A Cyclic Continuous Process for Converting Conglomerates into Optically Pure Enantiomers by Crystallization and Dissolution with the Assistance of ‘Tailor-made’ Polymers

An industrially feasible kinetic process for the conversion of d,l racemic mixtures that crystallize in the form of conglomerates into optically pure materials was elaborated. The method takes into consideration the presence of a single-enantiomer polymer that causes crystals that match it in chirality to lag far behind their enantiomers both in growth and in dissolution. This phase lag is exploited in a repeated cycle of growth and dissolution to collect crystals of one kind after partial growth and of the other before complete dissolution. Three major steps are involved: (a) Kinetically controlled crystallization of a racemic conglomerate in the presence of chiral polymers at temperature T1, modeled on the basis of the structure and morphology of the 3D crystals. The polymer inhibits the precipitation of the undesired enantiomorph, collecting the desired one by filtration; (b) Preferential dissolution of added racemic mixture of crystals of the substrate in the mother liquor enriched with the undesired enantiomer and the chiral polymer at temperature T2. This step takes advantage of concentration-gradients of the two enantiomers in the filtrate and the enatioselective dissolution induced by the chiral polymer; (c) The separation by filtration followed by racemization of the undesired enantiomer for additional cycles of resolution. The process is illustrated for the conversion of d,l methionine·HCl that crystallizes in the form of a conglomerate that displays twinning of enantiomorphous lamellae into the corresponding l or d Met·HCl in kilograms scale.