Synthesis Of(R)-?-arylmethyl-?-amino Acid And Application On The Sitagliptin

(R)-3-amino-4-aryl butyric acids as a class of ?-amino acids,are key structural elements of peptides,antibiotics,small drugs and many other physiologically activecompounds.Notably,the small drug Sitagliptin is a dipeptidyl peptidase ? inhibitor that is effective in the treatment of type 2 diabetes,it's phosphate as the first DPP-? inhibitor and has been approved by USFDA in October 2006.Moreover,sitagliptin containing an important intermediates is(R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid.Now,methods for the synthesis of(R)-3-amino-4-aryl butyric acid relied predominantly on ?-amino acids homologation,Metal catalysis,resolution,However,there are few reports on organocatalysts and biocatalysts.Compared with other methods,the organocatalysts has the advantages of low cost,low toxicity and environmental friendliness.Therefore,this paper hopes organocatalysts asymmetric synthesis of(R)-3-amino-4-aryl butyric acids,and then synthesis of sitagliptin and to optimize the synthesis process research.1.In this paper,the conjugation addition of 4-phenyl-2-dilute-butyraldehyde and Ntert-butoxycarbonylhydroxylamine was first studied.The optimum reaction conditions were found by investigating Br?nsted acid,solvent and catalyst on the reaction of the effect.20 mol% catalyst diphenyl proline trimethylsilyl ether,20 mol% additive pnitrobenzoic acid,dichloromethane as solvent,temperature 0°C.Subsequently,ten 5-hydroxyisoxazolidine compounds were synthesized by "one pot" method using aryl propylene as substrate,and 71%~86% yield and 82%~95% ee were obtained.Through further study,three paths of synthetic(R)-3-(tert-butoxycarbonylamino)-4-arylbutanoic acid were successfully explored: CM/conjugate addition,oxidation /reduction;CM/conjugate addition,reduction,oxidation and CM/conjugate addition/reduction,reduction,oxidation.Finally,we have studied the optimization of the main steps,and the important intermediates were characterized by IR,1H-NMR,13C-NMR and HRMS.2.Based on the successful synthesis of(R)-3-amino-4-aromatic butyric acid,this paper first designed the route of synthesis of sitagliptin by organic catalysis with the advantages of "one pot" and the green chemistry.Short,easy to operate,cheap and low cost of raw materials.Experiments were carried out by using 2,4,5-trifluorobromobenzene as the starting material,and the Sitagliptin was synthesized by the Grignard reaction/coupling reaction,CM/conjugation addition,reduction,oxidation/condensation,deprotection.The effects of temperature,material ratio,catalyst and hydrogen pressure on the reaction were studied.The total yield was 41%~45% by optimizing the main reaction steps,which laid a foundation for further amplification.