A Combined High-Throughput Screening and Reaction Profiling Approach toward Development of a Tandem Catalytic Hydrogenation for the Synthesis of Salbutamol

Abstract

A combined high-throughput screening and reaction profiling approach to the telescoping of two reductions in the synthesis of Salbutamol is described. Optimization studies revealed the beneficial effect of mildly acidic conditions, and the use of water as a cosolvent. Persistent formation of deoxygenated impurities using a Pd/C catalyst led to the initiation of reaction profiling studies, which revealed that the ketone intermediate formed after rapid debenzylation is the sole source of deoxygenated impurities, indicating that more rapid ketone hydrogenation should minimize this deoxygenation. A dual catalyst approach based on these insights has been developed, with both Pd/Pt and Ru/Pt catalyst systems as more selective than Pd-only systems. Based on reaction profiles that indicate the deoxygenation side reaction is first-order in the concentration of debenzylated ketone intermediate, Pt catalysts for rapid and selective ketone hydrogenation were paired with Pd and Ru catalysts known to perform selective debenzylation. Optimization of these dual catalyst processes led to conditions that were demonstrated on 20 g scale to prepare Salbutamol in 49% isolated yield after recrystallization.

The Evolution of High-Throughput Experimentation in Pharmaceutical Development and Perspectives on the Future

“…One of the most frequently screened organic transformations at GlaxoSmithKline is hydrogenation using heterogeneous catalysts, specifically the reduction of nitroarenes to anilines . Because of the molecular complexity of pharmaceutical intermediates and targets, a given substrate often has many potential sites of reduction; identification of active and chemoselective reaction conditions, including catalyst identity, solvent, and pH, is therefore paramount.…”

Synthesis of Chiral 1,2-Amino Alcohol-Containing Compounds Utilizing Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation of Unprotected α-Ketoamines

“…( R )-Phenylephrine is applied for the treatment of hypotension caused by shock or anesthesia . ( R )-Salbutamol is a β -2 adrenergic receptor agonist used to treat asthma, bronchitis, and COPD, as well as prevent exercise-induced bronchospasms, and ( R )-denopamine is a catecholamine neurotransmitter used to treat hemodynamic imbalances, low cardiac output, and hypotension (Figure ). The chiral 1,2-amino alcohol functionality is also present in a large number of natural products .…”

Dual Oxidation State Tandem Catalysis in the Palladium-Catalyzed Isomerization of Alkynyl Epoxides to Furans

“…The integration of multiple catalysts in a single reaction to mediate sequential chemical transformations, which is known as orthogonal tandem catalysis, has become widely recognized as a powerful synthetic tool . In the field of transition-metal catalysis, such processes typically use two different metals and, therefore, require careful control of reaction conditions to ensure compatibility of the two catalyst systems .…”