A kind of synthetic method of tolfenamic acid

Abstract

The invention discloses a method for synthesizing tolfenamic acid. The method includes the following steps: adding o-chlorobenzoic acid and alkali metal hydroxide into methyl isobutyl ketone to obtain a mixture, and then heating up and enabling the mixture to react; adding 3-chloro-2-methylaniline and an alumina supported inorganic base acid-binding agent into the reacted mixture obtained in the previous step, and then heating up and enabling the mixture to react; cooling, adding water to extract, skimming, acidizing and crystallizing an aqueous phase using hydrochloric acid, filtering to obtain filter cakes which are tolfenamic acid crude products, and then recrystallizing the crude products to obtain tolfenamic acid refined products. According to the invention, the alumina supported inorganic base can be used not only as the acid-binding agent but also as a catalyst of the reaction, thereby improving the cleanness of industrial synthetic reactions and reducing environmental pollution.

Description

technical field [0001] The invention relates to a preparation method of an analgesic, in particular to a synthesis method of tolfenamic acid, which belongs to the field of pharmaceutical chemical synthesis. Background technique [0002] The anthranilic acid derivative tolfenamic acid (Tolfenamic acid, TA, 2-[(3-chloro-2-methylphenyl)amino]benzoic acid) developed by Denmark GEA company is a widely used non-steroidal Anti-inflammatory drugs (NSAIDs), which inhibit the IC of cyclooxygenase COX-1 / COX-2 50 It is 15.0, which shows that tolfenamic acid has strong selectivity to COX-2, so it has strong anti-inflammatory and analgesic effects and less side effects. Over the years, many scholars at home and abroad have conducted various studies on TA, and reviewed the pharmacology and toxicology of TA, which will provide reference for the clinical application of TA. At present, TA is mainly used in the treatment of arthritis and migraine, and is also widely used in the treatment of ...

AI Technical Summary

Problems solved by technology

[0003] Chinese patent: 201210291976.X introduces a synthetic method of tolfenamic acid, adding o-chlorobenzoic acid and alkali metal hydroxide to methyl isobutyl ketone, heating and reacting, and then adding 3-chloro -2-Methylaniline, acid-binding agent and catalyst, heating reaction, extraction, acidification, filtration, to obtain the crude product of tolfenamic acid, recrystallization of the crude product to obtain the refined product of tolfenamic acid, adopt inorganic base or organic Alkali is an acid-binding agent, using cuprous bromide, cuprous chloride, copper powder or copper acetate as a catalyst, a large amount of organic base or organic metal salt waste will be formed after the reaction, and the selectivity is low, and the reaction product is difficult to separate