BCAT1抑制剂BAY-069的合成工艺优化  

Optimization of Synthetic Process for BCAT1 Inhibitor BAY-069

作　　者：李勇 罗文 李燕 谢华 赵桂龙 LI Yong;LUO Wen;LI Yan;XIE Hua;ZHAO Guilong(School of Pharmaceutical Sciences,Southern Medical University,Guangzhou 510515,China;Zhongshan Institute for Drug Discovery,Chinese Academy of Sciences,Zhongshan 528400,China;Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China)

机构地区：[1]南方医科大学药学院,广东广州510515 [2]中科中山药物创新研究院,广东中山528400 [3]中国科学院上海药物研究所,上海201203

出　　处：《合成化学》2024年第8期696-704,共9页Chinese Journal of Synthetic Chemistry

基　　金：广东省基础与应用基础研究项目(2023A1515012259,2021A1515010197);中山市基础与应用基础研究项目(200805173640573,210730214049987)。

摘　　要：BAY-069是目前体外活性最强的支链氨基酸转氨酶1(BCAT1)抑制剂,但其报道的合成路线存在原料成本较高、总收率极低和中间体结构表征不充分等缺点。本研究基于已有合成路线,重点对其合成工艺中的Ullmann偶联反应进行了系统优化。以1-硝基萘(1)为起始原料,经过7步反应和手性色谱柱手性拆分合成目标化合物BAY-069。所有中间体和目标化合物均经1 H NMR,13 C NMR和HR-MS表征。以Ullmann偶联反应为主要优化步骤的路线,其优化后的总收率为11.0%(3b→(±)-BAY-069),是原总收率1.6%(3a→(±)-BAY-069)的6.9倍。BAY-069 is the most potent branched-chain amino acid transaminase 1(BCAT1)inhibitor;however,its reported synthetic route suffered from many shortcomings,such as expensive starting material,extremely low overall yield and insufficient structural characterizations of intermediates.The present study performed systematic optimization of the key synthetic processes based on the reported synthetic route,such as Ullmann coupling.Thus,starting from 1-nitronaphthalene(1),BAY-069 was prepared in 7 steps followed by chiral resolution on chiral column,and all the intermediates and BAY-069 were fully characterized by 1 H NMR,13 C NMR and HR-MS.The overall yield for the optimized synthetic route with the key step being Ullmann coupling is 11.0%(3b→(±)-BAY-069),which is 6.7-fold higher than the original overall yield of 1.6%(3a→(±)-BAY-069).

关 键 词：BAY-069 支链氨基酸转氨酶1抑制剂 工艺优化 合成 Ullmann偶联反应 Sandmeyer反应 轴手性 

分 类 号：O626.29[理学—有机化学]