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

Abstract

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.

Continuous Suzuki-Miyaura Reactions with Novel Ce-Sn-Pd Oxides and Integrated Crystallization as Continuous Downstream Protocol

“…The coupling of a chemical reaction in flow with a continuous purification is a step further in the development of completely continuous end-to-end manufacturing and has become more and more popular in recent years [9,19]. Probably the most wellknown example is the work by the MIT-Novartis Center for the end-to-end manufacturing of the API aliskiren hemifumarate [8].…”

Design of a Continuous Tubular Cooling Crystallizer for Process Development on Lab‐Scale

“…The dispersion model was fitted to experimental data [39,41,47] in order to determine the Bodenstein number Bo, which is defined by Eq. (9). Here, D ax denotes the axial dispersion coefficient.…”

“…While the manufacturing of those products is conventionally carried out in batch mode, continuous processing offers multiple advantages to improve product quality [2], cost efficiency [3], safety [4,5], and to reduce timeto-market [6]. In renowned research projects with the collaboration of both industry and academia innovative continuous production concepts have been successfully demonstrated [7][8][9]. Nevertheless, product and process development are usually carried out in batch mode which hinders a later shift to continuous operation [2].…”

Modulare chemische Reaktoren für die Prozessentwicklung und Produktion in kontinuierlichen Mehrzweckanlagen

“…2 ist eine Ü bersicht an möglichen Kombinationen der beteiligten Phasen in der Mikrokanal-oder Kapillarströ- [60]. Hier sind für den kontinuierlichen Betrieb nur wenige Anwendungen bekannt [61]. Noch weniger ist über vier-phasige Strömun-gen in Rohren oder Kanälen bekannt.…”