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ORGANIC SPECTROSCOPY

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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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Fipronil, 芬普尼 , フィプロニル


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

  1. Jump up^ Raymond-Delpech, Valérie; Matsuda, Kazuhiko; Sattelle, Benedict M.; Rauh, James J.; Sattelle, David B. (2005-09-20). “Ion channels: molecular targets of neuroactive insecticides”Invertebrate Neuroscience5 (3-4): 119–133. doi:10.1007/s10158-005-0004-9ISSN 1354-2516.
  2. Jump up^ Maddison, Jill E.; Page, Stephen W. (2008). Small Animal Clinical Pharmacology(Second ed.). Elsevier Health Sciences. p. 229. ISBN 9780702028588.
  3. Jump up to:a b c d e f g “Fipronil”. Pesticides News48: 20. 2000.
  4. Jump up^ “Rasberry Crazy Ant”. Texas A&M. 2008-04-12. Archived from the original on 2007-07-14. Retrieved 2012-08-06.
  5. Jump up to:a b “Revive Rotoiti Autumn 2011”. Department of Conservation. 2011. Retrieved 11 April2012.
  6. Jump up^ “War on wasps in Abel Tasman”. 10 February 2016.
  7. Jump up^ “Vespex: Making wide-area wasp control a reality – WWF’s Conservation Innovation Awards”wwf-nz.crowdicity.com.
  8. Jump up^ (DOC), corporatename = New Zealand Department of Conservation. “Wasp control using Vespex”http://www.doc.govt.nz.
  9. Jump up^ “Fipronil insecticide: Novel photochemical desulfinylation with retention of neurotoxicity”Proceedings of the National Academy of Sciences93: 12764–12767. doi:10.1073/pnas.93.23.12764PMC 23994Freely accessible.
  10. Jump up to:a b “Fipronil Technical Fact Sheet, National Pesticide Information Center”. Retrieved 2015-12-07.
  11. Jump up^ “Cockroach Control”. Retrieved August 10, 2016.
  12. Jump up^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 11th edition, Biomedical Publications, Seal Beach, CA, 2017, pp. 894-895. ISBN 978-0-692-77499-1
  13. Jump up^ “Ecotoxicity for Fipronil”. Retrieved 2010-05-03.
  14. Jump up^ Amrith S. Gunasekara & Tresca Troung (March 5, 2007). “Environmental Fate of Fipronil” (PDF). Retrieved April 16, 2016.
  15. Jump up^ Jacob, CRO; Hellen Maria Soares; Stephen Malfitano Carvalho; Roberta Cornélio Ferreira Nocelli; Osmar Malspina (2013). “Acute Toxicity of Fipronil to the Stingless Bee Scaptotrigona postica Latreille”Bulletin of Environmental Contamination and Toxicology90 (1): 69–72. doi:10.1007/s00128-012-0892-4. Retrieved 23 September 2015.
  16. Jump up^ Paula Sackmann, Mauricio Rabinovich and Juan Carlos Corley J. (2001). “Successful Removal of German Yellowjackets (Hymenoptera: Vespidae) by Toxic Baiting” (PDF). pp. 811–816.
  17. Jump up^ “Short and long-term control of Vespula pensylvanica in Hawaii by fipronil baiting”Pest Management Science68: 1026–1033. doi:10.1002/ps.3262.
  18. Jump up^ Elise Kissling; BASF SE (2003). “BASF statement regarding temporary suspension of sales of crop protection products containing fipronil in France”.
  19. Jump up^ June 2000 BBC News story “Anti-locust drive ‘created havoc'”.
  20. Jump up to:a b “Fipronil” (PDF). National Pesticides Communication Network. p. 3. Retrieved 19 June 2012.
  21. Jump up to:a b c d e f g United States Environmental Protection Agency Office of Prevention, Pesticides and Toxic Substances (1996). “Fipronil. May 1996. New Pesticide Fact Sheet. US EPA Office of Prevention, Pesticides and Toxic Substances”.
  22. Jump up^ “Colony Collapse Disorder linked to Fipronil”. Retrieved 2010-06-17.
  23. Jump up^ Aufavure J., Biron D. G., Vidau C., Fontbonne R., Roudel M., Diogon M., Viguès B., Belzunces L. P., Delbac F., Blot N. (2012) Parasite – insecticide interactions: a case study of Nosema ceranae and fipronil synergy on honeybee. Scientific Reports 2:326 – DOI: 10.1038/srep00326
  24. Jump up^ Kairo G, Biron D.G, Ben A.F, Bonnet M, Tchamitchian S, Cousin M, … & Brunet J.L (2017) Nosema ceranae, Fipronil and their combination compromise honey bee reproduction via changes in male physiology]. Scientific reports, 7(1), 8556.
  25. Jump up^ “EFSA assesses risks to bees from fipronil”. 27 May 2013. Retrieved 29 May 2013.
  26. Jump up^ Carrington, Damian (16 July 2013). “EU to ban fipronil to protect honeybees”The Guardian. London.
  27. Jump up^ Cole, L. M.; Nicholson, R. A.; Casida, J. E. (1993). “Action of Phenylpyrazole Insecticides at the GABA-Gated Chloride Channel”Pestic. Biochem. Physiol46: 47–54. doi:10.1006/pest.1993.1035.
  28. Jump up^ Ratra, G. S.; Casida, J. E. (2001). “GABA receptor subunit composition relative to insecticide potency and selectivity”. Toxicol. Lett122: 215–222. doi:10.1016/s0378-4274(01)00366-6PMID 11489356.
  29. Jump up^ WHO. Pesticide Residues in Food – 1997: Fipronil; International Programme on Chemical Safety, World Health Organization: Lyon, 1997.
  30. Jump up^ Olsen RW, DeLorey TM (1999). “Chapter 16: GABA and Glycine”. In Siegel GJ, Agranoff BW, Fisher SK, Albers RW, Uhler MD. Basic neurochemistry: molecular, cellular, and medical aspects (Sixth ed.). Philadelphia: Lippincott-Raven. ISBN 0-397-51820-X.
  31. Jump up^ Ramesh C. Gupta (2007). Veterinary Toxicology. pp. 502–503. ISBN 978-0-12-370467-2.
  32. Jump up^ Mohamed F, Senarathna L, Percy A, Abeyewardene M, Eaglesham G, Cheng R, Azher S, Hittarage A, Dissanayake W, Sheriff MH, Davies W, Buckley NA, Eddleston M., Acute human self-poisoning with the N-phenylpyrazole insecticide fipronil–a GABAA-gated chloride channel blocker, J Toxicol Clin Toxicol. 2004;42(7):955-63.
  33. Jump up^ “Eggs containing fipronil found in 15 EU countries and Hong Kong”BBC News. 2017-08-11. Retrieved 2017-08-11.
  34. Jump up^ News, ABC. “EU: 17 nations get tainted eggs, products in growing scandal”ABC News. Archived from the original on 2017-08-11. Retrieved 2017-08-11.
  35. Jump up^ Boffey, Daniel (11 August 2017). “Egg contamination scandal widens as 15 EU states, Switzerland and Hong Kong affected”. The Guardian. Retrieved 11 August 2017.
  36. Jump up^ “Eggs at 44 farms in Taiwan found with excessive insecticide levels”. Taiwan News. 26 August 2017. Retrieved 26 August 2017.

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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Cadexomer Iodine


Image result for cadexomer iodine

Cadexomer Iodine

Cadex, Declat, Decrat, Dextrinomer iodine, Iodoflex, Iodosorb, NI-009

CAS 94820-09-4

Title: Cadexomer Iodine
Trademarks: Iodosorb (Perstorp)
Literature References: A hydrophilic modified starch polymer containing 0.9% (w/w) iodine within a helical matrix. Produced by the reaction of dextrin with epichlorohydrin coupled with ion exchange groups and iodine. Clinical use in venous ulcers: E. Skog et al., Br. J. Dermatol. 109, 77 (1983); M. C. Ormiston et al., Br. Med. J. 291, 308 (1985); L. Hillström, Acta Chir. Scand. Suppl. 544,53 (1988).
Therap-Cat: Vulnerary.
Keywords: Vulnerary.

Listed in 1984 (Perstorp, Finland). For the treatment of exudative and infectious wounds, such as venous ulcers. This product is in contact with wound exudate to form a non-adhesive protective layer and release antibacterial iodine

Image result for cadexomer iodine

Product of reaction of dextrin with epichlorohydrin coupled with ion-exchange groups and iodine

Cadexomer iodine is an iodophor that is produced by the reaction of dextrin with epichlorhydrin coupled with ion-exchange groups and iodine. It is a water-soluble modified starch polymer containing 0.9% iodine, calculated on a weight-weight basis, within a helical matrix.[1]

The Central Drugs Standard Control Organization (CDSCO) is the Central Drug Authority for discharging functions assigned to the Central Government under the Drugs and Cosmetics Act. One of the major functions of CDSCO is approval of new drugs in the country. During the month of March 2018, CDSCO has approved the following drugs classifying them as New Drug Approvals

Cadexomer Iodine Bulk & Powder 100 % w/w (contain 0.9 % w/v Iodine) or Cadexomer Iodine Ointment 500 mg (contains 0.9% w/v iodine)

For the treatment of chronic exuding wounds such as leg ulcers, pressure ulcers and diabetes ulcers infected traumatic and surgical wounds.

Cadexomer iodine is an iodophor that is produced by the reaction of dextrin with epichlorhydrin coupled with ion-exchange groups and iodine. It is a water-soluble modified starch polymer containing 0.9% iodine, calculated on a weight-weight basis, within a helical matrix.

In India, M/s Virchow Biotech Private Limited presented their proposal for grant of license to manufacture and market this product in India. The firm presented the Phase III Clinical trial report titled ‘Safety and efficacy of Dexadine (Cadexomer Iodine) in the treatment of chronic wounds’ before the CDSCO’s Subject Expert Committee on Antibiotics & Antivirals. After detailed deliberation, the committee recommended the manufacturing and marketing of the products (Cadexomer Iodine Ointment & Cadexomer Iodine Powder), as topical preparations for the treatment of chronic exuding wounds

History

Cadexomer iodine was developed in the early 1980s in Sweden by Perstorp AB, and given the name Iodosorb. The product was shown to be effective in the treatment of venous ulcers,.[2][3] More recently, it has been shown in studies in animals and humans that, unlike the iodophor povidone-iodine, Iodosorb causes an acceleration of the healing process in chronic human wounds. This is due to an increase in epidermal regeneration and epithelialization in both partial-thickness and full-thickness wounds.[4] In this way cadexomer iodine acts as a cicatrizant.

Properties

When formulated as a topical wound dressing Iodosorb adsorbs exudate and particulate matter from the surface of granulating wounds and, as the dressing becomes moist, iodine is released. The product thus has the dual effect of cleansing the wound and exerting a bactericidal action.

Uses

In addition to other manufacturers, Smith & Nephew distributes cadexomer iodine as Iodosorb and Iodoflex in many countries of the world for the treatment and healing of various types of wounds. The dosage forms are a paste dressing, an ointment and a gel, all of which contain 0.9% iodine.

PATENT

WO2001070242

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2001070242

PATENT

WO 2008117300

https://patents.google.com/patent/WO2008117300A2/und

Improved Process for the Preparation Of
Cadexomer Iodine

The present invention describes an improved method for the preparation of cadexomer iodine. Cadexomer iodine is a hydrophilic modified starch polymer containing 0.9%w/w iodine within the helical matrix. It is used for its absorbent and antiseptic properties in the management of chronic wounds such as venous leg ulcers, pressure sores, etc. It is applied as a powder or as an ointment over the wound.
Background of the invention
Cadexomer iodine is an iodophor that releases iodine. It contains 0.9%w/w iodine in hydrophilic modified starch carrier. It is used for its absorbent and antiseptic properties, in the management of venous leg ulcers and pressure sores, burn wounds etc. It is applied as a powder of microbeads or ointment containing iodine 0.9%w/w. When applied to the wound it absorbs fluids, removing exudates, pus and debris. As they swell, iodine is released which kills bacteria. When the color of the gel changes it indicates that the dressing should be changed. It is structurally represented as shown figure 1 , and chemically is known as2-hydroxy methylene cross-linked (1-4) α-D-glucan wther containing iodine.

R=H, CH2COOH

Figure: ! Structural representation of cadexomer iodine

The method of preparation of cadexomer iodine and it applications in clinical use is described in the US patent 4,010,259(1977). The process basically consists of two steps. The step one involves preparation of water insoluble, gel forming, and water swell able organic hydrophilic carrier. The next stage involves complexation of iodine with the above organic polymeric carrier.
The carrier is prepared by a polymerization /cross-linking reaction of a polyhydroxylic organic substance by means of a bifunctional organic cross-linking agent of the type Y-R-Z, wherein Y and Z each represent epoxy groups or halogen atoms and R is an organic residue. In this polymerization/cross linking reaction each of the functional groups Y and Z react with a hydroxy group of the polyhydroxylic organic material to form ether bonds. The linking has to proceed to the extent that the formed polymer becomes insoluble in water, but is capable of absorbing water.
The polyhydroxylic starting material used is dextrin or carboxy methyl dextrin and the cross linking agent used for the polymerization reaction is a bifunctional glycerol derivative such as epichlorohydrin, which is capable of forming ether bridges. The reaction between polyhdyroxy starting material and cross-linking agent epichlorohydrin is carried out by emulsion/suspension of polymerization reaction. This type reaction requires specially designed reactors with efficient stirring and an agent to disperse/ stabilize the reaction mass.
The reaction conditions mentioned in the patent uses toluene/water emulsion system, and which is stabilized/dispersed using toluene solution of a mixture of mono and di-esters of ortho phosphoric acid. This process has the following disadvantages:

Disadvantages of the prior art process

1. During cross-linking, the reaction mixture gets dried-up and sticks to the reaction vessel.
2. Efficient stirring is not possible due to formation of lumps.
3. Particles size of the cross-linked carrier is not uniform.
4. Iodine incorporation to carrier is not efficient; hence large excess has to be used.

5. The color of the product obtained by this process is dark brown, whereas product is expected to be golden yellow in color.

6. Results are not reproducible and batch-to-batch variations observed.
7. The stabilizer solution referred in the patent (US 4,010,259) is a solution of a mixture of mono and di-esters of ortho phosphoric acid, which is not available commercially..

Essentially similar procedures are described in Fr, Demande 2,320,1 12 (1977),
Australian 506,419 (1980), Finn 59,014(1981 ), Dan Dk 150,781 ( 1989). However the chemical nature and details of composition of stabilizer solution are not disclosed in these patents also.
An improved method for the preparation of cadexomer iodine is now developed free of these problems and which can easily scaled up to manufacturing level.

ADVANTAGES OF PRESENT INVENTION

1. The particle size of cadexomer iodine by the present process is fine and uniform, which is highly suitable for powder and ointment formulations.
2. Iodine incorporation to the cross-linked dextrin is efficient and consistent and swelling is appropriate
3. The color of cadexomer iodine obtained is golden yellow which is consistent and as per the expected color of the product.
4. The process is simple and economical and can be carried out in regular reactor with out any extra investment on the specialized equipment
5. Present process uses the dispersing agents, which are available commercially.

The details of the invention are described in examples given below which are provided to illustrate the invention only and therefore should not be construed to limit the scope of the present invention.

Example 1
Commercial dextrin (5Og) is dissolved in sodium hydroxide (50ml of 3.1N) containing sodium borohydride (0.75g), to this dispersing agent; sorbitan monooleate (Span 80, 3.75g) dissolved in toluene (125ml) is added. Then of epichlorohydrin (10 g) is added and reaction mixture is heated at 700C for 5h. After completion of 5h, water (600ml) is added to the reaction mixture, and then neutralized to a pH of 6.5 with hydrochloric acid (2N). The product is filtered washed with acetone (500ml). The product is again washed with water (1000ml) and finally with acetone (300ml). The wet product is treated with a solution of iodine (7.8g) in acetone (196ml) and stirred at 250C for 20 hours, then at O0C for 2 hours. The product is filtered in a sintered funnel under nitrogen atmosphere, washed with chilled acetone (150ml) and dried at 250C for 24h in a vacuum

desiccator.

Yield: 33g
Iodine content: .0.91 % w/w
Swelling capacity: 5.0ml/g

Example 2
Commercial dextrin (1Og) is dissolved in sodium hydroxide (10ml of 3.1N) containing sodium borohydride (0.15g); to this dispersing agent; cetrimide (0.25g) dissolved in toluene (25ml) is added. Then of epichlorohydrin (2.Og) is added and reaction mixture is heated at 700C for 5h. After completion of 5h, water (150 ml) is added, and then the reaction mixture was neutralized to a pH of 6.5 with hydrochloric acid (2N). The separated product was filtered and washed with acetone (100ml). Again the product washed with water (200ml) and finally with acetone (60ml). The wet product (carrier) is treated with a solution of iodine ( 1 ,6g) in acetone (40 ml) and stirred at 250C for 20 hours, then at O0C for 2 hours. The product is filtered in a sintered funnel under nitrogen atmosphere, washed with chilled acetone (40ml) and dried at 250C for 24h in a vacuum desiccator.

Yield: 4.2g
Iodine content: 0.91% w/w
Swelling capacity: 6.0ml/g

Example 3
Commercial dextrin (1Og) is dissolved in sodium hydroxide (10ml of 3.1N) containing sodium borohydride (0.15g), to this dispersing agent; glyceryl monostearate (0.25g) dissolved in toluene (25ml) is added. Then of epichlorohydrin (2.Og) is added and reaction mixture is heated at 700C for 5h. After the completion of 5h, water (150 ml) is added, and then the reaction mixture is neutralized to a pH of 6.5 with hydrochloric acid (2N). The separated product is filtered and washed with acetone (100ml). Again the product is washed with water (200ml) and finally with acetone (60ml). The wet product (carrier) is treated with a solution of iodine (1.6g) in acetone (40 ml) and stirred at 250C for 20 hours, then at O0C for 2 hours. The product is filtered in a sintered funnel under nitrogen atmosphere, washed with chilled acetone (40ml) and dried at 250C for 24h in a vacuum desiccator.

Yield: 3.3g
Iodine content: 0.9% w/w
Swelling capacity: 6.2ml/g

Example 4

Commercial carboxymethyl dextrin (20g) was dissolved in sodium hydroxide (20ml of 3.1N) containing sodium borohydride (0.3g), to this dispersing agent; glyceryl monostearate (1.Og) dissolved in toluene (75ml) is added. Then of epichlorohydrin (6.Og) is added and reaction mixture is heated at 700C for 5h After completion of 5h, water (280 ml) is added, then the reaction mixture is neutralized to a pH of 6.5 with hydrochloric acid (2N). The separated product is filtered and washed with acetone (250ml). Again the product is washed with water (500ml) and finally with acetone (150ml). The wet product (carrier) is treated with a solution of iodine (3.Ig) in acetone (60 ml) and stirred at 250C for 20 hours, then at O0C for 2 hours. The product is filtered in a sintered funnel under nitrogen atmosphere, washed with chilled acetone (60ml) and dried at 250C for 24h in a vacuum desiccator.

Yield: 16gms
Iodine content: 0.92 % w/w.
Swelling capacity: 5.8 ml per gram.

References

  1. Jump up^ Merck Index, 14th Edition, p262 Merck & Co. Inc.
  2. Jump up^ Skog, E. et al. (1983). A randomized trial comparing cadexomer iodine and standard treatment in the out-patient management of chronic venous ulcers. British Journal of Dermatology 109, 77. PMID 6344906
  3. Jump up^ Ormiston, M.C., Seymour, M.T., Venn, G.E., Cohen, R.I. and Fox, J.A. (1985). Controlled trial of Iodosorb in chronic venous ulcers. British Medical Journal (Clinical Research Edition) 291, 308-310. PMID 3962169
  4. Jump up^ Drosou Anna, Falabella Anna, and Kirsner Robert S. (2003) Antiseptics on Wounds: An area of controversy. Wounds 159(5) 149-166. http://cme.medscape.com/viewarticle/456300_2Retrieved 02/03/2009

Tang, M.B.; Tan, E.S.
Hailey-Hailey disease: Effective treatment with topical cadexomer iodine
J Derm Treat 2011, 22(5): 304

Early diagnosis and early corticosteroid administration improves healing of peristomal pyoderma gangrenosum in inflammatory bowel disease
Dis Colon Rectum 2009, 52(2): 311

Cadexomer iodine
Clinical data
AHFS/Drugs.com International Drug Names
ATC code
Identifiers
CAS Number
ChemSpider
  • none

//////////////Cadexomer Iodine, ind 2018, Cadex, Declat, Decrat, Dextrinomer iodine, Iodoflex, Iodosorb, NI-009,

Clofarabine


Clofarabine.svg

ChemSpider 2D Image | Clofarabine | C10H11ClFN5O3

Clofarabine.png

Clofarabine

  • Molecular FormulaC10H11ClFN5O3
  • Average mass303.677 Da
(2R,3R,4S,5R)-5-(6-Amino-2-chlor-9H-purin-9-yl)-4-fluor-2-(hydroxymethyl)tetrahydrofuran-3-ol
(2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-2-(hydroxyméthyl)tétrahydrofuran-3-ol
CAS 123318-82-1 [RN]
2-Chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-9H-purin-6-amine [ACD/IUPAC Name]
762RDY0Y2H
8422
9H-Purin-6-amine, 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)- [ACD/Index Name]
Cl-F-Ara-A
QA-3028
STOCK1N-71250
UD7473000
UNII:762RDY0Y2H

CENTRAL DRUGS STANDARD CONTROL ORGANIZATION
DIRECTOR GENERAL OF HEALTH SERVICES,
MINISTRY OF HEALTH AND FAMILY WELFARE,
GOVERNMENT OF INDIA

approved

Clofarabine Bulk & Injection 20 mg/20ml vial
For the treatment of patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. This indication is based upon response rate
16.01.2018

Clofarabine is a purine nucleoside antimetabolite marketed in the US and Canada as Clolar. In Europe and Australia/New Zealand the product is marketed under the name Evoltra. It is FDA-approved for treating relapsed or refractory acute lymphoblastic leukaemia(ALL) in children after at least two other types of treatment have failed. It is not known if it extends life expectancy. Some investigations of effectiveness in cases of acute myeloid leukaemia (AML) and juvenile myelomonocytic leukaemia (JMML) have been carried out. Ongoing trials are assessing its efficacy, if any, for managing other cancers.

Clofarabine is a purine nucleoside antimetabolite that is being studied in the treatment of cancer. It is marketed in the U.S. and Canada as Clolar. In Europe and Australia/New Zealand the product is marketed under the name Evoltra.

Clofarabine is used in paediatrics to treat a type of leukaemia called relapsed or refractory acute lymphoblastic leukaemia (ALL), only after at least two other types of treatment have failed. It is not known if the drug extends life expectancy. Some investigations of effectiveness in cases of acute myeloid leukaemia (AML) and juvenile myelomonocytic leukaemia (JMML) have been carried out.

For the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphocytic (lymphoblastic) leukemia after at least two prior regimens. It is designated as an orphan drug by the FDA for this use.

Approval

Clolar was Food and Drug Administration (FDA) approved 28 December 2004. (Under accelerated approval regulations requiring further clinical studies.)

Image result for us flag

Side effects

  • Tumor lysis syndrome (TLS). Clofarabine quickly kills leukaemia cells in the blood. The body may react to this. Signs include hyperkalemia, hyperuricemia, and hyperphosphatemia. TLS is very serious and can lead to death if it is not treated right away.
  • Systemic inflammatory response syndrome (SIRS): symptoms include fast breathing, fast heartbeat, low blood pressure, and fluid in the lungs.
  • Bone marrow problems (suppression). Clofarabine can stop the bone marrow from making enough red blood cellswhite blood cells, and platelets. Serious side effects that can happen because of bone marrow suppression include severe infection (sepsis), bleeding, and anemia.
  • Effects on pregnancy and breastfeeding. Girls and women should not become pregnant or breastfeed during treatment which may harm the baby.
  • Dehydration and low blood pressure. Clofarabine can cause vomiting and diarrhea which may lead to low body fluid (dehydration). Signs and symptoms of dehydration include dizziness, lightheadedness, fainting spells, or decreased urination.
  • Other side effects. The most common side effects are stomach problems (including vomiting, diarrhea, and nausea), and effects on blood cells (including low red blood cells count, low white blood cell count, low platelet count, fever, and infection. Clofarabine can also cause tachycardia and can affect the liver and kidneys.

Contraindications

  • pregnancy or planned pregnancy
  • breast-feeding
  • liver problems
  • kidney problems

Drug interactions

  • nephrotoxic drugs
  • hepatotoxic drugs

Delivery

  • By intravenous infusion.
  • Dosage is a 2-hour infusion (52 mg/m²) every day for five days. The cycle is repeated every 2 to 6 weeks.
  • Regular blood tests to monitor his or her blood cells, kidney function, and liver function.

Biology

Clofarabine is a second-generation purine nucleoside analog designed to overcome biological limitations observed with ara-A and fludarabine. A 2´(S)-fluorine in clofarabine significantly increased the stability of the glycosidic bond in acidic solution and toward phosphorolytic cleavage as compared to fludarabine.[1] A chlorine substitution at the 2-position of the adenine base avoids production of a 2-fluoroadenine analog, a precursor to the toxic 2-fluoro-adenosine-5´-triphosphate and prevents deamination of the base as compared to ara-A.[2]

Clofarabine can be administered intravenously or given orally. Clofarabine enters cells via hENT1, hENT2, and hCNT2, where upon it is phosphorylated by deoxycytidine kinase to generate clofarabine-5´-monophosphate. The rate-limiting step in clofarabine metabolism is clofarabine-5´-diphosphosphate. Clofarabine-5´-triphosphate is the active-metabolite, and it inhibits ribonucleotide reductase, resulting in a decrease cellular dNTP concentrations, which promotes greater incorporation of clofarabine-5´-triphosphate during DNA synthesis. Embedded clofarabine-5´-monophosphate in the DNA promotes polymerase arrest at the replication fork, triggering DNA repair mechanisms that without repair lead to DNA strand breaks in vitro and cytochrome c-mediated apoptosis in vitro. Studies using cell lines have shown that clofarabine-5´-triphosphate can also be incorporated into RNA.[3]

Mechanisms of resistance and turnover have been reported. Clofarabine-resistance arises from decreased deoxycytidine kinase activity in vitro.[4] ABC transporter ABCG2 promotes export of clofarabine-5´-monophosphate and thus limits the cytotoxic effects of this analog in vivo.[5] Biochemically, clofarabine-5’-triphosphate was shown to be substrate for SAMHD1, thus potentially limiting the amount of active compound in cells.[6]

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Synthesis

Production of Clofarabine
The reaction flask was added 2-chloro-9-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-beta-D arabinose yl) adenine 1.5g (3mmol) and methanol 40ml,mixed with stirring. Then it was added sodium methoxide, 0.05g (content> 50%), the reaction was stirred for 40min. Then the mixture was cooled to room temperature, adjusted to pH 7 with acetic acid, filtered, and the filter cake was washed with an ice-methanol 10ml, added to the methanol 40ml, and heated to 63 °C, and then cooled to -10 o C. Still 1h, filtered, and the filter cake was washed with an ice-methanol 10ml, drained, dried under reduced pressure to give an off-white powdery solid clofarabine 0.48g. The yield is 54%.

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CLIP

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http://pubs.rsc.org/en/content/articlehtml/2017/ra/c6ra27790j

CLIP

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SYN 1

JP 1993502014; US 5034518; WO 9014352

Reaction of 1,2:5,6-di-O-isopropylidene-3-O-tosyl-a-D-allofuranose (I) with KF in acetamide at 210 oC gives 3-deoxy-3-fluoro-1,2:5,6-di-O-isopropylidene-a-D-glucofuranose (II), which is treated with a 1:1 mixture of metha-nol and 0.7% aqueous H2SO4 to yield 3-deoxy-3-fluoro-1,2-isopropylidene-a-D-glucofuranose (III). Selective acylation of the sugar (III) with benzoyl chloride in pyridine affords the 6-O-benzoyl derivative (IV), which is treated with Amberlite IR-100 (H+) ion-exchange resin in hot dioxane to provide 6-O-benzoyl-3-deoxy-3-fluoro-D-glucofuranose (V). The oxidative cleavage of glucofuranose (V) by means of KIO4 in water results in rearrangement to give 5-O-benzoyl-2-deoxy-2-fluoro-3-O-formyl-D- arabinofuranose (VI), which is deformylated by means of NaOMe in methanol to provide 5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranose (VII). Acylation of the arabinofuranose (VII) with acetic anhydride in pyridine affords the 1,3-di-O-acetyl derivative (VIII), which is treated with HBr in AcOH/CH2Cl2 to yield 3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl bromide (IX). Condensation of compound (IX) with 2-chloroadenine (X) by means of potassium tert-butoxide in different solvents gives the acylated 2-chloroadenosine derivative (XI), which is finally deacylated by means of NaOMe in methanol

Carbohydr Res 1975,42(2),233

Drugs Fut 2004,29(2),112

J Med Chem 1992,35(2),397

US 2003114663; WO 0311877

CA 2400470; EP 1261350; WO 0160383

References

  1. Jump up^ Parker WB, Allan PW, Hassan AE, Secrist JA 3rd, Sorscher EJ, Waud WR (Jan 2003). “Antitumor activity of 2-fluoror-2’deoxyadenosine against tumors that express Escherichia coli purine nucleoside phosphorylase”. Cancer Gene Ther10 (1): 23–29. doi:10.1038/sj.cgt.7700520PMID 12489025.
  2. Jump up^ Bonate PL, Arthaud L, Cantrell WR Jr, Stephenson K, Secrist JA 3rd, Weitman S (Feb 2014). “Discovery and development of clofarabine: a nucleoside analogue for treating cancer”. nat Rev Drug Discov5 (10): 855–63. doi:10.1038/nrd2055PMID 17016426.
  3. Jump up^ Shelton J, Lu X, Hollenbaugh JA, Cho JH, Amblard F, Schinazi RF (Dec 2016). “Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs”. Chem Rev116 (23): 14379–14455. doi:10.1021/acs.chemrev.6b00209PMID 27960273.
  4. Jump up^ Lotfi K, Månsson E, Spasokoukotskaja T, Pettersson B, Liliemark J, Peterson C, Eriksson S, Albertioni F (1999). “Biochemical pharmacology and resistance to 2-chloro-2′-arabino-fluoro-2’deoxyadenosine, a novel analogue of cladribine in human leukemic cells”. Clin Cancer Res5 (9): 2438–44. PMID 10499616.
  5. Jump up^ Nagai S, Takenaka K, Nachagari D, Rose C, Domoney K, Sun D, Sparreboom A, Schuetz JD (Mar 2011). “Deoxycytidine kinase modulates the impact of the ABC transporter ABCG2 on clofarabine cytotoxicity”Cancer Res75 (1): 1781–91. doi:10.1158/0008-5472.CAN-10-1919PMC 3531552Freely accessiblePMID 21245102.
  6. Jump up^ Arnold LH, Kunzelmann S, Webb MR, Taylor IA (Jan 2015). “A continuous enzyme-coupled assay for triphosphohydrolase activity of HIV-1 restriction factor SAMHD1”Antimicrob Agents Chemother59 (1): 186–92. doi:10.1128/AAC.03903-14PMC 4291348Freely accessiblePMID 25331707.

External links

Clofarabine
Clofarabine.svg
Clinical data
Trade names Clolar, Evoltra
AHFS/Drugs.com Monograph
MedlinePlus a607012
License data
Routes of
administration
Intravenous
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.159.663
Chemical and physical data
Formula C10H11ClFN5O3
Molar mass 303.677 g/mol
3D model (JSmol)

//////////////////ind 2018, Clofarabine, Nucleotides

C1=NC2=C(N1C3C(C(C(O3)CO)O)F)N=C(N=C2N)Cl

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