Flupyrifurone is a neonicotinoid insecticide developed by Bayer in 2007 that acts on acetylcholine receptors in insects. It is mainly used to control the stinging and sucking mouthparts pests of vegetables, fruit trees and field crops, such as: aphids, whiteflies, psyllids, leafhoppers, scale insects, beetles, leaf miners, mealybugs, soft scales, citrus psyllids, weevils and thrips, etc., and the pest control effect against neonicotinoid insecticides is excellent, which can be used for resistance management strategies. Applications can be foliar sprays, watering and seed treatments. It was first registered in Central America (Guatemala and Honduras) in April 2014, and on August 3, 2018, flupyranone was officially registered in China, and the patent term in China expires on March 18, 2027.
Product Introduction
Chinese name:FlupyranoneEnglish Name:flupyradifuroneOther Names:ClothifurinChemical Name:4-[(6-chloro-3-pyridylmethyl)(2,2-difluoroethylamino)amino]furan-2(5H)-oneCAS Login Number:Molecular Formula:c12h11clf2n2o2Relative molecular weight:Structural Formula:
Three-dimensional structural formula:
Physicochemical Properties:The mass fraction of flupyranone was 994% of the pure product is a white powdery solid. Melting Point: 69 ; Boiling point: decomposition before boiling; Octanol-water partition coefficient (pH 7,20): 158；Density: 143 g/ml；Vapor pressure (20): 91×10-7pa；Henry's constant (25): 82×10-8pa·m3·mol-1。Solubility (20): Solubility in water is 32 g/l；The solubility in toluene is 37 g l, solubility in both ethyl acetate and methanol 250 g l.
Mechanism of action
Flupyranone is a nicotinic acetylcholine receptor (NACHR) competitive modulator that acts on the insect nervous system. Binds to acetylcholine sites on its receptors, causing a range of symptoms in insects, from overexcitement to lethargy and paralysis. The International Action Committee on Insecticide Resistance (IRAC) classifies flupyranone as a 4D (butylenolactone) subgroup in Group 4, and it is the only active ingredient in this subgroup.
Application and insecticidal spectrum
Applications:Vegetables, fruit trees, cotton, soybeans (seed treatment) and other field crops, etcInsecticidal spectrum:stinging and sucking mouthparts pests, such as Hemiptera: aphids, whiteflies, psyllids, leafhoppers, scale insects, mealybugs, soft scales; Coleoptera: beetles, weevils; Diptera: leafminers; Taenoptera: Thrips, etc., are effective against all growing pests, including larvae and adults. Common dosage forms:17% flupyranone solution.
Features:
1. Applicable crops and wide control spectrum: it can be used for vegetables, fruit trees, and field crops, etc., and can be highly selective to control the main stinging and sucking mouthparts pests, and is effective for all growing pests including larvae and adults.
2. Good systemic properties and stratification activity: After application, the active ingredient is absorbed by the roots, stems and leaves of the plant, and conducts to the apex with transpiration in the xylem, and can also be transmitted to the back of the leaf or distributed to neighboring plant cells through stratification. Therefore, it can effectively control pests in hidden places. 3. Flexible application methods: foliar spray, soil irrigation or drip irrigation can be used, and can also be used for seed treatment. 4. Fast knockdown speed and long-lasting effect: it can make the pests quickly stop feeding, the knockdown speed is fast, and the dead insects can be seen 2 3 days after the medicine, and the control effect is 92 for 3 days after the medicine87%～95.87%。On the 21st day after the drug, the prevention effect was still as high as 984% 100%, showing good fast-acting and long-lasting effect. 5. Wide period of medication: it can be used in all growth stages of crops, and even can be applied at the flowering stage.
6. Good mixability: it can be mixed with a variety of pesticides, such as halodioxapyr, dipropyl sulfate, spiromethane, etc., to improve the control effect and expand the insecticidal spectrum. 7. Environment-friendly: environmentally friendly and safe for bees.
Registration
Domestic Registration:
On August 3, 2018, Bayer AG was officially registered for the first time in China, with 96% flupyranone and 17% flupyranone solution. At present, there is no mixed preparation in the registered flupyranone products in China.
Foreign Registrations:In 2014, Sivanto Prime, a flupyranone product, was first marketed in Honduras and Guatemala in Central America for the control of stinging mouthparts pests on crops such as tomatoes, peppers, potatoes, cucumbers, watermelons and citrus. In the same year, flupyranone was launched in the cities of Dominica and Costa Rica. In 2015, flupyranone was launched in Mexico and Nicaragua. On January 15, 2015, the original drug and preparation of flupyranone were registered in the United States and launched in the same year. Its formulation, Sivanto 200 SL, is registered for use on fruit trees, vegetables and most field crops for the control of pests of stinging and sucking mouthparts. On November 25, 2015, Bayer AG's flupyrafurone TC and its two products, SIVANTO Prime and Buteo START 480 FS, were officially registered in Canada. It is used for root vegetables such as burdock, carrots, celery, ginseng, parsley, radish, turnips, etc., stem vegetables such as artichokes, canna, water chestnuts, taro, potatoes, sweet potatoes, yams, etc., to control aphids, leafhoppers, whiteflies, etc. On December 9, 2015, flupyranone was included in the EU Pesticide Registration Directive reg(EC) No 1107 2009, valid for 10 years. In 2016, the flupyranone product Altus (17096%) and FDF 50 SL (4.).24%) are registered in the U.S. for ornamental plants, greenhouse vegetables, and fruit and nut trees, and for vegetables, nut trees, fruits, and annual flowers. On August 30, 2016, the original drug of flupyranone was registered in Australia. Its single-dose product, Sivanto Prime 200 SL Insecticide, was registered in Australia on August 20, 2018 for the control of aphids, whiteflies, etc., for avocados, tomatoes, peppers, gourds, eggplants, green beans, macadamia nuts, mangoes, papayas, sweet potatoes, etc. In January 2017, the Brazilian National Health Surveillance Agency approved the registration of flupyranone in Brazil under the trade name Sivanto for use in coffee, citrus, kale and tobacco. In 2018, BYI 02960 480 FS (flupyranone 40.)68%) and Sivanto 400 SL (Flupyranone 33.)61%) are registered in the United States, the former for soybeans, and the latter for cereals (except rice), cotton, melon vegetables, legumes, leafy vegetables, root vegetables (except beets), and bulb vegetables. In 2018, the Pest Management Agency of Canada (PMRA) approved the registration of Bayer CropScience's flupyradifurone-based insecticides ALTUS and BCS2960 for the control of aphids, whiteflies, leafhoppers and aphids on Christmas trees on greenhouse vegetables and ornamental plants. In 2018, two products based on flupyranone, BCS 2960 (200 g L) and Altus (200 g L), were registered in Canada. BCS 2960 is registered for use in Christmas trees, greenhouse tomatoes, peppers, cucumbers, lettuce, ornamental plants, etc., to control aphids, leafhoppers, whiteflies. ALTUS is registered for greenhouse tomatoes, cucumbers, lettuce, peppers, eggplants, strawberries, ornamental plants, Christmas trees, etc., to control aphids, leafhoppers, whiteflies, etc. In 2019, Sivanto Prime was registered in Italy for the control of aphids and leafhoppers in fruit trees, grapes and ornamental plants; In January 2020, the product's shelf life in Italy was extended and extended to apple and pear trees, where it was applied after flowering to control apple aphids, apple red and pear aphids. On May 26, 2020, the flupyranone compound (tetrafluthrin 52.)5 g L + flupyranone 263 g l) is registered in Australia and is valid until 30 June 2025 for indoor and outdoor mosquito control. In 2020, Bayer AG BYI 02960 200SL and Acceleron I-425 were registered in Canada. BYI 02960 200SL is used for fruits, vegetables, field crops and Christmas trees to control aphids, leafhoppers, whiteflies, etc. Acceleron I-425 (480 g L) is a seed treatment agent used to control early soybean insect pests.
Recommended for future compounding
Flupyranone + difenethoxamin:It is used for rice, fruit trees, vegetables and tea to control a variety of pests.
Flupyranone + pymetrozine:It can be used to control most of the homoptera pests, especially aphids, whiteflies, leafhoppers and planthoppers, and is suitable for vegetables, rice, cotton, fruit trees and a variety of field crops.
Flupyranone + Propyl Ether:Both have systemic transfer activity and can affect larvae that hide behind the leaves. It has a killing effect on pests at all stages, and has a long effective period, so as to effectively control and achieve the purpose of pest control.
Flupyranone + spiroethyl ester:Both have a unique mechanism of action, which can effectively control the production of existing pesticides
Resistant pests, and can also be used as an important variety for the management of nicotinic pesticide resistance.
Flupyranone + trifluoropyrimidine:It is used for the control of homoptera pests (such as scale insects, whiteflies, pear psyllids, whiteflies, rice planthoppers, aphids, tea green leafhoppers, etc.), hemipteran pests (such as blind bugs, etc.) and tamaleoptera pests (such as thrips, etc.) on crops.
Flupyranone + chloroflutranid:Mainly used in crops lepidopteran pests (such as dimorphic borer, trimorphic borer, rice leaf roller, diamondback moth, cabbage worm, Spodoptera litura, beet armyworm, pod borer, leaf roller moth, cotton bollworm, etc.), homoptera pests (such as scale insects, whiteflies, pear psyllids, whiteflies, rice planthoppers, aphids, tea small green leafhoppers, etc.), hemipteran pests (such as blind bugs, etc.) and tasseloptera pests (such as thrips, etc.).
Flupyranone + chlorpyrifos thiazinone:The insecticidal speed is fast, especially for scale insects.
Flupyranone + Metamidine:It has a complementary effect in terms of efficacy, and has a significant effect on the control of citrus psyllids, and at the same time, it also has high activity against citrus red spiders.
Flupyranone + zolfenamide:The combination has good quick effect, long duration of effect, environmental friendliness, low toxicity, and has a good control effect on most of the pests due to the stinging and sucking mouthparts such as aphids, whiteflies, leafhoppers, beetles and other pests.
Flupyranone + cyclobromidiliprole:The combination has obvious synergistic crops, which can reduce the use rate of pesticides, and is environmentally friendly and safe.
Flupyranone + Dipropionate:This combination is conducive to the management of pest resistance, and is suitable for the control of planthoppers, leaf miners, thrips, aphids, scale insects and other pests on rice, vegetables and fruit trees.
Flupyranone + fluazole cyclomycline + fludioxonil:This combination can effectively control a variety of pests and diseases on potatoes, and has many advantages such as wide control spectrum, slow development of resistance, significant synergistic effect and low control cost.
Flupyranone + fludioxonil + prochloraz:This combination has a good effect on the control of vegetable pests and diseases, especially vegetable aphids, thrips, yellow curved beetles and vegetable powdery mildew.
Flupyranone + prothioconazole + fludioxonil:This combination has obvious synergistic effect, can reduce the amount of pesticides used, and is environmentally friendly and safe.
Synthetic routes
Creation process: The creation of flupyranone is inspired by the natural compound chlorophylline, which is an alkaloid with complex chemical structure, and has been considered as an excellent precursor of simple Nachr agonists for many years, with activities such as knockdown, food rejection and avoidance, and is used as a lead structure. This natural product contains an insecticidal butyrolactone group, which Bayer combined with two other chemical fragments to create a flupyranone, which greatly improves the insecticidal effect and selectivity. **For inquiries, there are currently 3 main synthetic routes:Route 1:In this route, ethyl chloroacetoacetate (2) is used as the starting material to react with potassium tert-butanol to generate ethyl 4-tert-butoxyacetoacetate (3), and then under the action of ***, the ring is transformed to obtain special window acid (4), special window acid (4) reacts with difluoroethylamine to obtain 4-(difluoroethylamino)miran-2 (5h) ketone (5), and finally (5) reacts with 2--5-chloromethylpyridine to obtain the target product flupyradifurone. 
Route 2:In this route, 2-chloro-5-chloromethylpyridine was used as the starting material to react with difluoroethylamine to obtain the intermediate N-((6-chloro-3-pyridine)methyl)-2,2-difluoroethylamine (6), and then (6) reacted with Tewindowic acid (4) to obtain the target product flupyradifurone. 
Route 3:In this route, dimethyl malonate (7) was used as the starting material to react with potassium hydroxide to obtain potassium salt monomethyl malonate (8), and then reacted with methyl chloroacetate to obtain methyl 2-methoxy-2-oxoethylmalonate (9), the intermediate 4-hydroxy-2-oxo-2,5-dihydro-3-furanocarboxylic acid sodium salt (10) was obtained by cyclization under the action of sodium methoxide, and the intermediate (10) and intermediate (6) were obtained under the action of the bisulfate clock to obtain the target product fluoropyropyranone ( flupyradifurone)。 
Although route 1 is relatively short, the special window acid is unstable, and the reaction yield of the last step is only 52%, resulting in a low yield of the whole synthetic route. Route 2 also has the defect of low reaction yield of the last step, and it is difficult to achieve industrialization. Route 3 raw materials are easy to obtain, the reaction conditions are mild, and it is suitable for industrial production.
Patent Situation
On March 31, 2007, Bayer filed a patent application for enoemine carbonyl compounds such as halopyranone, and has been authorized by Australia, the United Kingdom, China, Europe, Japan, South Korea, the United States and other countries and regions. Patents for the compound flupyranone in Europe, the United States, and China all expire in March 2027. These patents were filed by Bayer CropScience.
European Patents:EP2004606, applied for on March 19, 2007, patent expires on March 18, 2027; The name of the invention is: substituted enaminocarbonyl compounds.
U.S. Patents:US2009247551, applied for on March 19, 2007, patent expires on March 19, 2027; The name of the invention is: substituted enaminocarbonyl compounds.
Chinese Patents:CN101415682A, filed on March 19, 2007, expires on March 18, 2027; The name of the invention is: substituted alkene carbonyl compound.
Prospects
As a new neonicotinoid insecticide, flupyranone has a unique mechanism of action and less cross-resistance with other traditional insecticides, which makes flupyranone have great potential in the control of stinging and sucking mouthparts pests, especially in resistance control. At present, the resistance of stinging and sucking pests is increasing, and various insecticides are constantly being used repeatedly, and the promotion of insecticides with new mechanisms of action is imminent, which provides a good opportunity for the market promotion of flupyranone.
However, at the same time, according to its synthesis route, it can be seen that the production cost of flupyranone is relatively high, and the cost of its use is relatively high compared with the insecticide that is also used as a nicotinic acetylcholine receptor, but with the continuous improvement of production technology and the realization of large-scale production, the production cost of flupyranone is also expected to be further reduced, and it is expected to replace thiamethoxam and clothianidin in the future to become a new force of neonicotinoid insecticides.