Synthesis of ketamine from a nontoxic procedure: a new and efficient route
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Ó Indian Academy of Sciences Sadhana (0123456789().,-volV)FT3](0123456 789().,-volV)
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Synthesis of ketamine from a nontoxic procedure: a new and efficient route NEGAR ZEKRI, REZA FAREGHI-ALAMDARI* and BEHNAZ MOMENI-FARD Faculty of Chemistry and Chemical Engineering, Malek Ashtar University of Technology, 15875-1774, Tehran, Iran E-mail: [email protected]; [email protected] MS received 4 January 2020; revised 11 June 2020; accepted 12 June 2020
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. Keywords. Ketamine; anesthetic drug; acidic ionic liquid; nontoxic procedure; 2-hydroxycyclohexanone.
1. Introduction Ketamine (Figure 1) is an anesthetic and analgesic drug used in both human1–3 and veterinary4,5 medicines. It has also been used as antidepressant6 and in treating alcohol addiction7,8 and reflex sympathetic dystrophy.9,10 In 1970, it was used as a battlefield anesthetic.11 Many efforts have been made to synthesis this compound and its derivatives, due to its importance and aforementioned applications.12–17 In a most commonly used method (Stevens 1966), 2-chlorobenzonitrile reacts with cyclopentyl magnesium bromide reagent to synthesize ketone intermediate.18 Further, this intermediate was brominated with bromine, imination of the carbonyl functional group, followed by thermal rearrangement produced ketamine (Scheme 1). The Stevens method is based on the formation and thermal rearrangement of the imine
intermediate. This imine is synthesized from the bromination of 2-chlorophenyl cyclopentyl ketone with toxic bromine and then reaction with methylamine. Some of the drawbacks of these methods were use of toxic bromine, difficulty in thermal rearrangement step at a very high temperature with a low product yield. Further in 2012, the keta
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