有机化学 ›› 2014, Vol. 34 ›› Issue (6): 1154-1160.DOI: 10.6023/cjoc201401024 上一篇    下一篇

研究论文

一种新的合成氯法拉滨的方法

夏然a,b, 郭真b, 秦博文b, 汲智越b, 谢明胜b, 渠桂荣a,b, 郭海明a,b   

  1. a. 河南师范大学环境学院 新乡 453007;
    b. 河南师范大学化学化工学院 新乡 453007
  • 收稿日期:2014-01-14 修回日期:2014-02-22 发布日期:2014-03-03
  • 通讯作者: 渠桂荣, 郭海明 E-mail:quguir@sina.com;guohm518@hotmail.com
  • 基金资助:

    国家自然科学基金(Nos. 21072047,21172059,21272059,21202039和21372066)、河南省杰出青年基金(No. 114100510012)、河南省高校科技创新研究团队支持计划(No. 2012IRTSTHN006)、高等学校博士学科点专项科研基金(No. 20124104110006)资助项目.

A New Method for the Synthesis of Clofarabine

Xia Rana,b, Guo Zhenb, Qin Bowenb, Ji Zhiyueb, Xie Mingshengb, Qu Guironga,b, Guo Haiminga,b   

  1. a. School of Environment, Henan Normal University, Xinxiang 453007;
    b. School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007
  • Received:2014-01-14 Revised:2014-02-22 Published:2014-03-03
  • Supported by:

    Foundation of Henan Scientific Committee (No. 114100510012), the Program for Innovative Research Team from the University of Henan Province (No. 2012IRTSTHN006), the Research Fund for the Doctoral Program of Higher Education (No. 20124104110006).

氯法拉滨是临床上唯一可以特异性地治疗儿童白血病的药物,2004年被美国食品和药物管理局批准上市. 由于现有合成方法存在路线长、收率低和α/β异构体难以分离等问题,限制了该药物的广泛使用和进一步研究. 以廉价且商品化的2-氯腺苷为原料,通过乙酸酐保护糖环上的3个羟基,在水合肼和乙酸作用下,选择性地脱除2'位的乙酰基. 然后,以商品化的氟代试剂二乙胺基三氟化硫(DAST)进行2’位羟基的氟代反应,再使用NH3/MeOH饱和溶液脱除乙酰基可得氯法拉宾. 这4步反应的总收率为49%,且得到的产品全部为β构型. 同时,还发现2位取代基的位阻越大,越有利于选择性脱除2'位的乙酰基. 本方法可以在克级规模上进行生产,收率无下降,同时中间体及产物的纯化不需要通过柱层析分离,显示出良好的应用前景.

关键词: 氯法拉滨, 2-氯腺苷, 氟代, 合成, 核苷

Clofarabine is the active ingredient in the anti-pediatric leukemia drug, which was approved by U.S. Food and Drug Administration in 2004. However, the previous reported methods have long steps, low yield and difficult separation of α/β anomers, which restrict the wide use of the drug. In this manuscript, the cheap and commercial available 2-chloroadenosine was chose as the starting material to synthesize the clofarabine. By using acetic acid and hydrazine, the selective deprotection of acetyl group in 2'-position was accomplished. Subsequently, the fluorination step was realized by diethylaminosulfurtrifluoride (DAST). The clofarabine was synthesized with 4 steps in 49% total yield as a pure β-anomer. Meanwhile, the strong steric hindrance of 2-substitution was favorable for the 2'-deacetylation. Notably, the clofarobine could be synthesized at a gram scale using this method, which showed the good future of industrial application.

Key words: clofarabine, 2-chloroadenosine, fluorination, synthesis, nucleoside