A novel process for synthesis of tetrabenazine
A novel process for synthesis of tetrabenazine
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发表时间：
2012
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通讯作者：
Tang Jie
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作者：
Tang Jie
丁苯那嗪于2008年在美国被批准为首个治疗亨廷顿舞蹈病的药物。以三乙基苄基氯化铵（TEBAC）为催化剂，水为溶剂，在90℃下合成了7-二甲氧基-3，4-二氢异喹啉盐酸盐，考察了反应条件对收率的影响，得到了最佳反应条件（温度、时间、摩尔产率）为：Mannich反应，回流反应5 h，55%;胺交换，90℃，3.5h，68%。目标产物的化学结构经1HNMR，IR，MS和元素分析表征，HPLC纯度为98%。该工艺原料易得，反应条件温和，反应时间短，操作简单，环境友好。
Tetrabenazine was approved as the first drug to treat chorea associated with Huntington's disease in USA in 2008.A two-step process employing water as reaction medium method was proposed for synthesis of tetrabenazine.The first step in the process was synthesis of 3-dimethylaminomethyl-5-methyl-hexan-2-one from 5-methyl-2-hexanone via Mannich reaction,and the second step was that the intermediate was reacted further with 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride in water at 90℃ catalyzed by triethylbenzylammonium chloride(TEBAC)to give the target compound.The effect of reaction conditions on the yield was investigated.The optimal reaction conditions obtained(temperature,time,molar yield)were as follows: Mannich reaction,reflux for 5 h,55%;amine exchange,90℃ for 3.5 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 of potential value for commercial application because of cheap and available materials,milder conditions,shorter reaction time,simple operations and environmental friendly.