Asymmetric Synthesis of the Cyclohexyl Fragment in RORγt Inhibitor (BMS-986251) Enabled by a Dynamic Kinetic Resolution of Hageman’s Ester

IF 3.1 3区 化学 Q2 CHEMISTRY, APPLIED Organic Process Research & Development Pub Date : 2021-11-16 DOI:10.1021/acs.oprd.1c00339
William P. Gallagher*, John R. Coombs, Carlos A. Guerrero, Boguslaw M. Mudryk, Kishta Katipally, Candice L. Joe, Sanjeewa Rupasinghe, Jason Zhu, Francisco González-Bobes*
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引用次数: 1

Abstract

The cyclohexyl fragment 1 in BMS-986251 was synthesized starting from Hagemann’s ester 2 in 7 steps and 5 isolations. The route is highlighted by a dynamic kinetic resolution (DKR), a telescoped enol nonaflation followed by a palladium-catalyzed carbonylation, and a rhodium-catalyzed directed diastereoselective olefin hydrogenation. The optimized process was demonstrated on 1 kg scale, with an overall 51% yield and >99% ee and dr.

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Hageman 's酯的动态动力学拆分使rorγ - t抑制剂(BMS-986251)中环己基片段的不对称合成成为可能
以Hagemann 's ester 2为起始原料,经过7步5次分离合成了BMS-986251中的环己基片段1。该路线通过动态动力学解析(DKR)、伸缩烯醇不充气、钯催化羰基化和铑催化定向非对映选择性烯烃加氢来突出。优化后的工艺在1千克规模上进行了验证,总收率为51%,ee和dr。
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来源期刊
CiteScore
6.90
自引率
14.70%
发文量
251
审稿时长
2 months
期刊介绍: The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools,process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.
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