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

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

Conversion of a Benzofuran Ester to an Amide through an Enamine Lactone Pathway: Synthesis of HCV Polymerase Inhibitor GSK852A

HCV NS5B polymerase inhibitor GSK852A (<b>1</b>) was synthesized in only five steps from ethyl 4-fluorobenzoylacetate (<b>3</b>) in 46% overall yield. Key to the efficient route was the synthesis of the highly functionalized benzofuran core <b>15</b> from the β-keto ester in one pot and the efficient conversion of ester <b>6</b> to amide <b>19</b> via enamine lactone <b>22</b>. Serendipitous events led to identification of the isolable enamine lactone intermediate <b>22</b>. Single crystal X-ray diffraction and NMR studies supported the intramolecular hydrogen bond shown in enamine lactone <b>22</b>. The hydrogen bond was considered an enabler in the proposed pathway from ester <b>6</b> to enamine lactone <b>22</b> and its rearrangement to amide <b>19</b>. GSK852A (<b>1</b>) was obtained after reductive amination and mesylation with conditions amenable to the presence of the boronic acid moiety which was considered important for the desirable pharmacokinetics of <b>1</b>. The overall yield of 46% in five steps was a significant improvement to the previous synthesis from the same β-keto ester in 5% yield over 13 steps