Identification and Suppression of a dba-Derived Heck-Type Impurity in Negishi Coupling of 4-Iodopyridines

IF 2.3 4区化学 Q1 CHEMISTRY, ORGANIC

Asian Journal of Organic Chemistry Pub Date : 2026-10-12 DOI:10.1002/ajoc.70561

Yoshitaka Kitano, Mitsuhiro Arisawa

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引用次数: 0

Abstract

During Negishi coupling of 4-iodopyridine derivatives with aryl zinc reagents using tris(dibenzylideneacetone)dipalladium (Pd₂dba₃), a previously overlooked dba-derived Heck-type impurity was identified and structurally characterized. Although trace impurities are tightly regulated in the manufacture of active pharmaceutical ingredients (APIs), their suppression is highly desirable. Systematic screening of palladium sources, ligands, and solvents revealed that a catalyst system generated from Pd₂dba₃ and tricyclohexylphosphine (PCy₃) effectively suppresses the formation of the dba-derived impurity while maintaining high coupling efficiency. Under the optimized conditions, a variety of 4-arylpyridine derivatives were synthesized in good to excellent yields, and the level of the dba-derived impurity was reduced below the threshold specified in The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. This study provides a practical Negishi coupling protocol for the synthesis of pharmaceutically relevant 4-arylpyridines with minimized catalyst-derived impurities.

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4-碘吡啶根岸偶联中一种dba衍生heck型杂质的鉴定与抑制

在使用三（二苄基丙酮）双钯（Pd2dba3）对4-碘吡啶衍生物与芳基锌试剂进行根岸偶联的过程中，发现了一种以前被忽视的dba衍生的heck型杂质，并对其进行了结构表征。虽然微量杂质在活性药物成分（api）的生产中受到严格的管制，但它们的抑制是非常可取的。系统筛选钯源、配体和溶剂表明，由Pd2dba3和三环己基膦（PCy3）生成的催化剂体系有效抑制了dba衍生杂质的形成，同时保持了较高的偶联效率。在优化的条件下，合成了多种4-芳基吡啶衍生物，收率很高，dba衍生杂质的含量低于国际人用药品技术要求协调委员会（ICH）指南规定的阈值。本研究提供了一种实用的根岸偶联方案，用于合成具有药学相关性的4-芳基吡啶，并将催化剂衍生的杂质降至最低。

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

Asian Journal of Organic Chemistry CHEMISTRY, ORGANIC-

CiteScore

4.70

自引率

3.70%

发文量

372

期刊介绍： Organic chemistry is the fundamental science that stands at the heart of chemistry, biology, and materials science. Research in these areas is vigorous and truly international, with three major regions making almost equal contributions: America, Europe and Asia. Asia now has its own top international organic chemistry journal—the Asian Journal of Organic Chemistry (AsianJOC) The AsianJOC is designed to be a top-ranked international research journal and publishes primary research as well as critical secondary information from authors across the world. The journal covers organic chemistry in its entirety. Authors and readers come from academia, the chemical industry, and government laboratories.