Process Development toward a Key Fragment of the PCSK9 Inhibitor Enlicitide Decanoate

IF 3.5 3区化学 Q2 CHEMISTRY, APPLIED Organic Process Research & Development Pub Date : 2025-04-03 DOI:10.1021/acs.oprd.4c00504

Kai-Jiong Xiao, Yonggang Chen, Yingju Xu, Gao Shang, Lushi Tan, Fangzhou Xie, Chengqian Xiao, Yongpeng Yuan, Baoqiang Wan, Guiquan Liu, Jingjun Yin

引用次数: 0

Abstract

Here we report the development of a large-scale manufacturing process for the synthesis of the Northern Fragment of enlicitide decanoate (MK-0616), an orally bioavailable inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9). The key topics covered are (1) process development for the selective tryptophan allylation; (2) development of the one-pot process for two consecutive peptide coupling reactions; (3) process development for the one-pot cleavage of two N-tert-butyloxycarbonyl (N-Boc) groups and a tert-butyl ester; and (4) process development of the magnesium chloride (MgCl₂)-mediated selective macrolactamization. This optimized process was demonstrated to produce the key fragment at >150 kg scale per batch in the synthesis of enlicitide.

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PCSK9抑制剂烯酸酯关键片段的研究进展

在这里，我们报道了大规模生产工艺的发展，以合成enlicicitide decanoate （MK-0616）的北部片段，这是一种口服生物有效的蛋白转化酶枯草杆菌素/克辛9型（PCSK9）抑制剂。主要内容包括：(1)选择性色氨酸烯丙化的工艺发展；(2)开发了两个连续肽偶联反应的一锅工艺；(3)一锅裂解两个n -叔丁基氧羰基（N-Boc）基团和一个叔丁基酯的工艺开发；(4)氯化镁（MgCl2）介导的选择性大内酰胺化的工艺发展。结果表明，优化后的工艺能以每批150 kg的规模生产烯醛酸苷合成中的关键片段。

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来源期刊

Organic Process Research & Development 化学-应用化学

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.