate)=20/1];

(3) After the reaction is completed, it is washed and extracted with ethyl acetate, dried with anhydrous MgSO ₄ , filtered and concentrated to obtain the crude product of Intermediate C (C ₁ , C ₂ , C ₃ ); by silica gel column chromatography [ Eluent: V(petroleum ether)/V(ethyl acetate)=50/1] Purify to obtain compound intermediate C (C ₁ , C ₂ , C ₃ ), a colorless oily liquid, and the yield is 72% respectively , 58% and 63%.

Example 3 Synthesis of compound intermediate D (D ₁ , D ₂ , D ₃ )

1. Synthetic route

Among them, the condition (c) is LiBH ₄ , toluene, 100-105° C., 30-35 min.

2. Synthesis steps

(1) Weigh the purified intermediate C (C ₁ , C ₂ , C ₃ ) (0.5 g, 1.51 mmol, 1.51 mmol, 1.69 mmol) of the compound of Example 2 after purification, use nitrogen as protective gas, and add 20 mL of toluene solvent Then, add lithium borohydride (1.81mmol, 1.81mmol, 2.03mmol), and react in an oil bath at 100-105°C for 30-35min, and detect the end point of the reaction by TLC [Developer: V (petroleum ether)/V (acetic acid) Ethyl)=6/1];

(2) After the reaction is completed, slowly add 4M HCl solution under magnetic stirring to adjust the pH value of the system to 3~4, add 50mL of deionized water, directly extract with ethyl acetate for three times, and dry with anhydrous MgSO ₄ , Then filtered and concentrated to obtain the crude product of compound intermediate D (D ₁ , D ₂ , D ₃ ), which was passed through silica gel column chromatography [eluent: V (petroleum ether)/V (ethyl acetate) = 12/ 1] Purification to obtain compound intermediate D (D ₁ , D ₂ , D ₃ ), a white solid, with yields of 74%, 61% and 80%, respectively.

Example 4 Synthesis of Bifenthrin Derivatives 1-3

1. Synthetic route

Among them, condition (d) is (COCl) ₂ , CH ₂ Cl ₂ , DMF, 30-35 min, rt; condition (e) is CH ₂ Cl ₂ , Pyr, 2-3 h, rt.

2. Synthesis steps

(1) Weigh 1g (4.12mmol) of trifluthrin, under nitrogen protection, take 20mL of ultra-dry anhydrous CH ₂ Cl ₂ , and stir to make it completely dissolved, then add three times the amount of grass Acid chloride 12.37mmol, magnetic stirring for 20-30min, add 0.1mL of anhydrous N,N-dimethylformamide (DMF), and react at room temperature for 2h;

(2) Vacuum dry the product activated by the reaction to remove the solvent CH ₂ Cl ₂ and excess oxalyl chloride. During the operation, minimize outside air entering the reaction device; use nitrogen as a protective gas and add ultra-dry CH ₂ Cl ₂ solvent After stirring and dissolving at room temperature, add 8.24mmol of anhydrous pyridine with twice the mass, and stir the reaction for 30～35min, finally add 1.37mmol of compound intermediate D (D ₁ , D ₂ , D ₃ ), nitrogen at room temperature Under protection conditions, the reaction was stirred for 2 hours; the end of the reaction was detected by TLC [Developing solvent: V (petroleum ether)/V (ethyl acetate) = 50/1];

(3) After the completion of the reaction, ethyl acetate was added for washing extraction, dried with anhydrous MgSO ₄ , filtered and concentrated to obtain the crude product of target compound 1, 2, 3; by silica gel column chromatography [eluent: V( Petroleum ether)/V(ethyl acetate)=100/1] to obtain the target compound 1-3 as a white solid. And perform ¹ H NMR, ¹³ C NMR, HRMS and other analysis and characterization tests.

3. Results

(1) Compound 1, its molecular structure is as follows:

The structure was identified by nuclear magnetic resonance ¹ H NMR, ¹³ C NMR and HRMS analysis; (1R,S)-cis-(Z)-2,2-dimethyl-3-(2-chloro-3,3, 3-Trifluoro-1-propenyl)cyclopropanecarboxylic acid-2,6-dichloro-3-iodobenzyl ester (compound 1): white solid, yield: 71%, mp53～55℃; ¹ H NMR( 400MHz, CDCl ₃ )δ7.81(d,J=8.5Hz,1H), 7.09(d,J=8.6Hz,1H), 6.91(dp,J=9.2,1.2Hz,1H),5.55-5.33(m ,2H), 2.17(ddd,J=9.4,8.3,1.1Hz,1H),2.00(dd,J=8.4,4.6Hz,1H),1.31(s,3H),1.28(d,J=1.8Hz, 3H). ¹³ C NMR (100MHz, CDCl ₃ )δ169.86,141.11,137.15,132.74,130.09,129.67,129.52,121.91,120.74,97.55,63.13,32.92,31.13,28.91,28.47,15.20; high resolution mass spectrometry HRMS (APCI ): C ₁₆ H ₁₃ Cl ₃ F ₃ IO ₂ , theoretical value: 524.89051 [M+H] ⁺ , measured value: 524.89056.

(2) Compound 2, its molecular structure is as follows:

The structure was identified by nuclear magnetic resonance ¹ H NMR, ¹³ C NMR and HRMS analysis; (1R,S)-cis-(Z)-2,2-dimethyl-3-(2-chloro-3,3, 3-Trifluoro-1-propenyl)cyclopropanecarboxylic acid-2-trifluoromethyl-3-iodobenzyl ester (Compound 2): colorless oily liquid, yield: 68%; ¹ H NMR (600MHz, CDCl ₃ )δ7.93-7.87(m,1H),7.80(dd,J=8.3,1.7Hz,1H), 7.39(d,J=8.3Hz,1H), 6.91(dd,J=9.4,1.1Hz, 1H),5.31-5.18(m,2H),2.26–2.20(m,1H),2.09(d,J=8.3Hz,1H),1.34(s,3H),1.31(s,3H). ¹³ C NMR (150MHz, CDCl ₃ )δ169.77, 138.63, 137.57, 136.18, 129.80, 128.01, 127.75, 124.10, 121.97, 119.62, 99.07, 62.01, 32.79, 31.31, 29.22, 28.50, 15.05; High resolution mass spectrometry HRMS (APCI): C ₁₇ H ₁₄ ClF ₆ IO ₂ , theoretical value: 524.95584 [M+H] ⁺ , measured value: 524.95587.

(3) Compound 3, its molecular structure is as follows:

The structure was identified by nuclear magnetic resonance ¹ H NMR, ¹³ C NMR and HRMS analysis; (1R,S)-cis-(Z)-2,2-dimethyl-3-(2-chloro-3,3, 3-trifluoro-1-propenyl)cyclopropanecarboxylic acid-6-chloro-3-iodobenzyl ester (compound 3): white solid, mp47～50℃; yield: 73%; ¹ H NMR (600MHz, CDCl ₃ )δ7.72(d,J=2.1Hz,1H), 7.58(dd,J=8.4,2.2Hz,1H), 7.11(d,J=8.3Hz,1H), 6.93(dt,J=9.4, 1.1Hz,1H),5.21-5.10(m,2H),2.22(ddd,J=9.4,8.4,1.1Hz,1H),2.09(d,J=8.4Hz,1H),1.33(s,3H), 1.32(s,3H). ¹³ C NMR(150MHz, CDCl ₃ ) δ169.84,138.47,138.22,135.83,133.47,131.31,129.90,122.13,120.51,91.58,63.00,32.81,31.24,29.12,28.46,15.05; high resolution Mass spectrum HRMS (APCI): C ₁₆ H ₁₄ Cl ₂ F ₃ IO ₂ , theoretical value: 490.92949 [M+H] ⁺ , measured value: 490.93008.

Example 5 Synthesis of Bifenthrin Derivatives 4-18

1. Synthetic route

Among them, the condition (f) is PdCl ₂ (dppf), Pd(OAc) ₂ , K ₃ PO4, toluene, 100 to 105° C., 16 to 24 hours.

2. Synthesis steps

(1) Weigh 200mg (0.38mmol, 0.38mmol, 0.41mmol) of the purified compound 1, 2, 3 of Example 4, and add 4 times the mass of K ₃ PO ₄ (1.52mmol, 1.52mmol, 1.64mmol) ), and add 0.1 times the mass of PdCl ₂ (dppf) (0.038mmol) and 0.02 times the mass of Pd(OAc) ₂ (0.0076mmol), then add 2 times the mass of boric acid (monosubstituted or polysubstituted aromatic Boric acid, including non-heterocyclic aryl boronic acid or heterocyclic aryl boronic acid) (0.76 mmol), add 30 mL of toluene solvent, under the protection of nitrogen, magnetically stir, and react in an oil bath at 100°C for 16 hours or more; TLC detects the end point of the reaction [developer: V (petroleum ether)/V (ethyl acetate) = 50/1];

(2) After the reaction, add 50 mL of deionized water, directly extract with ethyl acetate three times, dry with anhydrous MgSO ₄ , then filter and concentrate to obtain the crude product; then pass through silica gel column chromatography [eluent: V (Petroleum ether)/V(ethyl acetate)=100/1] Purification, the target compound bifenthrin derivative (compound 4-p18) can be obtained as a colorless oily liquid. And carry out ¹ H NMR, ¹³ C NMR, HRMS and other analysis and characterization of its molecular structure.

3. Results

(1) Compound 4, its molecular structure is as follows:

The structure was identified by nuclear magnetic resonance ¹ H NMR, ¹³ C NMR and HRMS analysis; (1R,S)-cis-(Z)-2,2-dimethyl-3-(2-chloro-3,3, 3-Trifluoro-1-propenyl)cyclopropanecarboxylic acid-2,6-dichloro-3-phenylbenzyl ester (Compound 4): colorless oily liquid, yield: 62%; ¹ H NMR (400MHz, CDCl ₃ )δ7.37–7.30(m,3H), 7.30–7.25(m,3H), 7.19(d,J=8.3Hz,1H), 6.84(dt,J=9.3,1.1Hz,1H), 5.48 -5.30(m,2H),2.06(ddd,J=9.4,8.3,1.1Hz,1H),1.92(d,J=8.4Hz,1H),1.21(s,3H),1.18(s,3H). ¹³ C NMR (100MHz, CDCl ₃ ) δ 170.01, 140.71, 138.91, 135.93, 135.57, 132.43, 131.80, 130.24, 129.45, 128.35, 128.16, 121.85, 120.69, 62.21, 33.03, 31.07, 28.84, 28.48, 15.21; high resolution mass spectrometry HRMS (APCI): C ₂₂ H ₁₈ Cl ₃ F ₃ O ₂ , theoretical value: 477.03972[M+H] ⁺ , measured value: 477.04013.

(2) Compound 5, its molecular structure is as follows:

The structure was identified by nuclear magnetic resonance ¹ H NMR, ¹³ C NMR and HRMS analysis; (1R,S)-cis-(Z)-2,2-dimethyl-3-(2-chloro-3,3, 3-Trifluoro-1-propenyl)cyclopropanecarboxylic acid-2,6-dichloro-3-(4-fluoro)phenylbenzyl ester (Compound 5): colorless oily liquid, yield: 63%; ¹ H NMR(400MHz, CDCl ₃ )δ7.32(d,J=8.3Hz,1H), 7.29–7.24(m,2H), 7.19(d,J=8.3Hz,1H), 7.08–7.00(m,2H ), 6.85(dt,J=9.3,1.0Hz,1H),5.48–5.32(m,2H),2.13–2.05(m,1H),1.94(d,J=8.4Hz,1H),1.23(s, 3H), 1.20 (s, 3H). ¹³ C NMR (100MHz, CDCl ₃ ) δ 169.99,162.69,139.69,137.10,136.14,135.63,134.83,132.37,131.94,131.23,1330.21,128.22,122.05,120.51,115.50,115.29 , 62.17, 33.03, 31.08, 28.85, 28.49, 15.21; high resolution mass spectrometry HRMS (APCI): C ₂₂ H ₁₇ Cl ₃ F ₄ O ₂ , theoretical value: 495.0030 [M+H] ⁺ , measured value: 495.03061.

(3) Compound 6, its molecular structure is as follows:

The structure was identified by nuclear magnetic resonance ¹ H NMR, ¹³ C NMR and HRMS analysis; (1R,S)-cis-(Z)-2,2-dimethyl-3-(2-chloro-3,3, 3-Trifluoro-1-propenyl)cyclopropanecarboxylic acid-2,6-dichloro-3-(3,5-difluoro)phenylbenzyl ester (Compound 6): colorless oily liquid, yield: 51 %; ¹ H NMR(600MHz, CDCl ₃ )δ7.43(d,J=8.3Hz,1H), 7.27(d,J=8.3Hz,1H), 6.95–6.89(m,3H), 6.86(tt, J=8.9,2.3Hz,1H),5.54–5.41(m,2H), 2.18(ddd,J=9.4,8.3,1.1Hz,1H),2.02(d,J=8.4Hz,1H),1.32(s , 3H), 1.29 (s, 3H). ¹³ C NMR (150MHz, CDCl ₃ ) δ169.81,163.42,161.83,141.57,138.27,136.79,135.17,132.11,131.84,130.00,128.27,121.85,120.41,112.61,112.60, 103.59, 61.84, 32.83, 30.95, 28.76, 28.34, 15.06; high resolution mass spectrometry HRMS (APCI): C ₂₂ H ₁₆ Cl ₃ F ₅ O ₂ , theoretical value: 513.02088[M+H] ⁺ , measured value: 513.02118.

(4) Compound 7, its molecular structure is as follows:

The structure was identified by nuclear magnetic resonance ¹ H NMR, ¹³ C NMR and HRMS analysis; (1R,S)-cis-(Z)-2,2-dimethyl-3-(2-chloro-3,3, 3-trifluoro-1-propenyl)cyclopropanecarboxylic acid-2,6-dichloro-3-(2-fluoro)phenylbenzyl ester (Compound 7): colorless oily liquid, yield: 58%; ¹ H NMR (400MHz, CDCl ₃ ) δ 7.37--7.30 (m, 2H), 7.24 - 7.14 (m, 3H), 7.14 - 7.05 (m, 1H), 6.89 - 6.82 (m, 1H), 5.49 - 5.33 ( m,2H),2.09(t,J=8.8Hz,1H),1.95(d,J=8.4Hz,1H),1.23(s,3H),1.21(s, 3H). ¹³ C NMR(100MHz,CDCl ₃ )δ169.85,158.49,136.56,134.86,132.53,131.74,131.31,130.31,130.07,127.97,126.34,124.03,121.70,120.54,115.78,61.95,32.87,30.93,29.71,28.52,15.05; High resolution mass spectrometry HRMS (APCI ): C ₂₂ H ₁₇ Cl ₃ F ₄ O ₂ , theoretical value: 495.0030[M+H] ⁺ , measured value: 495.03116.

(5) Compound 8, its molecular structure is as follows:

The structure was identified by nuclear magnetic resonance ¹ H NMR, ¹³ C NMR and HRMS analysis; (1R,S)-cis-(Z)-2,2-dimethyl-3-(2-chloro-3,3, 3-Trifluoro-1-propenyl)cyclopropanecarboxylic acid-2,6-dichloro-3-(2-trifluoromethoxy)phenylbenzyl ester (Compound 8): colorless oily liquid, yield: 42%; ¹ H NMR(400MHz,CDCl ₃ )δ7.50–7.41(m,2H),7.40–7.35(m,2H),7.33–7.29(m,1H),7.25(d,J=8.2Hz, 1H), 6.92 (dd, J = 13.5, 9.2 Hz, 1H), 5.58–5.40 (m, 2H), 2.17 (t, J = 8.8 Hz, 1H), 2.03 (d, J = 8.4 Hz, 1H), 1.30 (s, 3H), 1.29 (s, 3H). ¹³ C NMR (100MHz, CDCl ₃ ) δ170.00,146.63,136.71,136.55,135.75,132.50,132.08,131.79,131.78,130.24,130.08,128.02,126.79,122.94 ,121.77,120.80,119.23,119.21,62.03,33.05,31.09,28.84,28.48,15.20; high resolution mass spectrometry HRMS (APCI): C ₂₃ H ₁₇ Cl ₃ F ₆ O ₃ , theoretical value: 561.02202[M+H] ⁺ , Measured value: 561.02271.

(6) Compound 9, its molecular structure is as follows:

The structure was identified by nuclear magnetic resonance ¹ H NMR, ¹³ C NMR and HRMS analysis; (1R,S)-cis-(Z)-2,2-dimethyl-3-(2-chloro-3,3, 3-Trifluoro-1-propenyl)cyclopropanecarboxylic acid-2,6-dichloro-3-(2-chloro)phenylbenzyl ester (compound 9): colorless oily liquid, yield: 63%; ¹ H NMR(400MHz, CDCl ₃ )δ7.43-7.38(m,1H), 7.34(d,J=8.3Hz,1H), 7.31-7.22(m,2H), 7.16(dd,J=7.8,3.0Hz ,2H), 6.85(dtd,J=9.2,3.9,2.9,1.4Hz,1H),5.47–5.25(m,2H),2.09(t,J=8.8Hz,1H),1.94(dd,J=10.9 ,8.4Hz,1H),1.23(d,J=2.1Hz,3H),1.20(d,J=2.4Hz,3H). ¹³ C NMR(100MHz,CDCl ₃ )δ168.82,137.14,136.59,135.92,135.42, 132.34,131.10,130.63,129.96,129.57,129.07,128.59,127.42,126.90,125.67,120.78,119.41,60.85,60.30,31.85,29.91,27.43,14.03; High resolution mass spectrometry HRMS (APCI): C ₂₂ H ₁₇ Cl ₄ F ₃ O ₂ , theoretical value: 511.00075[M+H] ⁺ , measured value: 511.00095.

(7) Compound 10, its molecular structure is as follows:

The structure was identified by nuclear magnetic resonance ¹ H NMR, ¹³ C NMR and HRMS analysis; (1R,S)-cis-(Z)-2,2-dimethyl-3-(2-chloro-3,3, 3-Trifluoro-1-propenyl)cyclopropanecarboxylic acid-2,6-dichloro-3-(2,3-dichloro)phenylbenzyl ester (Compound 10): colorless oily liquid, yield: 46 %; ¹ H NMR (400MHz, CDCl ₃ )δ7.46 (dd, J = 8.1, 1.6 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.31-7.04 (m, 3H), 6.85 ( dd,J=9.3,6.0Hz,1H),5.47–5.26(m,2H),2.16–2.05(m,1H),1.94(dd,J=9.6,8.4Hz,1H),1.23(d,J= 2.3Hz, 3H), 1.21 (d, J=3.0Hz, 3H). ¹³ C NMR (100MHz, CDCl ₃ ) δ169.82,139.69,137.88,136.95,136.77,136.19,133.51,131.80,130.59,130.44,130.04,129.11 ,128.45,128.08,127.24,121.90,120.84,61.78,32.86,30.94,29.70,28.47,15.06; high resolution mass spectrometry HRMS (APCI): C ₂₂ H ₁₆ Cl ₅ F ₃ O ₂ , theoretical value: 544.96178[M+H ] ⁺ , Measured value: 544.96275.

(8) Compound 11, its molecular structure is as follows:

The structure was identified by nuclear magnetic resonance ¹ H NMR, ¹³ C NMR and HRMS analysis; (1R,S)-cis-(Z)-2,2-dimethyl-3-(2-chloro-3,3, 3-Trifluoro-1-propenyl)cyclopropanecarboxylic acid-2,6-dichloro-3-(3,4-difluoro)phenylbenzyl ester (Compound 11): colorless oily liquid, yield: 57 %; ¹ H NMR(400MHz, CDCl ₃ )δ7.34(s,1H), 7.20–7.08(m,3H), 7.04–6.97(m,1H), 6.84(dt,J=9.4,1.1Hz,1H ), 5.46–5.30(m,2H),2.09(ddd,J=9.4,8.3,1.2Hz,1H),1.94(d,J=8.4Hz,1H),1.23(s,3H),1.20(s, 3H). ¹³ C NMR (100MHz, CDCl ₃ ) δ169.93,151.43,148.77,138.56,136.62,135.49,132.18,130.20,128.35,125.80,121.98,120.57,118.76,117.33,62.03,33.00,31.08,29.84,28.64, 15.17; High resolution mass spectrum HRMS (APCI): C ₂₂ H ₁₆ Cl ₃ F ₅ O ₂ , theoretical value: 513.02088 [M+H] ⁺ , measured value: 513.02208.

(9) Compound 12, its molecular structure is as follows:

The structure was identified by nuclear magnetic resonance ¹ H NMR, ¹³ C NMR and HRMS analysis; (1R,S)-cis-(Z)-2,2-dimethyl-3-(2-chloro-3,3, 3-Trifluoro-1-propenyl)cyclopropanecarboxylic acid-2-trifluoromethyl-3-(4-fluoro)phenylbenzyl ester (Compound 12): colorless oily liquid, yield: 60%; ¹ H NMR (400MHz, CDCl ₃ ) δ7.75 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.62-7.51 (m, 3H), 7.21-7.13 (m, 2H ), 6.93(dt,J=9.3,1.1Hz,1H),5.36(s,2H),2.21(ddd,J=9.3,8.4,1.1Hz,1H),2.07(d,J=8.3Hz,1H) , 1.31 (d, J = 2.2Hz, 6H). ¹³ C NMR (100MHz, CDCl ₃ ) δ169.80,163.10,144.07,135.44,134.64,129.81,128.98,128.90,128.77,126.91,126.70,126.46,122.50,120.38, 116.12, 115.91, 62.85, 32.77, 31.10, 28.93, 28.35, 14.89; high resolution mass spectrum HRMS (APCI): C ₂₃ H ₁₈ ClF ₇ O ₂ , theoretical value: 493.08108 [M+H] ⁺ , measured value: 493.08139.

(10) Compound 13, its molecular structure is as follows:

The structure was identified by nuclear magnetic resonance ¹ H NMR, ¹³ C NMR and HRMS analysis; (1R,S)-cis-(Z)-2,2-dimethyl-3-(2-chloro-3,3, 3-Trifluoro-1-propenyl)cyclopropanecarboxylic acid-2-trifluoromethyl-3-(3,5-difluoro)phenylbenzyl ester (Compound 13): colorless oily liquid, yield: 64 %; ¹ H NMR(400MHz,CDCl ₃ )δ7.78(d,J=8.1Hz,1H), 7.73–7.69(m,1H), 7.64–7.56(m,1H), 7.16–7.07(m,2H ), 6.96–6.82(m, 2H), 5.43–5.29(m, 2H), 2.26–2.18(m, 1H), 2.09(d, J=8.3Hz, 1H), 1.32(s, 3H), 1.31( s, 3H). ¹³ C NMR (100MHz, CDCl ₃ ) δ169.74,164.66,162.18,142.60,135.03,129.69,128.63,128.25,127.09,126.76,122.30,121.80,110.26,103.71,62.65,32.71,31.13,28.97, 28.34, 14.89; high resolution mass spectrum HRMS (APCI): C ₂₃ H ₁₇ ClF ₈ O ₂ , theoretical value: 511.07166[M+H] ⁺ , measured value: 511.07169.

(11) Compound 14, its molecular structure is as follows:

The structure was identified by nuclear magnetic resonance ¹ H NMR, ¹³ C NMR and HRMS analysis; (1R,S)-cis-(Z)-2,2-dimethyl-3-(2-chloro-3,3, 3-Trifluoro-1-propenyl)cyclopropanecarboxylic acid-6-chloro-3-thienylbenzyl ester (Compound 14): white solid, yield: 59%, mp50～52℃; ¹ H NMR (400MHz, CDCl ₃ )δ7.63(d,J=2.3Hz,1H), 7.51(dd,J=8.3,2.3Hz,1H), 7.40(d,J=8.3Hz,1H), 7.31(ddt,J=4.9 , 3.2, 1.6 Hz, 2H), 7.09 (dd, J = 5.0, 3.7 Hz, 1H), 6.96 (dt, J = 9.4, 1.1 Hz, 1H), 5.26 (q, J = 13.1 Hz, 2H), 2.22 (ddd, J = 9.5, 8.3, 1.1 Hz, 1H), 2.10 (d, J = 8.4 Hz, 1H), 1.35-1.30 (m, 6H). ¹³ C NMR (100MHz, CDCl ₃ ) δ 170.03, 142.82, 134.10 ,133.62,132.66,130.19,130.05,128.33,127.31,127.02,125.60,123.90,122.05,120.55,63.78,32.95,31.23,29.06,28.51,15.11; high resolution mass spectrometry HRMS (APCI): C ₂₀ H ₁₇ Cl ₂ F ₃ SO ₂ , theoretical value: 447.0206[M+H] ⁺ , measured value: 447.02087.

(12) Compound 15, its molecular structure is as follows:

The structure was identified by nuclear magnetic resonance ¹ H NMR, ¹³ C NMR and HRMS analysis; (1R,S)-cis-(Z)-2,2-dimethyl-3-(2-chloro-3,3, 3-Trifluoro-1-propenyl)cyclopropanecarboxylic acid-6-chloro-3-benzothienyl benzyl ester (Compound 15): white solid, yield: 54%, mp56～59°C; ¹ H NMR( 400MHz, CDCl ₃ )δ7.84(dd,J=7.5,1.5Hz,1H),7.78(dd,J=7.1,1.8Hz,1H),7.74(d,J=2.3Hz,1H),7.60(dd ,J=8.3,2.3Hz,1H),7.54(s,1H),7.43(d,J=8.3Hz,1H),7.41-7.32(m,2H),7.00(dd,J=9.4,1.1Hz, 1H),5.34–5.22(m,2H),2.29–2.21(m,1H), 2.13(d,J=8.3Hz,1H),1.35(d,J=2.1Hz,6H). ¹³ C NMR(100MHz ,CDCl ₃ )δ170.01,142.51,140.63,139.65,134.21,133.46,133.45,130.24,130.05,127.71,127.44,124.85,123.85,122.41,122.04,120.55,120.32,63.70,32.92,31.24,29.11,28.48,15.09; High resolution mass spectrometry HRMS (APCI): C ₂₄ H ₁₉ Cl ₂ F ₃ SO ₂ , theoretical value: 497.0361 [M+H] ⁺ , measured value: 497.0368.

(13) Compound 16, its molecular structure is as follows:

The structure was identified by nuclear magnetic resonance ¹ H NMR, ¹³ C NMR and HRMS analysis; (1R,S)-cis-(Z)-2,2-dimethyl-3-(2-chloro-3,3, 3-Trifluoro-1-propenyl)cyclopropanecarboxylic acid-6-chloro-3-(5-chloro)thienylbenzyl ester (Compound 16): white solid, yield: 66%, mp48-50°C; ¹ H NMR (400MHz, CDCl ₃ ) δ7.44 (dd, J = 1.8, 0.9 Hz, 1H), 7.32 (d, J = 1.7 Hz, 2H), 7.23-7.16 (m, 1H), 6.98 (d, J =3.9Hz,1H), 6.90–6.79(m,2H), 5.16(dd,J=4.3,2.1Hz,2H), 2.18–2.10(m,1H), 2.01(d,J=8.4Hz,1H) , 1.25 (d, J = 3.7 Hz, 6H). ¹³ C NMR (100MHz, CDCl ₃ ) δ 169.99,141.32,134.36,133.76,132.95,130.03,129.77,127.43,126.84,126.58,123.11,121.93,120.77,63.66, 32.93, 31.26, 29.08, 28.53, 15.12; high resolution mass spectrum HRMS (APCI): C ₂₀ H ₁₆ Cl ₃ F ₃ SO ₂ , theoretical value: 480.98159[M+H] ⁺ , measured value: 480.98187.

(14) Compound 17, its molecular structure is as follows:

The structure was identified by nuclear magnetic resonance ¹ H NMR, ¹³ C NMR and HRMS analysis; (1R,S)-cis-(Z)-2,2-dimethyl-3-(2-chloro-3,3, 3-Trifluoro-1-propenyl)cyclopropanecarboxylic acid-6-chloro-3-(5-methyl)thienylbenzyl ester (Compound 17): white solid, yield: 72%, mp 45～47°C; ¹ H NMR (600MHz, CDCl ₃ ) δ 7.57 (d, J = 2.3 Hz, 1H), 7.44 (dd, J = 8.4, 2.2 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.10 (d, J = 3.5Hz, 1H), 6.98 (d, J = 9.4 Hz, 1H), 6.74 (dt, J = 3.5, 1.1 Hz, 1H), 5.30-5.19 (m, 2H), 2.52 (s, 3H), 2.23 (t, J = 8.9 Hz, 1H), 2.11 (d, J = 8.3 Hz, 1H), 1.34 (s, 6H). ¹³ C NMR (150MHz, CDCl ₃ ) δ 170.01, 140.37, 133.91, 132.05 ,130.06,129.73,126.78,126.51,126.47,121.98,120.55,63.79,32.92,31.20,29.04,28.46,15.55,15.07; High resolution mass spectrometry HRMS (APCI): C ₂₁ H ₁₉ Cl ₂ F ₃ SO ₂ , theoretical value :461.03621[M+H] ⁺ , measured value: 461.03699.

(15) Compound 18, its molecular structure is as follows:

The structure was identified by nuclear magnetic resonance ¹ H NMR, ¹³ C NMR and HRMS analysis; (1R,S)-cis-(Z)-2,2-dimethyl-3-(2-chloro-3,3, 3-Trifluoro-1-propenyl)cyclopropanecarboxylic acid-6-chloro-3-(5-bromo)thienylbenzyl ester (Compound 18): white solid, yield: 43%, mp49～53℃; ¹ H NMR (600MHz, CDCl ₃ ) δ 7.85 (dd, J = 7.9, 1.5 Hz, 1H), 7.41-7.36 (m, 1H), 6.99 (t, J = 7.8 Hz, 1H), 6.91 (dt, J ＝9.4,1.1Hz,1H),5.28–5.20(m,2H),2.21(ddd,J＝9.4,8.3,1.1Hz,1H),2.07(d,J＝8.3Hz,1H),1.32(s, 3H), 1.31(s, 3H). ¹³ C NMR (150MHz, CDCl ₃ ) δ170.02,144.22,134.33,133.72,132.91,131.15,130.03,129.75,127.05,126.73,124.06,122.01,120.54,112.30,63.78,32.94 , 0.19, 29.02, 28.50, 15.09; high resolution mass spectrum HRMS (APCI): C ₂₀ H ₁₆ BrCl ₂ F ₃ SO ₂ , theoretical value: 524.93108 [M+H] ⁺ , measured value: 524.93024.

This example gives part of the link when the non-heterocyclic aryl group in R ₃ is phenyl, the heterocyclic aryl group is thienyl or benzothienyl, and the substituents are F, Cl, Br, OCF ₃ , CH ₃ The structure and results of the phenthrin derivatives (compounds 4-18) are based on the same synthetic principles and similar synthetic methods, and those skilled in the art can, based on the disclosure of the present invention and the prior art, according to actual synthesis needs and goals, When the non-heterocyclic aryl group in R ₃ is naphthyl, anthryl, phenanthryl or pyrenyl, and the heterocyclic aryl group is a 5- to 9-membered monocyclic or polycyclic ring containing one or more O or S heteroatoms When the heterocyclic aryl group (such as furanyl or pyranyl, etc.), the substituent is I or other C ₁ ～C ₆ alkyl groups (such as ethyl, n-propyl or isopropyl, etc.) except methyl The structure of phenthrin derivatives.

Example 6 A 24-well plate activity test method of 1st instar larvae of Aedes albopictus

1. Test method

(1) Sample concentration configuration: Use acetone as the solvent, and use bifenthrin and transfluthrin as the positive control group of bifenthrin derivatives (compounds 1-18), and use acetone as a solvent Double dilution method to make 32,16,8,4,2,1,0.5,0.25,0.125,0.0625,0.03125,0.015625,0.0078125μmol/mL and (7.8125,3.90625,1.953125,0.9765625,0.48828125,0.244140625,0.1220703125nmol /mL) and other 19 or unequal concentration gradients are placed in a 2mL centrifuge tube, each concentration is configured with 200mL (sample solution is stored at 4℃), the blank control group is the 100% acetone solvent.

(2) Larvae activity test method: The 24-well plate method was used to test all the drugs to be tested for insecticidal activity of Aedes albopictus larva, and tetraflufenthrin and biphenyl were used. Pyrethrin was used as a positive control group. Larvae semi-lethal concentration test: In this experiment, the semi-lethal concentration of Aedes albopictus larvae was tested for all compounds in the three series of bifenthrin derivatives, tetramethrin derivatives and thiomethrin derivatives in a sterile 24-well plate. Activity test. The specific method is as follows:

Use acetone (Aceton) solvent to obtain 19 gradients of diluted sample compounds using the two-fold dilution method, and then use a pipette to add 985 μL of dechlorinated water and 5 μL of food solution (13 mg/mL of Fish powder food solution), and add more than 5 first-instar larvae (5-10 larvae, with an appearance feature of 1 to 1.5mm body length, and white or off-white) into each well plate. Then add 10 μL of the appropriate sample compound solution with 8 consecutive concentration gradients to each well plate or expand the concentration gradient range to cover 0% to 100% mortality (usually starting from a high concentration of 32 μmol/mL), each The sample concentration was repeated three times in parallel; after incubating at room temperature of 26～28℃ for 24h (light:dark=12:12), confirm that the death form is if the larva is gently touched with a fine needle or the tip of a pipette If it doesn't move, it is regarded as death. The concentration effect of the sample was determined as the percentage of larvae that died in the well plate within 24 hours. Record the mortality or lethality of each well plate, and finally calculate the LC ₅₀ value of the half-lethal concentration of all test compounds to the first instar larvae. The statistical results are shown in Table 1 below.

(3) Evaluation of the validity of the larval activity experiment operation data: the individual differences and birth time differences of the first instar larvae are mainly considered, so the mortality of the blank group (the end of the bioassay after 24h) shall not exceed 5 % Or more, or after 24 hours in the blank group, the number of larvae surviving in each well is not less than the minimum number initially added.

Calculate the lethality of each concentration, perform curve fitting through the relationship between the concentration and the lethality, and obtain the LC ₅₀ value of the half-lethal concentration of all test sample compounds to the first instar larvae from the curve calculation data.

Among them, A ₁ is the number of single-well test larvae added in the 24-well plate, and B ₁ is the number of surviving single-well test larvae in the 24-well plate.

2. Results of the killing activity of bifenthrin derivatives 1-18 against the first instar larvae of Aedes albopictus

(1) The fitting curves of the lethality of bifenthrin derivatives 1-18 to the first instar larvae are shown in Figure 1 to Figure 5, respectively.

(2) See Table 1 for the killing activity of bifenthrin derivatives 1-18 against the first instar larvae of mosquitoes.

Table 1 The killing activity of bifenthrin derivatives 1-18 against the first instar larvae of mosquitoes

Note: Each experiment was repeated 3 times, the data in the table represents the average (n=3) ± standard deviation. LC ₅₀ is the median lethal concentration. The mosquito selection was a sensitive strain of Aedes albopictus, and the mortality rate of adults in the blank group was generally within 5%. ^a The half-lethal concentration for the first instar larvae of Aedes albopictus; ^b Transfluthrin, positive control group; ^c Bifenthrin, positive control group.

From the larval activity data in Table 1, it can be seen that, except for compounds 2, 12, 13 and 15, all other bifenthrin derivatives 1, 3, 4, 5, 6, 7, 8, 9, 10, 11 ,14,16,17,18 all have excellent killing activity on the first instar larvae, especially the 5 target compounds 4,5,7,9 and 11 with dichloro-substituted benzene ring in the middle benzene ring to kill the larvae The activities are close to or higher than the positive group of bifenthrin and tetrafluthrin. The LC ₅₀ value of the highest insecticidal activity of bifenthrin derivative 7 to first-instar larvae reached 0.02μM, which was nearly 4 times higher than that of the positive group of bifenthrin.

Example 7 Method for testing the activity of female adults of Aedes albopictus

1. Test method

(1) Sample concentration configuration: Use acetone as a solvent to combine all compounds of bifenthrin derivatives (1-18), and the positive control group uses bifenthrin and transfluthrin. The acetone solvent is made up of 1600, 800, 400, 200, 100, 50, 25, 12.5, 6.25, 3.125, 1.563, 0.781, 0.391, 0.195, 0.977, 0.488, 0.244, 0.122 μg/mL and other 18 or unequal concentration gradients using the double dilution method , Each concentration of 5mL solution is placed in a 10mL brown sample bottle (the sample solution is stored at 4°C), and the 100% acetone solvent selected for the blank control group.

(2) Female adult mosquito activity test method: The CDC bottle bioassay experiment was used to test the insecticidal activity of Aedes albopictus female adult mosquito on the compound with the drug to be tested, and tetraflurane Ester and bifenthrin were used as positive controls. The mortality of adult mosquitoes in the blank group was generally controlled within 3%.

Activity test of female adult mosquitoes: In the experiment of female adult mosquitoes, all the adult mosquitoes after pupalization are cultured in 10% sugar water and dechlorinated water for 3 to 5 days, and then the female adult mosquitoes are used for their blood-sucking properties to isolate female mosquitoes. The adult mosquito experiment adopts standard CDC bottle bioassay (contact method). The experiment first chooses to use acetone (Aceton) solvent and uses the two-fold dilution method to obtain 6 consecutive gradients of all the tested sample compounds after dilution, and then do each sample compound. Appropriate high and low 2 groups of different concentrations, each concentration is repeated 3 times in parallel, 1mL of sample solution is added to each Wheaton bottle, the diagnostic dose is in place, the concentration of the sample added is expressed as: μg/bottle, evenly coated on Place the entire Wheaton bottle on the inner wall of the bottle and place it in a dark, ventilated and cool place for 2 to 3 hours. After it is completely dry, add 15 to 25 or more female adult mosquitoes to each Wheaton bottle and record every 15 minutes The number of deaths of mosquitoes is confirmed to be the basic characteristic behaviors of adult mosquitoes in flight or standing. Finally, the lethality rates of 3 different diagnostic times of 30min, 60min and 120min for female adult mosquitoes at different levels of different concentrations in all samples to be tested were calculated. The statistical results are shown in Table 2 below.

(3) Validity evaluation of experimental operating data for adult mosquitoes: Mainly consider the individual differences and culture time differences of female adult mosquitoes. Therefore, the mortality of the blank group must be considered every time (the bioassay ends after 2h). If the mortality of the blank group after 2 hours is within 3%, the results of this experiment are valid and reliable; if the mortality of the blank group after 2 hours is between 3% and 10%, you need to use Abbott's formula to correct the test results ; If the mortality rate of the blank group is more than 10% after 2h, you need to abandon the results of this experiment and retest.

(4) Test method of half-lethal concentration of some sample compounds to female adult mosquitoes: The target compound with the strongest insecticidal activity is calculated in the previous step (2), and the bifenthrin derivative with the best activity is selected ( 1,7,16,18), as well as the positive control groups Bifenthrin and Transfluthrin, using their configured 18 sets of sample concentrations for testing, using 12 consecutive concentration gradients or more The sample compound solution is tested for the activity of adult female mosquitoes in order to cover 0%-100% mortality. Continuous testing for 120 minutes, all experimental operations are consistent with the previous step (2) operation process; the mortality rate corresponding to the concentration and time is obtained and calculated according to the curve , Using the nonlinear fitting curve to calculate the LC ₅₀ value of the LC _{50 in} 3 different time periods of 30 min, 60 min and 120 min. The statistical results are shown in Table 3 below.

Mortality rate of adult mosquitoes:

Abbott’s formula:

Calculate the lethality of each concentration, perform curve fitting through the relationship between the concentration and the lethality, and obtain the LC ₅₀ value of the half-lethal concentration of some test sample compounds to female adult mosquitoes from the curve calculation data.

Among them, A ₂ is the number of test female adult mosquitoes added in a single bottle in the Wheaton bottle, and B ₂ is the number of surviving female test adult mosquitoes in a single bottle of Wheaton bottle.

2. Test results of the killing activity of bifenthrin derivatives against female adult Aedes albopictus

(1) The test results of the killing activity of bifenthrin derivatives 1-18 against female adults of Aedes albopictus are shown in Table 2.

Table 2 Bifenthrin derivatives 1-18 against CDC bottle bioassay experimental killing activity of female adult mosquitoes

Note: Each experiment was repeated 3 times, the data in the table represents the average (n=3) ± standard deviation. μg/bottle means the diagnostic dose is added to each Wheaton bottle. The mortality rate of adult mosquitoes in the blank group is generally within 3%. ^a The lethality rate of the compound at two different concentrations of female adult mosquitoes within 30 min; ^b The lethality rate of compound at two different concentrations of female adult mosquitoes within 60 min; ^c The lethality rate of compound at two different concentrations of female adult mosquitoes within 120 min .

From the adult mosquito activity data in Table 2, it can be seen that when the diagnostic dose concentration is 12.5 μg/bottle and 1.56 μg/bottle, almost all bifenthrin derivatives have certain mosquito-killing activity. In particular, the anti-mosquito activity of compounds 1, 7, 16 and 18 is particularly obvious. It was tested at a concentration of 12.5 μg/bottle and a diagnosis time of 30 minutes. The anti-mosquito activity of 60 minutes and 120 minutes was basically the same as that of bifenthrin and four. Similar to flufenthrin, the mortality rate of adult mosquitoes is basically above 97%; in particular, compound 1, 7, 16 and 18 test samples at a diagnostic dose concentration of 1.56μg/bottle, the diagnosis time is 30min, 60min and 120min paired The killing activity of mosquitoes was significantly higher than that of the positive group of bifenthrin, but slightly weaker than that of tetrafluthrin against adult mosquitoes. In particular, the tested diagnostic dose concentration of compound 18 is 1.56μg/bottle, and its highest lethality rate to adult mosquitoes can reach 98%.

(2) Fitting curves of the lethality of some bifenthrin derivatives (1, 7, 16, 18) to female adult mosquitoes within 30 min, 60 min, and 120 min are shown in Figure 6 to Figure 9, respectively.

(3) The LC _{50 of} some bifenthrin derivatives (1, 7, 16, 18) against adult female mosquitoes is shown in Table 3.

Table 3 The LC _{50 of} some bifenthrin derivatives (1, 7, 16, 18) to female adult mosquitoes

Note: Each experiment was repeated 3 times, the data in the table represents the average (n=3) ± standard deviation. LC ₅₀ is the half-lethal concentration. The mosquitoes are selected as sensitive strains of Aedes albopictus. The mortality rate of adult mosquitoes in the blank group is generally within 3%. ^a The half lethal concentration of compound to female adult mosquitoes within 30 min; ^b The half lethal concentration of compound to female adult mosquitoes within 60 min; ^c The half lethal concentration of compound to female adult mosquitoes within 120 min.

From Table 2 of the adult mosquito lethality test results, it can be seen that compounds 1, 7, 16 and 18 have excellent killing activity against adult mosquitoes, and the activity at a concentration of 1.56 μg/bottle is significantly higher than the positive group bifenthrin; Therefore, in order to further understand the accurate comparison between the 4 target compounds and the positive group on the lethal effect of adult mosquitoes. The present invention uses the CDC bottle bioassay (contact method) to further expand the concentration range test for the four compounds and the two positive groups, and finally uses curve fitting to calculate the corresponding LC ₅₀ value of the lethal concentration.

It can be seen from the half-lethal concentration data in Table 3 that the LC _{50 of the} compound 1, 7, 16 and 18 for adult mosquitoes is lower than bifenthrin at 30 min and 60 min, that is, it is in these two time periods. The lethal effect of adult mosquitoes is significantly better than that of bifenthrin; at 30 min, the highest mosquito-killing activity is compound 18, with LC ₅₀ reaching 0.62 μg/bottle, which is close to higher than bifenthrin in activity 8 times, the other three compounds 1, 7 and 16 are also about 4 times higher than bifenthrin. At 60 min, the highest mosquito-killing activity was compound 18, with LC ₅₀ reaching 0.40 μg/bottle, and the activities of other compounds were significantly higher than bifenthrin by about 4 times. At 120 min, the highest anti-mosquito activity is compound 7 and 18, with LC ₅₀ reaching 0.28 μg/bottle and 0.26 μg/bottle, the activity is also higher than bifenthrin, and other compounds 1 and 16 are in activity with biphenyl Pyrethrin is basically similar. But at the same time, it can be seen that tetrafluthrin is significantly better than bifenthrin and its derivatives in adult mosquito activity.

Example 8 Kinetic test experiment on insecticidal and mosquito killing of some compounds against adult female mosquitoes

1. Test method

Adult mosquito insecticide and mosquito kinetics test experiment: the same CDC bottle bioassay experiment method is used to select the best active sample group bifenthrin derivatives (1,7,16,18) and the positive control group bifenthrin (Bifenthrin) and Transfluthrin (Transfluthrin) compounds were tested on the kinetics of the insecticidal activity of Aedes albopictus female adult mosquito. Select the tested sample compounds to conduct kinetic experiments with 6 different concentration gradients. All the tests are the same as the activity test steps of female adult mosquitoes. The number of female adult mosquitoes living/death in the Wheaton bottle is measured every 15 minutes, and finally calculated The fatality rate at the corresponding time point was calculated, and the test was continued for 120 minutes. And through calculation and statistics, the death rate of female adult mosquitoes was drawn over time. The changes of compounds 1, 7, 16, 18, bifenthrin and tetrafluthrin were shown in Figure 10 and Figure 10 11. As shown in Figure 12, Figure 13, Figure 14, Figure 15.

2. Results

(1) The insecticidal and mosquito kinetic curves of compounds 1, 7, 16, 18, bifenthrin and perfluthrin against adult female mosquitoes are shown in Figure 10, Figure 11, Figure 12, Figure 13, Figure 14. Figure 15.

It can be seen from Figure 10 to Figure 15 that in this example, 12.5μg/bottle, 6.25μg/bottle, 3.13μg/bottle, 1.56μg/bottle, 0.78μg/bottle and 0.39μg/bottle were applied to the 4 compounds. 6 continuous concentration gradient insecticidal activity kinetic tests; 4 target compounds have excellent killing activity against adult female mosquitoes, and as the sample concentration increases, the insecticidal activity gradually increases, that is, the 4 target compounds are The insecticidal activity of adult mosquitoes has a dose-dependent relationship; at the same time, with the extension of the test time, the mortality of female adult mosquitoes also gradually increases under the same concentration conditions, that is, the effect of the four target compounds on the insecticidal activity of adult mosquitoes Time dependent. At the same time, it can also be seen that under the same concentration and the same time, the insecticidal activity of compounds 7 and 18 is slightly better than the insecticidal activity of the other two compounds 1 and 16, and the activities of the four synthetic compounds are significantly better than that of the combined compound. Phenethrin, compound 18 has the highest activity.

Anti-mosquito activity conclusion

In summary, through the activity test experiments of the larvae and adult mosquitoes of Aedes albopictus in Examples 6-8, the present invention has carried out activity testing and screening on a total of 18 pyrethroid derivatives, and the results show that there are Bifenthrin derivatives 4, 5, 7, 9 and 11 have higher activity on larvae than the parent bifenthrin of the positive group, especially compound 7 has the same effect on larvae as the positive group bifenthrin 4.2 times, has excellent insecticidal activity against larvae. It shows that the bifenthrin derivative of the present invention has better anti-mosquito activity, can be widely used in the field of insecticide and mosquito killing, and can effectively solve the problem of resistance of existing pyrethroid insecticides.

As for the activity data of female adult mosquitoes, the lethal effects of bifenthrin derivatives 1, 7, 16, and 18 on adult mosquitoes are all higher than that of the positive group of bifenthrin. Among them, compound 18 has a higher diagnosis time for female adult mosquitoes. The LC ₅₀ value of the half-lethal concentration at 30 min can reach 0.62μg/bottle, which is nearly 8 times higher than bifenthrin in activity, showing excellent killing ability to female adult mosquitoes. The other three compounds 1, 7 and The anti-mosquito activity of 16 is also higher than bifenthrin. The main mechanism of action on adult mosquitoes is contact killing, which affects the stability of the Na ⁺ ion channel protein potential on the nerve cell membrane, forming a continuous discharge, leading to excitement, convulsion and death. It shows that the bifenthrin derivative of the present invention has better anti-mosquito activity and can improve metabolic stability, provides new safe, efficient and stable compounds for insecticide, and has high practical application and promotion value.

According to the synthesized target compound and the data result of the activity test, from the structure-activity relationship (SAR) analysis, it can be found that in the bifenthrin derivatives, the dichloro-substituted derivative compound 1 and the compound at the ortho position of the middle benzene ring 4-11 have excellent anti-mosquito activity, and when there is fluorine-containing substitution on the terminal benzene ring, such as compound 7, its anti-mosquito activity will be significantly improved, and it is better than the positive control bifenthrin ester. However, if the ortho-methyl or chlorine substitution of the middle benzene ring is replaced by trifluoromethyl, the anti-mosquito activity of its compounds such as 2, 12 and 13 will be greatly reduced, which is much lower than that of bifenthrin. Mosquito activity. When the terminal benzene ring on bifenthrin is replaced with a halogen-containing substituted thiophene ring, its activity will be further improved. Especially the thiophene ring substituted with Br at the terminal position has the highest anti-mosquito activity in adult mosquitoes. 8 times stronger than bifenthrin. The bifenthrin derivative of the present invention has high-efficiency insecticidal and mosquito killing effects on both larvae and adult mosquitoes, and can improve metabolic stability and reduce environmental toxicity.

Example 9 Embryo toxicity test of zebrafish zygotes

Taking compounds 7 and 18 as representatives of the bifenthrin derivatives of the present invention, the toxicity of the bifenthrin derivatives of the present invention and bifenthrin were compared.

1. Method

(1) Preparation of Holt-bulffer incubation solution: add the nutrient solution to a 2000mL volumetric flask. The inorganic salt medicines are: NaCl (7g), NaHCO ₃ (0.4g), KCl (0.1g), NaCl ( 0.235g); then filter with a disposable vacuum filter with a pore size of 0.22μM, with a pH of 7.2±0.1, and store at room temperature for later use.

(2) Refer to the OECD guidelines for testing. The experiment uses fertilized eggs to be tested for poisoning within 30 minutes, using acetone solvent, using the double dilution method, and configuring the sample test concentration to be 10, 5, 2.5, 1.25, 0.625, 0.313, 0.156, 0.078, 0.039, 0.020, 0.010, 0.005 mg/mL; the configuration samples are three compounds including compound 7, 18 and bifenthrin as the positive control group, and acetone solvent as the blank control group. Then it is diluted 1/10000 into the Holt-bulffer incubation solution, which is set as the sample incubation solution, and the volume of each concentration is 1mL.

(3) First observe with an ordinary binocular microscope and pick out qualified and active zebrafish zygotes, use a pipette to pick them up and carefully put them into a 96-well plate, put one fertilized egg in each hole, and the concentration of each group is parallel Repeat 3 times to make a total of 12 concentration gradients, and then suck out the excess liquid inside to remove, and then use a pipette to suck up the sample incubation solution and add 200μL of solution to each well in the 96-well plate. And put the zebrafish fertilized eggs in a 96-well plate with a light:dark time ratio of 14h:10h and a temperature of 28°C in an incubator. Observe the number of deaths or hatches of zebrafish zygotes every 24h, and record continuously for 3 days.

2. Results

The experimental results show that the hatching solution prepared with acetone solvent is basically non-toxic to the hatching of fertilized eggs, and the hatching is normal; the toxicity of No. 7 and 18 bifenthrin derivatives to zebrafish zygotes is significantly lower than that of the positive group Bifenthrin is 8 to 16 times. It shows that the bifenthrin modification of the present invention is successful. Compared with bifenthrin, the novel bifenthrin derivative provided by the present invention has significantly reduced toxicity to zebrafish zygotes and can reduce environmental toxicity.

Example 10 Bifenthrin and its derivatives to HepG2 cytotoxicity test

Taking compound 7 as a representative of the bifenthrin derivative of the present invention, the cytotoxicity of the bifenthrin derivative of the present invention and the bifenthrin was compared.

1. Method

(1) Using DMSO solvent, using the two-fold dilution method, configure the sample test concentration to be 100, 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78 μg/mL; configure the sample as compound 7 and bifenthrin as a positive control Group three other compounds.

(2) One day before the experimental test, inoculate HepG2 cells into each well of 80μL (about 10,000 HepG2 cells) cell suspension in a disposable sterile 96-well plate, and place it at 37°C, 5% CO ₂ Incubate overnight in an incubator. On the day of the experimental test, according to the experimental requirements, it is necessary to add 20 μL of the prepared sample solution to the 96 cell plate, with DMSO solvent as the blank control group, and incubate in an incubator at 37°C and 5% CO ₂ for 24 hours.

After the incubation time is over, add 10 μL of CCK8 to each well of the 96-well cell plate, and incubate it in a 37°C and 5% CO ₂ incubator for 1 to 2 hours, and then test the 96-well plate with a 450nm wavelength microplate reader. Absorbance to calculate the survival rate or mortality of HepG2 cells.

2. Results

The test result is shown in Figure 16. The calculated results after the test showed that: after 24 hours of the experiment, the HepG2 cells in the 96-well plate in the blank group and the test group could grow and survive normally, indicating that bifenthrin and compound 7 had basically no toxic effects on HepG2 cells. It shows that the bifenthrin derivative of the present invention has the advantages of high efficiency, low toxicity and stability.

The above specific implementation manners are preferred embodiments described to facilitate understanding of the present invention, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention can be implemented only by relying on the above-mentioned embodiments. Those skilled in the art should understand that any improvement to the present invention, the equivalent replacement of the raw materials selected in the present invention, the addition of auxiliary components, the selection of specific methods, etc. fall within the scope of protection and disclosure of the present invention.

Claims (10)

A novel bifenthrin derivative characterized in that its structural formula is shown in the following formula (I):

Wherein, when R ₁ is H, R ₂ is a Cl or CF ₃ substituted group, R ₃ is H, a substituted or unsubstituted non-heterocyclic aryl or heterocyclic aryl group; or when R ₁ is a Cl substituted group, R ₂ is H, Cl or CF ₃ substituent group, R ₃ is H, substituted or unsubstituted non-heterocyclic aryl or heterocyclic aryl; the non-heterocyclic aryl is phenyl, naphthyl, anthracenyl , Phenanthryl or pyrenyl; the heterocyclic aryl group is a 5- to 9-membered monocyclic or polycyclic heterocyclic aryl group containing one or more O or S heteroatoms. The novel bifenthrin derivative according to claim 1, wherein the substituents in the non-heterocyclic aryl group and the heterocyclic aryl group are selected from halogen and/or C ₁ ～C ₆ alkyl; substituted The position is ortho, para or meta, and the number of substituents is single or multiple substitution. The novel bifenthrin derivative according to claim 1 or 2, wherein the non-heterocyclic aryl group is a phenyl group, and the heterocyclic aryl group includes thienyl, benzothienyl, furyl or Pyranyl. The novel bifenthrin derivative according to claim 1 or 2, wherein when R ₁ is a Cl substituted group, R ₂ is a H or Cl substituted group, and R ₃ is H, containing halogen and/or C ₁ -C ₆ alkyl substituted or unsubstituted phenyl, thienyl or benzothienyl. The novel bifenthrin derivative according to claim 2, wherein the halogen is selected from F, Cl, Br or I; the C ₁ ～C ₆ alkyl is selected from methyl, ethyl, normal Propyl or isopropyl. The preparation method of the novel bifenthrin derivative according to claim 1, characterized in that it comprises the following steps: S1. Under protective gas atmosphere, add n-butyl lithium solution to ultra-dry tetrahydrofuran (THF) and anhydrous diisopropylamine, stir and cool to -78～-60℃, add substituted iodobenzene, React at -78～-60℃ for 2～3h, add dry ice and react at -60～-50℃ for 2～3h to obtain intermediate B containing carboxyl group; S2. Add the solvent to Intermediate B, then add oxalyl chloride and N,N-dimethylformamide, and react at room temperature for 0.8～1h, add anhydrous pyridine and ultra-dry methanol, and carry out the esterification reaction for 2～3h , To obtain intermediate C containing ester groups; S3. Add solvent and reducing agent to Intermediate C, and react for 30-35 min at 100-105°C in an oil bath to obtain Intermediate D containing ester groups; S4. Add solvent, perfluthrin, oxalyl chloride and N,N-dimethylformamide to the reactor successively, and react at room temperature for 0.8～1h; add anhydrous pyridine, stir and react for 30～35min, then add Intermediate D, undergo an esterification reaction for 2 to 3 hours to obtain a novel bifenthrin derivative in which R ₃ is a H atom; S5. Adding a new bifenthrin derivative in which R ₃ is an H atom to the solvent, adding K ₃ PO ₄ , PdCl ₂ (dppf), Pd(OAc) ₂ and mono- or poly-substituted aryl boronic acid, the aryl boronic acid selected from non-aromatic heterocyclic group or heterocyclic aromatic boronic acid and Suzuki coupling reaction at 100 ~ 105 ℃ an oil bath at 16 ~ 24h, to give wherein R ₃ is a substituted or unsubstituted non-hybrid Novel bifenthrin derivatives of ring aryl or heterocyclic aryl; The whole reaction from step S1 to step S5 is preferably carried out in a protective gas atmosphere. The preparation method according to claim 6, wherein in step S2 and step S4, the solvent is ultra-dry dichloromethane; in step S3 and step S5, the solvent is toluene. The preparation method according to claim 7, characterized in that in step S2, the molar ratio of intermediate B, oxalyl chloride, anhydrous pyridine and methanol is 1:2～3:2～3:1.5-2; In step S3, the molar ratio of intermediate C and reducing agent is preferably 1:1.2 to 1.5; the reducing agent is preferably lithium borohydride; In step S4, the molar ratio of trifluxanthrin, oxalyl chloride, anhydrous pyridine and intermediate D is preferably 3:2～3:2～3:1; In step S5, the molar ratio of the novel bifenthrin derivative in which R ₃ is a H atom, K ₃ PO ₄ , PdCl ₂ (dppf), Pd(OAc) ₂ and aryl boronic acid is preferably 1:4~5: 0.1～0.2: 0.02～0.03: 1.5～2. The use of the novel bifenthrin derivative according to claim 1 or 2 or the novel bifenthrin derivative prepared by the method according to any one of claims 6 to 8 as or preparing insecticides. An insecticide comprising the novel bifenthrin derivative according to claim 1 or 2 or a novel bifenthrin derivative prepared by the method according to any one of claims 6-8.

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