The separation of enantiomers is of great interest to the pharmaceutical industry given that more than 50% of pharmaceutically active ingredients are chiral, and 9 of the top 10 drugs have chiral active ingredients. One particular enantiomer is usually preferred over the racemic mixture. In general, asymmetric synthesis and separation of enantiomers by crystallization techniques have become the methods of choice for the production of chiral active pharmaceutical ingredient at large scale. Development of a crystallization method for an enantiomeric excess (ee) enhancement should include these three steps: (1) determine the thermodynamically stable phase of the racemate; (2) obtain key solubility data; (3) design of the crystallization process.In order to guarantee that any of these two approaches afford a product with the required enantiomeric excess, analytical development is paramount. This used to be straightforwardly accessible with compounds containing a chromophore in the structure, but working with molecules without this ability, it used to be a challenging task. In the course of one of our recent drug discovery programs, chiral �-aminoalcohols 1a and 1b (figure-1) were identified as key pieces for one of the most advanced series.In this poster we report the synthesis and separation of both compounds using chiral resolution crystallization techniques, combined with a new chiral methodology that allows running an in-situ derivatization of the chiral aminoalcohol salts.

In-situ derivatization and fast LC-MS monitoring of chiral aminoalcohol salts: New paradigm in chiral resolution crystallization approaches

246th National Meeting (2013)

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