Chiral Separation Of Pharmaceuticals Enantiomers By Ligand Exchange Methods Based On Chiral Ionic Liquids

There is an increasing demand for optically pure enantiomers in the chemical industry, which can be attributed largely to a heightened awareness that enantiomers of a racemic drug usually display markedly different pharmacological activities. Different methods are used to obtain enantiomeric purity, such as, synthesis from chiral pool, the asymmetric synthesis and chiral separation. Chiral ligand exchange chromatography is not only an analysis method of determination of enantiomeric purity accurately but also is especially effective for the separation of enantiomers. Chiral ligand exchange chromatography includes enantiomeric separations on chiral stationary (CSP) and chiral mobile phase (CMP)-type separations. The latter using a common non chiral column is low cost. To optimize the conditions of separation, we can change the type, concentration of the chiral selector and composition of mobile phase. When the absolute configuration of chiral selector is changed, the elute order of enantiomers is also changed.In this paper, the resolutions of tryptophan enantiomers(Trp), mandelic acid enantiomers (MA), and o-chloro-mandelic acid enantiomes (0-Cl-MA) by ligand exchange chromatography were completed on a C18column with the chiral ionic liquids containing imidazolium cations and L-proline anions ([Cnmim][Pro]) as chiral selectors. Some factors influencing resolution, such as alkyl chain length of ILs, concentrations of Cu2+and [Cnmim][Pro], and pH of the mobile phase, were investigated. And its thermodynamical process was studied.Based on ligand exchange mechanism, Trp enantiomers were successfully separated using [C6mim][Pro] as a chiral ligand coordinated with copper(Ⅱ). Separation conditions were optimized, where4mmol/L [C6mim][Pro] and8mmol/L Cu2+were dissolved in methanol/water (20:80, v/v) with pH4.00at a flow rate of1.0mL/min. Under this condition, the Trp enantiomers could be baseline separated and the separation factor and resolution were1.25and2.30, respectively. In the range of25℃-45℃, the values of△△H0and△△S0ere both negative, and|△△H0>|T△△S0|, which showed that the chiral separation of Trp enantiomers was an enthalpy-controlled process.Based on ligand exchange mechanism, MA enantiomers were successfully separated using [C4mim][Pro] as a chiral ligand coordinated with copper(Ⅱ). Under the optimal conditions, the separation of the two enantiomers was obtained with enantioseparation factor of1.22and resolution of2.24. And some thermodynamical parameters were evaluated. In the range of25℃-45℃, the values of△△H0and△△S0were both negative, and|△△H0|>|T△△S0|, which showed that the chiral separation of MA enantiomers was an enthalpy-controlled process. And the values of AH0of D-MA were larger than those of L-MA, indicating that L-MA had stronger affinity to the stationary phase, which is consistent with the elution order of monomers.Based on ligand exchange mechanism, O-C1-MA enantiomers were successfully separated using [C4mim][Pro] as a chiral ligand coordinated with copper(Ⅱ). Separation conditions were optimized, where4mmol/L [C4mim][Pro] and8mmol/L Cu2+were dissolved in methanol/water (15:85, v/v) with pH5.10at a flow rate of0.9mL/min. Under this condition, the O-Cl-MA enantiomers could be baseline separated. In the range of25℃-45℃, the values of△△H0and△△S0were both negative, and|△△H0|>|△△S0|, which showed that the chiral separation of O-Cl-MA enantiomers was an enthalpy-controlled process.