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IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2025-03-06 DOI:10.1021/acs.oprd.4c00539

Thomas J. Beauchamp, Kevin P. Cole, Howard B. Broughton, David A. Coates, Graham Robert Cumming, Jose Eugenio de Diego, Kwame Frimpong, Julio Gutierrez, William Holloway, Ian Hotham, Spencer Jones, Talbi Kaoudi, Peter Lander, Adam M. Levinson, Yu Lu, Charles Lugar, Katherine Partridge, J. Craig Ruble, Sofiane Saouane, Narasimha Rao Ummaneni, H. George Vandeveer, Brian Watson

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引用次数: 0

摘要

描述了化学开发和生产足够数量的IL-17A抑制剂LY3509754以进行临床前毒理学研究。LY3509754是一种复杂的小分子，具有三个立体中心，这构成了合成的大部分挑战。立体选择性氢化和生物催化使所有的立体中心都能得到。最大的挑战是手性甲氧基甲基侧链的安装，特别是在合理的原料中形成sp2-sp3 C-C键和建立苯胺立体中心。鉴于之前在结构类似物方面的经验，我们能够使用混合方法进行合成，并从之前的努力中大规模地获得关键构建块。历史知识与快速的路线探索和开发相结合，使我们能够在大约7个月内发明可扩展的LY3509754路线，并提供430 g，以加速临床前毒理学研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Preclinical Toxicology Supply for a Complex API Enabled by Asymmetric Catalysis and Rapid Chemical Development: IL-17A Inhibitor LY3509754

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Preclinical Toxicology Supply for a Complex API Enabled by Asymmetric Catalysis and Rapid Chemical Development: IL-17A Inhibitor LY3509754

The chemical development and production of sufficient amounts of IL-17A inhibitor LY3509754 to enable preclinical toxicology studies is described. LY3509754 is a complex small molecule that features three stereocenters, which comprised much of the synthetic challenge. Stereoselective hydrogenation and biocatalysis enabled access to all stereocenters. The most significant challenge was installation of the chiral methoxymethyl side chain, specifically, formation of the sp2–sp3 C–C bond from reasonable raw materials and establishment of the benzylic amine stereocenter. Given prior experience with structural analogs, we were able to use a hybrid approach to the synthesis, with key building blocks being available on large-scale from the previous efforts. Historical knowledge combined with rapid route scouting and development allowed us to invent a scalable route to LY3509754 in about seven months and deliver 430 g to accelerate the preclinical toxicology studies.

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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.