(M1030-08-47) Kilo Scale Synthesis in Daisy Chained Flow Reactors

Purpose: 2R, 6R)-hydroxynorketamine is a pharmaceutical undergoing trials as an antidepressant. Stevens and coworkers developed an atom efficient synthesis route with norketamine as an intermediate, and attempts have been made to conduct the synthesis of norketamine in flow at low throughputs (1,2). Here the entire synthesis of norketamine from 2-chlorophenylcyclopentyl ketone at a higher throughput is presented in four daisy chained reactors, built mainly from readily available parts, including a novel solvent swap cascade. Converting the process from batch to continuous flow has allowed for (i) safer handling of hazardous reagents on scale up, (ii) access to process conditions difficult to achieve in batch and (iii) reduced time between stages to minimise the risk of impurity formation.

Methods: The daisy chained system is shown in Figure 1 and 2 consisting of a bromination, amination, solvent swap and thermal rearrangement. Reaction scheme in Figure 3. The bromination system was constructed out of PTFE and pyrex to avoid corrosion by the acidic reagents. The 2.4 M 2-chlorophenylcyclopentyl ketone in dichloromethane solution (2mL/min) and liquid bromine (1.1eq.) were fed by separate PTFE peristalitic pumps into the cooled pyrex continuous stirred tank reactor (CSTR). This was connected to a condenser and scrubber system to remove evolved acidic gases. The reactor was drained by a peristalic pump at a flow rate chosen to keep the fill level in the CSTR ~ 50 mL. The eluent was mixed with a 6 M sodium hydroxide quench stream before entering the quench reactor. The quench was a PTFE tube filled with glass beads for mixing, where HBr and bromine was neutralized by the NaOH. On exiting the quench reactor the stream passed through two Zaiput membrane separators in parallel to remove the aqueous waste from the bromoketone in DCM. The bromoketone entered a transfer vessel between the bromination and amination stages. The bromoketone in DCM solution was drawn from the transfer vessel by an HPLC pump into the pressurized amination system. The bromoketone stream was mixed with liquid ammonia (3.88g/min), dispensed by a chilled pump. The reaction mixture then entered a room temperature stainless steel coil. On exiting the coil, the stream was mixed with a quench feed of water from an HPLC pump before passing through a chilled quench tube to remove ammonia from the DCM phase. The quenched stream passed through two Zaiput membrane separators connected in parallel, separating the aqueous waste from the imine in DCM. The imine in DCM was fed directly into the solvent swap cascade. The solvent swap was peformed in a series of five heated pyrex vessels connected to the same heater unit set to 110 °C, to preferentially distil off DCM. Ethanol was pumped into the highest vessel to be preheated before overflowing at a fill volume of 95 mL into vessel 2, with the imine solution fed from the amination directly into vessel 2. DCM, ethanol and residual ammonia in the gas phase were removed from vessel 2 through a water cooled condenser. The liquid phase containing the imine in ethanol with decreasing proportions of DCM flowed through the cascade under gravity to vessel 5, with a fill level of around 50 mL in each vessel. The gas phase of each vessel was connected to the vessel above to equalize the pressure. The imine in ethanol was drawn from vessel 5 by the solvent swap outlet pump into the transfer vessel for the thermal rearrangement. The thermal rearrangement was conducted in a hastelloy tubular reactor with static mixers at 160 °C and 17 bar, fed from the transfer vessel by an HPLC pump at around 9.5 mL/min. The outlet was monitored by onstream IR with samples of eluent taken every hour for HPLC and NMR analysis.

Results: A demonstration run was performed with the daisy chained flow system run at steady state for 24 hours. Around 1.4kg of racemic norketamine was produced with a purity of >91% by HPLC, with purity remaining consistent throughout the run and an average production rate of 56g/hr norketamine. The design of the system allowed onstream maintenance such as changing the separator membranes to be conducted, with only one operator required to monitor the entire system.

Conclusion: A system of four daisy chained flow reactors was constructed for the synthesis of norketamine from 2-chlorocyclopentyl ketone and run for over 24 hours. The system was successfully used for synthesis of over 1 kg of norketamine at good purity, demonstrating that continuous flow approaches continue to present time, cost and quality benefits for small molecule syntheses.

References: 1. Hernando, M. V.; Moore, J. C.; Howie, R. A.; Castledine, R. A.; Bourne, S. L.; Jenkins, G. N.; Licence, P.; Poliakoff, M.; George, M. W. High Yielding Continuous-Flow Synthesis of Norketamine Org. Process Res. Dev. 2022, 26 (4), 1145–1151
2. Stevens, C. L.; Glenn, F. E.; Pillai, P. M. Hydroxy Ketone Rearrangements. II. Kinetics and Mechanism of the Thermal Rearrangements of Optically Active .alpha.-Hydroxy Ketones. Example of a Cyclic Three-Component Equilibrium. J. Am. Chem. Soc. 1973, 95, 6301−6308

Acknowledgements:The authors would like to thank Innovate UK for their funding.


Figure 1: Simplified process diagram for daisy chained synthesis of norketamine


Figure 2: Photographs of four daisy chained reactors


Figure 3: Scheme for norketamine synthesis