ChemicalBook > Product Catalog > API > Antipyretic analgesics > Nonsteroidal Anti-Inflammatory Drugs (NSAIDS) > 1-(2,6-Dichlorophenyl)-2-indolinone
1-(2,6-Dichlorophenyl)-2-indolinone Chemical Properties
- Melting point:156-158°
- Boiling point:412.0±45.0 °C(Predicted)
- Density 1.431±0.06 g/cm3(Predicted)
- pkapKa 4 (Uncertain)
- Water Solubility 1.278mg/L(30 ºC)
- Merck 14,3081
- CAS DataBase Reference15307-86-5(CAS DataBase Reference)
- NIST Chemistry ReferenceBenzeneacetic acid, 2-[(2,6-dichlorophenyl)amino]-(15307-86-5)
- EPA Substance Registry SystemBenzeneacetic acid, 2-[(2,6-dichlorophenyl)amino]- (15307-86-5)
- RIDADR 3249
- RTECS AG6310000
- HazardClass 6.1(b)
- PackingGroup III
- Hazardous Substances Data15307-86-5(Hazardous Substances Data)
1-(2,6-Dichlorophenyl)-2-indolinone Usage And Synthesis
- Application in Particular DiseasesIn Osteoarthritis:
Topical diclofenac in a dimethyl sulfoxide carrier (Pennsaid) is a safe and effective treatment for Osteoarthritis pain. It is thought to act primarily by local inhibition of COX-2 enzymes.
- UsesDiclofenac possesses all of the properties unique to the series of propionic acid drugs, yet in terms of anti-inflammatory and analgesic strength it exceeds that of aspirin, analgin, and ibuprofen. It is used in acute rheumatism, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, arthrosis, back pain, neuralgia, and myalgia. It rarely causes side effects. The most common synonym is voltaren.
- Usesprostaglandin synthetic inhibitor
- IndicationsDiclofenac (Voltaren, Cataflam) is approved for use in rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, dysmenorrhea, and topically for the treatment treatment of ocular inflammation and actinic keratosis. Diclofenac exhibits approximately equal selectivity for COX-1 and COX-2. The most common adverse reactions are GI disturbances and headache.A reversible elevation of serum transaminases occurs in 15% of patients.
- Manufacturing ProcessFour grams of N-chloroacetyl-N-phenyl-2,6-dichloroaniline and 4 grams of
aluminum chloride are well mixed together and heated for 2 hours at 160°C.
The melt is cooled and poured onto about 50 grams of ice while it is still
warm. The oil which separates is dissolved in 50 ml of chloroform, the
chloroform solution is washed with 10 ml of water, dried over sodium sulfate
and concentrated under 11 torr. The residue is distilled. The 1-(2,6-
dichlorophenyl)-2-indolinone melts at 126°-127°C.
A solution of 186 grams of 1-(2,6-dichlorophenyl)-2-indolinone in 660 ml of ethanol and 660 ml of 2 N sodium hydroxide solution is refluxed for 4 hours. The solution is then cooled and left to stand for 4 hours at 0°-5°C. The crystals which form are filtered off and recrystallized from water. The sodium salt of 2-(2,6-dichloroanilino)-phenylacetic acid melts at 283°-285°C. The yield is 97% of theoretical, according to US Patent 3,558,690.
- Therapeutic FunctionAntiinflammatory
- Biological FunctionsDiclofenac (Voltaren) is a phenylacetic acid derivative that is a potent inhibitor of COX and that has analgesic, antiinflammatory, and antipyretic effects. Its use is accompanied by side effects similar to those of other NSAIDs. Indications for the drug include rheumatoid arthritis, osteoarthritis, and ophthalmic inflammation (use of an ophthalmic preparation).
- Mechanism of actionDiclofenac is unique among the NSAIDs in that it possesses three possible mechanisms of action: 1) inhibition of the arachidonic acid cyclooxygenase system (3 to 1,000 times more potent than other NSAIDs on a molar basis), resulting in a decreased production of prostaglandins and thromboxanes; 2) inhibition of the lipoxygenase pathway, resulting in decreased production of leukotrienes, particularly the pro-inflammatory LKB4; and 3) inhibition of arachidonic acid release and stimulation of its reuptake, resulting in a reduction of arachidonic acid availability.
- PharmacokineticsDiclofenac is rapidly and completely (～100%) absorbed on oral administration, with peak plasma levels being reached within 1.5 to 2.5 hours. The free acid (pKa = 4.0) is highly bound to serum proteins (99.5%), primarily albumin. Only 50 to 60% of an oral dose is bioavailable because of extensive hepatic metabolism.
- Clinical UseDiclofenac is synthesized from N-phenyl-2,6-dichloroaniline. It is available in 120 different countries and, perhaps, is the most widely used NSAID in the world. It was introduced in the United States in 1989 but was first marketed in Japan in 1974. It ranks among the top prescription drugs in the United States. Diclofenac possesses structural characteristics of both arylalkanoic acid and the anthranilic acid classes of anti-inflammatory drugs, and it displays anti-inflammatory, analgetic, and antipyretic properties.
- Chemical SynthesisDiclofenac, 2-[(2,6-dichlorophenyl)-amino]-phenylacetic acid (3.2.42), is
synthesized from 2-chlorobenzoic acid and 2,6-dichloroaniline. The reaction of these in
the presence of sodium hydroxide and copper gives N-(2,6-dichlorophenyl)anthranylic
acid (3.2.38), the carboxylic group of which undergoes reduction by lithium aluminum
hydride. The resulting 2-[(2,6-dicholorphenyl)-amino]-benzyl alcohol (3.2.39) undergoes
further chlorination by thionyl chloride into 2-[(2,6-dichlorophenyl)-amino]-benzylchloride (3.2.40) and further, upon reaction with sodium cyanide converts into 2-[(2,6-dicholorophenyl)-amino]benzyl cyanide (3.2.41). Hydrolysis of the nitrile group
leads to diclofenac (3.2.42) [107,108].
- MetabolismFour major metabolites resulting from aromatic hydroxylation have been identified. The major metabolite via CYP3A4 is the 4′-hydroxy derivative and accounts for 20 to 30% of the dose excreted, whereas the 5-hydroxy, 3′-hydroxy, and 4′,5-dihydroxy metabolites via CYP2C9 account for 10 to 20% of the excreted dose. The remaining drug is excreted in the form of sulfate conjugates. Although the major metabolite is much less active than the parent compound, it may exhibit significant biological activity, because it accounts for 30 to 40% of all of the metabolic products.
- Diclofenac sodium DICLOFENAC METHYL ESTER 1-PHENYL-2,3-DIHYDRO-1H-INDOLE 1-(2,6-DICHLORO-4-HYDROXPHENYL)-1,3-DIHYDROINDOL-2-ONE (2-CHLORO-PHENYL)-PHENYL-AMINE 1-Phenyloxindole 1-(2,6-Dichlorophenyl)-1,3-Dihydro-5-Hydroxy-2H-Indol-2-One 1-(2,6-Dichlorophenyl)-2-indolinone 2-Hydroxyphenylacetic acid 3,4'-DIAMINODIPHENYLMETHANE Ethyl 2-(Chlorosulfonyl)acetate Phenylacetic acid Phenylphosphonic dichloride Phenyl salicylate Diphenyl ether Diclofenac diethylamine PHENYL RESIN PHENYL VALERATE
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