Dalmolen Jan, Tiemersma-Wegman Theodora D, Nieuwenhuijzen José W, van der Sluis Marcel, van Echten Erik, Vries Ton R, Kaptein Bernard, Broxterman Quirinius B, Kellogg Richard M
Department of Organic and Molecular Inorganic Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands.
Chemistry. 2005 Sep 19;11(19):5619-24. doi: 10.1002/chem.200500440.
The resolution of racemates through their diastereomeric salts can be positively affected by the addition of small amounts of suitable nucleation inhibitors. This discovery is a logical extension of "Dutch Resolution", in which equimolar amounts of resolving agents that are members of the same family (i.e., structurally related) are used. We conducted a systematic search for nucleation inhibitors of the resolving agent 1-phenylethylamine. A wide range of amines that bear possible family resemblances to 1-phenylethylamine was investigated. It was found that (R)-1-phenylbutylamine is a good inhibitor of (R)-1-phenylethylamine. Results of turbidity measurements showed that, for the model case of mandelic acid resolution, the chief effect of this inhibitor was to widen the metastable zone for the more soluble diastereomer. This observation is in accordance with previous experience. Further scouting for possible family members revealed a wide variation in the effectiveness of inhibitors, dependent on their structure. By far the most effective inhibitors are bifunctional 1-phenylethylamine and/or 1-phenylbutylamine analogues. The effect of racemic inhibitors was found to approach that of enantiomerically pure inhibitors of the same absolute configuration of the 1-phenylethylamine used for resolution. The most effective inhibitors were tested for the resolution of a structural variety of racemates, and were shown to be broadly applicable.
