Investigation into an Unexpected Impurity: A Practical Approach to Process Development for the Addition of Grignard Reagents to Aldehydes Using Continuous Flow Synthesis,Organic Process Research & Development

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Investigation into an Unexpected Impurity: A Practical Approach to Process Development for the Addition of Grignard Reagents to Aldehydes Using Continuous Flow Synthesis
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2020-02-25 , DOI: 10.1021/acs.oprd.9b00515
Masahiro Hosoya ₁ , Shogo Nishijima ₁ , Noriyuki Kurose ₁

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This work presents a case study of process development using continuous flow synthesis. In developing a process for manufacturing drug substances in batch reactors, we unexpectedly obtained a significant amount of a trimerized byproduct on addition of MeMgBr to an aldehyde. Consideration of a plausible generation mechanism for the byproduct indicated that it arose from a reaction between the starting material and the Mg salt of the target product. This led us to try applying continuous flow synthesis to the process to shorten the time during which the starting material coexists with the Mg salt of the target product. This led to drastic suppression of the byproduct under very mild conditions and the establishment of a more robust process than that for batch reactors.

中文翻译：

意外杂质的研究：使用连续流合成法将格氏试剂添加到醛中的工艺开发实用方法

这项工作提出了使用连续流合成进行工艺开发的案例研究。在开发用于在间歇反应器中生产原料药的方法时，我们意外地将MeMgBr添加到醛中，获得了大量的三聚副产物。考虑到副产物的可能的生成机理表明，副产物是由起始原料与目标产物的Mg盐之间的反应引起的。这导致我们尝试将连续流合成应用于该过程，以缩短起始原料与目标产品的镁盐共存的时间。这导致在非常温和的条件下急剧抑制副产物，并建立了比间歇反应器更稳定的过程。

更新日期：2020-02-25

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