有机化学 ›› 2017, Vol. 37 ›› Issue (9): 2361-2368.DOI: 10.6023/cjoc201704002 上一篇    下一篇

研究论文

肠道病毒71型抑制剂TJAB1099的实用合成方法研究

贺万丽a,c, 赵杨杨a,c, 毛永红a, 赵佩佩a, 汪颖a,c, 蔡岩a,b   

  1. a 天津国际生物医药联合研究院 天津 300457;
    b 南开大学药物化学生物学国家重点实验室 天津 300071;
    c 南开大学药学院 天津 300071
  • 收稿日期:2017-04-01 修回日期:2017-04-26 出版日期:2017-09-25 发布日期:2017-05-10
  • 通讯作者: 赵佩佩, 汪颖, 蔡岩 E-mail:apple.12.26@163.com;wangying1412@163.com;caiyan_86@163.com
  • 基金资助:

    南开大学药物化学生物学国家重点实验室开放基金(No.201602003)及天津市科技计划(Nos.13ZCZDSY04200,14ZCZDSY00039)资助项目.

Practical Synthesis of TJAB1099:An Effective Anti EV71 Inhibitor

He Wanlia,c, Zhao Yangyanga,c, Mao Yonghonga, Zhao Peipeia, Wang Yinga,c, Cai Yana,b   

  1. a Tianjin International Joint Academy of Biomedicine, Tianjin 300457;
    b State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071;
    c College of Pharmacy, Nankai University, Tianjin 300071
  • Received:2017-04-01 Revised:2017-04-26 Online:2017-09-25 Published:2017-05-10
  • Contact: 10.6023/cjoc201704002 E-mail:apple.12.26@163.com;wangying1412@163.com;caiyan_86@163.com
  • Supported by:

    Project supported by the State Key Laboratory of Medicinal Chemical Biology Open Fund (Nankai University) (No. 201602003), and the Science and Technology Planning Project of Tianjin City (Nos. 13ZCZDSY04200, 14ZCZDSY00039).

肠道病毒71型(EV71)是目前我国手足口病的主要致病病原,EV71感染不仅造成轻症病例,还能造成重症和死亡病例,目前尚无有效治疗EV71感染的药物上市.TJAB1099是基于EV71的衣壳蛋白VP1结构设计出的有效抗病毒抑制剂分子,临床前研究证实其具有很好的成药性.主要研究了TJAB1099的有效制备方法.以2-氨基-4-溴吡啶为起始原料,经过6步化学转化,以12%的总收率得到纯度大于99%的抑制剂分子TJAB1099.合成过程中无需硅胶柱纯化操作.该路线经过多批次百克级的起始投料,收率稳定且抑制剂分子杂质含量稳定,完全可以满足其临床前实验所需的抑制剂制备量,并且也为其之后进一步的大规模生产打下基础.

关键词: 肠道病毒71型, 抑制剂, 合成方法

Enterovirus 71 (EV71) is the main pathogen caused Human Hand, Foot and Mouth Disease (HFMD) in China. It not only caused mild case, but also serious case. However, no effective commercialize drugs for the treatment of HFMD were available nowadays. TJAB1099 is an effective EV71 inhibitor which was designed based on the capsid protein VP1 of EV71. The preclinical study has revealed that it owns excellent druggability. Here an practical synthesis of TJAB1099, initiated with 2-amino-4-bromide pyridine is reported. The total synthetic steps are six and its total yield is 12%. The purity of TJAB1099 is more than 99%, and silic gel chromatography is not required in the whole process. This synthetic method has been examined by hectogram level starting feeding for several times, and the total yield and the content of impurities are stable. This method could meet the need of the inhibitor amount for the preclinical study, and it could lay the foundation of further large scale synthesis.

Key words: enterovirus 71, inhibitor, synthetic method