Development of Synthetic Routes, via a Tropinone Intermediate, to a Long-Acting Muscarinic Antagonist for the Treatment of Respiratory Disease

作者：Bream Robert N^*; Hayes Doug; Hulcoop David G; Whiteman Alexandra J

来源：Organic Process Research & Development, 2013, 17(4): 641-650.

DOI：10.1021/op3002933

This contribution describes the development of two synthetic routes to an investigational muscarinic antagonist for the treatment of chronic obstructive pulmonary disease. The first route used a starting material which was in plentiful supply within the GSK network and was used to make material for early clinical trials and safety assessment studies. Further investigations identified a second, potential long-term manufacturing route from commercially available building blocks, using substrate control to install the two stereocentres with excellent selectivity. A key step was a substrate-directed epoxide reduction which also gave rise to a minor byproduct through a skeletal rearrangement of the tropane ring. A deuterium-labeling experiment was carried out, which shed light on the origin of the byproduct, and also guided the improvement of reaction conditions.

• 出版日期2013-4