Available under a Creative Commons Attribution Non-Commercial Share Alike 4.0 International Licence
1.4 CHEMICAL SCIENCES, 1.6 BIOLOGICAL SCIENCES
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.
Cumming, G., Zhang, T., Scalabrino, G., Frankish, N. and Sheridan, H. (2017). Investigation of the Stereoselective Synthesis of the Indane Dimer PH46A, a New Potential Anti-inflammatory Agent. Journal of Organic Process Research & Development 21, pp.1972-1979. doi:10.1021/acs.oprd.7b00258
The Wellcome Trust UK, Enterprise Ireland