(497d) Kinetics and Mechanistic Understanding of the Difluoromethyl Alkylation of Hydroxychromenone

During a chemical reaction involving the difluoromethylation of hydroxychromenone, a problematic dimer impurity was observed. In light of the short timeline to further optimize this chemistry, a fit-for-purpose kinetics analysis was performed.

Reaction kinetics and response surface simulations were used to understand the design space required in order to maintain this dimer impurity within acceptable levels. The kinetics assessment not only led to a mechanistic understanding of this transformation, but also led to design space understanding and potential for improvements. With these insights, this process was successfully prepared on kg scale in a manufacturing environment, and a proof-of-concept using a CSTR at laboratory scale was demonstrated.

The work presented here was sponsored by AbbVie. AbbVie contributed to the design, research, and interpretation of data, writing, reviewing, and approving the presentation. All authors are employees of AbbVie.