二甲磺酸赖右苯丙胺的合成工艺研究

Study on synthetic process of lisdexamfetamine dimesylate

目的研究二甲磺酸赖右苯丙胺的合成工艺。方法以1-苯基-2-丙酮、S-苯乙胺为原料,在三乙酰氧基硼氢化钠作用下进行不对称还原胺化得到(S)-1-苯基-N-((S)-1-苯乙基)丙烷-2-胺(2),2在Pd/C作用下脱苄基得到(1S)-1-甲基-2-苯乙基胺(3);以L-赖氨酸盐酸盐为原料,经二碳酸二叔丁酯保护得到(S)-2,6-双((叔丁氧基羰基)氨基)己酸(4);中间体3和4在1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和1-羟基苯并三唑作用下经缩合反应得到(2S)-2,6-二-N-Boc-氨基-N-[(1S)-1-甲基-2-苯乙基]己酸胺(5),5在甲磺酸中脱Boc保护基并成盐制得目标物(2S)-2,6-二氨基-N-[(1S)-1-甲基-2-苯乙基]己酸胺二甲磺酸盐。结果与结论目标产物的结构经1H-NM R、13C-NM R、DEPT和HRM S谱确证,总收率为50.5%(以S-苯乙胺计)。本文采用的合成路线具有原料成本低、操作简单高效、立体选择性好、收率高等优点,更适宜工业化生产。

Lisdexamfetamine dimesylate [（ 2S）-2,6-diamino-N-[（ 2S）-1-phenylpropan-2-yl]hexanamide],brandly named Vyvanse,was developed by Shire pharmaceuticals company. It provided an approach to the treatment of attention deficit hyperactivit disorder（ ADHD）,which was approved by FDA in 2007. In this paper,a newsynthetic route has been established based on literatures. Lisdexamfetamine dimesylate was synthesized through five steps,including asymmetric reductive amination,debenzylation,amide condensation,deprotection and salt formation with an overall yield of about 50. 5%（ based on homochiral α-phenylethylamine）. The HPLC purity of the final product is 99. 86%. The lisdexamfetamine dimesylate and some important intermediates were confirmed by1H-NMR,13C-NMR,DEPT and HRMS. The improved process has several advantages over those reported procedures,such as cheap material,simple operations,high stereoselectivity and improved yield. In a word,it＇s more suitable for industrial production.