有机化学 ›› 2025, Vol. 45 ›› Issue (9): 3335-3342.DOI: 10.6023/cjoc202504010 上一篇    下一篇

研究论文

达普司他的合成新工艺

许志勇a, 林晓慧a, 朱园园b, 张双双a, 龙姣a,*(), 古双喜a,*()   

  1. a 武汉工程大学化工与制药学院 药物研究院 新型反应器与绿色化学工艺湖北省重点实验室 武汉 430205
    b 武汉工程大学化学与环境工程学院 武汉 430205
  • 收稿日期:2025-04-09 修回日期:2025-05-29 发布日期:2025-08-18
  • 基金资助:
    国家自然科学基金(22074114); 国家自然科学基金(22377097); 湖北省自然科学基金(2024AFB233); 湖北省教育厅科研基金(Q20221513); 湖北省博士后创新人才培养(2024HBBHCXB074); 武汉工程大学科学基金(K2023116)

A Novel Synthetic Process of Daprodustat

Zhiyong Xua, Xiaohui Lina, Yuanyuan Zhub, Shuangshuang Zhanga, Jiao Longa,*(), Shuangxi Gua,*()   

  1. a Hubei Key Laboratory of Novel Reactor and Green Chemical Technology, Pharmaceutical Research Institute, School of Chemical Engineering & Pharmacy, Wuhan Institute of Technology, Wuhan 430205
    b School of Chemistry and Environmental Engineering, Wuhan Institute of Technology, Wuhan 430205
  • Received:2025-04-09 Revised:2025-05-29 Published:2025-08-18
  • Contact: E-mail: longjiao@wit.edu.cn; shuangxigu@163.com
  • About author:

    Academic Papers of the 27th Annual Meeting of the China Association for Science and Technology.

  • Supported by:
    National Natural Science Foundation of China(22074114); National Natural Science Foundation of China(22377097); Natural Science Foundation of Hubei Province(2024AFB233); Science Research Foundation of Hubei Provincial Department of Education(Q20221513); Postdoctoral Innovation Talent Program of Hubei Province(2024HBBHCXB074); Science Foundation of Wuhan Institute of Technology(K2023116)

开发了一种高效实用的达普司他(Daprodustat)合成新工艺. 以N,N'-二环己基碳二亚胺(DCC)与丙二酸为原料, 通过缩合反应高效制备关键中间体1,3-二环己基-2,4,6(1H,3H,5H)-嘧啶三酮, 收率91%. 该中间体经1,1'-羰基二咪唑(CDI)活化, 与甘氨酸乙酯盐酸盐通过一锅法反应合成目标产物, 以92%的收率获得HPLC纯度>99.8%的达普司他. 经62 g规模反应验证, 工艺总收率达84%. 关键中间体的结构经核磁共振(NMR)和高分辨质谱(HRMS)确证. 与传统方法相比, 该工艺具有操作简便、反应时间短、合成成本低等优势, 为达普司他的工业化生产提供了重要参考.

关键词: 达普司他, 合成工艺, 一锅法

An efficient and practical synthetic process for Daprodustat was developed. Starting with N,N'-dicyclohexylcarbo- diimide (DCC) and malonic acid, the key intermediate 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione was synthesized via condensation reaction with 91% yield. Subsequent activation of this intermediate by 1,1'-carbonyldiimidazole (CDI), followed by a one-pot reaction with glycine ethyl ester hydrochloride, directly afforded Daprodustat in 92% yield with >99.8% HPLC purity. The process achieved an overall yield of 84% upon validation at 62-gram scale. Structural confirmation of the key intermediate was accomplished through nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HRMS). Compared with existing methods, this streamlined protocol demonstrates advantages including simplified operation, reduced reaction time, and lower production costs, offering significant potential for industrial-scale synthesis of Daprodustat.

Key words: Daprodustat, synthetic process, one-pot method