Investigation of the Stereoselective Synthesis of the Indane Dimer PH46A, a New Potential Anti-inflammatory Agent

• Published in: Organic process research & development Vol. 21; no. 12; pp. 1972 - 1979
• Main Authors: Cumming, Graham R, Zhang, Tao, Scalabrino, Gaia, Frankish, Neil, Sheridan, Helen
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 15.12.2017
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.7b00258

PH46A, belonging to a class of 1,2-Indane dimers, has been developed by our research group as a potential therapeutic agent for the treatment of inflammatory and autoimmune diseases. The initial synthetic route to PH46A gave a low overall yield, due in large part to the generation of undesired diastereoisomer 5 and the unwanted enantiomer (R,R)-8 during the synthesis. The aim of this work was to carry out a comprehensive investigation into the stereoselective synthesis of PH46A. Significant progress was made on the ketone reduction step, where the use of triisobutylaluminum [TiBA, Al­(iBu)3] afforded high selectivity for the target diastereoisomer (rac)-6, compared to the unfavorable ratio obtained using a previous process. This enabled a multikilo scale synthesis of PH46A in a GMP environment. Further, a brief proof-of-principle investigation was carried out using an achiral phase transfer catalyst (PTC) for alkylation at the methine carbon of the parent indanone.