High Yielding Continuous-Flow Synthesis of Norketamine

Abstract

A new continuous-flow process is presented for synthesis of the pharmaceutical intermediate norketamine ( 5 ). Our approach has been to take the well-established and industrially applied batch synthetic route to this promising antidepressant precursor and convert it to a telescoped multi-stage continuous-flow platform. This involves the α-bromination of a ketone, an imination/rearrangement sequence with liquid ammonia, and a thermally induced α-iminol rearrangement. Our approach is high yielding and provides several processing advantages including the reduction of many of the hazards conventionally associated with this route, particularly in the handling of liquid bromine, hydrogen bromide gas, and liquid ammonia. Each of these presents serious operational challenges in a batch process at scale.

Development of a continuous synthesis process for carbamazepine using validated in-line Raman spectroscopy and kinetic modelling for disturbance simulation

“…2,5 With the rising interest in the adoption of CM in the pharmaceutical industry, the continuous synthesis (CS) of a drug substance (DS) has also been increasing and can be an alternative means to batch synthesis and purification. [6][7][8][9][10][11][12][13] Quality by design, digital twin, and adaptive process control strategies are some examples in the development of CS within the pharmaceutical manufacturing. In 2021, Arden et al 14 elaborated that while adaptive, model-based controllers should be the next frontier within the pharmaceutical manufacturing sector, several fundamental areas to enable such platforms are lagging other industries.…”

Optimized Process and Quality Evaluation for Ketamine Hydrochloride

“…To support generic drug research and development, it is necessary to develop an efficient kilogram-scale process for producing ketamine hydrochloride. A previous study reported a three-stage continuous-flow process for the synthesis of norketamine . However, there are challenges associated with the continuous-flow bromination of Br 2 , and the amination of liquid ammonia is highly toxic and corrosive.…”

“…A previous study reported a threestage continuous-flow process for the synthesis of norketamine. 2 However, there are challenges associated with the continuous-flow bromination of Br 2 , and the amination of liquid ammonia is highly toxic and corrosive. As a result, the equipment requirements are more stringent.…”

An Automated Continuous Synthesis and Isolation for the Scalable Production of Aryl Sulfonyl Chlorides

“…Flow chemistry is being employed to improve the safety, speed, product quality, and environmental footprint of challenging reactions [ 22 , 23 , 24 ]. Broadly, the utilization of flow chemistry for API manufacturing is increasing significantly [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ], as encouraged by regulatory bodies [ 37 , 38 ]. Previous works have utilized flow chemistry to address the environmental and safety challenges associated with chlorosulfonation reactions [ 21 , 39 , 40 ].…”