Development of a Safe, Efficient, and Scalable Process for the Synthesis of Midazolam Hydrochloride

We describe the development of a concise large-scale process for the synthesis of midazolam hydrochloride. The key processes include a novel one-pot reductive amination–deprotection–cyclization process between 2-aminobenzophenone and Boc-protected 1,3-diaminopropan-2-one, followed by an intermolecular cyclization and oxidative dehydrogenation reaction. Three routes were developed and optimized, and the third-generation process was chosen as the best one, which delivered midazolam hydrochloride with an overall yield of up to 26.5% and purity of 99.8% by four distinct intermediates and a salt-formation step. The quality of the target molecule fully complies with all pertinent ICH criteria. Compared to the literature routes, the total steps, overall yield, and process security have all been significantly improved.