Understanding the mechanism of the formation of impurities in pharmaceutical intermediates and starting materials is crucial for a successful control strategy in the manufacturing of active pharmaceutical ingredients. This paper describes how amines containing residual dichloromethane can form substantial levels of formaldehyde during short-term storage. An investigation involving 22 different amines presents evidence underpinning the role of dichloromethane (DCM) in forming formaldehyde. Additionally, control experiments combined with existing knowledge on the reactivity of DCM with amine nucleophiles provide a mechanistic discussion on the generation of formaldehyde via known adducts from the reaction between amines, dichloromethane, and water. Finally, a case study involving a key intermediate of a drug candidate under investigation at Bristol Myers Squibb demonstrates the impact of residual DCM-derived formaldehyde in amine starting material on the formation of a daughter impurity during an amidation step.

中文翻译：

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残留二氯甲烷对胺类中的甲醛污染风险


了解药物中间体和起始材料中杂质形成的机制对于活性药物成分生产的成功控制策略至关重要。本文介绍了含有残留二氯甲烷的胺在短期储存过程中如何形成大量甲醛。一项涉及 22 种不同胺的调查提供了支持二氯甲烷 （DCM） 在形成甲醛中的作用的证据。此外，对照实验与 DCM 与亲胺试剂反应性的现有知识相结合，为胺、二氯甲烷和水之间的反应通过已知加合物生成甲醛提供了机理讨论。最后，一项涉及 Bristol Myers Squibb 正在研究的候选药物关键中间体的案例研究表明，胺起始材料中残留的 DCM 衍生甲醛对酰胺化步骤中子杂质形成的影响。