Study On The Synthesis Of Alogliptin Benzoate

With the improvement of living standards,the pace of life accelerated,population aging and the incidence of obesity increases,the incidence of diabetes is increasing year by year,complications in patients with a serious impact on the health and quality of life,has become a public health problem threatening human health.Takeda Pharmaceutical Company Limited developed Dipeptidyl Peptidase-4 inhibitors(DPP-4)Alogliptin.The benzoic acid salt(trade name:Nesina)was approved by Ministry of health,Labour and Welfare in April 2010.It was used in the treatment of type II diabetes,improve the quality of life of patients with diabetesBe directed against the disadvantages of Alogliptin synthetic process,such as low yield,harsh reaction conditions,serious pollution,high impurity content,et al.This paper reviews the research and development of DPP-4 inhibitors.Through by the analysis and comparison of different synthetic routes,determine the synthetic route suitable for industrial production and optimize the process.Anew synthesis process of Alogliptin benzoate with simple operation,low cost,high purity and low impurity content has been developed.The starting material of the synthetic route is o-Tolunitrile.It happens bromination with N-bromobutanimide(NBS)to get alpha-Bromo-o-tolunitrile.Then happens alkylation reaction with 6-Chloro-3-methyluracil in alkaline conditions to get 2-[(6-Chloro-3,4-dihydro-3-Methyl-2,4-dioxo-1(2H)-pyriMidinyl)Methyl]benzonitrile.Then happens substitution reaction with(R)-3-(Boc-Amino)piperidine in alkaline conditions,and then happens deprotection reaction with trifluoroacetic acid to get Alogliptin.At last,Alogliptin happens salification with benzoic acid to get Alogliptin benzoate.The results show that,the total yield of this synthesis process is 58.8%,the purity of product can reach 99.8%,the largest single impurity is 0.13%.Chemical structure of the product was confirmed by 1H NMR,13C NMR,MS,et al.