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Fipronil, 芬普尼 , フィプロニル

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2D chemical structure of fipronilChemSpider 2D Image | Fipronil | C12H4Cl2F6N4OS

120068-37-3.png

Fipronil

  • Molecular Formula C12H4Cl2F6N4OS
  • Average mass 437.148 Da
(±)-5-Amino-1-(2,6-dichloro-a,a,a-trifluoro-p-tolyl)-4-trifluoromethylsulfinylpyrazole-3-carbonitrile
(±)-Fipronil
120068-37-3 [RN]
1H-Pyrazole-3-carbonitrile, 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl)sulfinyl]-
Fluocyanobenpyrazole
T5NNJ AR BG FG DXFFF& CCN DSO&XFFF EZ &&(RS) Form [WLN]
Termidor
UNII:QGH063955F
NCGC00094574-08
QA-6027
SPECTRUM1505354
TL8000532
UNII-QGH063955F
UPCMLD-DP011:002
UQ4430250
芬普尼 [Chinese]
フィプロニル
1H-Pyrazole-3-carbonitrile, 5-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-((trifluoromethyl)sulfinyl)-
424-610-5 [EINECS]
5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethane)sulfinyl-1H-pyrazole-3-carbonitrile
5-amino-1-[4-(trifluoromethyl)phenyl]-4-(trifluoromethylsulfinyl)-3-pyrazolecarbonitrile
8090115 [Beilstein]
HSDB 7051; RM 1601
Fipronil
CAS Registry Number: 120068-37-3
CAS Name: 5-Amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile
Additional Names: 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinylpyrazole; (±)-5-amino-1-(2,6-dichloro-a,a,a-trifluoro-p-tolyl)-4-trifluoromethylsulfinylpyrazole-3-carbonitrile
Manufacturers’ Codes: MB-46030
Trademarks: Frontline (Merial); Termidor (BASF)
Molecular Formula: C12H4Cl2F6N4OS
Molecular Weight: 437.15
Percent Composition: C 32.97%, H 0.92%, Cl 16.22%, F 26.08%, N 12.82%, O 3.66%, S 7.34%
Literature References: GABA-gated chloride channel blocker. Prototype of the phenylpyrazole insecticides known as fiproles. Prepn: I. G. Buntain et al., EP 295117 (1988 to May & Baker); L. R. Hatton et al., US 5232940 (1993). Mechanism of action study: L. M. Cole et al., Pestic. Biochem. Physiol. 46, 47 (1993). Comprehensive description: F. Colliot et al., Brighton Crop Prot. Conf. – Pests Dis. 1992, 29-34.
Properties: White solid, mp 200.5-201°. Vapor pressure (20°): 2.8 ´ 10-9 mm Hg. Log P (n-octanol/water): 4.0. Soly: water 2 mg/l; acetone >50%; corn oil >10,000 mg/l. LD50 in rats (mg/kg): 100 orally; >2000 dermally (Colliot); in mice (mg/kg): 32 i.p. (Cole).
Melting point: mp 200.5-201°
Log P: Log P (n-octanol/water): 4.0
Toxicity data: LD50 in rats (mg/kg): 100 orally; >2000 dermally (Colliot); in mice (mg/kg): 32 i.p. (Cole)
Use: Pesticide.
Therap-Cat-Vet: Ectoparasiticide.

APPROVED CDSCO INDIA 25.06.2018

Fipronil  50mg/134mg/268mg/402 mg spot on solution for cats and dogs , For treatment of flea and tick infestation in cats and dogs (for veterinary use only)

Fipronil is a broad-spectrum insecticide that belongs to the phenylpyrazole chemical family. Fipronil disrupts the insect central nervous system by blocking GABA-gated chloride channels and glutamate-gated chloride (GluCl) channels. This causes hyperexcitation of contaminated insects’ nerves and muscles. Fipronil’s specificity towards insects is believed to be due to its greater affinity to the GABA receptor in insects relative to mammals and its effect on GluCl channels, which do not exist in mammals.[1]

Because of its effectiveness on a large number of pests, fipronil is used as the active ingredient in flea control products for pets and home roach traps as well as field pest control for corn, golf courses, and commercial turf. Its widespread use makes its specific effects the subject of considerable attention. This includes ongoing observations on possible off-target harm to humans or ecosystems as well as the monitoring of resistance development.[2]

Use

Fipronil is or has been used in:

  • Under the trade name Regent, it is used against major lepidopteran (moth, butterfly, etc.) and orthopteran (grasshopper, locust, etc.) pests on a wide range of field and horticultural crops and against coleopteran (beetle) larvae in soils. In 1999, 400,000 hectares were treated with Regent. It became the leading imported product in the area of rice insecticides, the second-biggest crop protection market after cotton in China.[3]
  • Under the trade names Goliath and Nexa, it is employed for cockroach and ant control, including in the US. It is also used against pests of field corngolf courses, and commercial lawn care under the trade name Chipco Choice.[3]
  • It has been used under the trade name Adonis for locust control in Madagascar and Kazakhstan.[3]
  • Marketed under the names Termidor, Ultrathor, and Taurus in Africa and Australia, fipronil effectively controls termite pests, and was shown to be effective in field trials in these countries.[3]
  • Termidor has been approved for use against the Rasberry crazy ant in the Houston, Texas, area, under a special “crisis exemption” from the Texas Department of Agriculture and the Environmental Protection Agency. The chemical is only approved for use in Texascounties experiencing “confirmed infestations” of the newly discovered ant species.[4] Use of Termidor is restricted to certified pest control operators in the following states: Alaska, Connecticut, Nebraska, South Carolina, Massachusetts, Indiana, New York, and Washington.[citation needed]
  • In Australia, it is marketed under numerous trade names, including Combat Ant-Rid, Radiate and Termidor, and as generic fipronil
  • In the UK, provisional approval for five years has been granted for fipronil use as a public hygiene insecticide.[3]
  • Fipronil is the main active ingredient of Frontline TopSpot, Fiproguard, Flevox, and PetArmor (used along with S-methoprene in the ‘Plus’ versions of these products); these treatments are used in fighting tick and flea infestations in dogs and cats.
  • In New Zealand, fipronil was used in trials to control wasps (Vespula spp.), which are a threat to indigenous biodiversity.[5] It is now being used by the Department of Conservation to attempt local eradication of wasps,[6].[7][8]

Effects

Toxicity

Fipronil is classed as a WHO Class II moderately hazardous pesticide, and has a rat acute oral LD50 of 97 mg/kg.

It has moderate acute toxicity by the oral and inhalation routes in rats. Dermal absorption in rats is less than 1% after 24 h and toxicity is considered to be low. It has been found to be very toxic to rabbits.

The photodegradate MB46513 or desulfinylfipronil, appears to have a higher acute toxicity to mammals than fipronil itself by a factor of about 10.[9]

Symptoms of acute toxicity via ingestion includes sweating, nausea, vomiting, headache, abdominal pain, dizziness, agitation, weakness, and tonic-clonic seizures. Clinical signs of exposure to fipronil are generally reversible and resolve spontaneously. As of 2011, no data were available regarding the chronic effects of fipronil on humans. The U.S. EPA has classified fipronil as a group C (possible human) carcinogen based on an increase in thyroid follicular cell tumors in both sexes of the rat. However, as of 2011, no human data is available regarding the carcinogenic effects of fipronil.[10]

Two Frontline TopSpot products were determined by the New York State Department of Environmental Conservation to pose no significant exposure risks to workers applying the product. However, concerns were raised about human exposure to Frontline spray treatment in 1996, leading to a denial of registration for the spray product. Commercial pet groomers and veterinarians were considered to be at risk from chronic exposure via inhalation and dermal absorption during the application of the spray, assuming they may have to treat up to 20 large dogs per day.[3] Fipronil is not volatile, so the likelihood of humans being exposed to this compound in the air is low.[10]

In contrast to neonicotinoids such as acetamipridclothianidinimidacloprid, and thiamethoxam, which are absorbed through the skin to some extent, fipronil is not absorbed substantially through the skin.[11]

Detection in body fluids

Fipronil may be quantitated in plasma by gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry to confirm a diagnosis of poisoning in hospitalised patients or to provide evidence in a medicolegal death investigation.[12]

Ecological toxicity

Fipronil is highly toxic for crustaceansinsects and zooplankton,[13] as well as beestermitesrabbits, the fringe-toed lizard, and certain groups of gallinaceous birds. It appears to reduce the longevity and fecundity of female braconid parasitoids. It is also highly toxic to many fish, though its toxicity varies with species. Conversely, the substance is relatively innocuous to passerineswildfowl, and earthworms.

Its half-life in soil is four months to one year, but much less on soil surface because it is more sensitive to light (photolysis) than water (hydrolysis).[14]

Few studies of effects on wildlife have been conducted, but studies of the nontarget impact from emergency applications of fipronil as barrier sprays for locust control in Madagascar showed adverse impacts of fipronil on termites, which appear to be very severe and long-lived. Also, adverse effects were indicated in the short term on several other invertebrate groups, one species of lizard (Trachylepis elegans), and several species of birds (including the Madagascar bee-eater).

Nontarget effects on some insects (predatory and detritivorous beetles, some parasitic wasps and bees) were also found in field trials of fipronil for desert locust control in Mauritania, and very low doses (0.6-2.0 g a.i./ha) used against grasshoppers in Niger caused impacts on nontarget insects comparable to those found with other insecticides used in grasshopper control. The implications of this for other wildlife and ecology of the habitat remain unknown, but appear unlikely to be severe.[3] Unfortunately, this lack of severity was not observed in bee species in South America. Fipronil is also used in Brazil and studies on the stingless bee Scaptotrigona postica have shown adverse reactions to the pesticide, including seizures, paralysis, and death with a lethal dose of .54 ng a.i./bee and a lethal concentration of .24 ng a.i./μl diet. These values are highly toxic in Scaptotrigona postica and bees in general.[15] Toxic baiting with fipronil has been shown to be effective in locally eliminating German wasps. All colonies within foraging range were completely eliminated within one week.[16][17][5]

In May 2003, the French Directorate-General of Food at the Ministry of Agriculture determined that a case of mass bee mortality observed in southern France was related to acute fipronil toxicity. Toxicity was linked to defective seed treatment, which generated dust. In February 2003, the ministry decided to temporarily suspend the sale of BASF crop protection products containing fipronil in France.[18] The seed treatment involved has since been banned.[citation needed] Fipronil was used in a broad spraying to control locusts in Madagascar in a program that began in 1997.[19]

Notable results from wildlife studies include:

  • Fipronil is highly toxic to fish and aquatic invertebrates. Its tendency to bind to sediments and its low water solubility may reduce the potential hazard to aquatic wildlife.[20]
  • Fipronil is toxic to bees and should not be applied to vegetation when bees are foraging.[20]
  • Based on ecological effects, fipronil is highly toxic to upland game birds on an acute oral basis and very highly toxic on a subacute dietary basis, but is practically nontoxic to waterfowl on both acute and subacute bases.[21]
  • Chronic (avian reproduction) studies show no effects at the highest levels tested in mallards (NOEC) = 1000 ppm) or quail (NOEC = 10 ppm). The metabolite MB 46136 is more toxic to the parent than avian species tested (very highly toxic to upland game birds and moderately toxic to waterfowl on an acute oral basis).[21]
  • Fipronil is very highly toxic to bluegill sunfish and highly toxic to rainbow trout on an acute basis.[21]
  • An early-lifestage toxicity study in rainbow trout found that fipronil affects larval growth with a NOEC of 0.0066 ppm and an LOEC of 0.015 ppm. The metabolite MB 46136 is more toxic than the parent to freshwater fish (6.3 times more toxic to rainbow trout and 3.3 times more toxic to bluegill sunfish). Based on an acute daphnia study using fipronil and three supplemental studies using its metabolites, fipronil is characterized as highly toxic to aquatic invertebrates.[21]
  • An invertebrate lifecycle daphnia study showed that fipronil affects length in daphnids at concentrations greater than 9.8 ppb.[21]
  • A lifecycle study in mysids shows fipronil affects reproduction, survival, and growth of mysids at concentrations less than 5 ppt.[21]
  • Acute studies of estuarine animals using oystersmysids, and sheepshead minnows show that fipronil is highly acutely toxic to oysters and sheepshead minnows, and very highly toxic to mysids. Metabolites MB 46136 and MB 45950 are more toxic than the parent to freshwater invertebrates (MB 46136 is 6.6 times more toxic and MB 45950 is 1.9 times more toxic to freshwater invertebrates).[21]

Colony collapse disorder

Fipronil is one of the main chemical causes blamed for the spread of colony collapse disorder among bees. It has been found by the Minutes-Association for Technical Coordination Fund in France that even at very low nonlethal doses for bees, the pesticide still impairs their ability to locate their hive, resulting in large numbers of forager bees lost with every pollen-finding expedition.[22] A synergistic toxic effect of fipronil with the fungal pathogen Nosema ceranae was recently reported[23]. The functional basis for this toxic effect is now understood: the synergy between fipronil and the pathogenic fungus induces changes in male physiology leading to infertility[24] A 2013 report by the European Food Safety Authorityidentified fipronil as “a high acute risk to honeybees when used as a seed treatment for maize and on July 16, 2013 the EU voted to ban the use of fipronil on corn and sunflowers within the EU. The ban took effect at the end of 2013.”[25][26]

Pharmacodynamics

Fipronil acts by binding to allosteric sites of GABAA receptors and GluCl receptors (of insects) as an antagonist (a form of noncompetitive inhibition). This prevents the opening of chloride ion channels normally encouraged by GABA, reducing the chloride ions’ ability to lower a neuron’s membrane potential. This results in an overabundance of neurons reaching action potential and likewise CNS toxicity via overstimulation.[27][28][29][30]

Acute oral LD50 (rat) 97 mg/kg
Acute dermal LD50 (rat) >2000 mg/kg

In animals and humans, fipronil poisoning is characterized by vomiting, agitation, and seizures, and can usually be managed through supportive care and early treatment of seizures, generally with benzodiazepine use.[31][32]

History

Fipronil was discovered and developed by Rhône-Poulenc between 1985 and 1987, and placed on the market in 1993 under the B2 U.S. Patent 5,232,940 B2. Between 1987 and 1996, fipronil was evaluated on more than 250 insect pests on 60 crops worldwide, and crop protection accounted for about 39% of total fipronil production in 1997. Since 2003, BASF holds the patent rights for producing and selling fipronil-based products in many countries.

2017 Fipronil eggs contamination

The 2017 Fipronil eggs contamination is an incident in Europe and South Korea involving the spread of insecticide contaminated eggs and egg products. Chicken eggs were found to contain Fipronil and distributed to 15 European Union countries, Switzerland, and Hong Kong.[33][34] Approximately 700,000 eggs are thought to have reached shelves in the UK alone.[35] Eggs at 44 farms in Taiwan were also found with excessive Fipronil levels.[36]

SYN

Figure US20130030190A1-20130131-C00009

SYN 2

SYN 3

SYN 4

PATENT

http://www.allindianpatents.com/patents/271132-a-process-for-the-synthesis-of-fipronil

5-Amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl
sulfinyl pyrazole or 5-Amino-[2,6-dichloro-4-(trif]uoromethyl)phenyl]-4-[-(1 (R,S)-trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile also known as Fipronil is a novel pesticide characterized by high efficiency, low toxicity and especially low residue.
There are various routes to synthesize Fipronil by oxidation of thiopyrazole with various other oxidizing agents in suitable solvents. Oxidation of sulfides is a very useful route for the preparation of sulfoxides. Literature is replete with the conversion of sulfides to sulfoxides and/or sulfones. However, most of the existing methods use expensive, toxic or rare oxidizing reagents, which are difficult to prepare, are very expensive and cannot be used on commercial scale. Many of these processes suffer from poor selectivity.
WO01/30760 describes oxidation of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthio-pyrazole with trifluoro-acetic acid and hydrogen peroxide in the presence of boric acid. The quantity

of trifluoroacetic acid used is 14.5 molar equivalents. The patent also
discloses the preparation of 5-amino-1-(2,6-dichloro-4-trifluoromethyl
phenyl)-3-cyano-4-trifluoromethylthio-pyrazole from 5-amino-1-(2,6-
dichloro-4-trifluoromethyl phenyl)-3-cyano pyrazole-4-yl disulphide.
European Patent publication No.295117 describes the preparation of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulphinyl pyrazole starting from 2,6-Dichloro-4-trifluoromethylaniline to give an intermediate 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthiopyrazole which is oxidized with meta-chloroperbenzoic acid in chloroform to give desired product.
Oxidizing agents such as perbenzoic acids do not provide effective and regioselective oxidation of electron deficient sulfides such as trifluoromethylsulphides which are less readily oxidized than other sulfides. Trifluoroacetic acid and trichloroacetic acid are found to be very efficient and regioselective oxidation medium for oxidation of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthio-pyrazole in presence of hydrogen peroxide. Trichloroacetic acid can not be used alone due to higher melting point. Trifluoroacetic acid on the other hand is very regioselective with respect to conversion and low by-products formation. However, it is expensive, water miscible, corrosive to metal as well as glass, comparatively lower boiling and it’s recovery (in anhydrous form) is complex in nature.
W000/35851/2000 talks about synthesis of 2,6-Dichloro-4-trifluoromethylaniline starting from 3,4,5-trichloro-benzotrifluoride in the presence of alkaline fluorides like lithium fluoride and ammonia in the

presence of N-methylpyrrolidone at 250°C to give 97% conversion and 87% selectivity. The main drawback of the above process is the synthesis of 3,4,5-trichlorobenzotrifluoride in high yield and purity. Chlorination of p-chlorobenzotrifluoride gives a mixture of 3,4,5-trichlorobenzotrifluoride in 72% GLC conversions, 3,4-dichloro and tetrachlorobenzotrifluoride. The process to get pure 3,4,5-isomer from this mixture by fractionation followed by crystallization is very tedious. Moreover in-spite of using very pure intermediates, substantial amount of an undesired isomer (3-amino-4,5-dichlorobenzotrifluoride) is also obtained.
Another approach to generate 3,4,5-trichlorobenzotrifluoride with high yield and purity is to perform denitrochlorination of 4-chloro-3,5-dinitrobenzotrifluoride in the presence of a catalyst as described in GB Patent 2154581A. Even though the process produces 3,4,5-trichlorobenzotrifluoide in high yield and purity, the reaction conditions are too drastic to be employed for an industrial process.
The known commercial processes for the manufacture of Fipronil uses corrosive and expensive chemical such as trifluoroaceticacid, hydrogen peroxide and m-chloroperbenzoicacid Trifluoroacetic acid is expensive and generally not used in large quantities, as well as of m-chloroperbenzoic acid is difficult to handle at commercial scale due to its un-stability and detonating effect. Also the raw material used such as 2,6-Dichloro-4-trifluoromethylaniline are not easily available or made. The overall process for the Fipronil as disclosed above is found to be unsatisfactory in one respect or the other.

Thus, there is felt a need for preparing Fipronil from easily available raw materials in a simple and economical manner at an industrial level, with high yields and purity.

PATENT

https://patents.google.com/patent/US20130030190A1/en

  • 5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl sulfinyl pyrazole or 5-Amino-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[-(1(R,S)-trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile also known as Fipronil is a novel pesticide characterized by high efficiency, low toxicity and especially low residue.
  • [0005]
    There are various routes to synthesize Fipronil by oxidation of thiopyrazole with various other oxidizing agents in suitable solvents. Oxidation of sulfides is a very useful route for the preparation of sulfoxides. Literature is replete with the conversion of sulfides to sulfoxides and/or sulfones. However, most of the existing methods use expensive, toxic or rare oxidizing reagents, which are difficult to prepare, are very expensive and cannot be used on commercial scale. Many of these processes suffer from poor selectivity.
  • [0006]
    WO01/30760 describes oxidation of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthio-pyrazole with trifluoro-acetic acid and hydrogen peroxide in the presence of boric acid. The quantity of trifluoroacetic acid used is 14.5 molar equivalents. The patent also discloses the preparation of 5-amino-1-(2,6-dichloro-4-trifluoromethyl phenyl)-3-cyano-4-trifluoromethylthio-pyrazole from 5-amino-1-(2,6-dichloro-4-trifluoromethyl phenyl)-3-cyano pyrazole-4-yl disulphide.
  • [0007]
    European Patent publication No. 295117 describes the preparation of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulphinyl pyrazole starting from 2,6-Dichloro-4-trifluoromethylaniline to give an intermediate 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthiopyrazole which is oxidized with meta-chloroperbenzoic acid in chloroform to give desired product.
  • [0008]
    Oxidizing agents such as perbenzoic acids do not provide effective and regioselective oxidation of electron deficient sulfides such as trifluoromethylsulphides which are less readily oxidized than other sulfides. Trifluoroacetic acid and trichloroacetic acid are found to be very efficient and regioselective oxidation medium for oxidation of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthio-pyrazole in presence of hydrogen peroxide. Trichloroacetic acid can not be used alone due to higher melting point. Trifluoroacetic acid on the other hand is very regioselective with respect to conversion and low by-products formation. However, it is expensive, water miscible, corrosive to metal as well as glass, comparatively lower boiling and it’s recovery (in anhydrous form) is complex in nature.
  • [0009]
    WO00/35851/2000 talks about synthesis of 2,6-Dichloro-4-trifluoromethylaniline starting from 3,4,5-trichloro-benzotrifluoride in the presence of alkaline fluorides like lithium fluoride and ammonia in the presence of N-methylpyrrolidone at 250° C. to give 97% conversion and 87% selectivity. The main drawback of the above process is the synthesis of 3,4,5-trichlorobenzotrifluoride in high yield and purity. Chlorination of p-chlorobenzotrifluoride gives a mixture of 3,4,5-trichlorobenzotrifluoride in 72% GLC conversions, 3,4-dichloro and tetrachlorobenzotrifluoride. The process to get pure 3,4,5-isomer from this mixture by fractionation followed by crystallization is very tedious. Moreover in-spite of using very pure intermediates, substantial amount of an undesired isomer (3-amino-4,5-dichlorobenzotrifluoride) is also obtained.
  • [0010]
    Another approach to generate 3,4,5-trichlorobenzotrifluoride with high yield and purity is to perform denitrochlorination of 4-chloro-3,5-dinitrobenzotrifluoride in the presence of a catalyst as described in GB Patent 2154581A. Even though the process produces 3,4,5-trichlorobenzotrifluoide in high yield and purity, the reaction conditions are too drastic to be employed for an industrial process.
  • [0011]
    The known commercial processes for the manufacture of Fipronil uses corrosive and expensive chemical such as trifluoroaceticacid, hydrogen peroxide and m-chloroperbenzoicacid Trifluoroacetic acid is expensive and generally not used in large quantities, as well as of m-chloroperbenzoic acid is difficult to handle at commercial scale due to its un-stability and detonating effect. Also the raw material used such as 2,6-Dichloro-4-trifluoromethylaniline are not easily available or made. The overall process for the Fipronil as disclosed above is found to be unsatisfactory in one respect or the other.
  • [0012]
    Thus, there is felt a need for preparing Fipronil from easily available raw materials in a simple and economical manner at an industrial level, with high yields and purity.

Figure US20130030190A1-20130131-C00009

    • Example 18

    • [0081]
      A mixture of 700 g of dichloroacetic acid and trichloroacetic acid was taken along with 300 g of chlorobenzene, 2 g of boric acid and 280 g of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thiopyrazole, the content were cooled to 15-20° C. Aqueous H20(44.2 g, 50%) was added and mass was stirred for 20 hrs. The mass was then processed and Fipronil was isolated by filtration. After work up as above, 269 g of Fipronil of purity 94% was obtained. The filtered Fipronil was then purified using chlorobenzene (5 ml/g) followed by mixture (1 ml/g, 80:20 v/v) of ethylacetate and chlorobenzene to get 232 g of Fipronil of greater than 97% purity.

Example 19 Purification of Fipronil

  • [0082]
    The fipronil prepared in example 18 of purity 97% was treated with a mixture (232 ml) of ethylacetate & chlorobenzene (80:20 v/v). This reaction mixture was heated to 85-90° C. & maintained for 1 hr. It was further cooled up to 30° C. in stages & filtered. Fipronil thus obtained had a purity of 98%. This cycle was repeated to obtain fipronil of above 98% purity.
  • [0083]
    The useful constituents from various streams of crystallization, leaching as above were reused and recycled, fipronil was isolated in 80-85% yield with purity of above 98%.

PATENT

CN 101250158 [2008 to Hunan Res Inst of of chemical Ind.]

WO2005/44806 A1, ; Page/Page column 7-8; 12 ;

WO2009/77853 A1, ; Page/Page column 28-29 ;

US 5,618,945 [1995, to Rhone-Poulenc]

CN 102060774

IN 178903 [1997, to Rallis India Ltd.]

WO 2009/077,853 [2009 to Vetoquinol SA ]

BG 109983 [2008 to BASF Agro B V]

US 8,507,693 [2013, to Gharda]

US 5,618,945 [1995, to Rhone-Poulenc]

WO 2007/122,440 [ 2007 to Gharda Chemicals Ltd.]

FR 2,925,493 [2009 to to Vetoquinol SA ]

CN 1176078 [ 2002 to Jiangsu Prov Inst of Pesticide]

EP 0,374,061 [ 1990 to Rhone Poulenc Agrochimie]

US 5,232,940 [1993, to May and Baker]

PAPER

Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), , # 24 p. 3371 – 3376

Synthesis 2008, 11, 1682-1684

Synthesis 2007, 22, 3507-3511

Tetrahedron Letters, , 2007, 48(48), 8518-8520

Tetrahedron Letters 2008 ,49. 3463-3465

References

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External links

Fipronil
2D chemical structure of fipronil
3D chemical structure of fipronil
Names
IUPAC name

(RS)-5-Amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethylsulfinyl)pyrazole-3-carbonitrile
Other names

Fipronil
Fluocyanobenpyrazole
Termidor
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.102.312
KEGG
PubChem CID
UNII
Properties
C12H4Cl2F6N4OS
Molar mass 437.14 g·mol−1
Density 1.477-1.626 g/cm3
Melting point 200.5 °C (392.9 °F; 473.6 K)
Pharmacology
QP53AX15 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

/////////////Fipronil, INDIA 2018, フィプロニル , HSDB 7051, RM 1601, veterinary, ind 2018

C1=C(C=C(C(=C1Cl)N2C(=C(C(=N2)C#N)S(=O)C(F)(F)F)N)Cl)C(F)(F)F

“ DRUG APPROVALS INTERNATIONAL” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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