(470c) Reactor Design for Continuous Synthesis of Pharmaceutical Intermediates: Correlation of Computational Fluid Dynamics and Design of Experiment Approaches

Authors: 
Roper, T. D., Virginia Commonwealth University
Bortner, M. J., Virginia Polytechnic Institute and State University
Armstrong, C., Virginia Commonwealth University
Pritchard, C., Virginia Polytechnic Institute and State University
Ibrahim, M., Virginia Commonwealth University
Cook, D., Virginia Commonwealth University
Desai, B., Virginia Commonwealth University
Chen, Y., Virginia Commonwealth University
Marquardt, B., MarqMetrix
Whitham, P., University of Washington
Zoueu, T., Institut National Polytechnique Félix HOUPHOUËT

Reactor design principals as applied to the continuous
production of pharmaceutical intermediates are important due to the increasing
need to control processes and reduce costs. 
The Bill and Melinda Gates Foundation is dedicated to the reduction of
costs of critical AIDS treatments for the developing world.  Investigations into the cost reduction of the
integrase inhibitor, dolutegravir, have encouraged
the exploration of continuous reactor design and optimization in the conversion
of keto-ester 1 into intermediate enamine-ester 3. Thermodynamic and kinetic studies of
the reaction have been used as inputs into comprehensive computational fluid
dynamic studies of the reaction in order to model mixing efficiency and extent
of reaction.  In a parallel approach,
design of experiment was used in order to study reactor design factors using
conversion as an output.  The result of
both approaches will be discussed along with attempts to develop a predictive
correlation for the production of this important intermediate in the dolutegravir synthesis.