Building a Quaternary Stereogenic Center on Dihydroazaindole Carboxylic Acid through Scalable Process Development

Due to their unique properties, dihydroazaindoles are important fragments of active pharmaceutical ingredients and are of great interest in the pharmaceutical industry. In this manuscript, a scalable and economical process for the synthesis of a complex ( R )-2-(4-fluorophenyl)-2-methyl-2,3-dihydro-1 H -pyrrolo[2,3- b ]pyridine-5-carboxylic acid ( R )-1 on multikilogram scale is described. The synthesis was advanced through a second-generation synthetic strategy that did not rely on chiral Supercritical Fluid Chromatography separation, which was the highest cost driver. Through systematic screening of chemical resolution, we found that compound ( R )-1 can be isolated with high (>99%) enantiomeric excess. Furthermore, the mother liquor from the first resolution process was recyclable to racemize the S -isomer into ( R )-1 and ( S ) - 1 mixtures, which could be used for an additional chemical resolution process. The precious palladium (Pd) complexes could be reduced from 20 mol % to 1 mol %, and the long lead time building blocks were safely prepared in-house. Advanced intermediates were efficiently synthesized by reducing isolation steps through one-pot process development. The regulatory starting material compound ( R )-1·HCl was isolated with a high purity profile after di- p -toluoyl- d -tartaric acid salt breaking and HCl salt formation.