Chin. J. Org. Chem. ›› 2017, Vol. 37 ›› Issue (7): 1748-1756.DOI: 10.6023/cjoc201701038 Previous Articles     Next Articles



田禾a, 吴景卫b, 刘钰强b, 谢亚非b, 王建武a, 赵桂龙b   

  1. a. 山东大学化学与化工学院 济南 250100;
    b. 天津药物研究院天津市新药设计与发现重点实验室 天津 300193
  • 收稿日期:2017-01-19 修回日期:2017-02-22 发布日期:2017-03-17
  • 通讯作者: 王建武, 赵桂龙;
  • 基金资助:


Efficient Synthetic Approaches to Uric Acid Transporter 1 Inhibitors Bearing Alkoxyl Group-Substituted Triazoles

Tian Hea, Wu Jingweib, Liu Yuqiangb, Xie Yafeib, Wang Jianwua, Zhao Guilongb   

  1. a. School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100;
    b. Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193
  • Received:2017-01-19 Revised:2017-02-22 Published:2017-03-17
  • Contact: 10.6023/cjoc201701038;
  • Supported by:

    Project supported by the Key Projects of Tianjin Science and Technology Support Plan (No.16YFZCSY00910) and the Natural Science Foundation of Shandong Province (No.ZR2015BM028).

Uric acid transporter 1 (URAT1) inhibitors bearing alkoxy group-substituted triazoles 3-(4-(4-cyclopropylnaphthalen-1-yl)-5-methoxy-4H-1,2,4-triazol-3-yl)propanoic acid (1a) and 3-(4-(4-cyclopropylnaphthalen-1-yl)-5-ethoxy-4H-1,2,4-triazol-3-yl)propanoic acid (1b) are structurally interesting lead compounds in drug design. The current synthetic approach to them suffers from quite low overall yields (3.3% and 3.0% for 1a and 1b, respectively). In order to explore the structure-activity relationship (SAR) of 1a and 1b, synthetic approach with higher overall yield is urgently needed. In the present study, two efficient synthetic approaches to 1a and 1b were developed (approaches A and B), with CuCl-catalyzed nucleophilic aromatic substitution (SNAr) reaction of bromotriazole with sodium alkoxides and SNAr reaction of methylsulfonyltriazole with sodium alkoxides as key steps, and the conditions for important steps were fully optimized. The two synthetic approaches are characterized by dramatically higher yields, and not only valuable to the further SAR exploration of 1a and 1b but also very helpful to the synthesis of heterocycles with alkoxyl groups.

Key words: URAT1 inhibitor, gout, hyperuricemia, synthetic route, SNAr, CuCl catalysis