Deracemization of a racemic compound via its conglomerate-forming salt using temperature cycling

Li, Wei W. and Spix, Laura and De Reus, Saskia C A and Meekes, Hugo and Kramer, Herman J M and Vlieg, Elias and ter Horst, Joop H. (2016) Deracemization of a racemic compound via its conglomerate-forming salt using temperature cycling. Crystal Growth and Design, 16 (9). pp. 5563-5570. ISSN 1528-7483 (https://doi.org/10.1021/acs.cgd.6b01034)

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Abstract

Salts of chiral molecules, which originally crystallize as racemic compounds, could form conglomerates. The utilization of such conglomerate salts, as intermediates for the deracemization of corresponding racemic compounds, expands the theoretical application range of Viedma Ripening by roughly 10-fold. In the present study, the use of temperature cycling on conglomerate forming salts as an alternative technique for Viedma Ripening was studied. The racemic compound Phenylalanine (Phe) was successfully deracemized via its conglomerate-forming salt with 2,5-xylenesulfonic acid (XSA) by continuous heating-cooling cycles applied to its suspension in glacial acetic acid, coupled with a solution racemization reaction. In addition, the dependence of the deracemization rate on the operational parameters was studied. Enhanced racemization reaction kinetics, either by a larger amount of free amino acid or by a higher concentration of catalyst, was shown to accelerate the deracemization process. It seems to indicate that a concentration difference between the two enantiomers, which could be diminished by a faster racemization rate, behaves as one of the major rate-limiting factors for the deracemization process. A larger mass fraction of solid dissolving and recrystallizing in the heating-cooling cycles, achieved by either a larger temperature swing or a smaller dry mass concentration, also leads to a faster deracemization. A change in cooling rate does not affect the deracemization rate significantly within the range tested, indicating a limited presence of secondary nucleation of the minor enantiomers. The results can be used as a preliminary foundation for process optimization as well as mechanisms investigation. The advantages and disadvantages of temperature cycling and Viedma Ripening, as deracemization methods in an industrial setting, are discussed.

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