Henrique A. Esteves, Subha Mukherjee, James Chadwick, Jennifer Albaneze-Walker, Whitney Nikitczuk, Jonathan Marshall, Joanne Ly, Antonio Ramirez, Emanuele Petruzzella, Junhe Ma
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引用次数: 0
Abstract
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.
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.
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