A kind of preparation method of non-steroidal anti-inflammatory drug tolmetine

Abstract

The invention discloses a preparation method of non-steroid anti-inflammatory drug tolmetin. The preparation method comprises the steps of: reacting N-methylpyrrole (II) with oxalyl chloride mono-ethyl ester in the presence of solvents, namely methyl benzene and acid binding agent, to obtain (1-methyl-1H-pyrrole-2-radical)-oxo-sodium acetate (III); by reduction with hydrazine hydrate, acidizing hydrochloric acid to form N-methylpyrrole-2-acetic acid (IV); condensing with methyl chloroformate at low temperature to produce 3-(1-methyl-1H-pyrrole-2-radical)-2-oxo-methyl propionate (V); condensing with p-toluoyl chloride to produce (1-methyl-5-(4-methyl-benzoyl)-1H-pyrrole-2-radical)-methyl acetate; and reacting with a sodium hydroxide solution to obtain a tolmetin product. Rare precious and dangerous raw materials are replaced by common safe raw materials, serious pollution problems and production operation problems are avoided, and meanwhile the production cost is reduced remarkably; the preparation method is suitable to large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and relates to a preparation method of a non-steroidal anti-inflammatory drug, in particular to a preparation method of a non-steroidal anti-inflammatory drug tolmetin. Background technique [0002] Tolmetine is a derivative of pyrrole acetic acid, which is a new type of anti-inflammatory analgesic. Its effect is similar to that of other non-steroidal anti-inflammatory drugs such as aspirin, but its side effects are relatively mild, and it is easier for patients to tolerate. Animal experiments have shown that its anti-arthritis effect is stronger than that of aspirin, but weaker than that of indomethacin and phenylbutazone. Its analgesic effect is equivalent to ibuprofen, stronger than aspirin and weaker than indomethacin. The antipyretic effect is also strong, and the absorption is fast and safe after oral administration. [0003] Existing tolmetine synthetic routes, according to bibliographi...

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Problems solved by technology

[0004] Japanese patent (kokai8202270): using dichloroethane as solvent, 1-methyl-2-ethoxyformylmethyl-1H-pyrrole-3-ethyl carboxylate as starting material, and aluminum trichloride, para Toluyl chloride is refluxed together, and finally tolmetin is obtained after sodium hydroxide and acidification treatment, the raw material is not easy to obtain, and the total yield is low, only 10%

[0005] German patent (Ger.Pat2339140): This method uses 1-methyl-1H-pyrrole-2-acetic acid as a raw material and phosgene as an acylating agent, which is highly toxic during the reaction and is not conducive to industrial production

[0006] Spanish patent (Span.Pat456334): 5-chloro-1H-methyl-pyrrole-2-methanol is used as raw material to react with highly toxic dimethyl sulfate. The cost of raw materials is high and it is not easy to obtain. This process also uses cyanide Potassium is used as a raw material, which is highly toxic and not suitable for industrial production

[0007] The process routes in the existing published literature are all unsatisfactory for industrial production

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