Synthesis of Sitaxsentan Sodium

The optimized synthesis route and process conditions of Sitaxsentan sodium were reported. 4-Methyl-pyrocatechol(1) reacted with dichloromethane(2) to give 5-methy 1-benzparallel[d][1,3]dioxolene(3), then chloromethylated into 5-chloromethyl-6-methyl-benzparallel[d][1,3]dioxolene(5), compound 5 reacted with magnesium(6) to obtain Grignard reagent(7). Sitaxsentan(9) was obtained through the reaction of N-methoxyl-N-methyl-3-[(4-chloro-3-methyl-5-isoxazole)-sulfamido]-2-thenylamide(Weinreb amide)(8) with Grignard reagent 7 in the presence of an acid, and Sitaxsentan sodium(10) was finally obtained from saturated dicarbonate solution. The structure of the product was proved by nuclear magnetic resonance analysis. The overall yield of compound 9 is 52.6%, and that of compound 10 is 54.2%. The optimal temperature of synthesizing compound 3 is 100 ℃ and tetrabutylammonium chloride accelerates the synthesis reaction of compound 3 as catalyst.The by-product was not obtained by using tetrabutylammonium chloride in place of tetrabutylammonium bromide as catalyst of synthesizing compound 5. The reaction time was reduced and the cost was decreased by changing the molar ratio of raw material and reaction order when compounds 9 and 10 were synthesized.