Study On The Synthetic Process Of Alogliptin Benzoate And The Synthesis Of The Related Substances

Alogliptin benzoate is an orally active specific dipeptidyl peptidase-Ⅳ inhibitor, it could enhance the activity of the glucagon-like peptide-1 and reduce high blood sugar levels in type 2 diabetes patients. Alogliptin benzoate was used to reduce the hige blood glucose levels of the type 2 diabetes patients alone or in combination. The drug has a good tolerability and a low incidence of side effects. At the present, all alogliptin benzoate in Chinese market were imported from abroad, because there is no legal source of active pharmaceutical ingredient in China. To break the foreign monopoly, it is very important to study on the synthetic process of alogliptin benzoate.In this paper, a synthetic route of alogliptin benzoate was chosen from all the reported processes, firstly 3-methyl-6-chloro-uracil is directly reacted with 2-bromomethyl-benzonitrile to give the 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2Hpyrimidin-1-ylmethyl)- benzonitrile, sencondly the resulting pruduct is then reacted with(R)-3- aminopiperidine dihydrochloride to yield alogliptin, finally alogliptin is reacted with benzoate to yield alogliptin benzoate. After the optimization of reaction conditions, the regular product which purity was higher than 99.5% was obtained and the total yield was up to 65%.After the optimization of the experimental conditions, the better reaction condition of each step of the synthesis was obtained.The potimum conditions of the preparetion of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H- pyrimidin-1-ylmethyl)- benzonitrile were as follows: the molar ratio of 3- methyl-6-chloro-uracil, 2-bromomethyl-benzonitrile and NaHCO3 was 1:1:1.5, with N, N- dimethylformamide as solvent, the reaction temperature was 80℃,and the reaction time was 3 h.The potimum condition of the preparetion of alogliptin was as follows: the molar ratio of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile,(R)-3- aminopiperidine dihydrochloride, NaHCO3 was 1: 1.2: 5,with 90% aqueous ethanol as solvent, the reaction temperature was 80℃,and the reaction time was 7 h.The optimum condition of the preparetion of alogliptin benzoate was as follows: the molar ratio of alogliptin and benzoate was 1:1, with ethanol as solvent, the reaction was refluxed for 4 hours, then stir for 2 h at room temperature.The total yield of the process was 65%, the purity of final product was higher than 99.5%, and the content of single impurity was less than 0.1%.The synthetic route had the characterisitic of simple operation, mild conditions, high yield, and good purity. And it had significant developing value and feasibility for industrial application.In addition, based on the synthetic routes, the 12 kinds of related substances were carried out the analysis of the source. Then the synthetic routes were designed and tried, finally 6 impurities of them were obtained and the chemical structures were comfirmed by 1H-NMR, MS and IR.