Synthesis and Optimization of Canagliflozin by Employing Quality by Design (QbD) Principles

Efforts toward a synthesis and process optimization of canagliflozin 1 are described. Canagliflozin synthesis was accomplished via purified open ring intermediate 12. The process was optimized by employing quality by design (QbD) methodologies, and a telescopic strategy was executed for the first three and last two steps in a total six-step sequence. Optimization of the Friedel Craft acylation reaction followed by Lewis acid mediated reductive elimination, n-BuLi mediated C-arylation, and reductive demethoxylation was performed to develop a robust process. These steps were found to be critical; therefore, critical process parameters (CPPs) were identified by employing design of experiment (DoE) methodology. In addition, control strategies for dealing with impurities are described.