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. 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.
 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:
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