The development of a ruthenium-catalyzed continuous flow ester hydrogenation using hydrogen (H2) gas is reported. The reaction was utilized for the reduction of an important precursor in the synthesis of abediterol, a β2-adrenoceptor agonist that has undergone phase IIa clinical trials for the treatment of asthma and chronic obstructive pulmonary disorder. The reaction was investigated within a batch autoclave by using a design of experiments (DoE) approach to identify important parameter effects. The optimized flow process was successfully operated over 6 h with inline benchtop 19F NMR spectroscopy for reaction monitoring. The protocol is shown to be high yielding (98% yield, 3.7 g h−1) with very low catalyst loading (0.065 mol%). The environmental impact of the Ru-catalyzed hydrogenation was assessed and compared to an existing stoichiometric lithium aluminum hydride (LAH) reduction and sodium borohydride (NaBH4) reduction. The process mass intensity (PMI) for the Ru-catalyzed hydrogenation (14) compared favorably to a LAH reduction (52) and NaBH4 reduction (133).

• Centre for Continuous Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering (RCPE)
• University of Graz
• AstraZeneca

• Intermediate

1. 19F NMR spectroscopy
2. β2-adrenergic receptor agonist
3. Intermediate
4. lithium aluminum hydride (LAH) reduction
5. Research Article
6. Ru-catalyzed ester hydrogenation
7. sodium borohydride (NaBH4) reduction