Sitaxsentan钠盐的合成

Synthesis of Sitaxsentan Sodium

用4-甲基-邻苯二酚(1)与二氯甲烷(2)反应生成5-甲基-苯骈[d][1,3]二氧杂戊烯(3),氯甲基化生成5-氯甲基-6-甲基-苯骈[d][1,3]二氧杂戊烯(5),与镁(6)制得格氏试剂(7);N-甲氧基-N-甲基-3-[(4-氯-3-甲基-5-异恶唑基)-磺酰胺基]-2-噻吩甲酰胺(Weinreb酰胺)(8)与格氏试剂(7)反应得到Sitaxsentan(9),收率为52.6%,经饱和碳酸氢钠溶液处理得Sitaxsentan钠盐(10),收率为54.2%,产物经核磁共振分析证明,结构正确。实验表明,合成化合物3时,合适的反应温度为100℃,四丁基氯化铵作催化剂促进反应完全进行;合成化合物5时,用四丁基氯化铵代替四丁基溴化铵做催化剂,避免了副产物的生成;合成化合物9和化合物10时,改变原料摩尔比及反应顺序有效地缩短了反应时间,降低了生产成本。

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.