A novel process for synthesis of tetrabenazine

李晓敏

doi:10.3969/j.issn.0438-1157.2012.02.032

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A novel process for synthesis of tetrabenazine

更新时间：2025-12-10

- A novel process for synthesis of tetrabenazine
- CIESC Journal Issue 2, Pages: 567-571(2012)
- 作者机构：
  
  江苏省原子医学研究所卫生部核医学重点实验室江苏省分子核医学重点实验室,江苏,无锡
- 作者简介：
- 基金信息：
- DOI：10.3969/j.issn.0438-1157.2012.02.032
  CLC： 626.324TQ463.54
- Online First：05 February 2012，
  
  Published：05 February 2012
- 稿件说明：
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李晓敏. A novel process for synthesis of tetrabenazine[J]. CIESC Journal, 2012, (2): 567-571.
DOI：

李晓敏. A novel process for synthesis of tetrabenazine[J]. CIESC Journal, 2012, (2): 567-571. DOI： 10.3969/j.issn.0438-1157.2012.02.032.

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。

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

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.

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