Abstract: Tetrabenazine was approved by Food and Drug Administration (FDA) in US as the first drug to treat chorea associated with Huntington’s disease in 2008. A convenient two-step method for synthesis of tetrabenazine with water as reaction medium was proposed. The process was started with 5-methyl-2-hexanone via Mannich reaction to afford 3-dimethylaminomethyl-5-methyl-hexan-2-one. The intermediate was reacted further with 6,7-Dimethoxy-3,4-dihydroisoquinoline hydrochloride at 90℃ catalyzed by triethylbenzylammonium chloride(TEBAC) in water to form the target compound. The influences of various reaction conditions on the yield were investigated. The optimal reaction conditions (temperature, time, molar yield) were as follows: Mannich reaction, reflux for 5 h, 55 %; amine exchange, 90 ℃ for 4 h, 68 %. The chemical structure of the target product with 98 % HPLC purity was characterized by 1H NMR, IR, MS and elemental analyses. The process is much of industrial value because of cheap and available materials, milder conditions, shorter reaction time, simple operations and environmental friendliness.

Key words: green chemistry, tetrabenazine, Huntington〖DK〗’s disease, pharmaceutical synthesis, aqueous media

摘要： 提出了一种以水为反应介质合成治疗亨廷顿舞蹈病(Huntington’s disease, HD)药物——丁苯那嗪的新方法。以价廉易得的5-甲基-2-己酮为原料，先与二甲胺发生Mannich 反应，再与6,7-二甲氧基-3,4-二氢异喹啉盐酸盐在水介质中90℃经胺交换反应得到目标产物。通过实验优化合成路线，确定了各步反应最优的反应条件(反应时间、反应温度、摩尔收率)分别为：Mannich 反应，回流，5 h，55 %；胺交换反应，90 ℃，4 h，68 %。目标产物经1H NMR、IR、MS和元素分析确证表征。合成工艺简化，仅有两步反应；合成工艺绿色化，具有条件温和、操作简便、环境友好的优点。

关键词: 绿色化学, 丁苯那嗪, 亨廷顿舞蹈病, 药物合成, 水介质