(117d) A Scalable Continuous Reaction and Isolation Process for the Production of Sulfonyl Chloride Pharmaceutical Intermediates

Chlorosulfonic acid is essential for many pharmaceutical processes due to its ability to selectively chlorosulfonate aryl rings via an S_E2 mechanism (1). The chlorosulfonates are precursors to a wide range of biologically active molecules including sulfonylureas (2) and sulfonamides (3). The hazardous and corrosive nature of chlorosulfonic acid is challenging to address particularly during scale up for an industrial manufacturing process (1). The approach taken to address these challenges was to perform this reaction in two consecutive continuous stirred tank reactors followed by a continuous isolation. The implementation of continuous manufacturing can be advantageous to improve the safety, speed, product quality, and environmental footprint of challenging reactions (4). The safety advantages of transitioning this reaction to continuous manufacturing include a reduced amount of heated chlorosulfonic acid, the gradual release of toxic gases, and limited operator exposure. The transition to a continuous isolation step can greatly improve space-time yield as the slow addition of the final product mixture to the isolation vessel was determined to be an essential parameter for maintaining the critical quality attributes.

Following the development of preliminary reaction and quenching conditions, multiple 100-g scale flow experiments were performed using two continuously stirred round bottom flasks, each with a one hour mean residence time. Peristaltic pumps were used with a combination of C-Flex and PTFE tubing to transfer the reaction mixture between each vessel. The initial smaller scale flow runs revealed a need for process monitoring of CSTR levels so that flow rates could be adjusted as needed. Mettler Toledo scales were connected to a Python terminal via a serial port connection and a custom script was implemented so that changes in relative levels of the starting material and each round bottom could be detected and recorded in real time. The isolation step was performed with periodic rapid pumping from the quenching vessel into the filtration step to prevent excessive solid product accumulation.

A 500-g continuous manufacturing run was next performed with a 20-L jacketed reactor used for the precipitation step. A high-purity sulfonyl chloride product was obtained in moderate yield as determined by HPLC assay, ¹H NMR, and LCMS. Process monitoring data from the Python script revealed that the increased flow rate of the larger scale manufacturing run led to problems with C-Flex tubing compatibility and to subsequent variable flow rates and skewed residence times. Peristaltic pump heads for PTFE tubing were therefore purchased and implemented for all future flow experiments. Further batch-scale chemistry development elucidated that a higher number of equivalents of chlorosulfonic acid was needed to react with the sulfonic acid intermediate and that the initial work-up should be done at sub-ambient conditions. In order to improve green chemistry metrics, experiments were conducted minimizing the amount of water used during the isolation step. Lastly, the recommended process improvements were implemented in 100-g scale and 500-g scale continuous manufacturing runs.

Literature Cited

1. Cremlyn, R.J., “Chlorosulfonic Acid: A Versatile Reagent,” Royal Society of Chemistry, Cambridge, UK (2002).
2. Sen S., Ruchika, Kumar D., Easwari T.S., and S. Gohri, “Therapeutic Aspects of Sulfonylureas: A Brief Review,” Journal of Chemical and Pharmaceutical Research, 8 (12), pp. 121-130 (Dec. 2016).
3. Kolaczek, A., Fusiarz, I., Lawecka, J., and D. Branowska, “Biological Activity and Synthesis of Sulfonamide Derivatives: A Brief Review,” CHEMIK, 68 (7), pp. 620-628 (2014).
4. Baumann, M., Moody, T.S., Smyth, M., and S. Wharry, “A Perspective on Continuous Flow Chemistry in the Pharmaceutical Industry,” Process Res. Dev., 24 (10), pp. 1802–1813 (2020).