Ketoprofen CAS 22071-15-4

Introduction：Basic information about Ketoprofen CAS 22071-15-4, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.

Ketoprofen Basic information

• Product Name: Ketoprofen
• Synonyms: ORUDIS;ORUVAIL;RARECHEM AL BO 1306;M-BENZOYLHYDRATROPIC ACID;2-(meta-benzoylphenyl) propionic acid;19583 RP;19583rp;2-(3-benzoylphenyl)-propionicaci
• CAS: 22071-15-4
• MF: C16H14O3
• MW: 254.28
• EINECS: 244-759-8
• Product Categories: ACTRON;Other APIs;Pharmaceutical raw material;API;Analgesics;Lipid signaling;Intermediates & Fine Chemicals;Pharmaceuticals;Pharmaceutical;Active Pharmaceutical Ingredients;APIs;Pharmaceutical ingredients;22071-15-4
• Mol File: 22071-15-4.mol

Ketoprofen Chemical Properties

• Melting point: 93-96°C
• Boiling point: 357.5°C (rough estimate)
• density: 1.1565 (rough estimate)
• refractive index: 1.5600 (estimate)
• storage temp.: 2-8°C
• solubility: Slightly soluble in chloroform and methanol.
• pka: pKa 5.94(MeOH/H2O) (Uncertain)
• form: solid
• color: White to Off-White
• biological source: synthetic
• Water Solubility: 209mg/L(room temperature)
• Merck: 14,5305
• Major Application: forensics and toxicology pharmaceutical (small molecule)
• InChI: 1S/C16H14O3/c1-11(16(18)19)13-8-5-9-14(10-13)15(17)12-6-3-2-4-7-12/h2-11H,1H3,(H,18,19)
• InChIKey: DKYWVDODHFEZIM-UHFFFAOYSA-N
• SMILES: CC(C(O)=O)c1cccc(c1)C(=O)c2ccccc2
• CAS DataBase Reference: 22071-15-4(CAS DataBase Reference)
• NIST Chemistry Reference: Ketoprofen(22071-15-4)
• EPA Substance Registry System: Benzeneacetic acid, 3-benzoyl-.alpha.-methyl- (22071-15-4)

Safety Information

• Hazard Codes: T
• Risk Statements: 25-36/37/38-23/24/25
• Safety Statements: 26-45-36/37/39
• RIDADR: 2811
• WGK Germany: 3
• RTECS: UE7570000
• TSCA: TSCA listed
• HazardClass: 6.1(b)
• PackingGroup: III
• HS Code: 29183000
• Storage Class: 6.1C - Combustible acute toxic Cat.3 toxic compounds or compounds which causing chronic effects
• Hazard Classifications: Acute Tox. 3 Oral Aquatic Acute 1 Eye Irrit. 2 Skin Irrit. 2
• Toxicity: LD50 orally in rats: 101 mg/kg (Ueno)

Ketoprofen Usage And Synthesis

Used in Particular Diseases

Acute Gouty Arthritis:
Dosage and Frequency: 75 mg four times a day

Description

Ketoprofen is a chemical that comes in the form of a white crystalline powder; odorless or nearly odorless. It is very soluble in methanol, soluble in ethanol, acetone or ether, and almost insoluble in water. The melting point is about 93-96 °C. For the arylalkanoic acid compounds. Has analgesic, anti-inflammatory and antipyretic effects. The anti-inflammatory effect is stronger than that of ibuprofen, with less side effects and low toxicity. Oral and easily absorbed from the gastrointestinal tract. After 1 administration, the peak plasma concentration can be reached in about 0.5 to 2 hours. t 1/2 is 1.6 to 1.9 hours. In the blood and plasma protein binding force is extremely strong. The excretion rate from urine is 30% to 90% within 24 hours. Mainly excreted in the form of glucuronic acid conjugates. For rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and gout, etc.

Description

Ketoprofen (3-benzoyl-α-methylphenylacetic acid) is a 2-arylpropionic acid potent non-steroidal anti-inflammatory drug. It was first synthesized by French chemist Rhone Poulenc in 1967. In 1973, it was introduced into France and the United States as an anti-inflammatory drug. It has good effects on rheumatism, rheumatoid arthritis, myelitis and gout, and its anti-inflammatory effect is stronger than that of ibuprofen. Ibuprofen. At the same dose, its anti-inflammatory and analgesic effect is 150 times that of aspirin, its antipyretic effect is 4 times that of indomethacin and 100 times that of aspirin. Because ketoprofen has high efficacy, short half-life, It has the advantages of simple metabolism and few and mild adverse reactions, and has been widely used in the treatment of various types of pain, inflammatory symptoms, colds and post-operative anti-inflammatory analgesia.

Chemical Properties

White Crystalline Solid

Originator

Profenid,Specia,France,1973

Uses

Anti-inflammatory; analgesic

Uses

Natural Vitamin B12. analog

Uses

Ketoprofen, a propionic acid derivative, is a nonsteroidal anti-inflammatory agent (NSAIA) with analgesic and antipyretic properties.

Definition

ChEBI: An oxo monocarboxylic acid that consists of propionic acid substituted by a 3-benzoylphenyl group at position 2.

Indications

Ketoprofen (Orudis) is indicated for use in rheumatoidand osteoarthritis, for mild to moderate pain, and indysmenorrhea. The most frequently reported side effectsare GI (dyspepsia, nausea, abdominal pain, diarrhea,constipation, and flatulence) and CNS related(headache, excitation). Edema and increased blood urea nitrogen have also been noted in more than 3% ofpatients. Ketoprofen can cause fluid retention and increasesin plasma creatinine, particularly in the elderlyand in patients taking diuretics.

Manufacturing Process

In an initial step, the sodium derivative of ethyl (3-benzoylphenyl)cyanoacetate is prepared as follows: (3-benzoylphenyl)acetonitrile (170 9) isdissolved in ethyl carbonate (900 g). There is added, over a period of 2 hours,a sodium ethoxide solution [prepared from sodium (17.7 g) and anhydrousethanol (400 cc)], the reaction mixture being heated at about 105° to 115°Cand ethanol being continuously distilled. A product precipitates. Toluene (500cc) is added, and then, after distillation of 50 cc of toluene, the product isallowed to cool. Diethyl ether (600 cc) is added and the mixture is stirred for1 hour. The crystals which form are filtered off and washed with diethyl ether(600 cc) to give the sodium derivative of ethyl (3-benzoylphenyl)cyanoacetate(131 g).
Then, ethyl methyl(3-benzoylphenyl)cyanoacetate employed as anintermediate material is prepared as follows: The sodium derivative of ethyl(3-benzoylphenyl)cyanoacetate (131 g) is dissolved in anhydrous ethanol (2liters). Methyl iodide (236 g) is added and the mixture is heated under refluxfor 22 hours, and then concentrated to dryness under reduced pressure (10mm Hg). The residue is taken up in methylene chloride (900 cc) and water(500 cc) and acidified with 4N hydrochloric acid (10 cc). The methylenechloride solution is decanted, washed with water (400 cc) and dried overanhydrous sodium sulfate. The methylene chloride solution is filtered througha column containing alumina (1,500 g). Elution is effected with methylenechloride (6 liters), and the solvent is evaporated under reduced pressure (10mm Hg) to give ethyl methyl(3-benzoylphenyl)cyanoacetate (48 g) in theform of an oil.
In the final production preparation, a mixture of ethyl methyl(3-benzoylphenyl)cyanoacetate (48 g), concentrated sulfuric acid (125 cc) andwater (125 cc) is heated under reflux under nitrogen for 4 hours, and water(180 cc) is then added. The reaction mixture is extracted with diethyl ether(300 cc) and the ethereal solution is extracted with N sodium hydroxide (300cc). The alkaline solution is treated with decolorizing charcoal (2 g) and thenacidified with concentrated hydrochloric acid (40 cc). An oil separates out,which is extracted with methylene chloride (450 cc), washed with water (100cc) and dried over anhydrous sodium sulfate. The product is concentrated todryness under reduced pressure (20 mm Hg) to give a brown oil (33.8 g).
This oil is dissolved in benzene (100 cc) and chromatographed through silica(430 g). After elution with ethyl acetate, there is collected a fraction of 21liters, which is concentrated to dryness under reduced pressure (20 mm Hg).The crystalline residue (32.5 g) is recrystallized from acetonitrile (100 cc) anda product (16.4 g), MP 94°C, is obtained. On recrystallization from a mixtureof benzene (60 cc) and petroleum ether (200 cc), there is finally obtained 2-(3-benzoylphenyl)propionic acid (13.5 g), MP 94°C.

Brand name

Actron (Bayer); Orudis (Wyeth); Oruvail (Wyeth), Alrheumat (Bayer, United Kingdom), Alrheumun (Bayer Pharma Deutschland, Germany), Gabrilen (Kreussler, Germany), Orudis (Rh?one-Poulenc Rorer, Canada, Denmark; Wyeth-Ayerst, USA).

Therapeutic Function

Antiinflammatory

General Description

Ketoprofen (Orudis, Rhodis) and suprofen (Profenal) areclosely related to fenoprofen in their structures, properties,and indications. Even though ketoprofen has been approvedfor OTC use (Orudis KT, Actron), its GI side effects aresimilar to indomethacin, and therefore its useshould be closely monitored, especially in patients with GIor renal problems.

Contact allergens

Ketoprofen is an anti-inflammatory drug, used bothtopically and systemically. It is above all a photoaller-gen, responsible for photoallergic or photo-worsenedcontact dermatitis, with sun-induced, progressive,severe, and durable reactions. Recurrent photosensitiv-ity is possible for many years. Photosensitivities areexpected to thiophene-phenylketone derivatives suchas tiaprofenic acid and suprofen, to ketoprofen esterssuch as piketoprofen, and to benzophenone derivatives(see above) such as fenofibrate and benzophenone-3.Concomitant photosensitivities without clinical rel-evance have been observed to fenticlor, tetrachloro-salicylanilide, triclosan, tribromsalan, and bithionol.

Biochem/physiol Actions

It serves as an efficient drug to treat ankylosing spondylitis, rheumatoid arthritis and osteoarthritis. It also has antipyretic and analgesic effects. Ketoprofen prevents the action of prostaglandin synthetase.

Pharmacokinetics

Ketoprofen is rapidly and nearly completely absorbed on oral administration, reaching peak plasma levels within 0.5to 2 hours. It is highly plasma protein bound (99%) despite a lower acidity (pKa = 5.9) than some other NSAIDs. Widevariation in plasma half-lives has been reported. It is metabolized by glucuronidation of the carboxylic acid, CYP3A4and CYP2C9 hydroxylation of the benzoyl ring, and reduction of the keto function.

Pharmacology

The pharmacologicallyactive isomer is mainly the S(+)-enantiomer, which is available in some countriesas the trometamol (2-amino-2-(hydroxymethyl)-1,3-propanediol) salt. As compared tothe racemate, absorption of the S(+)-isomer issaid to be faster, leading to an earlier onset ofaction . The peak plasma concentration after oral administrationoccurs within 2 h. Ketoprofen isbound to plasma protein up to 99% and showsa plasma elimination half-life of 1.5to 4 h.

Clinical Use

Ketoprofen, unlike many NSAIDs, inhibits the synthesis of leukotrienes and leukocytemigration into inflamed joints in addition to inhibiting the biosynthesis of prostaglandins. It stabilizes the lysosomalmembrane during inflammation, resulting in decreased tissue destruction. Antibradykinin activity also has beenobserved. Bradykinin is released during inflammation and can activate peripheral pain receptors. In addition toanti-inflammatory activity, ketoprofen also possesses antipyretic and analgetic properties. Although it is less potentthan indomethacin as an anti-inflammatory agent and an analgetic, its ability to produce gastric lesions is about thesame.

Safety Profile

Poison by ingestion,subcutaneous, intravenous, rectal, and intraperitoneal routes. Human systemic effects by an unspecified route:headache, nausea or vomiting, and degenerative changesin the brain, changes in kidney tubules. An experimentalteratogen.

Synthesis

Ketoprofen, 2-(3-benzoyl)propionic acid (3.2.37), is synthesized from 3-methylbenzophenone, which undergoes bromination and forms 3-bromo-methylbenzophenone (3.2.33). The reduction of the resulting product by sodium cyanide gives3-cyanomethylbenzophenone (3.2.34), which is reacted with the diethyl ester of carbonicacid in the presence of sodium ethoxide. The resulting cyanoacetic ester derivative (3.2.25)is alkylated by methyl iodide and the resulting product (3.2.36) undergoes acidic hydrolysis, forming ketoprofen (3.2.37) [104¨C106].

Veterinary Drugs and Treatments

Ketoprofen is labeled for use in horses for the alleviation of inflammationand pain associated with musculoskeletal disorders. Likeflunixin (and other NSAIDs), ketoprofen potentiallyhas many otheruses in a variety of species and conditions. There are approveddosage forms for dogs and cats in Europe and Canada. Some considerketoprofen to be the NSAID of choice for use short-term foranalgesia in cats.

Drug interactions

Concomitant use of alcohol or other NSAIDs after taking ketoprofen can increase gastrointestinal side effects and may cause ulcers. When ketoprofen is used together with aspirin or other salicylic acid drugs, the efficacy cannot be increased, but the incidence of gastrointestinal side effects and bleeding tendency increases. Concomitant use of ketoprofen with anticoagulants increases the risk of bleeding. Ketoprofen can enhance the effect of antidiabetic drugs and reduce the antihypertensive effect of antihypertensive drugs; ketoprofen and corticosteroids can be used together, which can significantly reduce the symptoms of inflammation. Ketoprofen should not be used with methotrexate to prevent poisoning. When ketoprofen is used with probenecid, verapamil, and nifedipine, the dose should be reduced; when ketoprofen is used with digoxin, the dose of digoxin should be adjusted.

Ketoprofen Preparation Products And Raw materials

• Raw materials: Sulfuric acid-->Iodomethane-->3-Benzoylphenylacetonitrile-->Sodium-->Ethanol-->3-BENZOYLPHENYLACETIC ACID
• Preparation Products: Phthalide-->3-ACETYLBENZOIC ACID