Development of a Scalable Route with Efficient Stereoisomer Control to YZJ-1139, an Orexin Receptor Antagonist

IF 3.5 3区 化学 Q2 CHEMISTRY, APPLIED
Zhenya Zeng*, Jiangbo Zhang, Miao Jia, Bo Wu, Xunzhi Cai, Xingsong Zhang, Yixiao Feng, Youhong Ma, Qingfu Gao, Zonglei Fei
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Abstract

An effort toward the synthesis and process development of the orexin receptor antagonist YZJ-1139(1) was described in this article. YZJ-1139(1) contains the azabicyclic nortropane structure with three chiral centers. By the original process, highly pure intermediates or API could be obtained by chromatography with a relatively low yield. To remove the undesirable stereoisomers as early as possible, intermediate 13 with (R)-α-phenethyl was synthesized by the Robinson–Sch?pf reaction and easily purified as hydrochloride. The single crystal X-ray study was used to confirm the stereo configuration of 13·HCl and 18·HCl. The protecting group could be easily removed by transfer hydrogenation, resulting in enantiomerically pure intermediate 3 as a d-tartarate. The overall yield for preparing YZJ-1139(1) was significantly increased, and this cost-efficient process might be promising in future commercial productions.

Abstract Image

食欲素受体拮抗剂YZJ-1139立体异构体调控途径的研究
本文综述了食欲素受体拮抗剂YZJ-1139(1)的合成及工艺研究进展。YZJ-1139(1)含有3个手性中心的氮杂环降戊烷结构。用原来的工艺,可以用色谱法得到高纯度的中间体或原料药,收率相对较低。为了尽早去除不需要的立体异构体,采用Robinson-Sch ?Pf反应,易于提纯为盐酸。单晶x射线研究证实了13·HCl和18·HCl的立体构型。保护基团可以很容易地通过转移氢化去除,从而得到对映体纯的中间体3作为d-酒石酸酯。制备YZJ-1139(1)的总收率显著提高,该工艺具有成本效益,在未来的商业化生产中具有广阔的应用前景。
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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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