Fipronil 氟虫腈

用于众多作物，防治多种害虫。并可作为卫生用药。2008年6月9日到期。拜耳公司开发；转让巴斯夫公司。2009年市场4.55亿美元。1993年上市。

氟虫腈

实物图氟虫腈是一种苯基吡唑类杀虫剂、杀虫谱广，对害虫以胃毒作用为主，兼有触杀和一定的内吸作用，其作用机制在于阻碍昆虫γ-氨基丁酸控制的氯化物代谢，因此对蚜虫、叶蝉、飞虱、鳞翅目幼虫、蝇类和鞘翅目等重要害虫有很高的杀虫活性，对作物无药害。该药剂可施于土壤，也可叶面喷雾。施于土壤能有效防治玉米根叶甲、金针虫和地老虎。叶面喷洒时，对小菜蛾、菜粉蝶、稻蓟马等均有高水平防效，且持效期长

简介
由法国罗纳-普朗克公司开发，获中国专利授权(CN86108643)，该化合物专利在2006年12月19日到期；同时，拜耳公司对氟虫腈及其中间体的制备方法也在我国获得专利授权(CN95100789.0)，此项专利的有效期将持续到2015年。
化学成分

综述
氟虫腈其英文通用名为fipronil，商品名Regent锐劲特，试验代号MB-46030，化学名 氟虫腈
称(RS)-5-氨基-1-(2,6-二氯-a,a,a-三氟-对-甲苯基)-4-三氟甲基亚磺酰基吡唑-3-腈，英文化学名：(±)-5-amino-1-(2,6-dichloro-a,a,a,-trifluoro-P-tolyl)-4-frifluoromethylsulfinylpyrazole-3-Carbonitrile，
分子式：C12H4Cl2F6N4OS，分子量：437.2

理化性质
纯品为白色固体，熔点200~201℃，密度1.477~1.626（20℃）。蒸气压3.7×10-7pa（20℃）；分配系数（25℃）logP=4.0。水中溶解度（20℃，mg/L）1.9（蒸馏水），1.9（PH=5），2.4（PH=9）；其它溶剂中溶解度（20℃，g/L）：丙酮545.9，二氯甲烷22.3，甲苯3.0，己烷<0.028。在PH=5、7的水中稳定，在PH=9时缓慢水解，DT50约为28天，在太阳光照下缓慢降解，但在水溶液中经光照可快速分解。
毒性
大鼠急性经口LD50：97mg/kg，小鼠急性经口LD50：95mg/kg；大鼠急性经皮LD50：>2000mg/kg，兔急性经皮LD50：354mg/kg，大鼠吸入LC50（4小时）：0.682mg/L，本品对兔眼睛和皮肤无刺激。无“三致”。野鸭LD50：>2000mg/kg；鹌鹑LD50：11.3mg/kg；鹌鹑LC50：49mg/kg，野鸭LC50：5000mg/kg。虹鳟、鲤鱼LC50（96小时）：248ppm。水蚤LC50（48小时）：0.19mg/L。对蜜蜂安全。
制剂SC、GR、FS、EC、WG、UL
应用
氟虫腈为GABA-氯通道抑制剂。与现有杀虫剂无交互抗性，对有机磷、有机氯、氨基甲酸酯、拟除虫菊酯等有抗性的或敏感的害虫均有效。适宜的作物有水稻、玉米、棉花、香蕉、甜菜、马铃薯、花生等，推荐剂量下对作物无药害同时对卫生害虫的蟑螂防治也有非凡的效果,如2%神农灭蟑螂饵剂。
使用方法
氟虫腈杀虫谱广，具有触杀、胃毒和中度内吸作用。既能防治地下害虫，又能防治地上害虫。既可用于茎叶处理和土壤处理，又可用于种子处理。25~50g有效成分/公顷叶面喷施，可有效防治马铃薯叶甲、小菜蛾、粉纹菜蛾、墨西哥棉铃象甲和花蓟马等。稻田中使用50~100g有效成分/公顷可很好的防治螟虫，褐飞虱等害虫。6~15g有效成分/公顷叶面喷施，可防治草原里蝗属和沙漠蝗属害虫。100~150g有效成分/公顷施于土壤，能有效地防治玉米根叶甲、金针虫和地老虎。250~650g有效成分/100千克种子处理玉米种子，能有效地防治玉米金针虫和地老虎。本品的主要防治对象包括蚜虫、叶蝉、鳞翅目幼虫、蝇类和鞘翅目等害虫。是被众多农药专家推荐为代替高毒有机磷农药的首选品种之一。

生产方法
目前氟虫腈工业化生产合成路线主要有两条，一是以2,6-二氯-4-三氟甲基苯胺为原料，经过重氮化得到重氮盐，再与2,3-二氰基丙酸乙酯反应得到；二是以2,6-二氯-4-三氟甲基苯肼为原料与富马腈反应，再氧化得到产品。
1.1 2,6-二氯-4-三氟甲基苯胺
2,6-二氯-4-三氟甲基苯胺主要合成路线有三条：①对三氟甲基苯胺法。对三氟甲基苯胺在溶剂中直接氯化得到2,6-二氯-4-三氟甲基苯胺。该法简单方便，但是对三氟甲基苯胺价格较贵，生产成本比较高，国外主要采用该法生产。②对氯三氟甲苯法。对氯三氟甲苯与二甲基甲酰胺和NaNH2在一定温度和压力下反应得到N,N-二甲基对三氟甲基苯胺，然后在光照下氯化，脱甲基并环上氯化得到目的产品。该法步骤较长，''三废''量较大。③3,4-二氯三氟甲苯法。以3,4-二氯三氟甲基苯胺为原料，与二甲基甲酰胺及氢氧化钠在压力釜中反应，在光照条件下氯化脱甲基并环上氯化得到产品。目前国内多家科研机构研究与开发此路线。此路线更趋于合理，产品质量高，''三废''量有一定减少。
1.2 2,6-二氯-4-三氟甲基苯肼
目前研究主要方向是以对氯三氟甲基苯为原料，在三氯化铁存在下深度氯化得到3,4,5-三氯三氟甲苯，然后与水合肼反应得到2,6-二氯-4-三氟甲基苯肼。
1.3 2,3-二氰基丙酸乙酯
2,3-二氰基丙酸乙酯合成方法，主要有分步法和一步法两种。分步法生产过程较为繁琐，生产过程中产生对人体有害的剧毒品且''三废''量比较大，因此目前主要采用一步法生产。一步法合成工艺为：将氰化钠和溶剂无水乙醇混合，充分溶解后，加入多聚甲醛，溶解后接着加入氰乙酸乙酯，氰化钠、多聚甲醛、氰乙酸乙酯投料比例为1:1:0.91(m:m)。然后使用盐酸酸化后，再经过萃取水洗得到粗品，最后精馏去除溶剂得到产品。目前国内泰州天源化工有限公司等数家企业采用该法生产2,3-二氰基丙酸乙酯。

我国规定2009年10月1日起禁用氟虫腈。

fipronil
Insecticide
IRAC 2B; fiprole

NOMENCLATURE
Common name fipronil (BSI, pa E-ISO)
IUPAC name (?-5-amino-1-(2,6-dichloro-a,a,a-trifluoro-p-tolyl)-4-trifluoromethylsulfinylpyrazole-3-carbonitrile
Chemical Abstracts name 5-amino-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(1R,S)-(trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile
CAS RN [120068-37-3] Development codes MB 46030; RPA-030 (both Rhône-Poulenc)

PHYSICAL CHEMISTRY
Mol. wt. 437.2 M.f. C12H4Cl2F6N4OS Form White solid. M.p. 200-201 ºC; (tech., 195.5-203 °C) V.p. 3.7 ´ 10-4 mPa (25 ºC) KOW logP = 4.0 (shake flask method) Henry 3.7 ´ 10-5 Pa m3 mol-1 (calc.) S.g./density 1.477-1.626 (20 °C) Solubility In water 1.9 (pH 5), 2.4 (pH 9), 1.9 (distilled) (all in mg/l, 20 °C). In acetone 545.9, dichloromethane 22.3, hexane 0.028, toluene 3.0 (all in g/l, 20 °C). Stability Stable in water at pH 5 and 7; slowly hydrolysed at pH 9 (DT50 c. 28 d). Stable to heat. Slowly degrades in sunlight (c. 3% loss after 12 d continuous irradiation); rapidly photolysed in aqueous solution (DT50 c. 0.33 d).

COMMERCIALISATION
History Discovered by Rhône-Poulenc in 1987. Reported by F. Colliot et al., (Proc. Br. Crop Prot. Conf. - Pests Dis., 1992, 1, 29). Introduced by Rhône-Poulenc Agrochimie (now Bayer CropScience) in 1993. Agricultural uses acquired by BASF AG in 2003. Manufacturers BASF

APPLICATIONS
Biochemistry Insecticide which acts as a potent blocker of the GABA-regulated chloride channel. Insects resistant or tolerant to pyrethroid, cyclodiene, organophosphorus and/or carbamate insecticides are susceptible to fipronil. Mode of action Broad-spectrum insecticide, toxic by contact and ingestion. Moderately systemic and, in some crops, can be used to control insects when applied as a soil or seed treatment. Good to excellent residual control following foliar application. Uses Control of multiple species of thrips on a broad range of crops by foliar, soil or seed treatment. Control of corn rootworm, wireworms and termites by soil treatment in maize. Control of boll weevil and plant bugs on cotton, diamond-back moth on crucifers, Colorado potato beetle on potatoes by foliar application. Control of stem borers, leaf miners, planthoppers, leaf folder/rollers and weevils in rice. Foliar application rates range from 10-80 g/ha; soil treatment rates 100-200 g/ha. Formulation types EC; FS; GR; SC; UL; WG. Selected products: 'Prince' (Nissan)

OTHER PRODUCTS
'Ascend' (BASF); 'Blitz' (BASF); 'Chipco Choice' (BASF); 'Cosmos' (BASF); 'Goliath' (BASF); 'Icon' (BASF); 'KB Guepes' (BASF); 'Metis' (BASF); 'Regent' (BASF); 'Termidor' (BASF); 'Texas' (BASF); 'Violin' (BASF); 'Frontline' (veterinary use) (Bayer CropScience) mixtures: 'Cardinal' (+ aldicarb) (BASF); 'Gazette Prince' (+ carbosulfan) (BASF); 'Jumper' (+ guazatine+ triticonazole) (BASF); 'Regent Plus' (+ aldicarb) (BASF); 'Trident' (+ aldicarb) (BASF); 'Zoom' (+ guazatine+ triticonazole) (BASF); 'Amistar-Prince' (+ azoxystrobin) (rice nursery box) (Syngenta, Nihon Nohyaku, Nissan); 'Delaus-Prince' (+ diclocymet) (Nissan); 'Dr. Oryze-Prince' (+ probenazole) (Meiji Seika, Hokko); 'Fuji-one Prince' (+ isoprothiolane) (Nihon Nohyaku); 'Pika Pika' (+ isoprothiolane+ pyroquilon) (Nihon Nohyaku); 'Vget Prince' (+ tiadinil) (Nihon Nohyaku)

ANALYSIS
Product by hplc with u.v. detection. Residues by glc with ECD.

MAMMALIAN TOXICOLOGY
Reviews FAO/WHO 89, 91 (see part 2 of the Bibliography). Oral Acute oral LD50 for rats 97, mice 95 mg/kg. Skin and eye Acute percutaneous LD50 for rats >2000, rabbits 354 mg/kg. Not a skin or eye irritant (OECD criteria). Not a skin sensitiser. Inhalation LC50 (4 h) for rats 0.682 mg/l (tech.; nose only exposure). NOEL (2 y) for rats 0.5 mg/kg diet; (18 mo) for mice 0.5 mg/kg diet; (52 w) for dogs 0.2 mg/kg b.w. daily (combined sexes). ADI (JMPR) 0.0002 mg/kg b.w. [2000]; group ADI for fipronil and fipronil desulfinyl. Other Non-mutagenic, non-teratogenic; no adverse effect on reproductive performance. Clinical signs of toxicity consistent with the interaction of the molecule at a neurotransmitter receptor were observed in all species tested, but were completely reversible. Toxicity class WHO (a.i.) II; EPA (formulation) II

ECOTOXICOLOGY
Birds Acute oral LD50 for bobwhite quail 11.3, mallard ducks >2000, pheasants 31, red-legged partridges 34, house sparrows 1120, pigeons >2000 mg/kg. Dietary LC50 (5 d) for bobwhite quail 49, mallard ducks >5000 mg/kg diet. Fish Acute LC50 (96 h) for bluegill sunfish 85, rainbow trout 248, European carp 430 mg/l. Daphnia LC50 (48 h) 0.19 mg/l; for D. carinata (48 h) 3.8 mg/l. Algae EC50 (96 h) for Scenedesmus subspicatus 0.068 mg/l; (120 h) for Selenastrum capricornutum >0.16, Anabaena flos-aquae >0.17 mg/l. Bees Highly toxic to honeybees, both by direct contact and by ingestion. However, no risk to bees when used as a soil or seed treatment. Worms Non-toxic.

ENVIRONMENTAL FATE
In plants, animals and the environment, fipronil is metabolised via reduction to the sulfide, oxidation to the sulfone, and hydrolysis to the amide. In the presence of sunlight, a photodegradate also forms via sulfoxide extrusion. The sulfide, sulfone and photodegradate are known to act at the GABA receptor site, whereas the amide does not. Animals In rats, once absorbed, the distribution and metabolism of fipronil is rapid. Elimination is mainly via the faeces as fipronil and its sulfone. The two major urinary metabolites were identified as conjugates of ring-opened pyrazole products. The distribution of radioactive residues in tissues was extensive after seven days. In goats and hens, the sulfone was the only metabolite identified in tissues. Plants When applied as an incorporated soil treatment to cotton, maize, sugar beet or sunflowers, uptake of fipronil into plants in all cases was low (c. 5%). At crop maturity, the major residue components observed in all plants were fipronil, the sulfone, and the amide. Following foliar application to cotton, cabbage, rice and potatoes, at crop maturity, fipronil and the photodegradate were the major residue components. Soil/Environment Results of lab. and field studies: Readily degraded: major degradates in soil (aerobic) are sulfone and amide, (anaerobic) are sulfide and amide. Photolysis of soil-applied fipronil gives the photodegradate together with sulfone and amide. Koc 427 (Speyer 2.2) to 1248 (sandy loam). Both fresh and aged column leaching studies (5 soils) indicate that fipronil and its metabolites present a low risk of downward movement in soil; this is supported by field dissipation studies. Following soil incorporated in-furrow granular applications, quantifiable residues were confined to the top 30 cm of soil, with no significant lateral movement or residues.