(149b) Crystallization-Based Integrated Process for the Resolution of a Pharmaceutically Relevant Intermediate

2,6-Pipecoloxilidide
(PPX) is an important intermediate for the synthesis of mepivacaine,
ropivacaine and bupivacaine,
which are frequently used local anesthetics of the amide type for several
purposes in medicine^[1]. Based on its chiral nature, an
enantioseparation of PPX is needed to exclude additional negative side effects
from the counter-enantiomer. By
combining three different techniques, chromatography, enantioselective crystallization
and racemization, an improved process with a higher yield was achieved in
comparison to the use of a single full-separation process. All 3 unit
operations were executed within a jointly used solvent system with full
recycling (counter-enantiomer of PPX and solvents) including a minimum
requirement of solvent exchanges / removals. The target molecule was obtained
with an enantiopurity of >99.5% in multi-gram scale.

Within this contribution the design of the
integrated process is presented with a focus on the final enantioselective
crystallization process. The relevant physical chemical properties of PPX are
presented, e.g. binary and ternary phase diagrams, polymorphism study, and
finally the successful design of an effective crystallization processes on
industrial scale.

 [1]      Kleemann, A.; Engel, J.; Kutscher,
B.; Reichert, D. Pharmaceutical
Substances -Synthesis, Patents and Applications of the most relevant APIs, 5th ed.; Georg Thieme Verlag KG:
Stuttgart, New York, 2009.