Impurity Dimethylcarbamoyl-OBt Detected in an API Induced by the Degradation of HBTU in DMF,Organic Process Research & Development

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Impurity Dimethylcarbamoyl-OBt Detected in an API Induced by the Degradation of HBTU in DMF
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2021-07-27 , DOI: 10.1021/acs.oprd.1c00168
Yi Yang ₁ , Lena Hansen ₁ , Jörgen Kjellgren Sjögren ₂ , Ileana Rodríguez León ₂ , Jean-Marie Receveur ₁ , Fabrizio Badalassi ₁

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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.

中文翻译：

在 DMF 中 HBTU 降解诱导的 API 中检测到杂质二甲基氨基甲酰基-OBt

在一批辉凌制药的肽活性药物成分 (API) 肽 Q 中检测到丰度为 0.09% 的非肽相关杂质。专门的模拟反应和与参考文献的比较表明，该杂质是由降解引起的在 HBTU 指导的肽酰胺化环化步骤中二甲基甲酰胺 (DMF) 溶液中的脲偶联试剂 HBTU。主题非肽相关杂质的结构已确认为 1-[((二甲基氨基)羰基]氧基)-1 H-苯并三唑或其异构体 1-(二甲基氨基甲酰基)-1 H -1,2,3-苯并三唑-3-ium-3-olate（本文均简称为二甲基氨基甲酰基-OBt）。也可以在N 中实现二甲基氨基甲酰基-OBt 的形成-甲基-2-吡咯烷酮（NMP）或乙腈（ACN）作为有机溶剂。这一发现与参与铀偶联试剂介导的酰胺化/酯化反应（如环化、侧链修饰和链段缩合）的无数肽和小分子的合成有关。在这种情况下，尤其是那些在 DMF、NMP 或 ACN 中进行主题 HBTU 介导的反应作为整个合成过程的最后一步的那些，应考虑对 API 中二甲基氨基甲酰基-OBt 作为杂质的审查。

更新日期：2021-08-20

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