Research On The Chiral Separation Of DL-norvaline By Preferential Crystallization

L-norvaline is an important chiral intermediate of perindopril that is used for hypertension diseases.It is usually obtained by a diastereomeric salt formation method or biological fermentation methold.However,there exist many practical problems,such as low resolution efficiency?low yield and product contain other acid.All these problems lead to a great increased in production cost,and a significant decrease in the production efficiency.To solve these problems,a systematic research on the separation and purification process of L-norvaline was performed in this paper.First,the thermodynamic properties of L-norvaline was studied systematically,the solubility of L-norvaline in three different binary solvents,including water + methanol,water + ethanol and water + 2-propanol,was determined by employing a gravimetric method over temperatures from 283.15 K to 318.15 K.It is found that the equilibrium solubility of L-norvaline is dependent on temperature and solvent.Furthermore,a model which can be called polar equation was applied to quantitatively describe the relationship between solubility and polarity of solvent mixtures.Additionally,the mixing thermodynamic properties of L-norvaline in three binary solvent mixtures were also discussed based on the NRTL model.Results show that the mixing processes of L-norvaline are endothermic and spontaneous.In addition,based on thermodynamic properties and partial metastable region data,the chiral separation solvent system of L-norvaline by preferential crystallization was screened and determined.Secondly,Powder X-ray diffraction(PXRD)was used to preliminarily determine the racemate type of the norvaline as a racemic compound,and the binary melting phase diagram of norvaline was construct by a differential scanning calorimeter(DSC).The chiral ternary solubility phase diagram of norvaline in ethanol-water system was determined by HPLC.The results show that the stable thermodynamic state of DL-norvaline is a racemic compound,and the eutectic composition of the system is determined to be 60%.Based on the phase diagram,the feasibility of preferential crystallization was explored and the priority crystallization process was determined.The effects of supersaturation,initial solution composition,and seed amount on the preferential crystallization process were investigated.Finally,according to the above studies,the preferred process for preferential crystallization can be obtained,but the product yield is low.Therefore,the chiral separation of norvaline is achieved by the preferential crystallization coupled with additive.First,the additives were systematically screened,including dibasic acids,amino acids,esters,etc.Six kinds of additives with a structure similar to that of norvaline were found to possess significant effects,and they could increase product yield by 30%.Based on the differences between the crystal structures of DL-norvaline and L-norvaline,the mechanism of the six additives was explored.The influence of additive to the solubility and nucleation of both DL-norvaline and L-norvaline was also examined,which was futher used to confirm the role of additives.In addition,HPLC and on-line instrument FBRM were used to examine the effect of additives on the preferential crystallization.It was found that the increase of additive content can promote the chiral separation of norvaline.