Synthesis of Nitroso Derivatives of Dihydropyridine Calcium Channel Blockers

IF 3.5 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2025-07-07 DOI:10.1021/acs.oprd.5c00153

Hui Liu*, Shixiang Zeng, Yujin Li and Zhiping Liu,

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Abstract

Regulatory authorities issued guidance on acceptable intake limits for nitrosoamine drug substance-related impurities. However, the formation of these potential nitrosamine contaminants in the dihydropyridine class of drugs has not been clearly established. In this work, the nitrosation of six dihydropyridine calcium channel blockers was investigated under a set of conditions. The nitrosation products were isolated and characterized by MS, NMR, and XRD. The results show that nitrosation occurred on the carbon atom instead of the nitrogen atom. Nifedipine exhibited the highest reactivity via oxidative aromatization and reduction to produce a C-nitroso compound. Treatment with nitrite in either 1 M hydrochloric acid or 30% acetic acid resulted mainly in pyridine products via oxidation. In contrast, the other dihydropyridine derivatives studied generated C-nitrosated products in addition to aromatized products upon treatment with butyl nitrite. The findings provide direct evidence to rule out the possibility of N-nitroso impurities being present in the dihydropyridine class of drug substances and products.

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二氢吡啶类钙通道阻滞剂亚硝基衍生物的合成

监管机构发布了亚硝基胺类药物相关杂质的可接受摄入量限制指南。然而，在二氢吡啶类药物中这些潜在亚硝胺污染物的形成尚未明确确定。本文研究了六种二氢吡啶类钙通道阻滞剂在一定条件下的亚硝化反应。对亚硝化产物进行了分离，并用MS、NMR和XRD对其进行了表征。结果表明，亚硝化反应发生在碳原子上，而不是氮原子上。硝苯地平通过氧化芳构化和还原生成c -亚硝基化合物的反应活性最高。在1 M盐酸和30%乙酸中，亚硝酸盐主要通过氧化生成吡啶产物。相比之下，研究的其他二氢吡啶衍生物在与亚硝酸盐丁酯处理后除了生成芳构化产物外，还生成了c -亚硝化产物。该发现提供了直接证据，排除了在二氢吡啶类药物物质和产品中存在n -亚硝基杂质的可能性。

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来源期刊

Organic Process Research & Development 化学-应用化学

CiteScore

6.90

自引率

14.70%

发文量

251

审稿时长

2 months

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.