Synthesis of ketamine from a nontoxic procedure: a new and efficient route

Abstract

Ketamine [2-(2-chlorophenyl)-2-methylamino-cyclohexan-1-one] has been used in both veterinary and human medicine. In this research, a new and efficient protocol has been developed for the synthesis of ketamine, by using hydroxy ketone intermediate. Synthesis of this drug has been done in five steps. At first, the cyclohexanone was made to react with 2-chlorophenyl magnesium bromide reagent followed by dehydration in the presence of an acidic ionic liquid, 1-methyl-3-[2-(dimethyl-4-sulfobutyl-ammonium) ethane] imidazolium hydrogen sulfate to obtain 1-(2-chlorophenyl)-cyclohexene. The oxidation of the synthesized alkene by potassium permanganate gave corresponding hydroxy ketone intermediate. The imination of this intermediate by methyl amine and finally the rearrangement of the obtained imine at elevated temperature resulted in the synthesis of ketamine. All of the intermediates and the product were characterized by 1H-NMR and IR spectroscopies. No need to use toxic bromine (which is used in most of the reported procedures for the synthesis of ketamine), high reaction yields and use of commercially available and safe materials and no need to use corrosive acids in the dehydration step are some of the advantages of this procedure over the common reported ones for the snthesis of ketamine. An efficient five-step protocol for the synthesis of ketamine was developed. Cyclohexanone reacted with 2-chlorophenyl magnesium bromide, followed by dehydration with acidic ionic liquid. Oxidation of the alkene gave corresponding hydroxy ketone intermediate. The imination of this intermediate and rearrangement of the obtained imine finally produced ketamine.