Development of Scalable Synthesis of Chiral Sultam via a Chiral Phosphoric Acid-Promoted tert-Butyl Carbamate Deprotection–Resolution Sequence or Diastereoselective Hydrogenation

IF 3.5 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2025-09-09 DOI:10.1021/acs.oprd.5c00263

Caroline A. Blakemore, Adam R. Brown, Todd W. Butler, Christopher W. am Ende, Nahian Khan, Sarai Lara-Boykin, Bryan Li, Guochun Ma, Javier Magano, Subham Mahapatra, Peter D. Morse, Giselle P. Reyes, Colin Rose, Neal W. Sach, Liam S. Sharninghausen, Jared Van Haitsma, Pengzhi Wang, Daniel W. Widlicka and Zebediah C. Girvin,

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Abstract

The discovery and process development for the synthesis of diastereopure sultam (1), a key chiral intermediate in route to a clinical candidate, are disclosed. Continuous route development to access (1) was required to satisfy both time and dynamic material needs during successive campaigns. Three distinct methods were developed to obtain diastereopure material. The first-generation process invoked time-intensive supercritical fluid chromatography (SFC) to access the diastereopure (2). Subsequent route development enabled a scalable, time-effective classical resolution approach that provided >20 kg of (1). Lastly, a Ruthenium-catalyzed diastereoselective hydrogenation approach was demonstrated on a hundred-gram scale and then coupled to the resolution technology to access (1), both reducing step count and improving overall yield relative to the resolution approach.

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通过手性磷酸促进氨基甲酸叔丁酯脱保护-分离序列或非对映选择性加氢可扩展合成手性苏坦的研究进展

本发明公开了合成非对透明苏坦(1)的发现和工艺发展，这是通往临床候选药物的关键手性中间体。为了满足连续战役期间的时间和动态物质需求，需要连续开发通往通道(1)的路线。开发了三种不同的方法来获得非纯材料。第一代工艺采用时间密集型超临界流体色谱法（SFC）来获取非均匀性(2)。随后的路线开发实现了一种可扩展的、时效性的经典分辨率方法，该方法可提供20kg的(1)。最后，在百克尺度上演示了钌催化非对映选择性加氢方法，然后与分解技术耦合得到(1)，相对于分解方法，既减少了步骤数，又提高了总收率。

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.