Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
Materials Science & Engineering, Bristol Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States.
J Org Chem. 2020 Aug 21;85(16):10988-10993. doi: 10.1021/acs.joc.0c01169. Epub 2020 Aug 7.
We describe an efficient synthetic route to differentially protected diester, 1-(-butyl) 4-methyl (1,2,4)-2-methylcyclohexane-1,4-dicarboxylate (+)-, via palladium-catalyzed methoxycarbonylation of an enol triflate derived from a Hagemann's ester derivative followed by a stereoselective Crabtree hydrogenation. Diester is a novel chiral synthon useful in drug discovery and was instrumental in the generation of useful SAR during a RORγt inverse agonist program. In addition, we describe a second-generation synthesis of the clinical candidate BMS-986251, using diester as a critical component.
我们描述了一种高效的合成路线，通过钯催化的烯醇三氟甲磺酸酯的甲氧羰基化反应，得到了 1-（正丁基）4-甲基（1,2,4）-2-甲基环己烷-1,4-二甲酸酯（+）-（+）-，然后进行立体选择性的 Crabtree 氢化反应。二酯是一种新型的手性合成子，在药物发现中很有用，并且在 RORγt 反向激动剂项目中生成有用的 SAR 方面发挥了重要作用。此外，我们还描述了使用二酯作为关键成分的临床候选药物 BMS-986251 的第二代合成方法。
