| Chiral separation and preparation of chiral technology is one of the major underlying issues in the field of pharmaceutical and chemical engineering chemical research. The availability of enantiopure compounds is of primary importance in the pharmaceutical and fine chemical industry. Chiral liquid- liquid extraction is considered as a very promising technology for the production and separation of enantiopure compounds because it can be operated continuously and econormically,can be scaled up to an industrial scale easily and possesses a wide range of applications. Compared with the conventional extraction in an organic/water two system, the aqueous two-phase extraction(ATPE) possesses more benefit of environmental protection and can keep the bioactivity of solute more effectively.ATPE is considered as an important improvement of conventional extraction technology. A series of aqueous two-phase systems(ATPS) consisted of small-molecule alcohol/salt were established in this thesis for extraction of naproxen(NAP) enantiomers with tartaric acid, Hydroxypropyl-β-cyclodextrin(HP-β-CD) and metal-β-cyclodextrin complex applied as chiral extractant. The main contents of this thesis are as follows:Firstly, separation of NAP enantiomers was achieved in an alcohol/ammonium sulphate ATPS. Influence of some important factors, such as type and concentration of extractant, the formation of ATPS、p H and temperature, on extraction performance was investigated. The optimized conditions were found at temperature of 20 ℃, NAP concentration of 5 mmol/L, p H of 5, HP-β-CD concentration of 50mmol/L, 7 m L of alcohol, 3.8 g of ammonium sulphate, under which the highest separation factor is1.42. S-NAP was preferentially recognized and lowering the temperature can improve the extraction performance.In Chapter 2, metal-β-cyclodextrin complexes were synthesized as chiral extractant. Alcohol/trisodium citrate ATPS was established for extraction of NAP enantiomers. Influence of some important factors including type of central ion,Cu2(Ⅱ)-β-CD concentration, p H, concentration of enantiomers, temperature on extraction performance was investigated. Results show that Cu2(Ⅱ)-β-CD has stronger recognition ability towards NAP enantiomers than that of Zn X-β-CD under identical conditions. The highest separation factor of 1.42 was obtained at p H of 11,Cu2(Ⅱ)-β-CD concentration of 70 g/L, NAP concentration of 10 mmol/L and temperature of 20 ℃. Separation factor increases with the raising of p H and withincrease of Cu2(Ⅱ)-β-CD concentration. Raising of temperature lead to the increase of distribution ratios and decrease of separation factor. The NAP anion mainly distributes in the lower phase. Cu2(Ⅱ)-β-CD tends to form complex with NAP anion,high p H is helpful to the separation process, which can enhance the solubility of NAP in ATPS and helps to improve the yield.In Chapter 3, Cu2(Ⅱ)-β-CD was applied as chiral extractant. Different ATPSs were established and their separation ability towards NAP enantiomers were compared with one another. Extraction of NAP enantiomers was performed in alcohol/dipotassium hydrogen phosphate. Some important factors that influence the extraction performance, including p H, concentration of extractant, the formation of ATPS and temperature, were investigated. Results show alcohol/dipotassium hydrogen phosphate ATPS give the highest ability towards NAP enantiomers when compared with PEG4000/dipotassium hydrogen phosphate ATPS and dichloromethane/dipotassium hydrogen phosphate two phase system. The optimized conditions were at p H of 10, content of dipotassium hydrogen phosphate of 21 %,content of alcohol of 28 %, Cu2(Ⅱ)-β-CD concentration of 70 g/L, NAP concentration of 6 mmol/L and temperature of 20 ℃. The highest separation factor is 1.43.This thesis provides a new method for separation of NAP enantiomers, provides guide for separation of hydrophobic chiral drug enantiomers and give reference to expanding the application of aqueous two-phase extraction. |
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