Continuous Nanofiltration and Recycle of an Asymmetric Ketone Hydrogenation Catalyst

Abstract

The continuous nanofiltration and recycle of a ruthenium diphosphine/diamine catalyst for the asymmetric hydrogenation of α-tetralone is demonstrated in a small scale flow system. Batch experiments show that the catalyst can be recycled under hydrogen pressure. Subsequent transient packed bed experiments serve to characterize the reaction and inform the design of the recycle experiments. The total internal volume of the resulting system is ∼50 mL, making this pilot useful for testing catalyst recyclability via nanofiltration during the early stages of process development. The high-pressure catalyst recycle system is run with an automatic control system to respond to membrane flux decline during the course of operation and enable long duration runs. In 24 h, we achieved a turnover number approaching 5000 for ruthenium diphosphine/ diamine catalyst used in the asymmetric hydrogenation of α-tetralone, demonstrating significant reuse of the catalyst since the substrate-to-catalyst ratio in the reactor approaches 250. During the 24 h period, the equivalent of 60 batch separation/recycle experiments is automatically performed. Ruthenium concentration in the product stream remains below 200 ppb. A slow decline in enantiomeric selectivity from 96% to 93% is observed during the run. ■ INTRODUCTIONHomogeneous organometallic catalysts are frequently applied in the production of fine chemicals, 1,2 but the transition metal center and ligands of these catalysts can pose separation problems downstream from the reactor. 3,4 Heavy metal contamination is strictly regulated in the pharmaceutical industry with often less than 5 ppm heavy metal content allowed in the final product. 4 Moreover, the cost of the metal and ligands provides motivation to separate catalysts from the product stream and preserve their activity. The pharmaceutical industry is finding new benefits of converting processes from batch to flow 5−7 that adds further incentive to recycling catalyst in flow. Although batch experiments are indispensable in early process development, the complications that could arise when recycling a catalyst in a flow system are best understood with a pilot flow system. Here, we demonstrate the design and operation of a small-scale (∼50 mL) pilot flow system to study the viability of nanofiltration as a separation technique for reusing a high pressure, second-generation Noyori asymmetric hydrogenation catalyst.Asymmetric hydrogenation of ketones is an important transformation in pharmaceutical synthesis. 8 For aryl ketones lacking an additional coordinating group, this transformation can use molecular hydrogen, an alcohol, or borane as the reductant. 9 The latter approach often uses Corey−Bakshi− Shibata (CBS) oxazaborolidine catalysts 10 that have been recycled previously using nanofiltration membranes. 11−13 In these cases, recycling generally increased turnover numbers (TONs) substantially while exhibiting some percent decline in enantiomeric excess (ee). Efficient ruthenium-containing organometallic catalysts have been developed...

Bifunctional homogeneous catalysts based on first row transition metals in asymmetric hydrogenation

“…From an industrial perspective [146,147], the development of highly active catalysts, i.e. high turnover number catalysts, at low costs and with possible applications in flow chemistry appear as the main goal to fulfil [148][149][150][151].…”

Recent Advances in Continuous‐Flow Enantioselective Catalysis

“…Jensen and co‐workers demonstrated a small‐scale (∼50 mL) pilot flow system to study the viability of nanofiltration. The asymmetric hydrogenation of α‐tetralone was studied by using a diphosphine/diamine catalyst 8 under high‐pressure hydrogen in a batch reactor . The optimized reaction time was 40 min, and a high selectivity (97 % ee ) was obtained.…”

Recent Progress in Continuous‐Flow Hydrogenation

“…This will cause too high cost in industrial production, so the recovery of homogeneous catalysts needs to be solved. In 2015, to study the viability of nanofiltration, Jensen and co‐workers demonstrated a small‐scale (∼50 mL) pilot flow system . To develop this flow system, they studied the first asymmetric hydrogenation of α‐tetralone using a diphosphine/diamine catalyst 3 under high pressure of hydrogen in a batch reactor.…”