Indometacin CAS 53-86-1

Introduction：Basic information about Indometacin CAS 53-86-1, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.

Indometacin Basic information

• Product Name: Indometacin
• Synonyms: 1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-ylacetic acid;indomethacin crystalline;indomethacin methanol solution;indomethacin usp;AURORA KA-6542;INDOCIN;INDOMETACIN;INDOMETACINE
• CAS: 53-86-1
• MF: C19H16ClNO4
• MW: 357.79
• EINECS: 200-186-5
• Product Categories: Active Pharmaceutical Ingredients;PHARMACEUTICALS;Other APIs;INDOCIN;Pharmaceutical raw chemicals;Lipid signaling;All Inhibitors;Inhibitors;Intermediates & Fine Chemicals;53-86-1
• Mol File: 53-86-1.mol

Indometacin Chemical Properties

• Melting point: 158-162 °C
• Boiling point: 499.4±45.0 °C(Predicted)
• density: 1.2135 (rough estimate)
• refractive index: 1.6800 (estimate)
• storage temp.: Store at RT
• solubility: ethanol: 50 mg/mL, clear, yellow-green
• pka: 4.5(at 25℃)
• form: White to off-white powder
• color: White to Light yellow to Light orange
• biological source: synthetic
• Water Solubility: Soluble in acetone (40 mg/mL - clear, yellow solution), ethanol (20 mg/mL), ether, castor oil; Soluble in chloroform (50 mg/mL - clear, yellow, extremely viscous solution); decomposed by strong alkali but stable in neutral or slightly acidic media; insoluble in water.
• Sensitive: Light Sensitive
• Merck: 14,4968
• BRN: 497341
• BCS Class: 2
• Stability: Stable. Incompatible with strong oxidizing agents.
• InChI: 1S/C19H16ClNO4/c1-11-15(10-18(22)23)16-9-14(25-2)7-8-17(16)21(11)19(24)12-3-5-13(20)6-4-12/h3-9H,10H2,1-2H3,(H,22,23)
• InChIKey: CGIGDMFJXJATDK-UHFFFAOYSA-N
• SMILES: COc1ccc2n(c(C)c(CC(O)=O)c2c1)C(=O)c3ccc(Cl)cc3
• CAS DataBase Reference: 53-86-1(CAS DataBase Reference)
• NIST Chemistry Reference: Indomethacin(53-86-1)
• EPA Substance Registry System: Indomethacin (53-86-1)

Safety Information

• Hazard Codes: T+,Xi,T
• Risk Statements: 28-36/37/38-39/23/24/25-23/24/25
• Safety Statements: 28-36/37-45-36-26
• RIDADR: UN 2811 6.1/PG 1
• WGK Germany: 3
• RTECS: NL3500000
• F: 8-10
• TSCA: TSCA listed
• HazardClass: 6.1
• PackingGroup: I
• HS Code: 29339900
• Storage Class: 6.1A - Combustible acute toxic Cat. 1 and 2 very toxic hazardous materials
• Hazard Classifications: Acute Tox. 1 Oral
• Hazardous Substances Data: 53-86-1(Hazardous Substances Data)
• Toxicity: LD50 i.p. in rats: 13 mg/kg (Klaassen)

Indometacin Usage And Synthesis

anti-inflammatory analgesic

Indomethacin is a kind of stronger corticoid anti-inflammatory and antipyretic and analgesic, by inhibiting cyclooxygenase reducing the synthesis of prostaglandin (PG), to prevent the formation of the nere impulses, inflammation tissue inhibiting inflammatory reaction, including inhibition of leukocyte chemotaxis and lysosomal enzyme release, etc., and produce antipyretic, analgesic and anti-inflammatory effects. Indomethacin anti-inflammatory, antipyretic effect is very strong, its anti-inflammatory effect is better than bute, 84 times better than hydrocortisone, and sugar cortical hormone, used in combination with aspirin, bute, can reduce their dosage, toxic and side effects, improve curative effect; Second is antipyretic effect, 10 times than amidopyrine ;its analgesic action is weak , only to the inflammatory pain has obvious analgesic effect, but the effect is good for inflammatory pain than Baotai loose, analgin and salicylic acid. Clinical is mainly used for the salicylic acid, drugs are less tolerance or curative effect is not obvious in the acute and chronic rheumatic or rheumatoid arthritis, ankylosing spondylitis, slippery bursa phlogistic, tenosynovitis, articular capsulitis, osteoarthritis and acute gout and cancerous pain, etc.In recent years, the researchers try to use indomethacin biliary colic, dysmenorrhea, migraine, glomerulonephritis, polyuria, salmonella gastroenteritis, orthostatic hypotension, bart syndrome and so on, all have good curative effect.It can also be used to treat eye pigment meningitis, keratitis, scleritis, glaucoma and fever caused by cancer or other difficult to control the fever. Dermatologist for lupus erythematosus (sle), white plug syndrome, scleroderma, nodular erythema, herpes zoster, joint type of psoriasis, etc. photosensitive dermatitis induced by topical treatment of eczema, allergic dermatitis, and local pain.

Pharmacokinetics

Oral medicine absorbed quickly and completely, can absorb more than 90% of the dosage of food with in 4 h, take medicine of acid containing aluminum and magnesium can be slightly slowed absorption, plasma protein conjugation rate is about 99%. After oral 25 mg, tmax is 1~4 h, the blood medicine peak concentration (Cmax) is 1.4 mu g/ml, when 50 mg, Cmax is 2.8 mu g/ml; Half-life (t1/2) of an average is 4.5 h, premature extended obviously. A small amount of indomethacin can through the blood-brain barrier. And through the placenta.This article in the liver metabolism go methyl chloride and chlorobenzene formyl chloride, and can be hydrolyzed into recycle indomethacin to absorb. Renal excretion from 60%, 10%~20% in prototype discharge; Part with droppings.33% from the bile excretion, 1.5% were prototype;In the breast milk also has a discharge (up to 0.5~2.0 mg daily).This product can not be dialysis to remove.

usage and dosage

1.Anti-rheumatism: adult dosage: oral: early quantity from 25 to 50 mg each time, 2~4 times a day, immediately take at food service or after a meal. Such as good tolerance, the daily dosage can be increased from 25 to 50 mg per week, the most mount should not be more than 200 mg a day. Arthritis patients such as persistent pain at night or morning stiffness, can give quantity of 100 mg in bed all day.
2. Resistance to gout: oral: At the beginning quantity is 100 mg once, then 50 mg, three times a day, until the pain relief, and then gradually reduced as soon as possible, until the drug withdrawal.
3. Antifebrile: adult dosage: oral: 25~50 mg each time, 3~4 times daily.Rectal drug delivery: every time 50 mg, 50 to 100 mg per day. Pediatric dosage: oral: 0.5~1 mg/kg each time, 3 times a day.
The above information is Chemicalbook Hanya edited.

Side effects

Adverse reactions of Indomethacin are high incidence , common adverse reactions are as follows:
1. nausea, vomiting, abdominal pain, diarrhea, anorexia, serious ulcers can occur and cause bleeding and perforation. After dinner, that can reduce the incidence.
2. common headache, dizziness, fatigue, occasional seizures, mental derangement, syncope, etc. Should be paid attention to in due course.
3.the skin pruritus, erythema, urticaria, and one of the few of asthma, breathing problems and even breathing, circulation inhibition.
4.Inhibition of hematopoietic system such as granulocytopenia, aplastic anemia, thrombocytopenia, and so on. Although rare, but more severe consequences.There are also some other similar to aspirin reaction, notes are also the same.

matters need attention

1.indomethacin and aspirin have cross allergic. Caused by aspirin allergic asthmatic patients, the application of this product can be induced bronchospasm. Other non steroidal anti-inflammatory drugs to which are allergic may also be allergic to this product.
2.This product is contraindicated with active ulcer disease, ulcerative colitis and history, epilepsy, Parkinson's disease, mental disease, liver and kidney function, the goods or aspirin or other nonsteroidal anti-inflammatory drug allergic person, angioedema or bronchial asthma. This product for the last 3 months of pregnancy can make fetal ductus arteriosus closure and result in persistent pulmonary hypertension, so pregnant women, disabled. This product can be discharged from the milk, breast-feeding women also disable.
3.This product is used for patients with cardiac insufficiency, and hypertension (because this product sodium can lead to water retention, hemophilia and other patients with hemorrhagic disease (because this product can make the bleeding time prolonged, aggravate bleeding tendency), aplastic anemia, granulocytopenia disease patients (this product is inhibition of hematopoietic system).Age < 14 years old children should not be commonly used drug, When it is applied，it should be closely observed.Easily occur in elderly patients with renal toxicity, which should also be careful.
4.Because indomethacin has inhibition to the platelet aggregation, which can make the bleeding time prolonged, the role after the drug was stopped sustainable. During the blood urea nitrogen and serum creatinine，levels are also often higher. During the medication，it should be regularly check routine blood and liver and kidney function. Case reports referred to in this article that the product can lead to corneal composure and retinal change (including macular degeneration), if it comes to the blurred vision eye exams should be done immediately.
5.Drug overdose (especially when dose > 150 mg a day) is easy to cause toxic reactions such as nausea, vomiting, tension headaches, sleepiness, spirit, behavior disorders, etc., with vomiting or gastric lavage, symptomatic and supportive treatment.

chemical property

White or slightly yellow crystalline powder. Melting point is 158-162℃, soluble in acetone, slightly soluble in ethanol, chloroform, ether, almost insoluble in water.

Uses

1.The product is anti-inflammatory, and antipyretic effect is obvious, mainly is used for salicylates to tolerance or the effect is not significant rheumatism and arthritis, ankylosing light spondylitis, osteoarthritis.
2.Non steroid anti-inflammatory analgesic

Used in Particular Diseases

Acute Gouty Arthritis:
Dosage and Frequency: 25–50 mg four times a day for 3 days, then taper to twice daily for 4–7 days

methods of production

Para aminophenylmethylether is through diazotization, reduction, cyclization, hydrolysis, acidification to get indomethacin.

Category

Poisonous

classification of toxicity

Highly toxic.

acute toxicity

Oral administration: LD50 2.42 mg/kg in rats; oral administration of 11.84 mg/kg of LD50: in mice.

Combustible hazard characteristics

Open flame fuel; high heat decomposition of toxic chloride and nitrogen oxide gas.

Storage and transportation characteristics

Low temperature and dry air ventilation; and oxidant, food additives separately.

Extinguisher

Foam, fog water, sand, carbon dioxide.

Description

Aqueous solutions of indomethacin are not stable because of the ease of hydrolysis of the p-chlorobenzoyl group.The original synthesis of indomethacin by Shen et al. involved the formation of 2-methyl-5-methoxyindole aceticacid and subsequentacylation after protection of the carboxyl group as the t-butyl ester. It was introduced in the United States in 1965. Itis still one of the most potent NSAIDs in use. It also is a more potent antipyretic than either aspirin oracetaminophen, and it possesses approximately 10 times the analgetic potency of aspirin.

Chemical Properties

Crystalline Solid

Originator

Indocin,MSD,US,1965

Uses

Indomethacin is used in rheumatoid arthritis, nonspecific infectious polyarthritis, goutyarthritis, osteoarthritis, ankylosing spondylitis, arthrosis, back pain, neuralgia, myalgia,and other diseases accompanied by inflammation.

Uses

Inhibits cyclooxygenase (IC50=0.1uM) selectively over liposygenases (IC50=100uM for 5-,12- and 15-LO). A clinically useful NAISD

Uses

antiinflammatory, antipyretic, analgesic

Indications

Indomethacin (Indocin) is used in the treatment ofacute gouty arthritis, rheumatoid arthritis, ankylosingspondylitis, and osteoarthritis. It is not recommendedfor use as a simple analgesic or antipyretic because of itspotential for toxicity.While indomethacin inhibits bothCOX-1 and COX-2, it is moderately selective for COX-1. It produces more CNS side effects than most of theother NSAIDs. Severe headache occurs in 25 to 50% ofpatients; vertigo, confusion, and psychological disturbancesoccur with some regularity. GI symptoms alsoare more frequent and severe than with most other NSAIDs. Hematopoietic side effects (e.g., leukopenia,hemolytic anemia, aplastic anemia, purpura, thrombocytopenia,and agranulocytosis) also may occur. Oculareffects (blurred vision, corneal deposits) have been observedin patients receiving indomethacin, and regularophthalmological examinations are necessary when thedrug is used for long periods. Hepatitis, jaundice, pancreatitis,and hypersensitivity reactions also have beennoted.

Definition

The antiinflammatory drug indomethacin.

Preparation

acylation of sodium 2-(4-methoxyphenyl)hydrazine-1-sulfonate with4-chlorobenzoyl chloride followed byheating yields 1-(4- chlorobenzoyl)-1-(4-methoxyphenyl)hydrazine. Condensation withlevulinic acid in a Fischer indole synthesis affords indomethacin.

Manufacturing Process

(A) 2-Methyl-5-Merhoxy-3-Indolylacetic Anhydride: Dicyclohexylcarbodiimide(10 g, 0.049 mol) is dissolved in a solution of 2-methyl-5-methoxy-3-indolylacetic acid (22 g, 0.10 mol) in 200 ml of THF, and the solution isallowed to stand at room temperature for 2 hours. The precipitated urea isremoved by filtration, and the filtrate is evaporated in vacuo to a residue andflushed with Skellysolve 6. The residual oily anhydride is used withoutpurification in the next step.
(B) t-Butyl 2-Methyl-5-Merhoxy-3-Indolylacetate: t-Butyl alcohol (25 ml) andfused zinc chloride (0.3 g) are added to the anhydride from Part A. Thesolution is refluxed for 16 hours and excess alcohol is removed in vacuo. Theresidue is dissolved in ether, washed several times with saturated bicarbonate,water, and saturated salt solution. After drying over magnesium sulfate, thesolution is treated with charcoal, evaporated, and flushed several times withSkellysolve B for complete removal of alcohol. The residual oily ester (18 g,93%) is used without purification.
(C) t-Buryl 1-p-Chlorobenzoyl-2-Methyl-5-Mefhoxy-3-Indolylacetate: A stirredsolution of ester (18 g, 0.065 mol) in dry DMF (450 ml) is cooled to 4°C in anice bath, and sodium hydride (4.9 g, 0.098 mol, 50% susp.) is added inportions. After 15 minutes, p-chlorobenzoyl chloride (15 g, 0.085 mol) isadded dropwise during 10 minutes, and the mixture is stirred for 9 hourswithout replenishing the ice bath. The mixture is then poured into one liter of5% acetic acid, extracted with a mixture of ether and benzene, washedthoroughly with water, bicarbonate, saturated salt, dried over magnesiumsulfate, treated with charcoal, and evaporated to a residue which partlycrystallizes. This is shaken with ether, filtered and the filtrate is evaporated toa residue (17 g) which solidifies after being refrigerated overnight.
The crude product is boiled with 300 ml of Skellysolve 6, cooled to roomtemperature, decanted from some gummy material, treated with charcoal,concentrated to 100 ml, and allowed to crystallize. The product thus obtained(10 g) is recrystallized from 50 ml of methanol and gives 4.5 g of analyticallypure material, MP 103° to 104°C.
(D) 1 -p-Chlorobenzoyl-2-Methyl-5-Methoxy-3-Indolylacetic Acid: A mixture of1 g ester and 0.1 g powdered porous plate is heated in an oil bath at 210°Cwith magnetic stirring under a blanket of nitrogen for about 2 hours. Nointensification of color (pale yellow) occurs during this period. After coolingunder nitrogen, the product is dissolved in benzene and ether, filtered, andextracted with bicarbonate. The aqueous solution is filtered with suction toremove ether, neutralized with acetic acid, and then acidified weakly withdilute hydrochloric acid. The crude product (0.4 g, 47%) is recrystallized fromaqueous ethanol and dried in vacuo at 65°C: MP 151°C.

Brand name

Amuno (MSD Sharp & Dohme, Germany), Arthrexin (Lennon Generics, South Africa), Confortid (Dumex, Denmark, Sweden, Finland), Doctucid (Coctum, Greece), Dynamectin (Dynamed, SouthAfrica), Flexidin (Mundipharma, Austria),Inacid (Merck Sharp & Dohme, Spain), Indobene (Merckle, Austria, CIS), Indocin(Merck, USA), Reumadolor (Bros, Greece),Zoflam (Norpharma, Denmark).

Therapeutic Function

Antiinflammatory

World Health Organization (WHO)

Indometacin was introduced in 1963 and it is one of the firstNSAIDs. Convulsions are rarely reported in relation with the use of this group ofagents. Indometacin farnesil is a pro-drug of indometacin, and the occurrence ofgastro-intestinal adverse effects could be expected. See also under nonsteroidalantiinflammatory agents.

Biological Functions

Indomethacin (Indocin) is an acetic acid derivative relatedfunctionally to sulindac (Clinoril), a prodrug witha long half-life, and etodolac (Lodine).They are metabolizedin the liver and excreted as metabolites in the bile and via the kidney. They are potent inhibitors ofCOX and thus extremely effective antiinflammatoryagents.

General Description

From the time of its introduction in 1965, indomethacin(Indocin) has been widely used as an analgesic to relieve inflammatorypain associated with RA, OA and ankylosingspondylitis, and, to a lesser extent, in gout. Although both itsanalgesic and anti-inflammatory activities are well established,its use is often limited because of frequent GI distressand potential drug interactions, especially with warfarinfurosemide, and lithium (i.e., it elevates blood levels oflithium as a result of reducing renal blood flow and thereforeincreases lithium toxicities).
Following oral administration, indomethacin is rapidlyabsorbed and is 90% protein bound at therapeutic plasmaconcentrations. The drug has a biological half-life ofabout 5 to 10 hours and a plasma clearance of 1 to 2.5 ml/kgper minute. It is metabolized to its inactive, O-desmethyl,N-deschlorobenzoyl-, and O-desmethyl, N-deschlorobenzoylindomethacinmetabolites.

General Description

Crystals.

Air & Water Reactions

Practically insoluble in water. Decomposes in alkali.

Reactivity Profile

A weak organic acid.

Fire Hazard

Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Some are oxidizers and may ignite combustibles (wood, paper, oil, clothing, etc.). Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated.

Pharmaceutical Applications

Indomethacin is a nonsteroidal anti-inflammatory agent used in pain and moderate to severeinflammation in rheumatic diseases and other musculoskeletal disorders. It is a COX (cyclooxygenase)inhibitor and therefore interrupts the production of prostaglandins.
A series of new silicon compounds, based on the structure of indomethacin, have been synthesised andare under investigation as novel anticancer agents. The carboxyl group of indomethacin was reacted witha series of amino-functionalised silanes. The resulting products have been shown to be significantly morelipophilic and more selective to COX-2. Furthermore, in vitro testing has shown an increased uptake of thenew compounds at the tumour site. The silane-functionalised indomethacin derivatives exhibited a 15-foldincreased antiproliferative effect when tested against pancreatic cancer .

Pharmaceutical Applications

Indomethacinis a nonsteroidal anti-inflammatory agent used in pain and moderate to severeinflammation in rheumatic diseases and other musculoskeletal disorders. It is a COX (cyclooxygenase)inhibitor and therefore interrupts the production of prostaglandins.

Biological Activity

Cyclooxgenase (COX) inhibitor; displays selectivity for COX-1 (IC 50 values are 230 and 630 nM for human COX-1 and COX-2 respectively). Widely used anti-inflammatory agent.

Biochem/physiol Actions

Cyclooxygenase (COX) inhibitor that is relatively selective for COX-1.

Clinical Use

Indomethacin is available for the short-term treatment of acute gouty arthritis, acute pain of ankylosing spondylitis,and osteoarthritis. An injectable form to be reconstituted also is available as the sodium trihydrate salt for IV use inpremature infants with patent ductus arteriosus. Because of its ability to suppress uterine activity by inhibitingprostaglandin biosynthesis, indomethacin also has an unlabeled use to prevent premature labor.

Side effects

All of these drugs produce analgesic effects, antipyresis,and antiinflammatory effects.Due to the high incidenceof gastric irritation, headache, nausea, and other side effects,including hematological effects and coronaryvasoconstriction, they are not useful as an initial treatmentfor pain. GI irritation and ulceration occur to alesser extent with etodolac. Indomethacin is useful inthe treatment of acute gout, osteoarthritis, ankylosingspondylitis, and acceleration of the closure of the ductusarteriosus in premature infants. The tocolytic effects ofindomethacin to prevent preterm labor are the result ofits effects on prostaglandin synthesis. However, the toxicityof the drug limits such application, since it increasesfetal morbidity. Indomethacin is contraindicatedin pregnancy, in asthmatics, and in those with gastric ulcersor other ulceration of the GI tract. Indomethacinmay increase the symptoms associated with depressionor other psychiatric disturbances and those associatedwith epilepsy and Parkinson’s disease. The drug shouldbe used with caution in such patients.

Synthesis

Indomethacin, 1-(n-chlorobenzoyl)-5-methoxy-2-methylindol-3-acetic acid(3.2.51), has been synthesized by various methods. All of the proposed methods of synthesis start with 4-methoxyphenylhydrazine. According to the first method, a reaction is done tomake indole from phenylhydrazone (3.2.46) by Fischer?ˉs method, using levulinic acidmethyl ester as a carbonyl component, hydrogen chloride as a catalyst, and ethanol as a solvent, to give the methyl ester of 5-methoxy-2-methyl-3-indolylacetic acid (3.2.47). Thisproduct is hydrolyzed by an alkali into 5-methoxy-2-methyl-3-indolylacetic acid (3.2.48),from which tert-butyl ester of 5-methoxy-2-methyl-3-indolylacetic acid (3.2.49) is formedby using tert-butyl alcohol and zinc chloride in the presence of dicyclohexylcarbodiimide.The resulting product undergoes acylation at the indole nitrogen atom by p-chorobenzoylchloride in dimethylformamide, using sodium hydride as a base. The resulting tert-butylester of 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylacetic acid (3.2.50), furtherundergoes thermal decomposition to the desired acid, indomethacin (3.2.51) [111,112].

Drug interactions

Potentially hazardous interactions with other drugs
ACE inhibitors and angiotensin-II antagonists:antagonism of hypotensive effect; increased risk ofnephrotoxicity and hyperkalaemia.
Analgesics: avoid concomitant use of 2 or moreNSAIDs, including aspirin (increased side effects);avoid with ketorolac (increased risk of side effectsand haemorrhage).
Antibacterials: possibly increased risk of convulsionswith quinolones.
Anticoagulants: effects of coumarins andphenindione enhanced; possibly increased risk ofbleeding with heparins, dabigatran and edoxaban -avoid long term use with edoxaban.
Antidepressants: increased risk of bleeding withSSRIs and venlaflaxine.
Antidiabetic agents: effects of sulphonylureasenhanced.
Antiepileptics: effects of phenytoin enhanced.
Antipsychotics: possible severe drowsiness withhaloperidol.
Antivirals: increased risk of haematological toxicitywith zidovudine; concentration possibly increased byritonavir.
Ciclosporin: increased risk of nephrotoxicity.
Cytotoxics: reduced excretion of methotrexate.
Diuretics: increased risk of nephrotoxicity,hyperkalaemia with potassium-sparing diuretics;antagonism of diuretic effect
. Lithium: lithium excretion reduced.
Pentoxifylline: possibly increased risk of bleeding.
Probenecid: excretion of indometacin reduced.
Tacrolimus: increased risk of nephrotoxicity.

Metabolism

Indometacin is metabolised in the liver primarily bydemethylation and deacetylation; it also undergoesglucuronidation and enterohepatic circulation.Indometacin is mainly excreted in the urine,approximately 60%, the pH of the urine can affect thisamount. Lesser amounts are excreted in the faeces.

storage

Room temperature

Indometacin Preparation Products And Raw materials

• Raw materials: p-Anisidine-->Levulinic acid-->4-Chlorobenzoyl chloride-->Dicyclohexylcarbodiimide-->5-METHOXY-2-METHYL-3-INDOLEACETIC ACID-->tert-Butanol-->Sodium hydride-->ACEMETACINTERT-BUTYLESTER
• Preparation Products: Acemetacin-->indomethacin farnesil-->2-(5-methoxy-2-methyl-1H-indol-3-yl)acetamide