Yi Yang*, Lena Hansen, Jörgen Kjellgren Sjögren, Ileana Rodríguez León, Jean-Marie Receveur, Fabrizio Badalassi*
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引用次数: 3
Abstract
A non-peptide-related impurity with an abundance of 0.09% was detected in a batch of Ferring Pharmaceuticals’ peptide active pharmaceutical ingredient (API) Peptide Q. A dedicated simulative reaction and comparison with the references revealed that the impurity was induced by the degradation of the uronium coupling reagent HBTU in the dimethylformamide (DMF) solution at the HBTU-directed peptide amidation cyclization step. The structure of the subject non-peptide-related impurity has been confirmed as 1-[((dimethylamino)carbonyl]oxy)-1H-benzotriazole or its isomer 1-(dimethylcarbamoyl)-1H-1,2,3-benzotriazol-3-ium-3-olate (both are abbreviated as dimethylcarbamoyl-OBt in this paper). The formation of dimethylcarbamoyl-OBt could also be realized in N-methyl-2-pyrrolidone (NMP) or acetonitrile (ACN) as the organic solvent. This finding is relevant to a myriad of syntheses of peptides and small molecules involved in uronium coupling reagent-mediated amidation/esterification reactions, such as cyclization, side-chain modification, and segment condensation. In such cases, particularly those that proceed with the subject HBTU-mediated reaction in DMF, NMP, or ACN as the very last step of the whole synthetic process, scrutiny of the API for dimethylcarbamoyl-OBt as an impurity should be considered.
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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