Abstract
The stereoisomeric system of rac-2-phenylglycinamide (PGA) and rac-N-acetyl tryptophan (NAT) is significant in the application of chiral resolution because it has been shown that this system can be used for enantioseparation of PGA and/or NAT using a novel deracemization route of the conglomerate salt formed. However, it was also found that the conglomerate salt eventually converted into different crystal forms that limited the time available for the separation. Herein, we try to understand the phase conversion occurring in this system using DSC, PXRD, and SC-XRD. The related structures of the salt (two polymorphs of the more stable homochiral (dd- and ll-) salts and one polymorph of the less stable heterochiral (dl- and ld-) monohydrate salts) are demonstrated and discussed relating to their relative stabilities. The successful deracemization was demonstrated using the heterochiral (dl- or ld-) monohydrate salts. However, following Ostwald’s rule of stages, only limited time is available for the deracemization before the metastable compound converts into the more stable homochiral (dd- and ll-) pair. Moreover, the occurrence of the (dd- and ll-) phase always coincides with the formation of yet another phase of the racemic compound containing four components in a crystal. Ostwald’s rule of stages here thus involves three steps and phases and is highly significant during the deracemization of the homochiral species.
Highlights
Chirality and enantiomerism are common in nature in biological systems
Note that initially the system consisted of a suspension of heterochiral monohydrate salts, i.e., DL- and LDsalts, which crystallize as a conglomerate
Even though the crystallization from an equimolar amount of rac-PGA and rac-N-acetyl tryptophan (NAT) leads to the formation of heterochiral (DL- and LD-) monohydrate salts, owing to their lower stability compared to other species existing in the system (the homochiral (DD- and LL-) salts and the racemic compound) under the same condition, we find that the system eventually evolves toward these more stable phases, following Ostwald’s rule of stages, which could threaten the deracemization efficiency
Summary
Chirality and enantiomerism are common in nature in biological systems. enantiomers have identical physical and chemical properties except for optical rotation and some other properties not helpful for enantioseparation in achiral environments, their behavior can be drastically different once inside the human body; i.e., one stereoisomer can be therapeutic, while the other stereoisomer can be inactive or even toxic. Among the techniques using crystallization, deracemization is an attractive approach since it enables the recovery of a single enantiomeric product from the starting racemic component with yields close to 100%.7−10 This can be achieved by simultaneous crystallization−dissolution together with in situ racemization in the liquid phase One process using this mechanism is Viedma ripening.[7,8,11] conglomerate formation is a prerequisite of this process, and only around 10% of chiral compounds satisfy this criterion. By implementing Viedma ripening, the solid phase species can be completely converted into a single stereoisomer This approach was used in the enantiopurification of PGA which is an important drug precursor[24] and a useful chiral auxiliary in organic synthesis.[25−27] The chiral purification was successfully achieved using racemization of only the chiral center of rac-PGA. The experiments were performed with a mobile phase containing hexane/ 2-propanol/trifluoroacetic acid with the ratios of 80%, 20%, and 0.1%, respectively, and with a flow rate of 0.50 mL/min at 35 °C
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