(610a) Development and Utilization of a Flow Process to Cascade Unstable Intermediates to Efficiently Produce High Quality Product

In recent years, there has been a shift in API manufacturing from traditional batch methods to continuous operation. Operating continuously affords several benefits over batch, including cycle-time reduction, handling of unstable intermediates and products, enhanced analytical data, and ability to operate at increased temperature and pressure conditions not safely feasible in large batch operations. An end-to-end process, including reaction and work-up steps, is desirable to capitalize on all of these advantages. A two-step telescoped flow process directly coupled with two continuous extraction and separation platforms was developed and optimized.

The two-step chemical transformation first includes a reaction in a packed bed reactor (PBR), followed by a coupling reaction within a plug flow reactor (PFR). The former reaction was optimized by generating a kinetic model for both the reaction and the catalyst deactivation rate. The latter reaction was optimized by continuous DoE studies exploring residence time, reactor temperature, and reagent equivalents since the residence time was very short. The outlet of the PFR was fed directly into the first continuous extraction and separation unit to perform the first extraction. The aqueous outlet was sent to waste and the organic solution containing the API was first collected into a small receiving vessel, followed by being pumped continuously into the second extraction unit where it was washed again. The aqueous stream was again discarded and the organic stream containing the API was collected in a receiving vessel followed by final purification steps in batch. These continuous work-up steps were optimized based on solvent volumes, salt wash concentration, and Robatel motor speeds.

This process benefitted from continuous operation in several ways. In addition to cycle time reduction and quickly moving chemically unstable intermediates into the next reaction or processing step, it also allowed for a greatly increased safety profile across both reaction steps. The PBR utilized much less hydrogen and catalyst inside the reactor at any given time and the small size of the PFR allowed for enhanced heat and mass transfer to efficiently remove the exotherm from the reaction. The unstable nature of the final product solution was also mitigated since the process stream flowed continuously into the first two extractions within one minute. Post all continuous operations, the API in solution remained stable for two weeks, which permitted ample time for bulk collection of material to be isolated in batch.