Synthesis Of Tolmetin And Tiaprofenic Acid In The Presence Of Manganese (Ⅲ) Complexes

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the clinical treatment of fever, pain and inflammation. Tolmetin and Tiaprofenic Acid are widely used in the clinical treatment to rheumatism, anchylosis, wrick, and postoperative pains etc. So it is important to study the synthesis of these drugs in order to reduce the cost of production and develop more pre-drug derivatives.As a metal complex, Manganese(III) acetate is specially important in organic synthesis. The reactions of free-radical induced by manganese(III) acetate have several advantages such as the quick speed of reaction, chemical selectivity, region selectivity and stereo selectivity, so it is a practical reagent with considerable applicable value and prospect. With the development of researches, many new chemical reactions were discovered, some new application fields were exploited, especially in the synthesis of heterocyclic compounds, natural organic compounds with biological activities, manganese(III) acetate plays a very important role in the synthesis of them. In this paper, manganese(III) acetate was used in the synthesis of Tolmetin and Tiaprofenic Acid, and the routes were shortened obviously, a new field which put the manganese(III) acetate into drug-synthesis was exploited at the same time.As a special form of energy, ultrasonic differs from heat-energy, light-energy and other forms notably. Compared with ordinary methods, the main advantages of sonocatalysis are shorter time, less reactant and higher yield, etc. In this paper, ultrasound irradiation was also used in the reactions which had metal complexes or metal existed. A better result was obtained compared with ordinary methods.This paper mainly studied on the synthesis of pyrrole and thiofuran species NSAIDs in the presence of manganese(III) acetate, especially worked on the representative drugs—Tolmetin and Tiaprofenic Acid, and the application of ultrasound irradiation was also discussed at the same time. It includes two parts as follows:(1) Synthesis of Tolmetin.N-methyl pyrrole was used as starting materials, (1-methyl-1H-pyrrol-2-yl)(p-tolyl)methanone was obtained after Vilsmeier-haack reaction with morpholino(p-tolyl)methanone, then in the presence of manganese(III) acetate, an important intermediate—triethyl 5-(4-methylbenzoyl)- 1-methyl-2-pyrrolemethanetricarboxylate was obtained, after hydrolysis Tolmetin was prepared. In this procedure, Grignard Reaction was used to yield (1-methyl-1H-pyrrol-2-yl)(p-tolyl)methanone, and at the same time ultrasound irradiation was used to accelerate the reaction and reduce solvent requirement.(2) Synthesis of Tiaprofenic Acid.Thiofuran was used as starting materials on the base of the synthesis of Tolmetin, phenyl(thiophen-2-yl)methanone was prepared after Friedel-Crafts reaction with benzoyl chloride, then in the presence of manganese(III) acetate, an important intermediate—diethyl a-methyl-5-benzoyl-2-thiophenemalonate was obtained, the rest procedures was almost the same with the synthesis of Tolmetin, Tiaprofenic Acid was prepared in a high yield.