Biocatalytic Synthesis of (R)-3-Aminotetrahydropyran through a Direct Transamination at Kilogram Scale

IF 3.5 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2025-07-01 DOI:10.1021/acs.oprd.5c00142

Hao Wu*, Xu Ma, Joe Ju Gao, Jose Santiago-Rivera, Clement Valentin, Jon C. Lorenz, Xiaole Shao, Jing Liu and Frederic Buono,

引用次数: 0

Abstract

Chiral amines with a low molecular weight are useful intermediates in the synthesis of active pharmaceutical ingredients (APIs). Here, we present a scalable one-step synthesis of (R)-3-aminotetrahydropyran through a straightforward biocatalytic transamination (vs previous five-step synthesis). The product was isolated by direct precipitation of salt without the need for organic solvent extraction or chromatography. The highlights of this process include differentiation of the two enantiotopic faces of the ketone substrate via a biocatalyst as well as providing a solution to isolate the reasonably volatile product directly from reaction mixture. The process was optimized using design of experiment (DoE) principle combined with enzyme kinetic studies and successfully demonstrated at kilogram scale, achieving 53% isolation yield and an enantiomeric ratio of 96:4 of the amine product.

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千克级直接转氨法生物催化合成(R)-3-氨基四氢吡喃

低分子量手性胺是合成活性药物成分的有效中间体。在这里，我们提出了一个可扩展的一步合成(R)-3-氨基四氢吡喃，通过直接的生物催化转氨法（与以前的五步合成相比）。该产品采用盐直接沉淀法分离，无需有机溶剂萃取或层析。该过程的亮点包括通过生物催化剂区分酮底物的两个对映面，以及提供直接从反应混合物中分离出合理挥发性产物的溶液。利用实验设计原理结合酶动力学研究对工艺进行了优化，并成功进行了公斤级验证，分离率为53%，胺产物对映体比为96:4。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.