Enabling the Scale-Up of a Key Asymmetric Hydrogenation Step in the Synthesis of an API Using Continuous Flow Solid-Supported Catalysis

Abstract

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...

Chiral catalysts immobilized on achiral polymers: effect of the polymer support on the performance of the catalyst

“…284 However, the commercially available Rh-(S,S)-EthylDuphos has been anchored efficiently via ionic interactions on phospho tungstic acid dispersed on the surface of aluminum oxide and the stability could be improved by combining a continuous flow process with an appropriate reactor design, allowing for the preparation of an active pharmaceutical ingredient in kilogram scale with excellent enantioselectivity. 285 The reactor set-up used suggests that the activation of release and catch strategies can be essential in this regard to limit the leaching and maintain the activity. Developing release and catch strategies is also important to implement the stability in systems based on MNPs (in particular PdNPs) supported on functional polymeric surfaces.…”

“…As has been mentioned above, flow setups have allowed the preparation of the desired final products in multigram 296 or even kilogram scale. 285 Takeda et al have shown that a polymer-supported dirhodium(II) complex could be applied under flow conditions for the enantioselective intermolecular cycloaddition of a diazodiketoester with styrene retaining the activity (78% yield) and enantioselectivity (99% ee) for 60 h on stream with only a small Rh leaching detected in the solution (2.1 ppm). 324 Some of the processes studied could be easily upscaled to produce 22 g of the desired product with a turnover number of 11 700.…”

Recent Advances in Continuous‐Flow Enantioselective Catalysis

“…Another report from Leitner′s group about a kilogram‐scale continuous‐flow process for the asymmetric hydrogenation of the corresponding enamide 14 has the same design philosophy . The named “Augustine approach” uses heteropolyacids, which are dispersed on a metal oxide surface and serve as anchors for cationic organometallic complexes.…”

Recent Progress in Continuous‐Flow Hydrogenation

“…The same design philosophy could be found in another report by the Leitner group. This report was related to a kilogram‐scale continuous‐flow process for the asymmetric hydrogenation of the enamide 8 . They called their design strategy “Augustine approach”; heteropolyacids were used in the strategy, which are dispersed on a metal‐oxide surface and serve as anchors for cationic organometallic complexes.…”