Development Of An Asymmetric Route For Large-Scale Synthesis Of A Glucocorticoid Agonist

Glucocorticoids are one of the most used classes of anti-inflammatory drugs. However, their chronic use causes deleterious side effects such as GC-induced osteoporosis. In an effort to discover non-steroidal anti-inflammatory agents, a trifluoromethylcarbinol and azaindazole containing glucocorticoid receptor agonist was identified from our Discovery Program and advanced as a development candidate. The evolution of the synthesis of this candidate from early discovery to multi-kilogram synthesis is described. The ultimate pilot plant route was based on a highly efficient synthesis of the trifluoromethylketone intermediate via an enolization/bromine magnesium exchange/electrophile trapping sequence and the discovery of a new asymmetric propargylation reaction of the resultant trifluoromethylketone.