Design, Development, and Scale-Up of a Stereoselective Synthesis of (1R,3R)-3-(3,5-Bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane Carboxylic Acid

IF 3.5 3区化学 Q2 CHEMISTRY, APPLIED Organic Process Research & Development Pub Date : 2024-12-20 DOI:10.1021/acs.oprd.4c00425

Pablo J. Cabrera, Fangzheng Li, Nakyen Choy, Tay Rosenthal, Steffen Good, Jeffrey Nissen, Avery Sader

引用次数: 0

Abstract

This report describes the design, development, and scale-up of a stereoselective synthesis of (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane carboxylic acid (1), a key intermediate toward the synthesis of a promising developmental agrochemical. The synthesis features d-mannitol as a sustainable chiral pool starting material, a double Heck coupling reaction, and the invention of diastereoselective dichlorocyclopropanation. Details disclosed include the route design, development of enabling steps, and learnings from a kilogram-scale campaign. The nine-step route was used to produce 1.5 kg of (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane carboxylic acid in 13% overall yield, 97.8% purity, and excellent enantiopurity (>99.5% ee).

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立体选择性合成(1R,3R)-3-（3,5-二（三氟甲基）苯基）-2,2-二氯环丙烷羧酸的设计、开发和放大

本报告介绍了(1R,3R)-3-(3,5-双(三氟甲基)苯基)-2,2-二氯环丙烷羧酸 (1) 的立体选择性合成的设计、开发和放大，该合成是合成一种具有发展前景的农用化学品的关键中间体。该合成以 d-mannitol 作为可持续的手性池起始原料，采用双 Heck 偶联反应，并发明了非对映选择性二氯环丙烷化反应。所披露的细节包括路线设计、使能步骤的开发以及从公斤级实验中汲取的经验。采用该九步路线生产出了 1.5 千克(1R,3R)-3-(3,5-双(三氟甲基)苯基)-2,2-二氯环丙烷羧酸，总收率为 13%，纯度为 97.8%，对映体纯度极佳 (>99.5%ee)。

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.