有机化学 ›› 2014, Vol. 34 ›› Issue (6): 1196-1200.DOI: 10.6023/cjoc201402025 上一篇    下一篇

研究简报

多靶点受体酪氨酸激酶抑制剂ABT-869的有效合成方法

侯学会a, 张京玉b, 刘宏民c   

  1. a. 河南牧业经济学院质量检测与管理系 郑州 450011;
    b. 河南中医学院药学院 郑州 450008;
    c. 郑州大学药学院 郑州 450001
  • 收稿日期:2014-02-20 修回日期:2014-03-06 发布日期:2014-03-13
  • 通讯作者: 侯学会, 刘宏民 E-mail:jyzhang2004@126.com;liuhm@zzu.edu.cn
  • 基金资助:

    河南省教育厅科学技术研究重点(Nos. 14A150052,12A150026)、郑州市科技攻关计划(No. 121PPTGG509-2)资助项目.

Synthesis of a Multiple Target Receptor Tyrosine Kinase Inhibitors ABT-869

Hou Xuehuia, Zhang Jingyub, Liu Hongminc   

  1. a. Department of Quality Detection and Management, Henan University of Animal Husbandry and Economy, Zhengzhou 450011;
    b. Henan University of Traditional Chinese Medicine, Zhengzhou 450008;
    c. School of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001
  • Received:2014-02-20 Revised:2014-03-06 Published:2014-03-13
  • Supported by:

    Project supported by the Education Department of Henan Province Science and Technology Research Projects (Nos. 14A150052, 12A150026), the Scientific Research Plan of Zhenzhou (No. 121PPTGG509-2).

ABT-869是结构新型有效的多靶点受体酪氨酸激酶抑制剂,目前正处在III期临床研究阶段. 从商业廉价易得的间氟苯胺出发,以较低的成本经过7步反应以42.3%的总收率实现了多靶点受体酪氨酸激酶抑制剂ABT-869全合成. 该工艺在关键步骤Suzuki偶联反应中使用了超声波反应器,极大地缩短反应时间,提高了收率,并且该工艺各步反应中间体不用纯化直接投入下步反应,最终产物只需结晶纯化即可达到大于99%的纯度,无需传统的柱层析分离,更适合于工业生产.

关键词: 受体酪氨酸激酶抑制剂, ABT-869, 合成

An efficient and convenient protocol for the synthesis of ABT-869, which is a multiple target receptor tyrosine kinase inhibitors with novel structure and high inhibitory activity, was developed in seven steps from cheap and commercially available of 3-fluoroaniline. The target molecular was obtained in 42.3% overall yield without any traditional purification (column chromatography or crystallization). Ultrasonic reaction technology was introduced in the Suzuki coupling reaction which is the key step of the preparation of ABT-869. The synthetic process was more suitable for industrialized production due to the advantages of available starting material, simplicity and cheapness, well yield and purity (HPLC>99.0%).

Key words: receptor tyrosine kinase inhibitors, ABT-869, synthesis