Chiral Resolution Of Racemic DL-Glutamic Acid By Crystallization Technology

Enantiomers（L and D）have almost identical physical and chemical properities in achiral environment,but often possess different properities in a chiral environment.For example,in the living system,the opposite chiral enantiomers of drugs often differ significantly in their pharmacological,toxicological,pharmacodynamic and pharmacokinetic properties.Hence,the chiral resolution of a racemate,which is an equimolar mixture of two enantiomers,into a single enantiomer is always one of research hotspots.Crystallization is an useful resolution method to separate the constituents of a racemate,as did by Pasteur’s experiment,but it is also a great challenge.Generally,crystallization from a racemic solution usually yields one of two basic classes of crystals namely,racemic compounds or conglomerates.A racemic compound is an equimolar mixture of two enantiomers homogeneously distributed throughout the crystal lattice,resulting in difficulties in enantiomers separation.By contrast,a conglomerate is a mechanical mixture of two pure enantiomorphs（D and L crystals）.Thus,obtaining conglomerates becomes the primary step for the chiral resolution of racemic DL-amino acids.Glutamic acid（Glu）has been widely used in industry and our daily life.However,similar to most other amino acids,DL-glutamic acid（DL-Glu）is normally crystallized as racemic compounds under ambient conditions.In order to deposit D-or L-Glutamic acid crystals alone from a racemic DL-Glu solution,four strategies were presented.These strategies are as follows.1.The solvent of crystallization solution is changed,the crystallization behavior will be altered.The D-crystals and L-crystals（the conglomerates）of glutamic acid can be deposited from a 60%(V_EtOH/V_solution)ethanol-water mixed solvent,providing an opportunity to separate the racemate of DL-Glu.We demonstrated the potential application of chiral L-cysteine self-assembled monolayers（L-Cys SAMs）to control chirality throughout crystallization,where D-enantiomer crystals preferentially crystallized on the chiral SAMs with relatively fast nucleation rate and the nucleation rate of L-glutamic acid was restrained.The conglomerates with D-glutamic acid excess were obtained on the L-Cys SAMs from a 60%(V_EtOH/V_solution)ethanol-water mixed solvent.More importantly,the pure D-crystals alone can be deposited from the mixed solvents by the co-effect of L-Cys SAMs and mixed solvents and a typical “in-series enriched method”.2.An ultrasonic field as a chiral force was first utilized in the chiral resolution of a racemate of DL-glutamic acid.Under the ultrasonic field,the conglomerate crystals with L-or D-enantiomer excess are obtained with a random distribution character.In order to control the chirality of the excess crystal,tiny amount of D-or L-Glu crystals as chiral seeds were added into the solution under the ultrasonic field to induce the crystalliztaion of the homochiral enantiomer.Besides,the ultrasonic field can cause the symmetry breaking and chiral amplification of conglomerate crystals.The pure D-or L-glutamic acid crystals can be obtained near perfectly from a racemic solution by three crystallization steps and all of the three steps proceed under an ultrasonic field.3.An important and efficient resolution method by crystallization is referred to “tailor-made additives”.In the presence of a chiral additive,the opposite chiral molecule is preferentially crystallized and the homochiral molecule is in a drastic decrease in their rate of growth（rule of reversal）.According to the charcteristic of the additive,the pure D-or L-glutamic acid crystals can be acquired by introducing enough L-arginine or L-phenylalanine additive with the mole fraction up to 40% into the racemic solution of DL-Glu.In order to reduce the dosage of the additives,this paper also proposed another crystallization separation method.The other is to crystallize twice and each crystallization procedure proceeds in the presence of 5 mol % chiral additive.4.The D-crystals or L-crystals of glutamic acid can be deposited from a racemic solution by using “tailor-made additives”（L-and D-Arg）and an ultrasonic field.The tailor-made additives cease the formation of DL-crystal,and retard the crystallization rate of the homochiral Glu and no effect is found for the opposite chiral Glu.Basing on this characteristic of the tailor-made additive,conglomerate crystals with a nonzero ee value were obtained.Utilizing the chiral amplification of the ultrasonic field,the ee value of the acquired crystals can be increased.Then the D-or L-Glu crystals can be obtained by multiple crystallization and recrystallization steps and all the recrystallization proceed under an ultrasonic field.Camparing with the existed separation methods,the proposed method illustrated in this paper shows the advantages of simple operation,high efficiency,environmental friendly,and low cost,most importantly,there is no hand picking work required in the whole processes.Hence,these crystallization separation technologies will have a superduper application prospect.