Aryl Addition Chemistry on Scale: A Case for the Application of Flow Chemistry to Minimize Unexpected Impurities

Aryl Addition Chemistry on Scale: A Case for the Application of Flow Chemistry to Minimize Unexpected Impurities

Nga Do, Michele T. Drexler*, Mark Olivier, Matt Weekly, and Jade Nelson 

Chemical Research & Development

Pfizer Global Research & Development

Groton, CT

During evaluation of the key aryl addition for scale of a pharmaceutical intermediate, two impurities were observed during the initial halogen-metal exchange reaction of the aryl bromide 1 with n-BuLi in 2-Me-THF solvent. These impurities (3 and 4) were observed at combined levels up to 50% (UPLC) area and were evident at all temperatures between -20°C and -78°C.  To minimize these impurities by providing more efficient heat and mass transfer for the system, flow chemistry was explored. This presentation will discuss the optimization of the halogen-metal exchange portion of the aryl addition chemistry and the application of a continuous reaction setup to provide a process for scaling the pharmaceutical intermediate.