Elevating 1-tert-Butyl-3-ethylcarbodiimide (TBEC) as a Reagent for Sustainable Peptide Synthesis: Quality Assessment and Minimizing Racemization, Precipitation, and Radical-Induced Side Reactions by TBEC/Oxyma Couplings in an Environmentally Sensible Solvent

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2023-06-23 DOI:10.1021/acs.oprd.3c00120

Jan Pawlas*, Ji-Hyung Choi, Christoph von Bargen, Sheila Maibom-Thomsen, Jon H. Rasmussen and Olivier Ludemann-Hombourger,

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引用次数: 1

Abstract

The finding that the widely used peptide coupling reagents DIC and Oxyma form the toxic H-CN (McFarland, A. D. Org. Process Res. Dev. 2019, 23, 2099) has prompted studies aimed at H-CN minimization, attained, for example, by solvent engineering (Erny, M. Org. Process Res. Dev. 2020, 24, 1341) and by substituting DIC with TBEC (Manne, S. R. Org. Process Res. Dev. 2022, 26, 2894). Here, an integrated study of TBEC/Oxyma as peptide couplers is reported, focusing not only on the performance of TBEC in the couplings but also on its cost, hazards associated with its use, sustainability of the route of synthesis, the end of life strategies, as well as the potential impact of impurities in the reagent on the synthesis. TBEC/Oxyma-mediated peptide couplings in NBP/EtOAc (1:4) proceeded with minimal racemization, free of precipitation, and radical side reactions irrespective of TBEC quality. These results hold great promise for broad adoption of TBEC/Oxyma in suitable green media as a coupling strategy for sustainable peptide synthesis from an R&D lab to a manufacturing plant.

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提升1-叔丁基-3-乙基碳二亚胺(TBEC)作为可持续合成多肽的试剂:质量评估和减少外消旋、沉淀和自由基诱导的副反应在环境敏感溶剂中的应用

广泛使用的肽偶联试剂DIC和Oxyma形成有毒的H-CN (McFarland, a.d. Org)。Process Res. Dev. 2019, 23,2099)促进了旨在最小化H-CN的研究，例如，通过溶剂工程(Erny, M. Org.)实现。化学工程学报，2014,32(1):1 - 4。工艺研究与开发，2022,26,2894)。本文对TBEC/Oxyma作为多肽偶联剂进行了综合研究，不仅关注了TBEC在偶联中的性能，还关注了其成本、使用危害、合成路线的可持续性、生命终止策略以及试剂中杂质对合成的潜在影响。与TBEC质量无关，NBP/EtOAc(1:4)中TBEC/氧介导的肽偶联发生了最小的外消旋、无沉淀和自由基副反应。这些结果为TBEC/Oxyma在合适的绿色介质中的广泛采用提供了巨大的希望，作为从研发实验室到制造工厂的可持续肽合成的耦合策略。

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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.