Full Oxidation of an α-Arylated Isochromane: Development of a Two-Step Sequence as an Alternative to the Carcinogenic Jones Reagent and Application to the Manufacturing Process of Servier Phase II Clinical Candidate S44819

IF 3.5 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2025-07-29 DOI:10.1021/acs.oprd.5c00193

Jean-Francois Giffard, Sylvain Lemaitre, François Bariere, Anthony Craquelin, Christophe Hardouin, Chloé Copin* and Alexandre Jean*,

引用次数: 0

Abstract

An original two-step sequence allowing the full oxidation of an α-arylated isochromane is described. This method has been safely implemented to manufacture diketone 2 at the kg scale, a key intermediate in the manufacturing route of a phase II post stroke Servier clinical candidate S44819. This second-generation synthesis showcased better safety, replicability, and sustainability compared to the first-generation synthesis using an excess amount of Jones reagent. Further functionalization of 2 by cyclodehydration and condensation with hydrazine is also demonstrated, allowing the manufacture of clinical candidate S44819 at the kg scale.

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α-芳基化异色胺的完全氧化：两步序列的开发作为致癌琼斯试剂的替代品以及在施维雅II期临床候选物S44819的生产过程中的应用

原始的两步序列允许α-芳基化等色胺的完全氧化被描述。该方法已被安全地用于生产公斤级二酮2，二酮2是施维雅II期卒中后临床候选药物S44819生产路线中的关键中间体。与使用过量琼斯试剂的第一代合成相比，第二代合成显示出更好的安全性、可重复性和可持续性。通过环脱水和肼缩合进一步功能化2，可以在kg级生产临床候选物S44819。

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.