Development and Scale-Up of a Continuous, High-Pressure, Asymmetric Hydrogenation Reaction, Workup, and Isolation

A fully continuous process including an asymmetric hydrogenation reaction operating at 70 bar hydrogen, aqueous extraction, and crystallization was designed, developed, and demonstrated at pilot scale. This paper highlights safety, quality, and throughput advantages of the continuous reaction and separations unit operations. Production of 144 kg of product was accomplished in laboratory fume hoods and a laboratory hydrogenation bunker over two continuous campaigns. Maximum continuous flow vessel size in the lab hoods was 22 L glassware, and maximum plug flow tube reactor (PFR) size in the bunker was 73 L. The main safety advantages of running the hydrogenation reaction continuous rather than batch were that the flow reactor was smaller for the same throughput and, more importantly, the tubular hydrogenation reactor ran 95% liquid filled at steady state. Therefore, the amount of hydrogen in the reactor at any one time was less than that of batch. A two-stage mixed suspension mixed product removal (MSMPR) cascade was used for continuous crystallization. Impurity rejection by continuous crystallization was superior to that by batch because scalable residence time and steady-state supersaturation enabled robust and repeatable control of enantiomer rejection in a kinetic regime, although this is a nonstandard approach, debatable as an impurity control strategy. The fully continuous wet-end process running in a laboratory infrastructure achieved the same weekly throughput that would be expected from traditional batch processing in a plant module with 400 L vessels.