Synthesis of 1-(tert-Butyl) 4-Methyl (1R,2S,4R)-2-Methylcyclohexane-1,4-dicarboxylate from Hagemann's tert-Butyl Ester for an Improved Synthesis of BMS-986251.,The Journal of Organic Chemistry

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Synthesis of 1-(tert-Butyl) 4-Methyl (1R,2S,4R)-2-Methylcyclohexane-1,4-dicarboxylate from Hagemann's tert-Butyl Ester for an Improved Synthesis of BMS-986251.
The Journal of Organic Chemistry ( IF 3.3 ) Pub Date : 2020-07-20 , DOI: 10.1021/acs.joc.0c01169
Lyndon A M Cornelius ₁ , Jianqing Li ₁ , Daniel Smith ₁ , Subramaniam Krishnananthan ₁ , Shiuhang Yip ₁ , Dauh-Rurng Wu ₁ , Joseph Pawluczyk ₁ , Darpandeep Aulakh ₂ , Amy A Sarjeant ₂ , James Kempson ₁ , Joseph A Tino ₁ , Arvind Mathur , T G Murali Dhar ₁ , Robert J Cherney ₁

Affiliation

We describe an efficient synthetic route to differentially protected diester, 1-(tert-butyl) 4-methyl (1R,2S,4R)-2-methylcyclohexane-1,4-dicarboxylate (+)-1, via palladium-catalyzed methoxycarbonylation of an enol triflate derived from a Hagemann’s ester derivative followed by a stereoselective Crabtree hydrogenation. Diester 1 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 1 as a critical component.

中文翻译：

由哈格曼叔丁基酯合成1-（叔丁基）4-甲基（1R，2S，4R）-2-甲基环己烷-1,4-二羧酸酯，用于改进BMS-986251的合成。

我们描述了一种有效的合成路线，可通过钯-来实现差动保护的二酯1-（叔丁基）4-甲基（1 R，2 S，4 R）-2-甲基环己烷-1,4-二羧酸（+）- 1催化由Hagemann酯衍生物衍生的烯醇三氟甲磺酸酯的甲氧基羰基化，然后进行立体选择性Crabtree氢化。Diester 1是一种新颖的手性合成子，可用于药物开发，并且在RORγt反向激动剂程序过程中有助于生成有用的SAR。此外，我们描述了使用二酯1作为关键成分的临床候选药物BMS-986251的第二代合成。

更新日期：2020-08-21

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