Studies On The Synthetic Process For Medetomidine

Dexmedetomidine hydrochloride is a highly selective adrenergic alpha-2 receptor agonist.Clinically,it is mainly used for sedation and analgesia in the surgery of intensive care patients.It can also inhibit the stress response,and maintain the hemodynamic stability.From the viewpoint of process research and development,the discovery synthesis methods of medetomidine have many drawbacks,such as imine needing to be protected,low yield or use of expensive raw material.Besides,some of reaction conditions are harsh,and some dangerous reagents are used.So,it is need to improve the process for the preparation of some key intermediates.Herein,medetomidine was prepared from 1-(2,3-dimethylphenyl)ethanone via epoxidation,ring-opening,nucleophilic addition and rearrangement reaction.And the process for the synthesis of 1-(2,3-dimethylphenyl)ethyl ketone and key intermediates 2-(2,3-dimethylphenyl)-2-methyl were also studied.The following findings were addressed:(1)Two types of synthetic routes were proposed to prepare 1-(2,3-dimethylphenyl)ethanone.Route A,(2,3-dimethylphenyl)ethanone was prepared from 2,3-dimethyl-benzoic acid via acylation,substitution and hydrolysis reaction,and the overall yield of the three steps was 71.7%;Route B,(2,3-dimethylphenyl)ethanone was prepared from 2,3-dimethylaniline via diazotization,coupling and hydrolysis reaction,and the overall yield was 13.9%.(2)(2,3-dimethylphenyl)-2-methyl ethylene oxide was synthesized by the reaction of(CH3)3S+HSO4-with 1-(2,3-dimethylphenyl)ethanone.The epoxidation reaction was optimized via simplex optimization method,and the improved yield was 60.1%.The optimal process conditions are nKOH:n1-(2,3-dimethylphenyl)ethylketone= 18.43:1.00,nmethanol:n1-(2,3-dimethyl phenyl)ethyl ketone= 2.2:1.0,reaction under 39? for 7.45 h.(3)Medetomidine was prepared from 2-(2,3-dimethylphenyl)-2-methyl ethylene oxide via isomerization and van derstone reaction.The overall yield of the three steps was 44.1%.