Variable Residence Time Reactor

Lee Proctor of Phoenix Chemicals presented a case study of the scale up a key intermediate in the manufacture of atorvastatin (LIPITOR) at the Novel Technologies Symposium in Manchester (3rd June 2003).

The Chemistry is shown below.

The E>cyanationreaction, which proceeds via the epoxides, is surprising low yielding when carried out under batch conditions.  Using a continuous process, which was optimised using the variable residence time (VRT) reactor and DOE approach, the yield could be improved from 50-55% (batch) to over 80% (after distillation) with a high purity and ee.  It was found that small amounts of water enhance the cyanation but also may cause hydrolysis of the product, hence the importance of controlling residence time.  Continuous pH control, coupled with continuous extraction of the product ensures a high yield.

The VRT reactor has the following advantages:

it facilitates rapid process screening and analysis using multivariated methods
it preserves true orthoganality between process flow and residence time, which is not always possible on other reactors.
Scale up from a lab reactor (capable of producing 22 kg/year) to a pilot (5 t/a) and production plant (40 t/a) was relatively straightforward.  Having the VRT capability on production could allow further optimisation of the process in the future and preserves flexibility for use in other processes.

The VRT was constructed using off-the-shelf components by chemists and engineers at Phoenix/p>.