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

doi:10.6023/cjoc201701038

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

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含烷氧基取代的三唑类结构的尿酸转运体1抑制剂的高效合成方法

田禾^a, 吴景卫^b, 刘钰强^b, 谢亚非^b, 王建武^a, 赵桂龙^b

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 E-mail:zhao_guilong@126.com;jwwang@sdu.edu.cn
基金资助:
天津市科技支撑计划重点项目基金（No.16YFZCSY00910）和山东省自然科学基金（No.16YFZCSY00910）资助项目.

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

Tian He^a, Wu Jingwei^b, Liu Yuqiang^b, Xie Yafei^b, Wang Jianwu^a, Zhao Guilong^b

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 E-mail:zhao_guilong@126.com;jwwang@sdu.edu.cn
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).

1. Efficient Synthetic Approaches to Uric Acid Transporter 1 Inhibitors Bearing Alkoxyl Group-Substituted Triazoles.PDF(1904KB)

Abstract

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 (S_NAr) reaction of bromotriazole with sodium alkoxides and S_NAr 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, S_NAr, CuCl catalysis

Cite this article

Tian He, Wu Jingwei, Liu Yuqiang, Xie Yafei, Wang Jianwu, Zhao Guilong. Efficient Synthetic Approaches to Uric Acid Transporter 1 Inhibitors Bearing Alkoxyl Group-Substituted Triazoles[J]. Chin. J. Org. Chem., 2017, 37(7): 1748-1756.

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含烷氧基取代的三唑类结构的尿酸转运体1抑制剂的高效合成方法

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

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