BCAT1抑制剂BAY-069的合成工艺优化

Optimization of Synthetic Process for BCAT1 Inhibitor BAY-069

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).