Development of an Improved Synthetic Process of Clonazepam by Preventing the Formation of a Trimeric Compound in the Presence of HCl,Organic Process Research & Development

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Development of an Improved Synthetic Process of Clonazepam by Preventing the Formation of a Trimeric Compound in the Presence of HCl
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2022-04-06 , DOI: 10.1021/acs.oprd.2c00023
Xuezhi Gao ₁ , Jiajian Xu ₁ , Chunfeng Liu ₁ , Peng Peng ₂ , Chuanmeng Zhao ₁ , Mengke Chen ₃ , Pengcheng Qiu ₁ , Fuli Zhang ₁

Affiliation

An improved synthesis process of clonazepam was developed with the key parameters determined. The trimer intermediate (9) of clonazepam prepared by using the one-pot method was isolated and identified for the first time. It was further confirmed that the depolymerization of 9 at high temperature was the rate-determining step for the preparation of clonazepam by using the one-pot method, which results in a low yield and purity. 2-Amino-N-(2-(2-chlorobenzoyl)-4-nitrophenyl) acetamide hydrochloride (7·HCl) was a key intermediate separated in the improved process, and the method of its synthesis with high purity to avoid the production of 9 was further reported. The improved process performed better in terms of efficiency and robustness. Besides, the high-performance liquid chromatography purity and total yield of clonazepam obtained by using the improved method were 99.98% and 57%, respectively.

中文翻译：

通过防止在 HCl 存在下形成三聚体化合物来改进氯硝西泮的合成工艺

开发了改进的氯硝西泮合成工艺，确定了关键参数。首次分离鉴定了采用一锅法制备的氯硝西泮三聚体中间体( 9 )。进一步证实，采用一锅法制备氯硝西泮时， 9在高温下解聚是定速步骤，收率低，纯度低。2-氨基-N- (2-(2-氯苯甲酰基)-4-硝基苯基)乙酰胺盐酸盐(7·HCl)是改进工艺中分离的关键中间体，其合成方法纯度高，避免产生9被进一步报道。改进的过程在效率和稳健性方面表现更好。此外，采用改进方法得到的氯硝西泮的高效液相色谱纯度和总收率分别为99.98%和57%。

更新日期：2022-04-06

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