关键词: 绿色化学, 丁苯那嗪, 亨廷顿舞蹈病, 药物合成, 水介质

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