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Tolmetin

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Tolmetin Basic information
Tolmetin Chemical Properties
Safety Information
MSDS
Tolmetin Usage And Synthesis
  • OriginatorTolectin,McNeil,US,1976
  • Usesinhibits synthesis of prostaglandins and exhibits expressed analgesic, anti-inflammatory, and fever-reducing properties. It is used for relieving weak to moderate pain in rheumatoid arthritis and osteoarthritis.
  • UsesTolmetine is an NSAID.
  • DefinitionChEBI: A monocarboxylic acid that is (1-methylpyrrol-2-yl)acetic acid substituted at position 5 on the pyrrole ring by a 4-methylbenzoyl group. Used in the form of its sodium salt dihydrate as a nonselective nonsteroidal anti-inflammatory drug.
  • IndicationsTolmetin (Tolectin) is indicated for the relief of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and moderate pain. It is ineffective in gouty arthritis for unknown reasons.Tolmetin can inhibit both COX-1 and COX-2 but has a moderate selectivity for COX-1. The most frequently reported side effects are GI disturbance and CNS reactions (e.g., headache, asthenia, and dizziness). These effects are less frequently observed than after aspirin or indomethacin use. Blood pressure elevation, edema, and weight gain or loss have been associated with tolmetin administration. Tolmetin metabolites in urine have been found to produce pseudoproteinuria in some laboratory tests.
  • Manufacturing Process5-(p-Toluoyl)-1-methylpyrrole-2-acetonitrile - To a cooled suspension of 26.6 g (0.2 mol) aluminum chloride in 80 ml dichloroethane is added dropwise 30.8 g (0.2 mol) p-toluoyl chloride. The resulting solution is added dropwise to a solution of 1-methylpyrrole-2-acetonitrile in 80 ml dichloroethane cooled externally with an ice bath. After the addition, the resulting solution is stirred at room temperature for 20 minutes and then refluxed for 3 minutes. The solution is poured into ice acidified with dilute hydrochloric acid. The organic and aqueous fractions are separated. The aqueous fraction is extracted once with chloroform.
    The organic fractions are combined and washed successively with N,N_x0002_dimethyl-1,3-propanediamine, dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic fraction is dried over anhydrous magnesium sulfate. The solvent is then evaporated off. Upon trituration of the residue with methanol, a solid crystallizes, 5-(p-toluoyl)-1-methylpyrrole-2-acetonitrile, which is removed by filtration and purified by recrystallization from benzene.
    Additional product is isolated from the mother liquors which are combined, concentrated in vacuo and the resulting oily residue column chromatographed on neutral alumina using hexane, benzene and ether as successive solvents. The product is isolated by concentrating in vacuo the first few major compound-bearing fractions (10% ether in benzene). The solids are combined and recrystallized from methanol and then from benzene-hexane, melting point 102°C to 105°C.
    5-(p-Toluoyl)-1-methylpyrrole-2-acetic acid - A solution of 3.67 g (0.015 mol) of 5-(p-toluoyl)-1-methylpyrrole-2-acetonitrile, 24 ml of 1 N sodium hydroxide and 50 ml of 95% ethanol is stirred and refluxed for 24 hours. The resulting solution is poured into ice acidified with dilute hydrochloric acid. A white solid precipitates which is extracted into ether. The ether phase is washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated and a white solid, 5-(p-toluoyl)- 1-methylpyrrole-2-acetic acid is obtained which is recrystallized twice from isopropanol, melting point 155°C to 157°C.
  • Therapeutic FunctionAntiinflammatory
  • Biological FunctionsTolmetin (Tolectin) is an antiinflammatory, analgesic, and antipyretic agent that produces the usual gastric distress and ulceration observed with NSAIDs. However, tolmetin is better tolerated than aspirin and produces less tinnitus and vertigo. Tolmetin is a substitute for indomethacin in indomethacin-sensitive patients and is unique among such drugs in that it can be used to treat juvenile arthritis.
  • General DescriptionTolmetin sodium (Tolectin), is an arylacetic acid derivativewith a pyrrole as the aryl group. This drug is well absorbed and has a relatively short plasma half-life (1 hour). It is recommendedfor use in the management of acute and chronicRA. Its efficacy is similar to aspirin and indomethacin, butwith less frequency of the adverse effects and tinnitus associatedwith aspirin. It does not potentiate coumarin-likedrugs nor alter the blood levels of sulfonylureas or insulin.However, tolmetin, and especially its closely related drug,zomepirac (i.e., with a p-chlorobenzoyl group and an additionalmethyl group on the pyrrole ring), can produce a rarebut fatal anaphylactic reaction because of irreversible bindingof their unstable acyl glucuronides. Zomepirac waswithdrawn from market because it is eliminated only via theester-type, acyl glucuronide. It is possible that tolmetin isless toxic in this regard because it undergoes additional hepaticbenzylic hydroxylation via its p-methyl group and isexcreted as its stable ether glucuronide.
  • Chemical SynthesisTolmetin, 1-methyl-5-n-tolylpyrrol-2-acetic acid (3.2.61) is synthesized from 1- methylindole, which is aminomethylated using formaldehyde and dimethylamine, forming 2-dimethylaminomethyl-1-methylindol (3.2.57). The product is methylated by methyl iodide, giving the corresponding quaternary salt (3.2.58). Reaction of the product with sodium cyanide gives 1-methylpyrrole-2-acetonitrile (3.2.59), which is acylated at the free α-position of the pyrrole ring by 4-methylbenzoylchloride in the presence of aluminum chloride. The resulting 1-methyl-5-n-toluylpyrrol-2-acetonitrile (3.2.60) undergoes further alkaline hydrolysis, giving corresponding acid, tolmetin (3.2.61) [116–118].

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