Syntheses of Ketamine and Related Analogues: A Mini Review

Abstract

Ketamine [2-(2-chlorophenyl)-2-(methylamino)cyclohexanone] is a dissociative anaesthetic, first developed in 1963 by Parke-Davis. It finds widespread application in the treatment of battlefield injuries, and in emergency departments for use in children. In recent times the clinical interest in ketamine has increased due to the positive impact it has in treating depression and the rapid onset of its antidepressant effect. This review covers the synthetic effort towards ketamine and related analogues over the past 60 years to give readers an overview of past, current, and future research outlook pertaining to ketamine-like molecules.1 Introduction2 Early Work3 Synthesis3.1 Ketamine3.2 Norketamine3.3 Ketamine Analogues4 Future Outlook and Conclusion

New materials used for the synthesis of 2‐chlorophenyl cyclopentyl ketone seized from an illicit ketamine manufacturing unit

“…Subsequently, 2‐CPNCH was reacted with zinc powder and acetic acid to form norketamine. Through N ‐methylation of norketamine by using formaldehyde and sodium cyanoborohydride, ketamine was obtained [10, 11]. In addition, Yen et al.…”

“…The synthesis of ketamine has been studied for the purposes of medicine use or against illicit drug manufacturing [6][7][8][9][10][11][12][13][14][15][16]. In real life, two processes for syntheses of ketamine as indicated in Figure 1A,B were commonly found in illicit ketamine manufacturing units [6][7][8][9][10][11][12][13].…”

“…With an assistance of aluminum chloride used as a catalyst, and as well as a suitable operational condition, the yield (92%) of 2-chlorophenyl cyclopentyl ketone was achieved [9]. Through N-methylation of norketamine by using formaldehyde and sodium cyanoborohydride, ketamine was obtained [10,11]. In addition, Yen et al reported that 2-CPNCH reacted with zinc powder and formic acid to form norketamine.…”

“…On the other hand, Zhang et al. developed a new process for synthesis of ketamine in 2017, as depicted in Figure 1B(a) [10–12]. They used 2‐(2‐chlorophenyl)cyclohexan‐1‐one and ceric ammonium nitrate in the presence of copper(II) acetate to synthesize 2‐(2‐chlorophenyl)‐2‐nitrocyclohexanone (2‐CPNCH).…”

Process for (S)-Ketamine and (S)-Norketamine via Resolution Combined with Racemization

“…12,13 Stimulated by the stronger potency of (S)-ketamine for the NMDA receptor, many asymmetric synthetic routes have been reported over the years. 14 For example, the first asymmetric synthetic process of (S)-ketamine was reported by Kiyooka and colleagues. 15 The innovative procedure was conducted in 10 steps and (S)-ketamine was obtained in 21% yield (97% ee).…”