Synthesis And Crystal Structure Analysis Of N-(1-(Phenylacetyl)-L-prolyl) Glycine Ethyl Ester

As a new type of nootropic,N-?1-?Phenylacetyl?-L-prolyl?Glycine Ethyl Ester,generates excellent effects on improving immunity and memory,which is mainly used for the treatment of Alzheimer's disease.N-phenylacetyl-L-proline was synthesized by direct acylation in an anhydrous organic solvent via a solid-liquid phase reaction.The reaction parameters were further analyzed and optimized.A satisfactory yield of 92.47%can be obtained with a 1.5:1:1.2:0.05 molar ratio of L-proline,phenylacetyl chloride,acid-binding agent of Na₂CO₃ and tetrabutylammonium bromide under a heating process?0?for 4 h,then 40?for 2 h?.N-phenylacety-L-proline was further analyzed by IR,¹H NMR,¹³C NMR,elemental analysis and X-ray single-crystal diffraction,and the crystal structure of N-phenylacety-L-proline confirmed the presence of hydrogen bonds between its molecules.According to the two different methods,N-?1-?Phenylacetyl?-L-prolyl?Glycine Ethyl Ester was prepared by N-phenylacetyl-L-proline and glycine ethyl ester hydrochloride.It was synthesized under the activation of isobutyl chloroformate with glycine ethyl ester hydrochloride in alkaline environment.It was founded that a high yield of 87.62%with a purity of 95.4%could be obtained by using 1:1.2:1.15:3 molar ratio of N-phenylacetyl-L-pro-line,glycine ethyl ester,isobutyl chlorocarbonate and triethylamine in a mixed solvent of dichloromethane and dimethylformamide at 20?for 30 h.The single crystal of N-?1-?Pheny-lacetyl?-L-prolyl?Glycine Ethyl Ester was obtained by solvent evaporation.By analyzing its structure,the existence of hydrogen bond between the molecules was verified.On the other hand,N-?1-?Phenylacetyl?-L-prolyl?Glycine Ethyl Ester could also be prepared by dehydration condensation of carbodi-imide,that is to say,N-phenylacetyl-L-pr-oline,under the action of dicyclohexyl-carbodiimide/4-dimethylaminopyridine,reacted with glycine ethyl ester salt in alkaline environment.With 1:1.2:1:2.5:0.03 molar ratio of N-pheny-lacetyl-L-proline,dicyclohexyl-carbodiimide,glycine ethyl ester hydrochloride,triethylamine and 4-dimethylaminopyridine,a mixed solvent of dichloromethane and diethylene oxide,a reaction temperature of 20?and reaction time of 48 h,98.5%yield with 98.9%purity could be obtained.Comparing with the active ester method of chlorine formic acid butyl ester,this approach has mild reaction conditions and simple operation,which avoids the side reactions effectively.Furthermore,due to the insolubility of the side-product dicyclohexyl urea,the post-treatment?repeated freezing crystallization?is simple.Therefore,the designed route can obtain a high quality product,which is more suitable for industrial production.