GLP-1R小分子激动剂Danuglipron关键中间体的合成工艺优化研究  

Optimization of the Synthetic Process for the Synthesis of Key Intermediates of Danuglipron,a GLP-1R small Molecule Agonist

作　　者：江伟业 钟毅[1] Jiang Weiye;Zhong Yi(China Pharmaceutical University,Nanjing 210000,China)

机构地区：[1]中国药科大学,江苏南京210000

出　　处：《广东化工》2025年第5期55-58,共4页Guangdong Chemical Industry

摘　　要：糖尿病是一种由于胰岛素分泌不足或外周组织对胰岛素不敏感引起的代谢性疾病。Danuglipron是辉瑞公司研发的治疗二型糖尿病的GLP-1R(glucagon-like peptide-1 receptor,GLP-1R)小分子激动剂,在临床2a期、双盲临床试验中表现出优良的降糖与减重效果。但是该分子结构复杂,合成繁琐。本文以1-(叔丁氧基羰基)-4-(6-氯吡啶-2-基)哌啶-4-羧酸为起始物料,通过脱羧反应、BuchwaldHartwig偶联反应以及脱Boc保护基反应得到了关键中间体3-氟-4-((6-(哌啶-4-基)吡啶-2-基)氧基)甲基苄腈,分别对三步反应进行了工艺参数进行了优化。优化后的路线较文献报道的方法收率更高、能耗更低、操作更简便、避免了柱层析纯化,为工业化生产提供了参考。Diabetes mellitus is a metabolic disease caused by insufficient insulin secretion or insensitivity of peripheral tissues to insulin.Danuglipron,a GLP-1R small molecule agonist developed by Pfizer for the treatment of Type 2 Diabetes Mellitus,has demonstrated excellent glucose-lowering and weight-loss effects in clinical phase 2a,double-blind clinical trials.However,the molecule is structurally complex and tedious to synthesize.In this paper,1-(tertbutoxycarbonyl)-4-(6-chloropyridin-2-yl)piperidine-4-carboxylic acid was used as the starting material,and the key intermediate 3-fluoro-4-((6-(piperidin-4-yl)pyridin-2-yl)oxy)methylbenzenecarbonitrile was obtained by decarboxylation reaction as well as Buchwald-Hartwig coupling reaction,and the process parameters of the three-step reaction were optimized respectively.The optimized route has higher yield,lower energy consumption,easier operation and avoids column chromatographic purification than the methods reported in literature,which provides a reference for industrial production.

关 键 词：Danuglipron 中间体 合成 工艺优化 

分 类 号：R91[医药卫生—药学]