Reaction of Irbesartan with Nitrous Acid Produces Irbesartan Oxime Derivatives, rather than N-Nitrosoirbesartan,Organic Process Research & Development

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Reaction of Irbesartan with Nitrous Acid Produces Irbesartan Oxime Derivatives, rather than N-Nitrosoirbesartan
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2022-03-21 , DOI: 10.1021/acs.oprd.1c00494
Jinsheng Lin ₁ , Qiang Zhou ₁ , Ru Jia ₁ , Wentao Liu ₁ , Huacui Hou ₁ , Jian Ma ₁ , Dan Li ₁ , Nuo Chen ₁ , Wenbin Chen ₁ , Jian Ye ₁ , Wenping Hu ₁ , Wenquan Zhu ₁ , Min Li _{1,

2}

Affiliation

In October 2021, a number of batches of irbesartan and irbesartan hydrochlorothiazide finished products were recalled from the US market, due to the presence of an unacceptable level of the probably carcinogenic nitrosamine N-nitrosoirbesartan. Nevertheless, there is no revealing of the exact structure of this hypothetical N-nitrosoirbesartan. In the current study, we performed a set of 10 reactions of irbesartan with nitrous acid under various conditions and found no trace of this hypothetical N-nitrosoirbesartan by a sensitive and accurate liquid chromatography–mass spectrometry (LC–MS) method with a limit of detection (LOD) of 30 ppb. With the use of LC-photodiode-array (PDA)/UV-high-resolution MSⁿ and one-dimensional (1D)/two-dimensional (2D) nuclear magnetic resonance (NMR) spectroscopy, the reaction products formed are found to be the two isomeric oxime derivatives of irbesartan, with the Z-isomer as the predominant product. Furthermore, no trace of this hypothetical N-nitrosoirbesartan can be detected in representative commercial batches of irbesartan. Despite the fact that in silico evaluation suggests that the two irbesartan oximes may be controlled as regular impurities, analysis of representative irbesartan commercial batches by the LC–MS method indicates that the oximes are not detected (LOD: 30 ppb).

中文翻译：

厄贝沙坦与亚硝酸反应产生厄贝沙坦肟衍生物，而不是 N-亚硝基厄贝沙坦

2021年10月，由于可能致癌的亚硝胺N-亚硝基厄贝沙坦含量超标，多批次厄贝沙坦和厄贝沙坦氢氯噻嗪成品被美国市场召回。然而，没有揭示这种假设的N-亚硝基厄贝沙坦的确切结构。在目前的研究中，我们在不同条件下进行了一组 10 次厄贝沙坦与亚硝酸的反应，通过灵敏且准确的液相色谱-质谱 (LC-MS) 方法，没有发现这种假设的N-亚硝基厄贝沙坦的踪迹，限制为检测 (LOD) 为 30 ppb。使用 LC 光电二极管阵列 (PDA)/UV 高分辨率 MS ⁿ和一维（1D）/二维（2D）核磁共振（NMR）光谱，发现形成的反应产物是厄贝沙坦的两种异构肟衍生物，Z-异构体是主要产物。此外，在具有代表性的商业批次厄贝沙坦中没有检测到这种假设的N-亚硝基厄贝沙坦的踪迹。尽管计算机评估表明两种厄贝沙坦肟可以作为常规杂质进行控制，但通过 LC-MS 方法对代表性厄贝沙坦商业批次的分析表明未检测到肟（LOD：30 ppb）。

更新日期：2022-03-21

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