(83c) 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.