(648a) Development of a Scalable Friedel-Crafts Acylation: A Mechanistic Approach

Albrecht, J., Bristol-Myers Squibb
Beutner, G., Bristol-Myers Squibb
Fanfair, D., Bristol-Myers Squibb
Fan, J., Bristol-Myers Squibb Company
Lawler, M., Bristol-Myers Squibb
Tripp, J., Bristol-Myers Squibb Co,
Sweeney, J., Bristol-Myers Squibb
Conlon, D., Bristol-Myers Squibb Company

The commercial route of a late-stage asset under development was initially performed via a Friedel-Crafts reaction with chloroacetyl chloride followed by an alkylation.  Due to the projected demand and manufacturing cost, the development of an efficient, scalable route was essential to the project.  The first generation process was successful in laboratory scale reactions; however, steady erosion in yield with increasing batch size was observed in production scale campaigns.  This scale dependence was found to result from polymerization of the input material.  Mechanistic studies of the chemistry, aided by in-line FTIR, identified the unfavorable equilibrium between intermediates.

Efforts to understand and mitigate the risk of polymerization lead the team to an alternate approach.  A second generation process was subsequently developed to replace the single lower yielding step with two robust high yielding reactions.  This new process was found to provide a higher overall yield to the isolated product, as demonstrated at the vendor.  This presentation will provide a case study on the challenges of the scale dependent first generation process and the mechanistic approach taken to identify and design the advantages of the second generation process.