Hexahydrofurano[2,3-b]furan nicotinic acid compounds and preparation methods and applications thereof

Abstract

The present invention relates to a hexahydrofuran [2,3-b] furan nicotine compound and its preparation method and application, wherein the compound is formed by condensing a compound II as a starting material, through a compound III-1, a compound III-2 or a compound III-3, and a corresponding intermediate; the compound can be used as an insecticide of an effective ingredient, and can be prepared into a pesticide composition with a hexahydrofuran [2,3-b] furan nicotine compound as an insecticide active ingredient. The compound of the present invention has excellent control effects on various pests, and can greatly meet the demand for efficient and safe insecticides for crop protection. The compound provided in the above technical scheme can be used to prepare insecticides in the fields of agriculture, gardening, etc., and has the advantages of high efficiency, low toxicity and environmental friendliness.

Description

Technical Field

[0001] The present invention relates to the technical field of pesticides, and in particular to a hexahydrofurano[2,3-b]furan nicotine compound which can be used as an active ingredient of a harmful organism control agent, and a preparation method and application thereof. Background Art

[0002] In the mid-1990s, during the research of the anti-AIDS drug Amprenavir, medical scientists divided Amprenavir into four parts (P2, P1, P1`, P2`) and modified them separately. Ghosh and researchers reported that after the single furan ring of the P2 part was changed to a bifuran ring, the bifuran ring had significant improvements in both enzyme inhibition activity and in vitro antiviral activity, mainly due to the force of two additional hydrogen bonds between the two furan ring oxygen bonds; replacing P2 with a bifuran ring and keeping the other three parts unchanged is the existing HIV protease inhibitor Darunavir.

[0003]

[0004] In addition, new HIVPIs with bifuran rings such as brecanavir, GS-8374 and SPI-256 have been developed and have shown high efficacy in the treatment of multidrug-resistant HIV. The structure of bifuran alcohol is a common feature of this type of HIVPIs with good drug activity. Alcohol derivatives of bifuran rings have good resistance to drug resistance. Studies have shown that the two oxygens of the biTHF ligand effectively form hydrogen bonds with the NH of Asp 30 and Asp 29 located in the S2 binding domain of HIV-1 protease. It has been confirmed that the size of the ring, the position of the oxygen and the stereochemistry of the bifuran ligand are crucial.

[0005] Dinotefuran is a new nicotinoid insecticide developed by Mitsui Company. Its structure is quite different from other nicotine insecticides. Previous nicotine insecticides all contained chlorinated thiazole rings or chlorinated pyridine rings. Dinotefuran uses tetrahydrofuran ring as heterocyclic ring and is often called "furan nicotine". However, it still has the advantages of low toxicity, high efficiency, contact killing, good systemicity, and long duration of efficacy. It has the advantages of super high efficiency, broad spectrum, small dosage, long lasting effect, and no phytotoxicity to crops. Moreover, its greatest feature is that it is more water-soluble, which means that dinotefuran is more easily absorbed. It is particularly worth mentioning that its oral toxicity to bees is only 1 / 4.6 of that of thiamethoxam, and its contact toxicity is half of that of thiamethoxam.

[0006] Since nicotine pesticides are generally highly toxic to bees, although they play a huge role in protecting crops from insect pests, they also have a huge impact on the environment, attracting the attention of governments around the world and being banned or restricted. Although dinotefuran has reduced its toxicity to bees to a certain extent, it is still necessary to develop new nicotine insecticides that are more efficient and safer to meet the needs of agricultural production. Summary of the invention

[0007] The purpose of the present invention is to provide a hexahydrofurano[2,3-b]furan nicotinoid compound and a preparation method and application thereof, which has excellent control effects on various pests and can greatly meet the demand for efficient and safe insecticides in crop protection.

[0008] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0009] A hexahydrofurano[2,3-b]furan nicotinoid compound, the general formula of the compound is:

[0010]

[0011] Among them, R 1 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 3 carbon atoms, a benzyl group, an alkoxyalkyl group having 2 to 4 carbon atoms in the entire group, an alkoxycarbonyl group having 1 to 3 carbon atoms, a phenoxycarbonyl group, an alkylcarbonyl group having 1 to 6 carbon atoms, an alkenylcarbonyl group having 2 to 3 carbon atoms, a cycloalkylcarbonyl group having 3 to 6 carbon atoms, a benzoyl group, a benzoyl group substituted by one or more alkyl groups having 1 to 4 carbon atoms, a benzoyl group substituted by one or more halogen atoms, a 2-furylcarbonyl group or an N,N-dimethylcarbamoyl group;

[0012] R 2 is a hydrogen atom, an amino group, a methyl group, an alkylamino group having 1 to 5 carbon atoms, a disubstituted alkylamino group having 2 to 5 carbon atoms in the entire group, a 1-pyrrolidinyl group, an alkenylamino group having 3 carbon atoms, an alkynylamino group having 3 carbon atoms, a methoxyamino group, an alkoxyalkylamino group having 2 to 4 carbon atoms in the entire group, a methylthio group, -N(Y 1 )Y 2 ;

[0013] In-N(Y 1 )Y 2 Middle, Y 1Y is alkoxycarbonyl of 1-3 carbon atoms, phenoxycarbonyl, phenoxycarbonyl, alkylcarbonyl of 1-6 carbon atoms, alkenylcarbonyl of 2-3 carbon atoms, cycloalkylcarbonyl of 3-6 carbon atoms, benzoyl, benzoyl substituted by one or more alkyl groups of 1-4 carbon atoms, benzoyl substituted by one or more halogen atoms, 2-furylcarbonyl or N,N-dimethylcarbamoyl or benzyl; 2 is a hydrogen atom or an alkyl group of 1 to 5 carbon atoms;

[0014] Z = N-NO 2 =CH-NO 2 、=N-CN; n is 0-4.

[0015] In addition, when Z is =N-NO 2 =CH-NO 2 When R 1 More preferably, R is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an alkenyl group having 3 carbon atoms; 2 More preferred are amino groups and alkylamino groups having 1 to 3 carbon atoms, and n is preferably 0-1.

[0016] When Z is =N-CN, where R 1 More preferably, it is a hydrogen atom or an alkyl group of 1 to 3 carbon atoms; R 2 More preferred are amino, methyl, and alkylamino groups having 1 to 3 carbon atoms; and n is preferably 0-1.

[0017] At the same time, a method for preparing the above-mentioned hexahydrofurano[2,3-b]furan nicotine compound is provided. The compound is prepared by using compound II as a starting material and condensing compound III-1, compound III-2 or compound III-3 with a corresponding intermediate. The reaction equation is:

[0018]

[0019] Among them, the structural formulas of compounds I-1 to 9 are as follows:

[0020]

[0021] In addition, the above-mentioned hexahydrofurano[2,3-b]furannicotinoid compounds can be used as insecticides with active ingredients, and can be prepared into pesticide compositions with the hexahydrofurano[2,3-b]furannicotinoid compounds as insecticide active ingredients.

[0022] As an active ingredient of insecticide, hexahydrofurano[2,3-b]furanonicotinoid compounds have excellent control activity against insects, and the compounds can be used as insecticides to protect agricultural and horticultural plants. Insects include lepidopteran pests such as cotton bollworm, broad bean aphid, beet armyworm, diamondback moth, cabbage looper, rice leaf roller and striped stem borer, etc., homopteran pests such as leafhoppers, planthoppers, aphids, whiteflies, etc., dipteran pests such as houseflies, leaf miners, mosquitoes, etc., and pests such as Orthoptera and Coleoptera. It should be noted that the harmful organisms that can be controlled by the compounds of the present invention are not limited to the above-mentioned examples.

[0023] The pesticide composition comprises a hexahydrofurano[2,3-b]furan nicotinoid compound and a pesticide carrier, wherein the content of the hexahydrofurano[2,3-b]furan nicotinoid compound is 1-99%.

[0024] The pesticide composition has the pesticide formulation of emulsifiable concentrate, suspension, wettable powder, water-dispersible granule, aqueous emulsion or microemulsion.

[0025] When the pesticide formulation of the pesticide composition is an emulsifiable concentrate preparation, it includes the following components by mass fraction: 1 to 99 parts of the active insecticide ingredient; 10 to 30 parts of the emulsifier; and 20 to 50 parts of the solvent. The specific production steps of the emulsifiable concentrate preparation are to first add the active insecticide ingredient into the solvent and completely dissolve it, then add the emulsifier and the synergist, stir evenly to form a uniform and transparent oily liquid, and then fill it to obtain the emulsifiable concentrate preparation.

[0026] When the pesticide formulation of the pesticide composition is a suspension, it includes the following components by mass fraction: 1 to 99 parts of insecticide active ingredients; 5 to 20 parts of dispersants; 1 to 5 parts of antifreeze agents; 0.1 to 2 parts of thickeners; 0.1 to 0.8 parts of defoamers; 0 to 10 parts of penetration enhancers; 0.1 to 5 parts of pH value regulators; and the balance of water. The specific production steps of the suspension are to first mix other adjuvants, mix them evenly through high-speed shearing, add the insecticide active ingredients, grind the balls in a ball mill for 2 to 3 hours, and make the particle diameters all below 5 mm, and then the suspension preparation of the composition of the present invention can be prepared.

[0027] When the pesticide formulation of the pesticide composition is a wettable powder, it includes the following components by mass fraction: 1 to 99 parts of the active ingredient of the insecticide; 3 to 10 parts of the dispersant; 1 to 5 parts of the wetting agent; and the rest of the filler. The specific production steps of the wettable powder are: according to the above formula, the active ingredient of the insecticide, the dispersant, the wetting agent and the filler are mixed, stirred evenly in a stirring kettle, and mixed evenly after passing through a jet mill to prepare the wettable powder of the composition of the present invention.

[0028] When the pesticide formulation of the pesticide composition is a water-dispersible granule, it includes the following components by mass fraction: 1 to 99 parts of the active ingredient of the pesticide; 3 to 10 parts of the dispersant; 1 to 10 parts of the wetting agent; 1 to 5 parts of the disintegrant; and the rest of the filler. The specific production steps of the water-dispersible granules are: according to the above formula, the active ingredient of the pesticide and the dispersant, the wetting agent, the disintegrant and the filler are uniformly mixed, crushed with an ultra-fine airflow pulverizer, kneaded, and then added to a fluidized bed granulation dryer for granulation, drying, sieving, and sampling and analysis, and the water-dispersible granules of the composition of the present invention can be prepared.

[0029] When the pesticide formulation of the pesticide composition is an aqueous emulsion, it includes the following components by mass fraction: 1 to 99 parts of insecticide active ingredients; 3 to 30 parts of emulsifiers; 5 to 15 parts of solvents; 2 to 15 parts of stabilizers; 1 to 5 parts of antifreeze; 0.1 to 8 parts of defoamers; 0.2 to 2 parts of thickeners; and the balance of water. The specific production steps of the aqueous emulsion are: first, the active ingredients of the insecticide, the solvent, the emulsifier, and the cosolvent are added together to dissolve into a uniform oil phase; part of the water, the antifreeze agent, the antimicrobial agent and other pesticide adjuvants are mixed together to form a uniform aqueous phase; the oil phase is added to the aqueous phase while stirring at high speed in the reactor, water is slowly added until the phase transition point is reached, the shearing machine is turned on for high-speed shearing, and the remaining water is added, and shearing is performed for about half an hour to form an oil-in-water type aqueous emulsion, thereby preparing the aqueous emulsion of the composition of the present invention.

[0030] When the pesticide formulation of the pesticide composition is a microemulsion, it includes the following components by mass fraction: 1 to 99 parts of the active ingredient of the insecticide; 10 to 30 parts of the emulsifier; 1 to 8 parts of the antifreeze agent; 0.5 to 10 parts of the dispersant; 20 to 50 parts of the conventional solvent cosolvent. The active ingredient of the insecticide is completely dissolved with the cosolvent, and then the emulsifier, antifreeze agent, dispersant and other ingredients are added, uniformly mixed, and finally water is added. After sufficient stirring, the microemulsion can be prepared.

[0031] Among them, the emulsifier is selected from one or more of calcium dodecylbenzene sulfonate and fatty acid polyoxyethylene ether, alkylphenol polyoxyethylene ether sulfosuccinate, styrylphenol polyoxyethylene ether, nonylphenol polyoxyethylene ether, castor oil polyoxyethylene ether, fatty acid polyoxyethylene ester, polyoxyethylene fatty alcohol ether, sorbitan monostearate, sorbitan monostearate polyoxyethylene ether, phenethylphenol polyoxyethylene polyoxypropylene ether, alkylphenol formaldehyde resin polyoxyethylene ether, ethylene oxide-propylene oxide block copolymer, Tween-80, and tristyrylphenol polyoxyethylene ether.

[0032] The solvent is one or more of xylene or biodiesel, toluene, diesel, methanol, ethanol, ethylene glycol, n-butanol, isopropanol, turpentine, solvent oil, dimethylformamide, dimethyl sulfoxide, water and the like.

[0033] The dispersant is selected from one or more of polycarboxylates, lignin sulfonates, alkylphenol polyoxyethylene ether condensate sulfates, alkyl sulfonate calcium salts, naphthalenesulfonic acid methanol condensate sodium salts, alkylphenol polyoxyethylene ethers, fatty acid polyoxyethylene esters, fatty amine polyoxyethylene ethers, and glycerol fatty acid ester polyoxyethylene ethers.

[0034] The wetting agent is selected from one or more of alkyl sodium sulfate, calcium alkylbenzene sulfonate, naphthalene sulfonate, pull-opening powder BX, wetting penetrant F, alkylbenzene sulfonate polyoxyethylene triphenyl phenyl phosphate, alkylphenol polyoxyethylene ether formaldehyde condensate sulfate, alkylphenol polyoxyethylene ether phosphate, phenethylphenol polyoxyethylene ether phosphate, saponin powder, silkworm feces, and soapberry powder.

[0035] The disintegrant is selected from one or more of bentonite, urea, ammonium sulfate, aluminum chloride, citric acid, succinic acid, and sodium bicarbonate.

[0036] The thickener is selected from one or more of xanthan gum, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, magnesium aluminum silicate, and polyvinyl alcohol.

[0037] The stabilizer is selected from one of sodium citrate, resorcinol and polyoxyethylene ether formamide.

[0038] The antifreeze agent is selected from one or more of ethylene glycol, propylene glycol, glycerol, urea, and inorganic salts such as sodium chloride.

[0039] The defoamer is selected from one or more of silicone oil, organic silicon, silicone compounds, C10-20 saturated fatty acid compounds, and C8-10 fatty alcohols; the filler is selected from one or more of kaolin, diatomaceous earth, bentonite, attapulgite, white carbon black, starch, and light calcium carbonate.

[0040] The hexahydrofurano[2,3-b]furannicotinoid compounds provided in the above technical scheme have excellent control effects on harmful insects. When the compounds are used to prepare insecticides in the fields of agriculture, horticulture, etc., they have the advantages of high efficiency, low toxicity, and environmental friendliness, and effectively meet the needs of agricultural production. DETAILED DESCRIPTION

[0041] In order to make the purpose and advantages of the present invention more clearly understood, the present invention is specifically described below in conjunction with embodiments. It should be understood that the following text is only used to describe one or several specific embodiments of the present invention, and does not strictly limit the scope of protection of the specific claims of the present invention.

[0042] Example 1

[0043] Preparation of (3S,3aS,6aR)-3-azidohexahydrofuro[2,3-b]furan (II-1-1)

[0044]

[0045] Compound II (2 g, 15.4 mmol), 4-dimethylaminopyridine (2.6 g, 21.56 mmol) and dichloromethane (10 mL) were added to a 100 mL four-necked round-bottom glass flask. A nitrogen stream was introduced into the system. The temperature was controlled to -5 to 0 °C. Trifluoromethanesulfonic anhydride (4.56 g, 16.17 mmol) and dichloromethane (10 mL) were mixed and slowly dripped into the reaction system. With the addition of trifluoromethanesulfonic anhydride, a white solid gradually appeared in the system. After the addition, the temperature was maintained at -5 to 0 °C and the reaction was continued for 15 min. The mixture was filtered and the filter cake was washed with dichloromethane. The combined organic phases were washed with 0.05 M dilute hydrochloric acid, saturated sodium bicarbonate and saturated brine respectively. The organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a light yellow oily liquid, which was placed in an ice bath for use. Because the product of this step is unstable and the obtained product is relatively pure, it can be directly used in the next step without purification.

[0046] The above product (4 g, 14.9 mmol) was dissolved in 20 ml of dry DMF and stirred until dissolved. Then sodium azide (1 g, 15.3 mmol) was weighed and added to the reaction system. The temperature was raised to 50°C for reaction. The reaction was completed by TLC. The product was extracted with ethyl acetate in small amounts for multiple times. The ethyl acetate layer was washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and subjected to column chromatography (PE:EA=3:1) to obtain 1.4 g of a yellow oily product (3S,3aS,6aR)-3-azidohexahydrofuran[2,3-b]furan) with a yield of 62%.

[0047] The NMR data are as follows: 1 H NMR (400 MHz, CDCl 3 ,ppm)δ5.84(d,J=4.9Hz,1H),4.03(dd,J 1 =10.3,J 2 =4.0Hz,1H),3.98-3.85(m,4H),2.97-2.85(m,1H),2.30-2.18(m,1H),1.81-1.72(m,1H).

[0048] Example 2

[0049] Preparation of (3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-amine (III-1)

[0050]

[0051] Dissolve the azide compound (II-1-1) (2g, 12.9mmol) in 30ml of MeOH (30ml), add 0.5g of catalyst Pd / C (5%), evacuate the air from the system, connect the hydrogen port, stir at room temperature to react, and monitor the reaction by TLC until it is complete. After the reaction is completed, the reaction solution is filtered, concentrated, and column chromatography (EA) is performed to obtain 1.3g of light yellow oily product, (3S, 3aS, 6aR)-hexahydrofuran [2, 3-b] furan-3-amine.

[0052] The NMR data are as follows: 1 H NMR (400 MHz, CDCl 3 ,ppm)δ5.74(d,J=5.0Hz,1H),3.91(dd,J 1 =9.4, J2=4.3Hz,1H),3.79-3.74(m,2H),3.55(d,J=9.4Hz,1H),3.30-3.25(m,1H),2.54-2.46(m,1H),2.15-1.95(m,1H),1.77-1.62(m,4H).

[0053] Example 3

[0054] Preparation of ((3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-toluenesulfonate) (III-2)

[0055]

[0056] Compound II (2 g, 15.4 mmol), 4-dimethylaminopyridine (2.6 g, 21.56 mmol) and dichloromethane (10 mL) were added to a 100 mL four-necked round-bottom glass flask. After the solid was fully dissolved, p-toluenesulfonyl chloride (3 g, 15.4 mmol) was added. The reaction was carried out at room temperature and the reaction was monitored to be complete. 20 ml of sodium hydroxide solution (0.1 mol) was added to the reaction flask and stirred at room temperature for 1 h. The organic phase was extracted and separated, and the organic phase was washed with a saturated NaCl solution. The organic phase was dried and spin-dried to obtain about 2.2 g of a white solid ((3R, 3aS, 6aR) hexahydrofuran [2, 3-b] furan-3-toluenesulfonate).

[0057] Example 4

[0058] Preparation of ((3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-methylamine) (III-3)

[0059]

[0060] 15ml of dichloromethane (re-distilled) was added to a 100ml four-necked flask, and compound II (2g, 15.38mmol) and DMAP (2.6g, 21.56mmol) were added in sequence under nitrogen protection, and the system temperature was controlled at 0°C. After being fully dissolved, a dichloromethane solution (20ml) dissolved with trifluoromethanesulfonic anhydride (4.56g, 16.17mmol) was slowly and uniformly added to the above system, and the temperature was always controlled at 0°C. As the reaction proceeded, a white solid gradually precipitated. After the reaction was completed by TLC detection, it was filtered, and the excess DMAP was washed with 0.1M hydrochloric acid, and then washed with saturated sodium bicarbonate and saturated brine respectively, and then the organic phase was dried with anhydrous sodium sulfate, and concentrated to obtain 1.3g of light yellow oily liquid. Since the ester is highly active and unstable, it is directly reacted in the next step without purification.

[0061] Sodium cyanide (0.7g, 13.75mmol) and redistilled N,N'-dimethylformamide (20ml), remove the air from the system, introduce nitrogen and control the temperature at -5~0℃; dissolve the product from the previous step (2g, 6.2mmol) in redistilled N,N'-dimethylformamide (10ml), slowly and uniformly add it to the reaction system, and continue to react at -5~0℃ for 1 hour. Reaction at room temperature, TLC detection reaction is complete. Add 40ml of water to the reaction system, extract with ethyl acetate in small amounts for multiple times (20ml×6), wash the organic phase with saturated sodium chloride solution, then dry and concentrate, and purify the product by column chromatography (PE:EA=2:1) to obtain 0.55g of white solid. Yield 65%.

[0062] The NMR data are as follows: 1 H NMR (500 MHz, CDCl 3 ,ppm)δ5.84(d,J=5.0Hz,1H),4.18-4.10(m,1H),4.03(dd,J 1 =9.3, J2=4.4Hz,1H),3.98-3.92(m,1H),3.92-3.85(m,1H),3.25-3.10(m,1H),2.93-2.86(m,1H),2.27-2.17(m,1H),1.87-1.78(m,1H).

[0063] The above white solid (1 g, 7.2 mmol), NiCl 2 6H 2O (0.85 g, 3.6 mmol) were added into a 100 ml four-necked flask in sequence, and 20 ml of anhydrous methanol solvent was added and stirred until completely dissolved; the temperature of the reaction system was controlled at -5 to 0 °C, sodium borohydride (0.7 g, 18 mmol) was added into the reaction system in batches, and the temperature was maintained to continue the reaction for 0.5 h, and then the reaction was carried out at room temperature; after the reaction was completed, the reaction was filtered, the filtrate was concentrated, and the product was purified by column chromatography (DCM: EtOH = 4:1) to obtain 0.75 g of light yellow liquid ((3R, 3aS, 6aR)-hexahydrofuran [2,3-b] furan-3-methylamine) with a yield of 75%.

[0064] The NMR data are as follows: 1 HNMR (300MHz, CDCl 3 ,ppm)δ5.64(s,1H),3.89(dd,J 1 =8.6,J 2 =4.3Hz,1H),3.62(q,J=7.3Hz,3H),2.76-2.52(m,1H),1.93(s,3H),1.47(t,J=7.3Hz,4H).

[0065] Example 5

[0066] This embodiment provides a method for preparing 1(E)-1-((3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl)-3-methyl-2-nitroguanidine compound (I-1), and the reaction equation is:

[0067]

[0068] 4g of water was added to a 100ml three-necked flask, compound III-1 (2g, 15.5mmol) was weighed, sodium chloride (1g, 18.48mmol) was added to the reaction flask, the system temperature was cooled to -10°C, and then 0.09g (2.3mmol) of 32% sodium hydroxide solution was added to the above system, and then N,O-dimethyl-N'-nitroisourea (2.1g, 15.4mmol) was added to the reaction system, and the reaction was continued at -10°C for 5h, and then the system temperature was raised to 0°C, and the reaction was carried out at this temperature for 12h. After the reaction was completed, the insoluble solid was filtered off, the filter residue was washed with water several times, the filtrate was concentrated, and the white solid product was purified by column chromatography (EA:PE=3:1), and dried to obtain 1.2g, with a yield of 33.7% and a melting point of 140.8-141.8°C.

[0069] The NMR data are as follows: 1 H NMR (400 MHz, CDCl 3)δ5.77(d,J=5.0Hz,1H),3.94(dd,J=9.4,4.2Hz,1H),3.83–3.78(m,2H),3.59(d,J =9.5Hz,1H),3.33–3.28(m,2H),2.91–2.84(m,1H),2.58–2.47(m,1H),1.76(s,3H).

[0070] Example 6

[0071] This embodiment provides a method for preparing a 2(E)-1-(((3R,3aS,6aR)-hexahydrofurano[2,3-b]furan-3-yl)methyl)-3-methyl-2-nitroguanidine compound (I-2), and the reaction equation is:

[0072]

[0073] Add 4g of water to a 100ml three-necked flask, weigh compound III-3 (2g, 14.1mmol), add sodium chloride (0.98g, 14.91mmol) to the reaction flask, cool the system to -10°C, then add (0.09g, 2.3mmol) 32% sodium hydroxide solution to the above system, then add N,O-dimethyl-N'-nitroisourea (1.87g, 14.1mmol) to the reaction system, continue to stir and react at -10°C for 5h, then heat the system to 0°C and continue to react for 12h. After the reaction is completed, filter out the insoluble solid, wash the filter residue with water several times, concentrate the filtrate, and column chromatography (EA:PE=3:1) to obtain 1.3g of white solid with a yield of 38.2%. Melting point: 144.3-145.3°C.

[0074] The NMR data are as follows: 1 H NMR (400 MHz, CDCl 3 )δ5.74(d,J=5.0Hz,1H),4.01(dd,J=9.7,5.4Hz,1H),3.96–3.86(m,2H),3.79(dd,J=9.6,1.1Hz,1H),3.47–3.25(m,2H), 2.97(d,J=5.1Hz,3H),2.68–2.57(m,1H),2.44(d,J=6.5Hz,1H),2.21(ddd,J=17.7,12.9,8.7Hz,1H),1.87–1.79(m,1H).

[0075] Example 7

[0076] This embodiment provides a method for preparing a (E)-N-((3S,3aS,6aR)-hexahydrofurano[2,3-b]furan-3-yl)-2-nitroethylene-1,1-diamine compound (I-3), and the reaction equation is:

[0077]

[0078] Add 20 ml of anhydrous ethanol to a 100 ml three-necked flask, weigh compound III-1 (2 g, 15.5 mmol), N-cyano-S, S-dimethyl dithiocarbonate (2.7 g, 18.6 mmol) and add to the reaction bottle, stir until the raw materials are fully dissolved, heat to 50 ° C, and monitor by TLC until the reaction is completed. After the reaction is completed, the solvent is removed by vacuum rotary evaporation, and the concentrate is purified by column chromatography (EA: PE = 2: 1) to obtain 3.2 g of white solid product, with a yield of 85%.

[0079] The product (2g, 9.3mmol) from the previous step and a 25-28% aqueous solution of ammonia (1.26g, 18.6mmol) were added to the reactor, and 10ml of methanol was added to the reaction system and stirred until completely dissolved. The mixture was sealed in a reactor, heated to 80°C, and reacted for 12h. The reaction mixture was cooled to room temperature, concentrated, and purified by column chromatography (EA) to obtain 1.2g of a white solid with a yield of 78% and a melting point of 210.1-221.8°C.

[0080] The NMR data are as follows: 1 H NMR (400 MHz, CDCl 3 )δ10.57(s,1H),10.17(s,1H),6.55(s,1H),5.85(s,1H),5.29(d,J=9.4Hz,1H),4 .10(dd,J=10.1,3.9Hz,1H),3.94(s,1H),2.90(s,1H),2.29(s,1H),1.72(s,2H).

[0081] Example 8

[0082] This embodiment provides a method for preparing 3(E)-N-ethyl-N'-((3S,3aS,6aR)-hexahydrofurano[2,3-b]furan-3-yl)-2-nitroethylene-1,1-diamine compound (I-4), and the reaction equation is:

[0083]

[0084] Add 20 ml of anhydrous ethanol to a 100 ml three-necked flask, weigh compound III-1 (2 g, 15.5 mmol), N-cyano-S, S-dimethyl dithiocarbonate (2.7 g, 18.6 mmol) and add to the reaction bottle, stir until the raw materials are fully dissolved, heat to 50 ° C, and monitor by TLC until the reaction is completed. After the reaction is completed, the solvent is removed by vacuum rotary evaporation, and the concentrate is purified by column chromatography (EA: PE = 2: 1) to obtain 3.2 g of white solid product, with a yield of 85%.

[0085] The product (2g, 9.3mmol) from the previous step and a 68%-72% aqueous solution of ethylamine (5g, 9.3mmol) were added to the reactor, and 10ml of methanol was added to the reaction system and stirred until completely dissolved. The mixture was sealed in a reactor, heated to 80°C, and reacted for 12h. The reaction mixture was cooled to room temperature, concentrated, and purified by column chromatography (EA) to obtain 1.4g of a white solid with a yield of 73% and a melting point of 230.3-231.5°C.

[0086] The NMR data are as follows: 1 H NMR (400 MHz, CDCl 3 )δ10.57(s,1H),10.17(s,1H),6.55(s,1H),5.85(s,1H),5.29(d,J=9.4Hz,1H),4.10(dd,J=10 .1,3.9Hz,1H),3.94(s,1H),3.26(s,2H),2.90(s,1H),2.29(s,1H),1.72(s,2H),1.32(s,3H).

[0087] Example 9

[0088] This embodiment provides a method for preparing a 6N-((Z)-3-((3S,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl)thiazolidine-2-ylidene)guanidine compound (I-5), and the reaction equation is:

[0089]

[0090] Under nitrogen protection, weigh N-(imidazoline-2-ylidene)nitramine (0.45g, 3.5mmol) and dissolve it in 20ml of dry DMF, then add 60% NaH (0.42g, 10.5mmol), stir and react at room temperature for one hour, then add p-toluenesulfonate III-2 (1g, 3.5mmol) to the reaction system, heat to 50°C, and react for 7h. After the reaction is completed, cool to room temperature, distill under reduced pressure, add a small amount of water to dissolve, extract with ethyl acetate several times, wash the organic phase with saturated sodium chloride solution, then dry with anhydrous sodium sulfate, concentrate and purify by column chromatography (EA:PE=2:1) ​​to obtain 0.3g of light yellow oily liquid, yield: 24.7%.

[0091] The NMR data are as follows: 1 H NMR (400 MHz, CDCl 3 )δ5.84(d,J=5.0Hz,1H),4.50–4.44(m,1H),4.13–4.00(m,4H),3.88–3.82(m,2H) ,3.48(t,J=7.9Hz,2H),3.13–3.02(m,1H),2.30–2.16(m,1H),1.89–1.73(m,1H).

[0092] Example 10

[0093] This embodiment provides a method for preparing a 6N-((Z)-3-((3S,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl)thiazolidine-2-ylidene)guanidine compound (I-6), and the reaction equation is:

[0094]

[0095] Under nitrogen protection, 2-cyano-imino-1,3-thiazolidine (0.45 g, 3.5 mmol) was weighed and dissolved in 20 ml of dry DMF, then 60% NaH (0.42 g, 10.5 mmol) was added, stirred at room temperature for one hour, and then p-toluenesulfonate III-2 (1 g, 3.5 mmol) was added to the reaction system, the temperature was raised to 50°C, and the reaction was performed for 7 hours. After the reaction was completed, it was cooled to room temperature, distilled under reduced pressure, dissolved in a small amount of water, extracted with ethyl acetate several times, the organic phase was washed with a saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, concentrated, and purified by column chromatography (EA: PE = 2: 1) to obtain 0.2 g of a light yellow oily liquid, with a yield of 24.7%.

[0096] The NMR data are as follows: 1 H NMR (400 MHz, CDCl 3)δ5.84(d,J=5.0Hz,1H),4.50–4.44(m,1H),4.13–4.00(m,4H),3.88–3.82(m,2H) ,3.48(t,J=7.9Hz,2H),3.13–3.02(m,1H),2.30–2.16(m,1H),1.88–1.75(m,1H).

[0097] Embodiment 11

[0098] This embodiment provides a method for preparing a 5(E)-2-cyano-1-methyl-3-((3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl)guanidine compound (I-7), and the reaction equation is:

[0099]

[0100] Add 20 ml of anhydrous ethanol to a 100 ml three-necked flask, weigh compound III-1 (2 g, 15.5 mmol), N-cyano-S, S-dimethyl dithiocarbonate (2.7 g, 18.6 mmol) and add to the reaction flask, stir until the raw materials are fully dissolved, heat to 80 ° C, and monitor by TLC until the reaction is completed. After the reaction is completed, the solvent is removed by vacuum rotary evaporation, and the concentrate is purified by column chromatography (EA: PE = 2: 1) to obtain 3.2 g of white solid product, with a yield of 85%.

[0101] The NMR data are as follows: 1 H NMR (400 MHz, CDCl 3 ,ppm)δ5.84(d,J=5.0Hz,1H),4.33(s,1H),4.16-3.72(m,5H),2.96-2.86(m,1H),2.58(s,3H),2.29-2.16(m,1H),1.92-1.79(m,1H).

[0102] Weigh the white solid product (2g, 9.3mmol) of the first step, add 68%-72% ethylamine aqueous solution (5g, 9.3mmol) into the reactor, then add 10ml of ethanol into the reaction system, stir until completely dissolved. Seal the reactor, heat to 80℃, and react for 12h. Cool to room temperature, concentrate the reaction solution, and purify the product by column chromatography (EA) to obtain 1.4g of white solid, with a yield of 73% and a melting point of 215.2-216.7℃.

[0103] The NMR data are as follows: 1 H NMR (400 MHz, CDCl 3)δ10.57(s,1H),10.17(s,1H),6.55(s,1H),5.85(s,1H),5.29(d,J=9.4Hz,1H),4.10(dd,J=10 .1,3.9Hz,1H),3.94(s,1H),3.26(s,2H),2.90(s,1H),2.29(s,1H),1.72(s,2H),1.32(s,3H).

[0104] Example 12

[0105] This embodiment provides a method for preparing a 7(E)-N'-cyano-N-((3S,3aS,6aR)-hexahydrofurano[2,3-b]furan-3-yl)acetamidine compound (I-8), and the reaction equation is:

[0106]

[0107] In a 100 ml three-necked flask, add 20 ml of anhydrous ethanol, weigh amino compound III-1 (2 g, 15.5 mmol) and N-cyanoacetimidomethyl ester (1.5 g, 15.5 mmol) and add them to the reaction flask in turn to dissolve, reflux reaction, and detect the reaction by TLC. After the reaction solution is cooled to room temperature, it is concentrated and purified by column chromatography (EA: EtOH = 2:1) to obtain the product, 2.1 g of white solid, yield 70%, melting point: 110.5-111.7 ° C.

[0108] The NMR data are as follows: 1 H NMR (400MHz, CDCl3) δ7.14(d,J=5.5Hz,1H),5.81(d,J=5.0Hz,1H),4.29–4.24(m,1H),4.03(dd,J=10.3, 4.3Hz,1H),3.92(d,J=5.9Hz,1H),3.91–3.85(m,1H),2.93(d,J=35.3Hz,1H),2.32(s,2H),1.80(s,2H).

[0109] Example 13

[0110] This embodiment provides a method for preparing 8(E)-N'-cyano-N-(((3S,3aS,6aR)-hexahydrofurano[2,3-b]furan-3-yl)methyl)acetamidine compound (I-9), and the reaction equation is:

[0111]

[0112] In a 100 ml three-necked flask, add 20 ml of anhydrous ethanol, weigh compound III-3 (2 g, 14 mmol) and methyl N-cyanoacetimidate (1.37 g, 14 mmol) and add them to the reaction flask in turn to dissolve, reflux reaction, and detect the reaction by TLC. After the reaction solution is cooled to room temperature, it is concentrated and purified by column chromatography (EA:EtOH=2:1) ​​to obtain the product, 1.9 g of white solid, with a yield of 65.5%, and a melting point of 114.5-116.0°C.

[0113] The NMR data are as follows: 1 H NMR (400MHz, DMSO) δ8.90(s,1H),5.57(t,J=4.9Hz,1H),3.81(dd,J=9.1,5.7Hz,1H),3.73(dt,J=9.5,4.6Hz,2H),3.54 (dd,J=9.1,2.8Hz,1H),3.34(s,1H),2.51(s,2H),2.21(s,3H),2.05–1.93(m,2H),1.73(ddt,J=12.4,6.1,3.2Hz,1H).

[0114] Embodiment 14

[0115] The present embodiment provides a pesticide composition in the form of an aqueous emulsion, which comprises the following components in mass fractions: 20 parts of the active compound synthesized in Example 5, 6 parts of ethylene oxide-propylene oxide block copolymer, 12 parts of toluene, 7.5 parts of polyoxyethylene ether formamide, 5 parts of ethylene glycol / propylene glycol composite antifreeze agent, 0.8 parts of silicone, 2 parts of xanthan gum, and 46.7 parts of water.

[0116] First, the active compound, solvent, emulsifier and cosolvent are added together to dissolve into a uniform oil phase; part of water, antifreeze agent, antimicrobial agent and other pesticide adjuvants are mixed together to form a uniform water phase; the oil phase is added to the water phase while stirring at high speed in a reactor, water is slowly added until the phase transition point is reached, a shearing machine is turned on for high-speed shearing, and the remaining water is added, and shearing is performed for about half an hour to form an oil-in-water emulsion, which can be used to prepare the emulsion in water of the composition of the present invention, and the emulsion in water with an active ingredient content of 20% is obtained by uniformly mixing together.

[0117] Embodiment 15

[0118] This embodiment provides a pesticide composition in the form of a microemulsion, which comprises the following components in mass fractions: 20 parts of the compound synthesized in Example 5, 20 parts of tristyrylphenol polyoxyethylene ether, 5 parts of glycerol, 5 parts of alkylbenzene sulfonate calcium salt, 5 parts of isopropanol, and 45 parts of water.

[0119] The active compound is completely dissolved with a solvent, and then other ingredients such as an emulsifier, an antifreeze agent, a dispersant, etc. are added and mixed evenly, and finally water is added and stirred thoroughly to prepare a microemulsion with an active ingredient content of 20%.

[0120] Example 16

[0121] This embodiment provides a pesticide composition in the form of an emulsifiable concentrate, which comprises the following components in mass fractions: 20 parts of the compound synthesized in Example 5 are dissolved in a mixed solvent consisting of 25 parts of xylene and 25 parts of dimethylformamide, and then 30 parts of Tween-80 emulsifier are added.

[0122] Firstly, the active compound effective ingredient is added into the solvent and completely dissolved, then the emulsifier and synergist are added and stirred evenly to form a uniform transparent oily liquid, and then the liquid is filled to obtain an emulsifiable concentrate with an active ingredient content of 20%.

[0123] Test example

[0124] Insecticidal effect on broad bean aphids

[0125] The compounds prepared in Examples 5 to 13 and dinotefuran 97% TC were weighed, 10 mg of the original drug was added to 10 mL of 0.05% Tween water to make a 1000 ppm stock solution, and then diluted to 100 ppm. Each sample was repeated 3 times, and a blank control was set at the same time. The cut broad bean seedling leaves were immersed in the drug solution of each concentration for 15 seconds, and then taken out and inserted into the bottle containing penicillin of the corresponding concentration. 3-day-old nymphs were placed in the bottle, and the results were observed after 3 days, the number of dead and alive insects was checked, and statistical analysis was performed.

[0126] Table 1: Mortality and rating statistics

[0127]

[0128] The mortality rates of compounds No.I-1, No.I-2, No.I-8 and No.I-9 at a concentration of 100 ppm on the third day were greater than 90%.

[0129] The implementation modes of the present invention are described in detail above in conjunction with the embodiments, but the present invention is not limited to the above-mentioned implementation modes. For ordinary technicians in this technical field, after knowing the contents recorded in the present invention, they can make several equivalent changes and substitutions thereto without departing from the principle of the present invention, and these equivalent changes and substitutions should also be regarded as belonging to the protection scope of the present invention.

Claims

1. A hexahydrofurano[2,3-b]furan nicotinoid compound, characterized in that: The compound is a 6N-((Z)-3-((3S,3aS,6aR)hexahydrofurano[2,3-b]furan-3-yl)thiazolidine-2-ylidene)guanidine compound, and the preparation reaction equation thereof is: ； The preparation method is as follows: under nitrogen protection, weigh 0.45 g, 3.5 mmol of N-(imidazoline-2-ylidene)nitramine and dissolve it in 20 ml of dry DMF, then add 0.42 g, 10.5 mmol of NaH with a content of 60%, stir and react at room temperature for one hour, then add 1 g, 3.5 mmol of p-toluenesulfonate III-2 to the reaction system, heat to 50°C, and react for 7 hours; after the reaction is completed, cool to room temperature, distill under reduced pressure, add water to dissolve, extract with ethyl acetate, wash the organic phase with a saturated sodium chloride solution, then dry with anhydrous sodium sulfate, concentrate, and purify by column chromatography with EA:PE=2:1 to obtain a light yellow oily liquid.

2. An insecticide comprising the hexahydrofurano[2,3-b]furan nicotinoid compound as claimed in claim 1 as an active ingredient.

3. A pesticide composition comprising an insecticide active ingredient and a pesticide carrier, characterized in that: The active ingredient of the insecticide is the hexahydrofurano[2,3-b]furan nicotinoid compound as described in claim 1.

4. The pesticide composition according to claim 3, characterized in that: The content of hexahydrofuran [2,3-b] furan nicotinoid compounds in the pesticide composition is 1-99%.

5. A pesticide composition as claimed in claim 3, characterized in that: The pesticide composition has the pesticide formulation of emulsifiable concentrate, suspension, wettable powder, water-dispersible granule, aqueous emulsion or microemulsion.

6. The pesticide composition according to claim 5, wherein the pesticide formulation of the pesticide composition is an emulsifiable concentrate, characterized in that: The emulsifiable concentrate preparation includes the following components in mass fractions: 1 to 99 parts of insecticide active ingredient; 10 to 30 parts of emulsifier; 20 to 50 parts of solvent; and 1 to 5 parts of synergist.

7. The pesticide composition according to claim 5, wherein the pesticide formulation of the pesticide composition is an aqueous emulsion, characterized in that: The aqueous emulsion includes the following components in mass fractions: 1 to 99 parts of insecticide active ingredient; 3 to 30 parts of emulsifier; 5 to 15 parts of solvent; 2 to 15 parts of stabilizer; 1 to 5 parts of antifreeze agent; 0.1 to 8 parts of defoaming agent; 0.2 to 2 parts of thickener; and the balance is water.

8. The pesticide composition according to claim 7, characterized in that: The emulsifier is selected from calcium dodecylbenzene sulfonate and fatty acid polyoxyethylene ether, alkylphenol polyoxyethylene ether sulfosuccinate, styrylphenol polyoxyethylene ether, nonylphenol polyoxyethylene ether, castor oil polyoxyethylene ether, fatty acid polyoxyethylene ester, polyoxyethylene fatty alcohol ether, sorbitan monostearate, sorbitan monostearate polyoxyethylene ether, phenylethylphenol polyoxyethylene polyoxypropylene ether, alkylphenol formaldehyde resin polyoxyethylene ether, ethylene oxide-propylene oxide block copolymer, Tween-80, tristyrylphenol polyoxyethylene ether; The solvent is one or more of xylene or biodiesel, toluene, diesel, methanol, ethanol, ethylene glycol, n-butanol, isopropanol, turpentine, solvent oil, dimethylformamide, dimethyl sulfoxide, and water solvent; The stabilizer is selected from one of sodium citrate, resorcinol, and polyoxyethylene ether formamide; the antifreeze agent is selected from one or more of ethylene glycol, propylene glycol, glycerol, urea, and inorganic salts; the inorganic salt is sodium chloride; The defoaming agent is selected from one or more of silicone oil, organosilicon, silicone compounds, C10-20 saturated fatty acid compounds, and C8-10 fatty alcohols; The thickener is selected from one or more of xanthan gum, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, magnesium aluminum silicate, and polyvinyl alcohol.

Images