Simultaneous Crystallization of d- and l-Asparagines in the Presence of a Tailor-Made Additive by Natural Cooling Combined with Pulse Heating

A new optical resolution technique by natural cooling crystallization combined with pulse heating was proposed, in which a “tailor-made” additive was used as a separation agent. As a model chiral compound, the conglomerate of asparagine ( d,l -Asn) was examined. By simple batch natural cooling crystallization, the primary nucleation of l -Asn was delayed significantly by the presence of an additive l -cysteine ( l -Cys) at 5 mol % (of dissolved d,l -Asn), while that of the other enantiomer d -Asn remained almost unchanged. The nucleation of l -Asn was delayed more with an increase in l -Cys concentration. At the same time, the distribution of the product crystals became bimodal. The large crystals were d -Asn with 100% optical purity, while the small crystals consisted of a mixture of d -Asn and l -Asn crystals. The d -Asn crystals in the mixture were completely eliminated by a pulse-heating operation added after cooling. As a result, the perfect optical resolution was attained; the large crystals (over 400 μm) were d -Asn with 100% optical purity and the small crystals (200 μm or less) were l -Asn with 100% optical purity. Among the other additives tested, l -histidine ( l -His) was effective, but l -valine ( l -Val), l -methionine ( l -Met), l -phenylalanine ( l -Phe) and l -glutamine ( l -Gln) were not effective for optical resolution.