The development of a continuous flow process for asymmetric hydrogenation with a heterogenized molecular catalyst in a real industrial context is reported. The key asymmetric step in the synthesis of an API (active pharmaceutical ingredient) has been developed on a kilogram scale with constant high single-pass conversion (>95.0%) and enantioselectivity (>98.6% ee) through the asymmetric hydrogenation of the corresponding enamide. This performance was achieved using a commercially available chiral catalyst (Rh/(S,S)-EthylDuphos) immobilized on a solid support via strong interaction resulting from the requirement of electroneutrality. The factors affecting the long-term catalyst stability and enantioselectivity were identified using small-scale continuous flow setups. A dedicated automated software-controlled high-pressure pilot system with a small footprint was then built and the asymmetric hydrogenation on kilogram-scale was realized with a space time yield (STY) of up to 400 g L −1 h −1 at predefined conversion and enantiopurity levels. No catalyst leaching was detected in the virtually metalfree product stream, thereby eliminating costly and time-consuming downstream purification procedures. This straightforward approach permitted an easy and robust scale-up from gram to kilogram scale fully matching the pharmaceutical quality criteria for enantiopurity and low metal content, thus demonstrating the high versatility of fully integrated continuous flow molecular catalysis.
■ INTRODUCTIONContinuous processing has long been recognized as a promising method for process intensification in the chemical industry. Although continuous manufacturing is traditionally the realm of large scale production, it only recently has begun attracting increased attention from the pharmaceutical industry. 1−4 It is now clear that continuous flow processing can contribute to minimizing costs and intensifying production, 5 especially in the synthesis of complex molecules where constant quality standards are required and expensive catalyst and/or high pressure are needed. Small and flexible reactor systems can also allow the integration of multiple operations either consecutively or even simultaneously, 6 for example the incorporation of continuous workups and product extraction post-reaction. 7,8 Both upstream and downstream operations can be integrated into a single process unit rather than being separated in space or time, allowing a more efficient process. These technologies offer unique scale-up opportunities because of the improved control on mass and heat transfers and the possibility to scale out with relatively small reactor footprints. Such reactor systems can also be automated with online analysis allowing for faster optimization and better control of the overall performance. 9,10 The advantages of fully integrated continuous flow systems are best exemplified in the context of homogeneous catalysis where often additional purification steps are required to remove or potentially recycle an expensive organometallic catalyst. 6,11...
The first fully characterized phase in the Nb-Ru-B system, Nb 3 Ru 5 B 2 , was successfully synthesized as polycrystalline powders as well as single crystals and characterized by EDX analysis and X-ray diffraction methods. It is the first ternary phase of the type A 3 T 5 B 2 adopting the Ti 3 Co 5 B 2 structure type and containing a group eight transition metal at the T sites. According to COHP bonding analysis the * Priv.-Doz. Dr. B. P. T. Fokwa
The continuous flow asymmetric hydrogenation of (hetero)aromatic enamides has been realized using a Rh-Quinaphos catalyst immobilized in a supported ionic liquid phase (SILP) and employing supercritical CO 2 modified with toluene (modCO 2 ) as the mobile phase. This approach allows expansion of the scope of the original SILP/scCO 2 system to nonvolatile substrates with poor solubility in pure CO 2 . The potential of a SILP catalyst in combination with modCO 2 was demonstrated for an industrial case study using the continuous flow hydrogenation for the synthesis of a key intermediate of an active pharmaceutical ingredient (API) from AstraZeneca's portfolio. Toluene was selected as the most promising modifier, and the influence of the ratio of modifier to CO 2 was evaluated in detail. The catalyst support was found to play a major role for maintaining constant performance and the use of hydrophobic fluorous reverse-phase silica (FRP-SiO 2 ) instead of dehydroxylated silica strongly enhanced the long-term stability under continuous flow operation. Virtually a single enantiopure product was obtained over a prolonged time-on-stream of 90 h (quantitative single-pass conversion, ee > 99%) reaching a total turnover number of 10 300 at a space−time yield (STY) of 24 g L −1 h −1 . No metal contamination was detected in the product solutions, indicating effective catalyst retention.
The title compound is prepared by arc‐melting of the elements and characterized by single crystal XRD and LMTO scalar‐relativistic electronic structure calculations.
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