New resolving bases for ibuprofen and mandelic acid: qualification by binary phase diagrams

New resolving bases for ibuprofen 1 and mandelic acid 2 were studied and qualified by their binary phase diagrams of the corresponding salts. It was shown that analysis of the binary phase diagrams gives a good prediction for a resolution process. A comparison of resolving bases revealed that (S)-phenylglycinol (S)-7 is the best resolving base for ibuprofen 1. By the same procedure, various resolving bases for mandelic acid 2 were studied. The known resolving base (S)-MBA 9 was found to be the best for this acid. © 1997 Elsevier Science Ltd. All rights reserved. I n t r o d u c t i o n Resolution of enantiomers is an important method for the industrial production of enantiopure compounds. The most frequently applied method is formation and selective crystallization of diastereomeric salts. The major problem of this approach is identifying a suitable resolving agent. Until now, no suitable method is available to predict a resolving agent for a given racemate. 1 The conditions required for an efficient resolution are: the diastereomeric salts consist of a mechanical mixture of crystals of the pure diastereomers (eutectic mixture); both salt pairs can be crystallized separately and have substantial differences in physico-chemical properties, especially solubilities. 2 Opt imum conditions (e.g. concentration, temperature) for a resolution process can be quantified by construction of the ternary (solubility) phase diagram. However, this requires a large amount of experimental data. It is a well known fact that binary (melting) phase diagrams are often a good approximation for ternary diagrams especially for selection and qualification of a resolving agent for a given substrate. 3,4 Thus, the efficiency of a resolution depends on the location of the eutectic. The formation or existence of a eutectic mixture, a primary condition for a resolution, can be determined. Moreover, the diagram allows calculation of the maximum yield (Rmax) and efficiency 5 (S). Starting from the racemic composition (x0.5) and going to the isolation of a pure diastereomer, the following equations can be used to calculate these parameters: 6 0.5 Xeu Rma~ = X 100% (Rm~x = 0 50%) (1) 1 Xeu 1 2Xeu S = k t = ~ ( S = 0 1 ) (2) 1 Xeu where x is the molar fraction of the less soluble diastereomer, Xeu the eutectic composition, k the chemical yield (k=2 for 100%) and t the optical purity (t=-I for 100% ee). A more successful resolution is expected when the diagram has a steeper slope, i.e. a larger difference between the melting points * Corresponding author. Email: zwanenb@sci .kun.nl