Tolmetin, synthesis

Pyrrole was discovered in 1834 by Friedlieb Ferdinand Runge in coal tar, where it is present in a concentration of less than 0.01%. Production from coal tar is, therefore, not economical. Pyrrole is synthesized by the reaction of furan with ammonia. Pyrrole is used in the production of polypyrrole and pharmaceuticals, such as the anti-inflammatory drug tolmetin. In tolmetin synthesis, the acidity of pyrrole is made use of. It is transformed into the potassium salt, which reacts with methyl chloride to form 1-methylpyrrole. The reaction of methylpyrrole with formaldehyde and dimethylamine produces the Mannich base, which is then quatemized... 

Tohnetin, like all of the drugs described above, inhibits 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. Synonyms for tolmetin are tolectin, tolmex, and others. 

These five-membered rings have lone pair(s) delocalised from the heteroatom round the ring and are electron-rich . They react all too easily with electrophiles and are unstable in acid whether protic or Lewis. We have to find reactions that can be used in neutral or only weakly acidic solution. The synthesis of tolmetin 99 illustrates the two most important reactions.14 The disconnection of the ketone would lead naturally to an AICI3-catalysed Friedel-Crafts reaction between the acid chloride 100 and the pyrrole 101. 

Molecular models of anti-inflammatory drugs naproxen, ibuprofen and tolmetin. These nonsteroidal anti-inllam-matory agents are thought to relieve pain by inhibiting the synthesis of prostaglandins, which are involved in the perception of pain and the production of fever and inflammation. Ibuprofen is also known as Motrin, Advil, and Nuprin. Naproxen sodium is Aleve, and tolmetin is Tolectin. Each has been used to treat symptoms of arthritis and to relieve the pain caused by gout bursitis tendinitis sprains, strains, and other injuries and menstrual cramps. Ibuprofen and naproxen are available over-the-counter in the United States. 

Tolmetin sodium is a NSAID, which decreases inflammation, pain, and fever, probably through inhibition of cyclooxygenase activity and prostaglandin synthesis. It is indicated in the treatment of chronic and acute rheumatoid arthritis and osteoarthritis and juvenile rheumatoid arthritis. Tolmetin and ketoroiac are structurally related heteroaryl acetic acid derivatives with different pharmacological features. Diclofenac is a phenylacetic acid derivative that was developed specifically as an antiinflammatory agent. 

Indomethacin and Tolmetin Sodium are two typical examples of heteroarylaeetin aeid analogue of NSAID. Give the synthesis of one of them while differentiating their ehemieal struetures. 

Storage Hygroscopic Uses Intermediate prod, of Fluorescent brightener 354, tolmetin Manuf./Distrib. Aceto http //www.aceto.com] Advanced Synthesis Tech. http //www.advancedsynthesis.com] Aldrich http //www.sigma-aldrich.com] Biddle Sawyer http //WWW. biddiesawyer. com] FI uka http //www.sigma-aidrich. com Int l. Fiber http //www.ifcfiber.com] Sigma... 

Insertion into C-H bond. Carbalkoxycarbenes also insert into the C-H bond of N-methylpyrrole (via nitrogen-ylides ) to yield an important intermediate in the synthesis of two drugs, tolmetin XLVI(a) and zomepirac XLVI(b) [85] (Me Neil Pharmaceuticals). 

An alternative method of the synthesis of tolmetin, which is gaining in importance, is based on methylamine, acetonedicarboxylic add and chloroacetaldehyde. 

Recently, a well-known trivalent iodine reagent, DIB with low toxicity and high stability was used in the synthesis of substituted pyrroles. The multi-component reaction (MCR) of primary amines 28, nitrostyrenes 29 and acetylac-etone 27 was smoothly performed in the presence of DIB to form substituted pyrroles 30 in good yields. This facile and simple DIB-mediat MCR is applicable for the synthesis of biologically significant tolmetin 31 and related pyrroles (Scheme 2) [18]. 

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