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.
A Biginelli reaction of β-ketonitriles, aldehydes and urea in principle can yield 5-cyano substituted dihydropyrimidinones. Although potentially very useful, this substituted heterocycle is often difficult to synthesize via the three component reaction, presumably due to the lack of stability of β-ketonitriles. The present work describes the development of reaction conditions yielding the desired product. Interesting mechanistic observations have also been noted. Thirteen new compounds (derivatives) of 5-cyanodihydropyrimidin were synthesized.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.