Department of Process Research, Merck Research Laboratory, Rahway, New Jersey 07065, USA.
J Org Chem. 2010 Mar 5;75(5):1343-53. doi: 10.1021/jo902573q.
A practical asymmetric synthesis of a novel aminopiperidine-fused imidazopyridine dipeptidyl peptidase IV (DPP-4) inhibitor 1 has been developed. Application of a unique three-component cascade coupling with chiral nitro diester 7, which is easily accessed via a highly enantioselective Michael addition of dimethyl malonate to a nitrostyrene, allows for the assembly of the functionalized piperidinone skeleton in one pot. Through a base-catalyzed, dynamic crystallization-driven process, the cis-piperidionone 16a is epimerized to the desired trans isomer 16b, which is directly crystallized from the crude reaction stream in high yield and purity. Isomerization of the allylamide 16b in the presence of RhCl(3) is achieved without any epimerization of the acid/base labile stereogenic center adjacent to the nitro group on the piperidinone ring, while the undesired enamine intermediate is consumed to <0.5% by utilizing a trace amount of HCl generated from RhCl(3). The amino lactam 4, obtained through hydrogenation and hydrolysis, is isolated as its crystalline pTSA salt from the reaction solution directly, as such intramolecular transamidation has been dramatically suppressed via kinetic control. Finally, a Cu(I) catalyzed coupling-cyclization allows for the formation of the tricyclic structure of the potent DPP-4 inhibitor 1. The synthesis, which is suitable for large scale preparation, is accomplished in 23% overall yield.
已开发出一种新型氨基哌啶并咪唑并吡啶二肽基肽酶 IV（DPP-4）抑制剂 1 的实用不对称合成方法。应用独特的三组分级联偶联反应，其中手性硝基二酯 7 很容易通过马来酸二甲酯与硝代苯乙烯的高度对映选择性迈克尔加成获得，可一锅法组装功能化的哌啶酮骨架。通过碱催化、动态结晶驱动过程，顺式-哌啶酮 16a 发生外消旋化，得到所需的反式异构体 16b，其可直接从粗反应混合物中以高产率和高纯度结晶得到。在 RhCl(3)存在下，烯丙酰胺 16b 的异构化反应不会导致与哌啶酮环上硝基相邻的酸碱不稳定手性中心发生外消旋化，同时通过利用 RhCl(3) 产生的痕量 HCl，消耗了未反应的烯胺中间体至<0.5%。通过氢化和水解获得的氨基内酰胺 4 可直接从反应溶液中作为其结晶 pTSA 盐分离出来，因为通过动力学控制，分子内 transamidation 被大大抑制。最后，Cu(I) 催化偶联-环化反应允许形成强效 DPP-4 抑制剂 1 的三环结构。该合成方法适合大规模制备，总收率为 23%。
