1093861-60-9

Basic information

• Product Name: AFOXOLANER
• Synonyms: 4-[5-[3-Chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide;Afoxolaner
• CAS NO: 1093861-60-9
• Molecular Formula: C₂₆H₁₇ClF₉N₃O₃
• Molecular Weight: 625.8701088
• Mol File: 1093861-60-9.mol
• Article Data: 5

Chemical Properties

• Appearance: /
• Density: 1.53±0.1 g/cm3(Predicted)
• PKA: 12.45±0.46(Predicted)
• CAS DataBase Reference: AFOXOLANER(CAS DataBase Reference)
• NIST Chemistry Reference: AFOXOLANER(1093861-60-9)
• EPA Substance Registry System: AFOXOLANER(1093861-60-9)

Safety Data

• Hazardous Substances Data: 1093861-60-9(Hazardous Substances Data)

Usage

Definition

Afoxolaner is used to treat and control flea and tick infestations in dogs. After being ingested by a dog, afoxolaner is distributed throughout the dog’s body. When fleas or ticks bite the dog, they are exposed to the drug and killed during their blood meal.

Mechanism of action

Afoxolaner (the active ingredient of NEXGARD) and other isoxazolines with insecticidal and tickicidal efficacy are non-competitive GABA (gamma-aminobutyric acid) receptor antagonists, much more selective for GABA receptors in insects or ticks, than for those in mammals, including humans. They bind to chloride channels in nerve and muscle cells, which blocks the transmission of neuronal signals. Affected parasites are paralyzed and die.This mechanism exists not only in insects but also in mammals and other vertebrates. However the binding affinity of afoxolaner to GABA receptors of invertebrates is much higher than to GABA receptors in vertebrates. For this reason it is significantly less toxic to mammals than to insects and other pests.

Metabolism

Afoxolaner is an isoxazoline compound. It works by blocking the transmissions of neuronal signals in insects. They do this by binding to chloride channels in nerve and muscle cells, causing the receptors to stop working. This in turn paralyses the parasites and kills them.Afoxolaner toxicity to fleas ensures that they die within 24 hours of it being administered. But the dog is unaffected, due to the specific selective nature of the drug.

Pharmacokinetics

Afoxolaner orally administered to dogs was rapidly absorbed into blood. Max. blood levels were reached 2 to 12 hours after administration. Mean half-life in blood ranged from 7.7 to 17.8 days. Bioavailability was estimated to be approx. 74%. Half-life was higher in Collies than in Beagles, but no serious adverse effects were observed after treatment of Collies at 25 mg/kg bw (i.e. ~10x the therapeutic dose).Absorbed afoxolaner binds strongly (>99%) to blood proteins but it seems not to cause displacement of other drugs with high protein binding capacities.In dogs afoxolaner is slowly broken down into various metabolites, the major ones being a hydroxylate and a glucuronide. Elimination of both the metabolites and the parent compound occurrs mainly via biliary excretion and to a lesser extent through urine.

Description

Afoxolaner is an insecticide and acaricide belonging to the isoxazoline family. Afoxolaner acts at ligand-gated chloride channels, in particular those gated by the neurotransmitter gamma-aminobutyric acid (GABA), thereby blocking pre- and post-synaptic transfer of chloride ions across cell membranes.

Uses

Afoxolaner (brand name NexGard?) is used to treat and control flea and tick infestations in dogs. After being ingested by a dog, afoxolaner is distributed throughout the dog's body. When fleas or ticks bite the dog, they are exposed to the drug and killed during their blood meal.

Synthesis

The synthesis of?afoxolaner is as follows:Add to the 100ml reaction flaskIntermediate 4 (8.57g),?HBTU (8.65g, 22.38mmol),?DMF (20ml),Intermediate 5, mix well and add triethylamine. Make the pH of the mixed liquid system=10,Stir at room temperature for 40 minutes, TLC monitors the progress of the reaction,After full reaction,Add 40ml of water, stir and crystallize,Suction filtration, wash the filter cake with 20ml water,Dry the filter cake under reduced pressure,Then use a mixture of ethyl acetate and petroleum ether(1:2) or ethanol and water (1:2)The mixture is recrystallized,The white powder product Aphrana 1-2, (8.10g, yield 77%, purity 99.47%) was obtained.

Enzyme inhibitor

This orally active isoxazoline-based pesticide (FW = 901.18 g/mol; CAS 1093861-60-9; IUPAC Name: 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]- 4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl) amino]ethyl]-1-naphthalenecarboxamide, is highly active against fleas (Ctenocephalides felis) and ticks (Dermacentor variabilis) in dogs. Afoxolaner is more potent, when tested in vitro, than any other compound ever tested in the membrane feeding system, including the avermectins. At an oral dose of 2.5 mg/kg, afoxolaner reaches pharmacologically effective plasma concentrations (0.1–0.2 μg/mL), blocking native and expressed insect GABA-gated chloride channels with nanomolar potency. Afoxolaner has comparable potency between wild-type channels as well as channelspossessing the dieldrin resistance-conferring Alanine-302-Serine mutation. Lack of cyclodiene cross-resistance for afoxolaner suggests that afoxolaner blocks GABA-gated chloride channels by binding at a site topologically distinct from the cyclodienes.

Synthetic route

4-[3-[3-chloro-5-(trifluoromethyl)phenyl]-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide (1125812-56-7) → 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino))ethyl-1-naphthalenecarboxamide (1093861-60-9)

Conditions	Yield
With hydroxylamine sulfate; sodium hydroxide In tetrahydrofuran; water at 25℃; Product distribution / selectivity;	84%
With sodium hydroxide; hydroxyammonium sulfate In tetrahydrofuran; water at 25℃; for 1.16667h;	77%

4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]naphthalene-1-carboxylic acid + 1-oxo-1-N-(2,2,2-trifluoroethyl)-1,2-diaminoethane hydrochloride (1171331-39-7) → 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino))ethyl-1-naphthalenecarboxamide (1093861-60-9)

Conditions	Yield
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 0.666667h; pH=10;	77%

C12H9NO4 → 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino))ethyl-1-naphthalenecarboxamide (1093861-60-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine; dmap; di-tert-butyl dicarbonate / toluene / 24 h / 20 °C 2: triethylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 0.67 h / 20 °C / pH 10 View Scheme

4-bromonaphthalene-1-carboxylic acid (16650-55-8) → 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino))ethyl-1-naphthalenecarboxamide (1093861-60-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); XPhos / 1,2-dimethoxyethane / 50 °C / Molecular sieve; Inert atmosphere 2: triethylamine; dmap; di-tert-butyl dicarbonate / toluene / 24 h / 20 °C 3: triethylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 0.67 h / 20 °C / pH 10 View Scheme

Upstream product

• 1125812-58-9 1-(3-chloro-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroethan-1-one 
• 29139-00-2 4-acetyl-1-naphthalene carbonitrile 
• 359821-38-8 2-ammonia-N-(2,2,2-trifluoroethyl)acetamide 
• 16650-55-8 4-bromonaphthalene-1-carboxylic acid 
• 1171331-39-7 1-oxo-1-N-(2,2,2-trifluoroethyl)-1,2-diaminoethane hydrochloride 
• 1125812-56-7 4-[3-[3-chloro-5-(trifluoromethyl)phenyl]-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide 

Relevant articles and documents

Synthesis of arfampanaga

The invention relates to synthesis of arfampanaga; and specifically, 1-(3-chloro-5-(trifluoromethyl) phenyl)-2, 2, 2-trifluoroethane-1-ketone and 4-acetyl-1-naphthylacetonitrile are used as starting materials, and the nitrile group of the intermediate in the last step is directly reacted with 2-amino-N-(2, 2, 2-trifluoroethane-1-ketone) in the presence of Zn (OTf) 2/hydroxylamine hydrochloride through condensation reaction to realize the preparation of the arfanaga.

NAPHTHALENE ISOXAZOLINE INVERTEBRATE PEST CONTROL AGENTS

Disclosed are compounds of Formula 1, wherein R1 is halogen, C1-C2 haloalkyl or C1-C2 haloalkoxy;R2 is H, halogen or cyano;R3 is H, halogen or CF3;R4 is H, C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl; andR5 is C1-C6 alkyl or C1-C6 haloalkyl, each substituted with one substituent independently selected from hydroxy, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C7 alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 haloalkylaminocarbonyl and C3-C9 halodialkylaminocarbonyl. Also disclosed are compositions containing the compounds of Formula 1 and methods for controlling an invertebrate pest comprising contacting the invertebrate pest or its environment with a biologically effective amount of a compound or a composition of the invention.

METHOD FOR PREPARING 5-HALOALKYL-4,5-DIHYDROISOXAZOLE DERIVATIVES

Disclosed is a method for preparing a compound of Formula: (1); wherein R1 is CHX2, CX3, CX2CHX2 or CX2CX3; each X is independently Cl or F; Z is optionally substituted phenyl; and Q is phenyl or 1-naphthalenyl, each optionally substituted as defined in the disclosure; comprising contacting a compound of Formula: (2).