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

• Published in: Organic process research & development Vol. 26; no. 4; pp. 1318 - 1326
• Main Authors: Gao, Xuezhi, Xu, Jiajian, Liu, Chunfeng, Peng, Peng, Zhao, Chuanmeng, Chen, Mengke, Qiu, Pengcheng, Zhang, Fuli
• Format: Journal Article
• Language: English
• Published: American Chemical Society 15-04-2022
• Subjects: process; clonazepam; benzodiazepines; improved synthesis
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.2c00023

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.